We have previously reported the efficacy of the Patient Oriented Clerkship (POC) in the clinical clerkship in Showa University Hospitals, by a trial with old four-year pharmacy program students. In the unique clerkship, each student has a patient in charge, and follows his/her clinical conditions throughout the rotation. The aim of the POC is that having the students learn spontaneously (Active Learning) and actively (Adult Learning) promoted by student's commitment and responsibility by communicating with patients and health professionals in a team. As the POC requires students both Active Learning and Adult Learning, we define the POC as Active Adult Learning (AAL). Having a patient in charge for each student gives them many opportunities to participate in the medical team and foster their problem solving skills. Our previous study eventually showed positive results of the POC in the one-month short clerkship in the four-year program. On the other hand, the effect of the unique hospital clerkship in the new six-year program is not known. We conducted a student survey to clarify the learning effect in the new six-year education system which was revised and 2.5 month clinical clerkship was scheduled according to the model core clerkship curriculum. This report is the first report to show a challenge of the AAL/POC clerkship in the new six-year pharmacy education program.

RATIONALE Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes. OBJECTIVES To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity. METHODS A total of 279 eligible patients with COPD (stages I-IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient. MEASUREMENTS AND MAIN RESULTS Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32±24 (SD) ml/yr (n=261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63±2,-31±1, and -2±1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils. CONCLUSIONS Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.

BACKGROUND: Remodeling of the pulmonary artery by an inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) is problematic in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Effective treatment that achieves reverse remodeling is required. The aim of this study was to assess the pro-apoptotic effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PASMCs obtained from patients with IPAH. METHODS: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by (3)H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. RESULTS: Treatment with imatinib (0.1 to 10μg/mL) significantly inhibited PDGF-BB (10ng/mL)-induced proliferation of PASMCs from IPAH patients. Imatinib (1μg/mL) did not induce apoptosis in quiescent IPAH-PASMCs, but it had a pro-apoptotic effect on IPAH-PASMCs stimulated with PDGF-BB. Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF-BB stimulation. PDGF-BB induced phosphorylation of Akt at 15min, and Akt phosphorylation was inhibited by imatinib in IPAH-PASMCs. Akt-I-1/2 (1μmol/L), an Akt inhibitor, in the presence of PDGF-BB significantly increased apoptotic cells compared with the control condition. Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs. CONCLUSION: Imatinib has anti-proliferative and pro-apoptotic effects on IPAH-PASMCs stimulated with PDGF. The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro-apoptotic effect.

BACKGROUND: It has been reported that that the amount of 4-hydroxy-2-nonenal (HNE), which is a major lipid peroxidation product and a cytotoxic aldehyde, is increased in the human failing myocardium. This study was designed to determine whether HNE has a pro-oxidant effect in cardiac myocytes and whether HNE causes Ca(2+) overload. METHODS AND RESULTS: Exposure to HNE for 10 minutes in the presence of ferric nitrilotriacetate induced the production of hydroxyl radical (.OH) in the rat myocardium as assessed by electron spin resonance spectroscopy, and HNE induced the generation of reactive oxygen species (ROS) in a dose-dependent manner as assessed by 2', 7'-dichlorofluorescein diacetate fluorescence. HNE increased intracellular Ca(2+) concentration ([Ca(2+)](i)) as assessed by fura-2 ratio in a dose- and time-dependent manner. After 20 minutes of HNE (400 micromol/L) exposure, hypercontracture was induced in 67% of the cells. Catalase, an antioxidative enzyme that can decompose hydrogen peroxide (H(2)O(2)), significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture. Carvedilol, a beta-blocker with potent antioxidant activity, also significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture, but propranolol had no effect on either [Ca(2+)](i) increase or hypercontracture. CONCLUSIONS: HNE induces the formation of ROS, especially H(2)O(2) and .OH, in cardiomyocytes and subsequently ROS cause intracellular Ca(2+) overload. HNE formation may play an important role as a mediator of oxidative stress in heart failure.

OBJECTIVE: The aim of this study was to evaluate right and left ventricular functions in patients with pulmonary arterial hypertension after living-donor lobar lung transplantation compared with those without hypertension. METHODS: Thirty-three recipients of living-donor lobar lung transplantation were divided into two groups: those with pulmonary arterial hypertension (PAH group; n = 12) and those without (non-PAH group; n = 21). Their systolic pulmonary artery pressure was 93.1 +/- 6.7 mm Hg versus 31.4 +/- 2.9 mm Hg, respectively. Right and left ventricular ejection fractions, systolic pulmonary artery pressure, and cardiac index were serially measured by radionuclide ventriculography and right heart catheterization, respectively. RESULTS: Pretransplant right and left ventricular ejection fractions were lower in the PAH group (29.8%+/- 7.0%, 49.9%+/- 6.6%) than in the non-PAH group (49.7%+/- 3.3%, 65.2%+/- 1.9%)(P =.010,.068). Two months after living-donor lobar lung transplantation, right ventricular ejection fraction and systolic pulmonary artery pressure in the PAH group (57.3%+/- 5.1%, 25.7 +/- 1.8 mm Hg) improved dramatically, equal to those in the non-PAH group. In contrast, left ventricular ejection fraction and cardiac index in the PAH group (50.9%+/- 3.7%, 2.66 +/- 0.12 L x min(-1) x m(-2)) were still significantly lower than in the non-PAH group (65.4%+/- 2.8%, 3.13 +/- 0.15 L x min(-1) x m(-2))(P =.0038,.037). At 6 to 12 months, the PAH group demonstrated a significant rise in left ventricular ejection fraction and cardiac index that reached similar values in the non-PAH group measured at 2 months. These values were stable for up to 3 years. CONCLUSIONS: Right ventricular function recovered early after living-donor lobar lung transplantation in the PAH group. In contrast, recovery of left ventricular function required 6 to 12 months. Improved cardiac function was sustained for up to 3 years, suggesting long-term durability of cardiac function recovery after living-donor lobar lung transplantation.

ABSTRACT Background and objective: Transcutaneous blood gas-monitoring systems with miniaturized SpO(2)(peripheral blood oxygen saturation)/PCO(2) combined sensors (TOSCATM) have been widely used. There are no reports of the inter- and intra-individual variability in transcutaneous measurements of PaCO(2)(PtcCO(2)) in response to acute progressive changes in PaCO(2). This study examined inter- and intra-individual variability of PtcCO(2) measurements under semi-steady-state conditions, and characterized the behaviour of PtcCO(2) in response to acute progressive changes in PaCO(2). Methods: Subjects breathed mixed gases through a mouthpiece connected to an automatic arterial blood gas controller. Using end-tidal PCO(2) and PO(2) as guides, PaCO(2) was controlled to increase and/or decrease between baseline and >/= 60 mm Hg, in a stepwise (n = 9) or progressive fashion (n = 6). Arterial blood was sampled when needed. Results: Intra-individual correlation coefficients between PtcCO(2) and PaCO(2) were excellent in all subjects (0.971-0.989); however, the slope of the regression line varied among subjects (1.040-1.335). Bias and limits of agreement (+/- 2 SD from bias) between PtcCO(2) and PaCO(2) were -1.8 mm Hg and -7.7 to 4.1 mm Hg. Changes in PtcCO(2) in response to acute progressive changes in PaCO(2) also varied among subjects. Conclusion: The PtcCO(2) measurement system allows reliable estimation of PaCO(2) in a given subject. However, caution is needed when comparing absolute values between subjects or when acute changes in PaCO(2) occur.

BACKGROUND: Amiodarone (AMD) is a strong antiarrhythmic drug but has severe side effects such as pulmonary toxicity. There are no indicators or drugs that can prevent the development of amiodarone-induced pulmonary toxicity (AIPT). METHODS: We collected data for 96 consecutive patients treated with AMD and analyzed clinical factors related to AIPT. In addition, we examined the effect of AMD and angiotensin II (Ang II) on human lung alveolar epithelial cells (AEC) and verified the protective efficacy of an Ang II type 1 receptor blocker (ARB) in vitro. RESULTS: During a follow-up period of 33.8+/-34.6 months, AIPT developed in 11 patients (11.5%). There were no differences in the dose of AMD, left ventricular ejection fraction, serum KL-6 and %DLCO level before starting AMD between patients with and those without AIPT. However, repeated episodes of congestive heart failure (CHF) were observed more frequently in patients with AIPT than in patients without AIPT (81.8% vs. 41.2%, P<0.011). In vitro examination, AMD progressively increased apoptosis of AEC and Ang II enhanced this effect of AMD (P<0.001). However, ARB inhibited the enhancement by Ang II of the AMD-induced apoptosis effect (P<0.001). Furthermore, patients with AIPT were administrated a lower dose of angiotensin system antagonists than were those without AIPT (P<0.05). CONCLUSIONS: The results indicate that Ang II induced by CHF increases the risk of AMD-induced pulmonary toxicity. An angiotensin-converting enzyme inhibitor or ARB should be given at a sufficient dose during AMD treatment.

The role of zinc, an endogenous N-methyl-d-aspartate (NMDA) receptor antagonist, in long-term potentiation (LTP) at hippocampal CA1 synapses is poorly understood. In the present study, the effect of exogenous zinc and zinc chelators on CA1 LTP was examined by using hippocampal slices. CA1 LTP after tetanic stimulation (100 Hz, 1 s) was potentiated in the presence of 5 muM ZnCl(2), but not in the presence of 30 muM. In varying the frequency (10-100 Hz, 1 s), zinc (5 muM) caused a significant shift of the frequency-response curve and lowered the threshold in LTP induction. The present study is the first to demonstrate that CA1 LTP is potentiated by low micromolar concentrations of zinc. Endogenous zinc is likely to reach low micromolar concentrations in the extracellular compartment in CA1 LTP induction. On the other hand, zinc has no effect on field excitatory postsynaptic potentials (fEPSPs) after tetanic stimulation in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, in which LTP was abolished, indicating that NMDA receptor activation is necessary for the potentiation of CA1 LTP by zinc. The pretreatment with ZnAF-2DA, a membrane-permeable zinc chelator, which was used to block the increase in intracellular Zn(2+), inhibited LTP and also LTP potentiated by zinc. It is likely that Zn(2+) taken up during LTP induction potentiates CA1 LTP via NMDA receptor activation.

Several reports have suggested a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. We have focused on the relationship between deleted mitochondrial DNA (mtDNA) and bipolar disorder. To investigate this relationship, we developed a methodology for quantification of the common 4977-bp deletion of mtDNA based on real-time polymerase chain reaction with SYBR Green. In this study, we assessed accumulation of the common deletion in postmortem frontal cortex from 147 individuals (48 controls, 49 patients with bipolar disorder, 50 patients with schizophrenia). We demonstrated age-dependent accumulation of the common deletion of mtDNA (p=1.09E-10). Females showed significantly higher accumulation of the deletion than did males (p=0.002). There was no significant association between accumulation and the two studied major mental disorders in the frontal cortex (p>0.2). However, there was no statistically significant correlation between the common deletion and aging in female patients with bipolar disorder (p=0.133), and no significant sex difference in patients with bipolar disorder (p=0.509). These results indicate that aging and sex have effect on accumulation of the common deletion of mtDNA in the prefrontal cortex depending on the diagnosis.

OBJECTIVES: The goal of our work was to examine the relationships of atrial fibrillation (AF) with genetic, clinical, and electrophysiological backgrounds in Brugada syndrome (BrS). BACKGROUND: Atrial fibrillation is often observed in patients with BrS and indicates that electrical abnormality might exist in the atrium as well as in the ventricle. SCN5A, a gene encoding the cardiac sodium channel, has been reported to be causally related to BrS. However, little is known about the relationships of atrial arrhythmias with genetic, clinical, and electrophysiological backgrounds of BrS. METHODS: Seventy-three BrS patients (49 +/- 12 years of age, men/women = 72/1) were studied. The existence of SCN5A mutation and clinical variables (syncopal episode, documented ventricular fibrillation [VF], and family history of sudden death) were compared with spontaneous AF episodes. Genetic and clinical variables were also compared with electrophysiologic (EP) parameters: atrial refractory period, interatrial conduction time (CT), repetitive atrial firing, and AF induction by atrial extra-stimulus testing. RESULTS: Spontaneous AF occurred in 10 (13.7%) of the BrS patients and SCN5A mutation was detected in 15 patients. Spontaneous AF was associated with higher incidence of syncopal episodes (60.0% vs. 22.2%, p < 0.03) and documented VF (40.0% vs. 14.3%, p < 0.05). SCN5A mutation was associated with prolonged CT (p < 0.03) and AF induction (p < 0.05) in EP study, but not related to the spontaneous AF episode and other clinical variables. In patients with documented VF, higher incidence of spontaneous AF (30.8% vs. 10.0%, p < 0.05), AF induction (53.8% vs. 20.0%, p < 0.03), and prolonged CT was observed. CONCLUSIONS: Spontaneous AF and VF are closely linked clinically and electrophysiologically in BrS patients. Patients with spontaneous AF have more severe clinical backgrounds in BrS. SCN5A mutation is associated with electrical abnormality but not disease severity.