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The mitogen-activated protein kinase (MAPK) cascade is a highly conserved signaling module composed of MAPK kinase kinases (MAPKKKs), MAPK kinases (MAPKK) and MAPKs. The MAPKKK Mkh1 is an initiating kinase in Pmk1 MAPK signaling, which regulates cell integrity in fission yeast (Schizosaccharomyces pombe). Our genetic screen for regulators of Pmk1 signaling identified Shk1 kinase binding protein 5 (Skb5), an SH3-domain-containing adaptor protein. Here, we show that Skb5 serves as an inhibitor of Pmk1 MAPK signaling activation by downregulating Mkh1 localization to cell tips through its interaction with the SH3 domain. Consistent with this, the Mkh1(3PA) mutant protein, with impaired Skb5 binding, remained in the cell tips, even when Skb5 was overproduced. Intriguingly, Skb5 needs Mkh1 to localize to the growing ends as Mkh1 deletion and disruption of Mkh1 binding impairs Skb5 localization. Deletion of Pck2, an upstream activator of Mkh1, impaired the cell tip localization of Mkh1 and Skb5 as well as the Mkh1-Skb5 interaction. Interestingly, both Pck2 and Mkh1 localized to the cell tips at the G1/S phase, which coincided with Pmk1 MAPK activation. Taken together, Mkh1 localization to cell tips is important for transmitting upstream signaling to Pmk1, and Skb5 spatially regulates this process., (© 2016. Published by The Company of Biologists Ltd.)

The activity of some prefrontal (PF) cortex neurons distinguishes short from long time intervals. Here, we examined whether this property reflected a general timing mechanism or one dependent on behavioral context. In one task, monkeys discriminated the relative duration of 2 stimuli; in the other, they discriminated the relative distance of 2 stimuli from a fixed reference point. Both tasks had a pre-cue period (interval 1) and a delay period (interval 2) with no discriminant stimulus. Interval 1 elapsed before the presentation of the first discriminant stimulus, and interval 2 began after that stimulus. Both intervals had durations of either 400 or 800 ms. Most PF neurons distinguished short from long durations in one task or interval, but not in the others. When neurons did signal something about duration for both intervals, they did so in an uncorrelated or weakly correlated manner. These results demonstrate a high degree of context dependency in PF time processing. The PF, therefore, does not appear to signal durations abstractedly, as would be expected of a general temporal encoder, but instead does so in a highly context-dependent manner, both within and between tasks., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Warfarin dosage requirements show considerable inter-individual variability. There are some reports of warfarin dose regimens correlating with single nucleotide polymorphisms (SNP) for CYP2C9, VKORC1 and other genes in adults. In children, however, reports are scarcer than in adults and the number of genes examined is more limited. We explored the effects of genetic variation on warfarin dose requirement in Japanese pediatric patients., Methods: A total of 45 patients who were prescribed warfarin at the Yokohama City University Hospital were included in this study. The influence of genetic polymorphisms on stable warfarin dosage requirement was investigated by genotyping SNPs of the VKORC1, CYP2C9, CYP4F2, and GGCX genes (rs9923231, rs1057910, rs2108622, and rs699664, respectively) in each patient., Results: Patients with the TT genotype in rs9923231 in VKORC1 required significantly lower maintenance dosages than those with the TC genotype (p = 0.001). Multiple regression analysis showed that, while VKORC1 status and patient height account for 78.2 % of the variability in maintenance warfarin dosage, genetic polymorphisms in VKORC1 account for 27 %, although polymorphisms in CYP4F2 and GGCX had no effect on dosage and the effect of CYP2C9 could not be evaluated., Conclusions: Polymorphisms in VKORC1 partially affected daily warfarin dosage requirements. VKORC1 genotype and height are the primary determinants influencing warfarin dosage in Japanese pediatric patients. Further studies with larger sample sizes are needed to confirm our results.

The prefrontal cortex (PF) is involved in outcome-based flexible adaptation in a dynamically changing environment. The outcome signal dissipates gradually over time, but the temporal dynamics of this dissipation remains unknown. To examine this issue, we analyzed the outcome-related activity of PF neurons in 2 monkeys in a distance discrimination task. The initial prestimulus period of this task varied in duration, allowing us to dissociate the effects of time and event on the decline in previous outcome-related activity -previous correct versus previous error. We observed 2 types of decline in previous outcome representation: PF neurons that ceased to encode the previous outcome as time passed (time-dependent) and neurons that maintained their signal but it decreased rapidly after the occurrence of a new external event (event-dependent). Although the time-dependent dynamics explained the decline in a greater proportion of neurons, the event-dependent decline was also observed in a significant population of neurons.

PKN, a conserved family member related to PKC, was the first protein kinase identified as a target of the small GTPase Rho. PKN is involved in various functions including cytoskeletal arrangement and cell adhesion. Furthermore, the enrichment of PKN3 mRNA in some cancer cell lines as well as its requirement in malignant prostate cell growth suggested its involvement in oncogenesis. Despite intensive research efforts, physiological as well as pathological roles of PKN3 in vivo remain elusive. Here, we generated mice with a targeted deletion of PKN3. The PKN3 knockout (KO) mice are viable and develop normally. However, the absence of PKN3 had an impact on angiogenesis as evidenced by marked suppressions of micro-vessel sprouting in ex vivo aortic ring assay and in vivo corneal pocket assay. Furthermore, the PKN3 KO mice exhibited an impaired lung metastasis of melanoma cells when administered from the tail vein. Importantly, PKN3 knock-down by small interfering RNA (siRNA) induced a glycosylation defect of cell-surface glycoproteins, including ICAM-1, integrin β1 and integrin α5 in HUVECs. Our data provide the first in vivo genetic demonstration that PKN3 plays critical roles in angiogenesis and tumor metastasis, and that defective maturation of cell surface glycoproteins might underlie these phenotypes.

Selective inhibition of protein kinase Cθ (PKCθ) may be useful in inducing T cell-specific immunosuppression with a reduced rate of side effects. To our knowledge, however, no reports have been published regarding the selective inhibition of PKCθ by small-molecule compounds in animal models of allograft rejection. Here, we investigated the effect of the newly synthesized PKCθ selective inhibitor AS2521780 in mono- and combination therapies on acute rejection in ACI-to-Lewis rat cardiac and non-human primate (NHP) renal transplantation models. In the rat cardiac transplantation model, AS2521780 significantly prolonged graft survival to 14days at 10mg/kg twice daily (b.i.d.) and to 20days at 30mg/kg b.i.d. In contrast, acute rejection occurred in all recipients in the non-treated group by Days 5 or 6 post-transplantation. Significant improvements (P<0.001) in graft survival were observed following treatment with a combination of AS2521780 at 3mg/kg b.i.d. and a suboptimal dose of tacrolimus (0.02mg/kg) or mycophenolate mofetil (15mg/kg). In the NHP renal transplantation model, AS2521780 at 3mg/kg b.i.d. and tacrolimus at 1mg/kg (suboptimal dose) significantly improved graft survival compared to tacrolimus alone (P<0.05). The present study of AS2521780 in rat cardiac and NHP renal transplantation models demonstrates the potential of PKCθ as a novel drug target for organ transplantation. As AS2521780 was well tolerated and the dose of tacrolimus or mycophenolate mofetil can be reduced when used in combination with this drug, immunosuppressive regimens containing selective inhibitors of PKCθ might have good safety profiles., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Rhesus monkeys performed two tasks, both requiring a choice between a red square and a blue circle. In the duration task, the two stimuli appeared sequentially on each trial, for varying durations, and, later, during the choice phase of the task, the monkeys needed to choose the one that had lasted longer. In the matching-to-sample task, one of the two stimuli appeared twice as a sample, with durations matching those in the duration task, and the monkey needed to choose that stimulus during the choice phase. Although stimulus duration was irrelevant in the matching-to-sample task, the monkeys made twice as many errors when the second stimulus was shorter. This across-task interference supports an order-dependent model of the monkeys' choice and reveals something about their strategy in the duration task. The monkeys tended to choose the second stimulus when its duration exceeded the first and to choose the alternative stimulus otherwise. For the duration task, this strategy obviated the need to store stimulus-duration conjunctions for both stimuli, but it generated errors on the matching-to-sample task. We examined duration coding in prefrontal neurons and confirmed that a population of cells encoded relative duration during the matching-to-sample task, as expected from the order-dependent errors., (Copyright © 2015 the American Physiological Society.)

Japan has just enacted a national law for alcohol, that named "Basic Act on Measures Against Alcohol-related Health Harm". This article includes 5 topics; i) General psychiatrists have the roles and responsibilities in this law, ii) All psychiatrists need to know about alcohol-related health harm and alcohol-related problem, iii) Alcohol dependence is attributed to change of neurotransmitter in the brain, iv) Mood disorder is more likely to be complicated by alcohol dependence and/or hazardous drinking. Some of the patients with the above-mentioned complicated disease have alcohol-induced mood disorder, v) If the patient has alcohol-induced mood disorder, it will place priority on alcoholism treatment and will be important to quickly resolve with abstinence. Finally, the proposals are made as follows; i) Making a guideline, ii) Physicians skilled at SBIRT (Screening, Brief Intervention, and Referral to Treatment) should be qualified as a certifying physician, and having the qualification should allow reimbursing medical institutions for the alcohol related service provided.

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K(+) channel and Ca(2+) channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2min every 10min for 30min after drug exposure for the vehicle and each drug concentration. IKr and IKs blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca(2+) channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the IKr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE(-/-) mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE(-/-) mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis.

Two rhesus monkeys performed a distance discrimination task in which they reported whether a red square or a blue circle had appeared farther from a fixed reference point. Because a new pair of distances was chosen randomly on each trial, and because the monkeys had no opportunity to correct errors, no information from the previous trial was relevant to a current one. Nevertheless, many prefrontal cortex neurons encoded the outcome of the previous trial on current trials. A smaller, intermingled population of cells encoded the spatial goal on the previous trial or the features of the chosen stimuli, such as color or shape. The coding of previous outcomes and goals began at various times during a current trial, and it was selective in that prefrontal cells did not encode other information from the previous trial. The monitoring of previous goals and outcomes often contributes to problem solving, and it can support exploratory behavior. The present results show that such monitoring occurs autonomously and selectively, even when irrelevant to the task at hand.

Timing is a very abstract representation that shares with other magnitudes, such as numerosity, the peculiarity of being independent from any particular sensory modality. Not only we can time stimuli in different modalities but we can also compare the durations of different visual, auditory and somatosensory stimuli. Furthermore, even though time is not directly associated with space, and we are inclined to consider space and time as two different perceptual dimensions of our existence, an increasing number of studies challenge this idea by showing that timing and spatial processing have some relationship that involves sharing computation resources and that time may have a spatial representation. A more general theory, called theory of magnitude (ATOM), considers both timing and spatial computations, together with other magnitudes, as originating from a general magnitude system [Walsh VA, Trends Cogn Sci 7(11):483-8, 2003]. The neural underpinnings of time and its relationship to the processing of spatial information have started to be investigated only recently, but the field is rapidly growing. It is addressing the representation of time in several cortical and subcortical brain areas. Information processing of time and space are not strictly specialized in neural and cognitive mechanisms and we believe that studying them only separately may restrict our understanding of these processes. In this chapter, we will firstly introduce the role of the prefrontal cortex (PF) in coding relative durations. We will point out that the comparison of durations makes use of intermediate computations based on the order of the events. Secondly, we will describe the comparison mechanisms that are implemented by PF to make perceptual decisions about durations in relation to those involved in making decisions about spatial locations and distances. We will distinguish the decision processes from the goal choices, and we will examine which computational resources are shared between different magnitudes and which are domain-specific. We will summarize our results within the context of a more general PF function in promoting the generation of goals from the current context, consisting of domain- and modality-specific coding of stimuli of different modalities or magnitudes.

This study aimed at investigating the effect of distraction on working memory and its underlying neural mechanisms in children with attention-deficit/hyperactivity disorder (ADHD). To this end, we studied hemodynamic activity in the prefrontal cortex using near-infrared spectroscopy while 16 children with ADHD and 10 typically developing (TD) children performed a working memory task. This task had two conditions: one involved a distraction during the memory delay interval, whereas the other had no systematic distraction. The ADHD patients showed significantly poorer behavioral performance compared with the TD group, particularly under the distraction. The ADHD group exhibited significantly higher level of prefrontal activation than did TD children. The activity level was positively correlated with the severity of ADHD symptoms. These results suggest that the impairment in the inhibition of distraction is responsible for the working memory deficits observed in ADHD children. Inefficient processing in the prefrontal cortex appears to underlie such deficits.

Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes.

Chemoattractant receptor homologous molecule expressed on T helper type 2 cells (CRTH2) is a PGD2 receptor found on eosinophils, basophils, and Th2 type T cells which exhibits chemotaxis and functions in activation cascades. However, while a number of CRTH2 antagonists, including ramatroban, are known to exert activity in certain animal models, activity in a guinea pig model of EA-induced airway hyperresponsiveness has not been demonstrated. The newly developed CRTH2 antagonist ASP5642 has shown antagonistic activity against human and guinea pig CRTH2 in previous studies and has also been found effective in treating guinea pig models of airway inflammation and airway hyperresponsiveness. While previous studies have used animals such as rats and mice to evaluate CRTH2 antagonist effects, ours is the first attempt to evaluate CRTH2 function in a guinea pig asthma model, which may prove useful in evaluating the compound's effects in humans, given the comparable airway function between the two species taken together, these data from the present study strongly suggest the utility of ASP5642 in investigating the role of CRTH2 in inflammatory responses and as a drug treatment for human asthma., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Selenium-binding protein 1 (Selenbp1) is suggested to play a role in tumor suppression, and may be involved in the toxicity produced by dioxin, an activator of aryl hydrocarbon receptors (AhR). However, the mechanism or likelihood is largely unknown because of the limited information available about the physiological role of Selenbp1., Methods: To address this issue, we generated Selenbp1-null [Selenbp1 (-/-)] mice, and examined the toxic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in this mouse model., Results: Selenbp1 (-/-) mice exhibited only a few differences from wild-type mice in their apparent phenotypes. However, a DNA microarray experiment showed that many genes including Notch1 and Cdk1, which are known to be enhanced in ovarian carcinoma, are also increased in the ovaries of Selenbp1 (-/-) mice. Based on the different responses to TCDD between C57BL/6J and DBA/2J strains of mice, the expression of Selenbp1 is suggested to be under the control of AhR. However, wasting syndrome by TCDD occurred equally in Selenbp1 (-/-) and (+/+) mice., Conclusions: The above pieces of evidence suggest that 1) Selenbp1 suppresses the expression of tumor-promoting genes although a reduction in Selenbp1 alone is not very serious as far as the animals are concerned; and 2) Selenbp1 induction by TCDD is neither a pre-requisite for toxicity nor a protective response for combating TCDD toxicity., General Significance: Selenbp1 (-/-) mice exhibit little difference in their apparent phenotype and responsiveness to dioxin compared with the wild-type. This may be due to the compensation of Selenbp1 function by a closely-related protein, Selenbp2., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In Annex 1 countries, nitrous oxide (N2 O) emissions from swine and poultry excreta have been calculated and the N2 O reduction potential of each country by using amino acids in feed could also be calculated, then a comparison made among the countries. The N2 O reduction rates were approximately 25% for these Annex 1 countries and amino acids were able to make a large contribution to that reduction. Greenhouse gases (GHG) which are N2 O combined with methane (CH4 ) were estimated to reduce by 24.8% in Japan when amino acids were introduced into the feed, but only a 7.2% reduction was estimated in France. Purification, which is mainly used for manure treatment in Japan, emits much more N2 O and less CH4 , whereas the liquid system which is mainly used in France emits more CH4 and less N2 O based on the emission factors from the United Nations Framework Convention on Climate Change data base. Changing the French manure treatment system to the Japanese style with amino acids in feed would reduce GHG emissions by 23.4%. Reduction of the arable land use in Japan by changing crop formulations supported by adding amino acids to feed was also quantified as about 10% and led to an increase in the production of meat using the same arable land area., (© 2013 Japanese Society of Animal Science.)

Therapeutic angiogenesis has emerged as one of the most promising therapies for severe ischemic cardiovascular diseases with no optional therapy. Several investigators have reported that transplantation of cultured adipose-derived regenerative cells (cADRCs) to ischemic tissues promotes neovascularization and blood perfusion recovery; however, cell therapy using cultured cells has several restrictions. To resolve this problem, the angiogenic capacity of freshly isolated ADRCs (fADRCs) obtained from Lewis rats was compared with cADRCs, both in vivo and in vitro. Flow cytometric analysis showed that fADRCs contained several cell types such as endothelial progenitor cells and endothelial cells; however, these cells were present in a very small proportion in cADRCs. Transplantation of fADRCs in mice significantly improved blood perfusion, capillary density, and production of several angiogenic factors in transplanted ischemic limbs compared with a saline-injected group, whereas these effects were not observed in the cADRCs-injected group. fADRCs also showed significantly higher expression levels of angiogenic factors than cADRCs in the in vitro study. Furthermore, fADRC stimulated tube formation more remarkably than cADRC in an in vitro tube formation assay. These results suggested that fADRCs have an effective angiogenic capacity, and they would be more valuable as a source for cell-based therapeutic angiogenesis than cADRCs or other stem/progenitor cells.

Background: Aging is an established risk factor for contrast-induced nephropathy (CIN). However, little information is available on the incidence and clinical outcome of CIN for the elderly patients in Japan., Objectives: We determined the incidence and clinical outcome of CIN in the Japanese elderly patient., Methods: We studied 292 patients who had mild renal dysfunction (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) at baseline and underwent coronary angiography. Patients were divided into two groups base on their age: the elderly group (age ≥ 75, n=108) and the control group (age<75, n=184). CIN was defined as a 25% increase in serum creatinine or an increase in serum creatinine by>0.5 mg/dl above the baseline value at or within 2 days post procedure., Results: Patients in the elderly group had a higher incidence of CIN (14%) than those in the control group (9%). In patients who developed CIN, there was no significant difference between the two groups in baseline GFR and GFR on days 1, 2, 7 and 30 after the procedure. However, the relative increase in GFR above baseline on day 7 (-4.0 ± 6.1 vs -8.3 ± 8.0 ml/min P=0.096) and day 30 (1.5 ± 9.4 vs -10.1 ± 9.6 ml/min P=0.0017) in the elderly group was higher than that in the control group. Furthermore, death occurred in 3 patients in the elderly group (20%) whereas no patient died in the control group (P=0.092)., Conclusion: Aging (age ≥ 75) is a risk factor for CIN in Japanese. CIN in the elderly patients may be associated with prolonged renal dysfunction and poor prognosis.

Background: It has been reported that the clinical characteristics of infective endocarditis are changing during the course of the decades. However, most of the available data are obtained in the early 2000s or earlier. We therefore evaluated the more recent clinical spectrum of infective endocarditis., Methods: Fifty-four consecutive patients diagnosed as infective endocarditis based on the Duke criteria at our hospital from January 2006 to December 2010 were evaluated., Results: Of 54 cases, 31 (57%) were male and 23 (43%) were female, with mean age of 57 +/- 17 years. Twenty-three (43%) patients were older than 65 years. The number of patients with diabetes mellitus or undergoing chronic hemodialysis, or cancer were 9 (17%), 5 (9%), and 5 (9%), respectively. In 25 patients (46%), endocarditis occurred without any underlying cardiac disease. The frequencies of streptococcal endocarditis and staphylococcal endocarditis were almost identical [18 (33%) vs. 17 (32%)]. Methicillin resistant staphylococcus aureus was found in 6 patients (11%)., Conclusions: A survey of patients with infective endocarditis from 2006 to 2010 revealed a trend towards increased staphylococcal endocarditis in compromised patients without prior cardiac disorders.

Aim: To evaluate the effects of eicosapentaenoic acid (EPA) on regional arterial stiffness assessed by strain rate using tissue Doppler imaging., Methods: Nineteen eligible patients were prospectively studied (mean age 62 ± 8 years, 68% men). Subjects with large vessel complications and/or diabetes mellitus were excluded. The strain rate of the ascending aorta was measured by tissue Doppler imaging as an index of regional arterial stiffness, and brachial-ankle pulse wave velocity (baPWV) was measured as an index of degree of systemic arteriosclerosis. These indices were compared before and after administration of EPA at 1800 mg/d for one year., Results: The plasma concentration of EPA increased significantly after EPA administration (3.0% ± 1.1% to 8.5% ± 2.9%, P < 0.001). There were no significant changes in baPWV (1765 ± 335 cm/s to 1745 ± 374 cm/s), low-density lipoprotein cholesterol levels (114 ± 29 mg/dL to 108 ± 28 mg/dL), or systolic blood pressure (131 ± 16 mmHg to 130 ± 13 mmHg) before and after EPA administration. In contrast, the strain rate was significantly increased by administration of EPA (19.2 ± 5.6 s(-1), 23.0 ± 6.6 s(-1), P < 0.05)., Conclusion: One year of administration of EPA resulted in an improvement in regional arterial stiffness which was independent of blood pressure or serum cholesterol levels.

We compared neuronal activity in the dorsolateral (PFdl), orbital (PFo), and polar (PFp) prefrontal cortex as monkeys performed three tasks. In two tasks, a cue instructed one of two strategies: stay with the previous response or shift to the alternative. Visual stimuli served as cues in one of these tasks; in the other, fluid rewards did so. In the third task, visuospatial cues instructed each response. A delay period followed each cue. As reported previously, PFdl encoded strategies (stay or shift) and responses (left or right) during the cue and delay periods, while PFo encoded strategies and PFp encoded neither strategies nor responses; during the feedback period, all three areas encoded responses, but not strategies. Four novel findings emerged from the present analysis. (1) The strategy encoded by PFdl and PFo cells during the cue and delay periods was modality specific. (2) The response encoded by PFdl cells was task and modality specific during the cue period, but during the delay and feedback periods it became task and modality general. (3) Although some PFdl and PFo cells responded to or anticipated rewards, we could rule out reward effects for most strategy- and response-related activity. (4) Immediately before feedback, only PFp signaled responses that were correct according to the cued strategy; after feedback, only PFo signaled the response that had been made, whether correct or incorrect. These signals support a role in generating responses by PFdl, assigning outcomes to choices by PFo, and assigning outcomes to cognitive processes by PFp.

Background: Both obesity and left ventricular (LV) diastolic dysfunction are associated with an increased risk of cardiovascular morbidity and mortality. There is a paucity of data as to whether obesity is independently associated with LV diastolic dysfunction., Methods: Adult patients with sinus rhythm referred for a transthoracic echocardiography between July, 2007, and December, 2007, were prospectively included. Exclusion criteria were patient who had a history of congenital or valvular heart disease, treatment with pacemaker implantation or implantable cardioverter defibrillator, myocardial infarction, or impaired LV systolic function. Diastolic function was classified by an algorithm incorporating data from mitral and pulmonary venous flow indices, and Doppler tissue imaging. Body mass index (BMI) was evaluated as a categorical variable (normal weight <25.0 kg/m(2); overweight 25.0 to <30.0 kg/m(2); and obese ≥30 kg/m(2)). Logistic models were used to assess the risk of abnormal LV diastolic function associated with BMI categories., Results: Of a total number of 692 patients who met all study criteria (mean 59 ± 15 year-old; 50% women, 48% hypertension, 16% diabetes, 26% overweight, 8% obese), 538 (78%) had abnormal LV diastolic function. In multivariate analyses adjusting for age, sex, and cardiovascular risk factors, obesity was independently associated with LV diastolic dysfunction (odds ratio [OR]: 2.98, 95% confidence interval [CI]: 1.12-7.88; P = 0.03) compared to normal weight. LV mass did not weaken this association (OR: 2.88, 95% CI: 1.08-7.68; P = 0.04). Overweight was not independently associated with LV diastolic dysfunction., Conclusion: Obesity was associated with LV diastolic dysfunction independent of cardiovascular risk factors and LV mass., (© 2012 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.)

It is often difficult to noninvasively differentiate a post-infarction left ventricular (LV) pseudoaneurysm from a post-infarction true aneurysm. A 66-year-old woman with a past history of inferior acute myocardial infarction was admitted to our hospital because of acute decompensated heart failure. Two-dimensional transthoracic echocardiography showed an aneurysm with a narrow orifice in the inferoposterior basal area. The pulmonary to systemic flow ratio (Q p/Q s) was 2.2:1, which corresponded to moderate left-right shunting. Three-dimensional transesophageal echocardiography (3D-TEE) showed the orifice in the perforated right ventricular basal area with a color jet through the orifice from the LV to the right ventricle. Collectively, based on the 3D-TEE findings, we diagnosed the case as inferoposterior pseudoaneurysm with a left-to-right shunt caused by myocardial infarction.

Pioglitazone has been shown to reduce the occurrence of fatal and nonfatal myocardial infarction (MI) in type 2 diabetes mellitus (DM). However, the mechanisms of such favorable effects remain speculative. The aim of this study was to investigate the effect of pioglitazone on arterial baroreflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA) in 30 DM patients with recent MI. Patients were randomly assigned to those taking pioglitazone (n = 15) and those not taking pioglitazone (n = 15) at 4 weeks after the onset of MI. BRS, MSNA, calculated homeostasis model assessment of insulin resistance index (HOMA-IR), and plasma adiponectin were measured at baseline and after 12 weeks. Pioglitazone increased plasma adiponectin (from 6.9 ± 3.3 μg/dL to 12.2 ± 7.1 μg/dL) and reduced HOMA-IR (from 4.0 ± 2.2 to 2.1 ± 0.9). In the pioglitazone group, MSNA decreased significantly (from 37 ± 7 bursts/min to 25 ± 8 bursts/min) and BRS increased significantly (from 6.7 ± 3.0 to 9.9 ± 3.2 ms/mm Hg) after 12 weeks. Furthermore, a significant relationship was found between the change in MSNA and HOMA-IR (r = 0.6, P = 0.042). Thus, pioglitazone decreased the sympathetic nerve traffic through the improvement of insulin resistance in DM patients with recent MI, which indicate that the sympathoinhibitory effects of pioglitazone may, at least in part, have contributed to the beneficial effects of pioglitazone.

Functional neuroimaging studies show that perceptual judgments about time and space activate similar prefrontal and parietal areas, and it is known that perceptions in these two cognitive domains interfere with each other. These findings have led to the theory that temporal and spatial perceptions, among other metrics, draw on a common representation of magnitude. Our results indicate that an alternative principle applies to the prefrontal cortex. Analysis at the single-cell level shows that separate, domain-specific populations of neurons encode relative magnitude in time and space. These neurons are intermixed with each other in the prefrontal cortex, along with a separate intermixed population that encodes the goal chosen on the basis of these perceptual decisions. As a result, domain-specific neural processing at the single-cell level seems to underlie domain generality as observed at the regional level, with a common representation of prospective goals rather than a common representation of magnitude., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The concept of the "mnemonic scotoma," a spatially circumscribed region of working memory impairment produced by unilateral lesions of the PFC, is central to the view that PFC is critical for the short-term retention of information. Presented here, however, are previously unpublished data that offer an alternative, nonmnemonic interpretation of this pattern of deficit. In their study, Wajima and Sawaguchi [Wajima, K., & Sawaguchi, T. The role of GABAergic inhibiton in suppressing perseverative responses in the monkey prefrontal cortex. Neuroscience Research, 50(Suppl. 1), P3-P317, 2004] applied the GABA(A) antagonist bicuculline methiodide unilaterally to the PFC of two monkeys while they performed an oculomotor delayed-response task. Consistent with previous studies, errors for the initial memory-guided saccade were markedly higher when the cued location fell into the region of the visual field affected by the infusion. These erroneous saccades tended to select an alternative target location (out of a possible 16) that had not been cued on that trial. By extending the analysis window, however, it was observed that the second, "corrective" saccade often acquired the location that had been cued on that trial. Further analysis of the erroneous initial saccades indicated that they tended to be directed to a location that had been relevant on the previous trial. Thus, the deficit was not one of "forgetting" the cued location. Rather, it was one of selecting between currently and previously relevant locations. These findings suggest a need for a reconsideration of the concept of the mnemonic scotoma, which in turn invites a reconsideration of functional interpretations of sustained neuronal activity in PFC.

A 73-year-old female patient with a past history of right ventricular infundibular stenosis was admitted to our intensive care unit because of right ventricular dysfunction. On the fifth day of hospitalization, she suddenly experienced dyspnea without chest pain despite the improvement of her condition by initial medical treatment. Although electrocardiography revealed no ST-segment elevation, echocardiography and myocardial perfusion using 99m Tc-MIBI revealed new development of severe symmetrical akinesia and reduced perfusion of the left ventricular (LV) apex and mid-ventricle. LV apical ballooning syndrome was diagnosed based on the minimal elevation of cardiac enzymes (peak cardiac troponin I 0.18 ng/ml) despite the presence of large regions of focal myocardial damage in the myocardium and the absence of positive ECG diagnosis and urgent coronary angiography. Previous coronary angiography revealed normal coronary arteries and the left anterior descending artery without full irrigation around the apex making apical ballooning. On the 12th day of hospitalization, despite the use of positive inotropic treatment, it was impossible to maintain hemodynamic stability, and the patient died prior to the functional recovery of the left ventricle.

When we encode faces in memory, we often do so in association with biographical information regarding the person. To examine the neural dynamics underlying such encoding processes, we devised a face recognition task and recorded cortical activity using magnetoencephalography. The task included two conditions. In the experimental condition, face stimuli were preceded by biographical information regarding the person whose face was to be memorized, whereas in the control condition, nonsense syllables were presented before face stimuli. Behavioral results indicated that the biographical information about a person facilitated the recognition memory of their face. Magnetoencephalography signals showed clear visually evoked magnetic fields mainly in the occipitotemporal cortex, in response to the face stimuli that were to be encoded. The phasic peak was observed at 100-200 ms after onset of a face stimulus, which was followed by late latency deflections (200-400 ms). Comparison of the signal between conditions revealed that the preceding semantic information does modulate the neuromagnetic responses to the face stimuli. This modulation occurred primarily at the late latency component in the sensors over the occipitotemporal cortex. In addition, the effects of conditions were also observed in the signals from more anterior sensors, which occurred earlier than the effects in the occipitotemporal cortex. These results provide insights into the neural dynamics underlying the encoding of faces in association with their biographical information., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Contrast-induced nephropathy (CIN) is associated with increased morbidity and mortality rates. Although a previous study reported that pretreatment with sodium bicarbonate is more effective than sodium chloride for prophylaxis of CIN, this has not been a universal finding. We performed a prospective randomized trial to investigate whether CIN can be avoided using sodium bicarbonate. In total 155 patients with a glomerular filtration rate (GFR) <60 ml/min/1.73 m(2) who were undergoing coronary angiography were enrolled. We assigned patients to sodium chloride plus sodium bicarbonate (bicarbonate group, n = 78) or sodium chloride alone (chloride group, n = 77). Infusion of sodium bicarbonate at 1 ml/kg/hour continued from 3 hours before to 6 hours after coronary angiography. CIN was defined as a 25% increase in serum creatinine from baseline value or an absolute increase of ≥0.5 mg/dl, which appeared within 2 days of contrast. Baseline GFR was not significantly different between the 2 groups. Patients in the bicarbonate group had a higher GFR than those in the chloride group on day 2 (45.8 ± 13.4 vs 40.9 ± 14.6 ml/min/1.73 m(2), p = 0.031) and at 1 month (49.5 ± 14.7 vs 43.7 ± 15.5 ml/min/1.73 m(2), p = 0.019). CIN occurred in 10 patients (13%) in the chloride group but in only 2 patients (2.6%) in the bicarbonate group (p = 0.012). Sodium chloride plus sodium bicarbonate is more effective than sodium chloride alone for prophylaxis of CIN and can lead to retention of better long-term renal function., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Left atrial (LA) enlargement has been acknowledged as a significant predictor of cardiovascular morbidity and mortality., Methods: To evaluate the accuracy of two-dimensional and three-dimensional echocardiography for determining LA volume, LA volume measurements by echocardiography were compared with those measured by 64-slice multidetector computed tomography (MDCT) as a reference standard., Results: Fifty-seven consecutive patients (mean age, 66 ± 11 years; 59% men) referred to echocardiography and MDCT on the same day were prospectively evaluated. LA volume by three-dimensional echocardiography was correlated closely with that by MDCT (r = 0.95, P < .0001), with 8% underestimation. LA volume by two-dimensional echocardiography was correlated less well with that measured by MDCT (r = 0.86, P < .0001) and consistently underestimated LA volume by 19%, particularly as the left atrium enlarged., Conclusions: LA volume assessment by three-dimensional echocardiography was correlated closely with that measured by MDCT, albeit with an 8% underestimation. Three-dimensional echocardiography is a feasible noninvasive method to evaluate LA volume., (Copyright © 2011 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Objective: Nitric oxide (NO) is an important modulator of cardiovascular function. In this study, we examined whether cytosolic phospholipase A2α (cPLA2α), an initial enzyme in the arachidonic acid pathway, is involved in blood pressure (BP) elevation in a murine model of chronic NO inhibition., Methods and Results: cPLA2α gene-deficient mice (cPLA2α-/-) and wild-type mice (WT) were administered the NO synthesis inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) for 4 weeks. Before treatment, BP was comparable in both groups; it increased significantly in the WT but not in the cPLA2α-/- after treatment. Bone marrow transplantation experiments showed that cPLA2α in blood cells and plasma eicosanoid concentrations were not involved in BP elevation by L-NAME treatment. Activation of cPLA2α and subsequent production of eicosanoids in the aortic endothelium but not in aortic smooth muscle cell, heart, or kidney was observed after L-NAME treatment. Aortic ring assays revealed that endothelial function was comparable in both groups of mice before treatment. L-NAME treatment disturbed endothelial function in WT but not in cPLA2α-/-., Conclusions: These results suggest that endothelial cPLA2α may play a principal role in L-NAME-induced hypertension and may be a target molecule for maintaining endothelial function under NO inhibition.

A novel series of biphenylylmethylimidazole derivatives and related compounds were synthesized as inhibitors of 17,20-lyase, a key enzyme in the production of steroid hormones, and their biological activities were evaluated. In an attempt to identify potent and selective inhibitors of 17,20-lyase over the related CYP3A4 enzyme, a homology model for human 17,20-lyase was developed using the X-ray crystallographic structure of the mammalian CYP2C5 enzyme. With the aid of molecular modeling, optimization of the biphenyl moiety was performed to give an acetamide derivative, which was resolved by HPLC to give the active (-)-enantiomer. The obtained active enantiomer showed not only potent inhibition of both rat and human 17,20-lyase,with IC(50) values of 14 and 26 nM, respectively, but also excellent selectivity (>300-fold) for inhibition of 17,20-lyase over CYP3A4. Moreover, the active enantiomer significantly reduced both serum testosterone and DHEA concentrations in a monkey model after single oral administration. Asymmetric synthesis of the active enantiomer was also developed via a chiral intermediate using a diastereoselective Grignard reaction., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Considerable neuroimaging research in humans indicates that the frontal pole cortex (FPC), also known as Brodmann area 10, contributes to many aspects of cognition. Despite these findings, however, its fundamental function and mechanism remain unclear. Recent neurophysiological results from the FPC of monkeys have implications about both. Neurons in the FPC seem to encode chosen goals at feedback time and nothing else. Goals, the places and objects that serve as targets for action, come in many forms and arise from many cognitive processes. The FPC's signal, although surprisingly simple for neurons at the apex of a prefrontal hierarchy, could promote learning about which kinds of goals and goal-generating processes produce particular costs and benefits, thereby improving future choices., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Abstract behavior-guiding rules and strategies allow monkeys to avoid errors in rarely encountered situations. In the present study, we contrasted strategy-related neuronal activity in the dorsolateral prefrontal cortex (PFdl) and the orbital prefrontal cortex (PFo) of rhesus monkeys. On each trial of their behavioral task, the monkeys responded to a foveal visual cue by making a saccade to one of two spatial targets. One response required a leftward saccade, the other required a saccade of equal magnitude to the right. The cues instructed the monkeys to follow one of two response strategies: to stay with their most recent successful response or to shift to the alternative response. Neurons in both areas encoded the stay and shift strategies after the cue appeared, but there were three major differences between the PFo and the PFdl: (1) many strategy-encoding cells in PFdl also encoded the response (left or right), but few, if any, PFo cells did so; (2) strategy selectivity appeared earlier in PFo than in PFdl; and (3) on error trials, PFo neurons encoded the correct strategy-the one that had been cued but not implemented-whereas in PFdl the strategy signals were weak or absent on error trials. These findings indicate that PFo and PFdl both contribute to behaviors guided by abstract response strategies, but do so differently, with PFo encoding a strategy and PFdl encoding a response based on a strategy.

To compare with our previous findings on relative-duration discrimination, we studied prefrontal cortex activity as monkeys performed a relative-distance discrimination task. We wanted to know whether the same parts of the prefrontal cortex compare durations and distances and, if so, whether they use similar mechanisms. Two stimuli appeared sequentially on a video screen, one above a fixed reference point, the other below it by a different distance. After a delay period, the same two stimuli reappeared (as choice stimuli), and the monkeys' task was to choose the one that had appeared farther from the reference point during its initial presentation. We recorded from neurons in the dorsolateral prefrontal cortex (area 46) and the caudal prefrontal cortex (area 8). Although some prefrontal neurons encoded the absolute distance of a stimulus from the reference point, many more encoded relative distance. Categorical representations ("farther") predominated over parametric ones ("how much farther"). Relative-distance coding was most often abstract, coding the farther or closer stimulus to the same degree, independent of its position on the screen. During the delay period before the choice stimuli appeared, feature-based coding supplanted order-based coding, and position-based coding-always rare-decreased to chance levels. The present results closely resembled those for a duration-discrimination task in the same cortical areas. We conclude, therefore, that these areas contribute to decisions based on both spatial and temporal information.

Cyclooxygenase inhibitors are often prescribed to relieve severe ischemic leg pain in critical ischemic limb patients. Prescription of high doses of aspirin and selective cyclooxygenase-2 inhibitors is reported to increase cardiovascular events through suppression of the vasodilative prostanoid prostaglandin I(2) in endothelium. Here, we evaluated the influence of aspirin and etodolac, a selective cyclooxygenase-2 inhibitor, on neovascularization using a murine ischemia hind limb model. C57BL/6J mice were treated with aspirin or etodolac for twenty-eight days after induction of ischemia. We exploited a concentration of the agents that suppressed cyclooxygenase activity efficiently, especially in prostaglandin I(2) production. Recovery of limb blood perfusion and capillary density in ischemic limbs was significantly suppressed by etodolac treatment when compared to the aspirin treated group and untreated group. Production of 6-keto prostaglandin F(1alpha) and prostaglandin E(2) was lower in the aspirin treated group when compared with the etodolac-treated group. Also, these concentrations were lower in both treatment groups compared with the untreated group. Immunohistochemical analysis suggested cyclooxygenase-2 was expressed in endothelium but not in inflammatory cells in ischemic tissue from the acute to chronic phase. Cyclooxygenase-1 was expressed strongly in inflammatory cells in the acute phase. Furthermore, bone marrow-derived mononuclear cell transplantation improved neovascularization, whereas aspirin and etodolac did not inhibit these effects. Production of arachidonic acid metabolites by transplanted cells was independent of the improvement of neovascularization. In conclusion, cyclooxygenase-2 inhibition reduces ischemia-induced neovascularization., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

The frontal pole cortex (FPC) expanded markedly during human evolution, but its function remains uncertain in both monkeys and humans. Accordingly, we examined single-cell activity in this area. On every trial, monkeys decided between two response targets on the basis of a 'stay' or 'shift' cue. Feedback followed at a fixed delay. FPC cells did not encode the monkeys' decisions when they were made, but did so later on, as feedback approached. This finding indicates that the FPC is involved in monitoring or evaluating decisions. Using a control task and delayed feedback, we found that decision coding lasted until feedback only when the monkeys combined working memory with sensory cues to 'self-generate' decisions, as opposed to when they simply followed trial-by-trial instructions. A role in monitoring or evaluating self-generated decisions could account for FPC's expansion during human evolution.

We examined activity in the frontal cortex as monkeys performed a duration-discrimination task. Two stimuli, one red and the other blue, appeared sequentially on a video screen--in either order. Later, both stimuli reappeared, and to receive a reward the monkeys had to choose the stimulus that had lasted longer during its initial presentation. Some neurons encoded stimulus duration, but a larger number of cells represented their relative duration, which was encoded in three ways: whether the first or second stimulus had lasted longer; whether the red or blue stimulus had lasted longer; or, less commonly, as the difference between the two durations. As the monkeys' choice approached, the signal encoding which stimulus (red or blue) had lasted longer increased as the order-based signal dissipated. By representing stimulus durations and relative durations--both bound to stimulus features and event order--the frontal cortex could contribute to both temporal perception and episodic memory.

The primate prefrontal cortex contributes to stimulus-guided behavior, but the functional specializations among its areas remain uncertain. To better understand such specializations, we contrasted neuronal activity in the dorsolateral prefrontal cortex (PFdl) and the orbital prefrontal cortex (PFo). The task required rhesus monkeys to use a visual cue to choose a saccade target. Some cues instructed the monkeys to repeat their most recent response; others instructed them to change it. Responses were followed by feedback: fluid reward if correct, visual feedback if incorrect. Previous studies, using different tasks, have reported that PFo neurons did not encode responses. We found PFo did encode responses in this task, but only near feedback time, after the response had been completed. PFdl differed from PFo in several respects. As reported previously, some PFdl neurons encoded responses from the previous trial and others encoded planned responses. PFo neurons did not have these properties. After feedback, PFdl encoded rewarded responses better than unrewarded ones and thus combined response and outcome information. PFo, in contrast, encoded the responses chosen, rewarded or not. These findings suggest that PFdl and PFo contribute differently to response knowledge, with PFo using an outcome-independent signal to monitor current responses at feedback time.

Neurophysiological research has explored most of the prefrontal cortex of macaque monkeys, but the relatively inaccessible frontal-pole cortex remains unexamined. Here we describe a method for gaining access to the frontal-pole cortex with moveable microelectrodes. The key innovation is a direct approach through the frontal air sinus. In addition, the small size of the frontal-pole cortex in macaques led to the design of a smaller recording chamber than typically used in behavioral neurophysiology. The method has proven successful in two subjects, with no adverse health consequences.

We reported previously that as monkeys used abstract response strategies to choose spatial goals, 1 population of prefrontal cortex neurons encoded future goals (F cells), whereas a largely separate population encoded previous goals (P cells). Here, to better understand the mechanisms of goal selection and maintenance, we studied correlated activity among pairs of these neurons. Among the 3 possible types of pairs, F-F and F-P pairs often exhibited significant correlations when and after monkeys selected future goals but P-P pairs rarely did. These correlations were stronger when monkeys shifted from a previous goal than when they stayed with that goal. In addition, members of F-F pairs usually preferred the same goal and thus shared both prospective coding and spatial tuning properties. In contrast, cells composing F-P pairs usually had different spatial preferences and thus shared neither coding nor spatial tuning properties. On the assumption that the neurons composing a pair send convergent outputs to target neurons, their correlated activity could enhance their efficacy in context-dependent goal selection, goal maintenance, and the transformation of goal choices into action.

The prefrontal cortex plays an essential role in various cognitive functions, such as planning and reasoning, yet little is known about how such neural mechanisms develop during childhood, particularly in young children. To better understand this issue, the present article reviews the literature on the development of the prefrontal cortex during early childhood, focusing mainly on the changes in structural architecture, neural activity, and cognitive abilities. Neuroanatomically, the prefrontal cortex undergoes considerable maturation during childhood, including a reduction of synaptic and neuronal density, a growth of dendrites, and an increase in white matter volume, thereby forming distributed neural networks appropriate for complex cognitive processing. Concurrently, behavioral performance of various cognitive tasks improves with age, and intercorrelations among performance on each task become weak through development. Furthermore, the correlation between subcategories of intelligence test decreases as general intellectual efficiency increases. In addition, recent neuroimaging findings suggest that the prefrontal cortex is already functional in 4-year olds and becomes organized into focal, fine-tuned systems through later development. The literature reviewed suggests that fractionation of the functional neural systems plays a key role in the development of prefrontal cortex and such fractionating process has already commenced in preschool children.

Background: UFT is an anticancer agent consisting of 1-(2-tetrahydrofuryl)-5-fluorouracil (5-FU) combined with uracil in a molar ratio of 1: 4. Its mechanisms of action are, presumably, inhibition of deoxyribonucleic acid (DNA) synthesis by thymidylate synthetase (TS) and impairment of ribonucleic acid (RNA) function by the incorporation of 5-fluorouridine-5'-triphosphate into RNA. This study was conducted to examine the TS inhibition rate (TS-IR) and the concentration of 5-FU incorporated in RNA per milligram of tissue treated with UFT (F-RNA)., Methods: We administered UFT to 12 patients with bladder cancer. We also administered UFT to 20 rats bearing bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), and to 10 BBN-untreated control rats. We then determined the total TS concentration, TS-IR, and F-RNA in the human bladder tumor and normal tissues and in the BBN-treated and BBN-untreated rat organs, including the urinary bladder., Results: In the bladder cancer patients, the mean F-RNAs in the bladder tumor and normal tissue were 0.133 +/- 0.137 and 0.056 +/- 0.062 ng/mg, respectively, without a significant difference (P < 0.1). The mean TS-IR was 35.3 +/- 19.6% in the tumor tissue and 38.0 +/- 16.6% in the normal bladder tissue, and this difference was also not significant. In the rat bladder cancer model, the total TS concentration and F-RNA in the tumor after the administration of UFT were 15.32 pmol/g and 0.780 ng/mg, respectively, being markedly higher than the corresponding values (1.22 pmol/g and 0.129 ng/mg) in the control normal bladder tissue., Conclusion: The impairment of RNA metabolism by F-RNA incorporated in RNA did not seem to be the critical mechanism of the antitumor effect of UFT at the usual clinical dose, as neither TS-IR nor F-RNA (as antitumor parameters) seemed to increase significantly after a clinical dose of UFT. However, the inhibition of DNA synthesis and the impairment of RNA were independent mechanisms of the action of high-dose UFT in the experimental rat bladder tumors, as both total is concentration and F-RNA were increased significantly.