Longitudinal PBL in Undergraduate Medical Education Develops Lifelong-Learning Habits and Clinical Competencies in Social Aspects.

Problem-based learning (PBL) is popular in medical education in Japan. We wished to understand the influence of PBL on the clinical competence of medical residents, using self-assessment and observer assessment. Tokyo Women's Medical University (TWMU) implemented PBL longitudinally (long-time) for four years, and on this basis we analyzed whether long-time PBL education is useful for clinical work. A self-assessment questionnaire was sent to junior and senior residents who were alumni of several schools, and an observation-based assessment questionnaire to senior doctors instructing them. Respondents were asked if they had used the PBL process in daily clinical tasks, and if so in what processes. Senior doctors were asked whether TWMU graduates perform differently from graduates of other schools. TWMU graduates answered "used a lot" and "used a little" with regard to PBL at significantly higher rates than other graduates. As useful points of PBL, they mentioned extracting clinical problems, solving clinical problems, self-directed leaning, positive attitude, collaboration with others, presentation, doctor-patient relations, self-assessment, and share the knowledge with doctors at lower levels and students. Observer assessments of TWMU graduates by senior doctors represented them as adaptive, good at presenting, good at listening to others' opinions, practical, selfish, and eager in their instructional practice. Longitudinal PBL can be a good educational method to develop lifelong-learning habits and clinical competencies especially in terms of the social aspect.

Reflection and feedback in ambulatory education.

BACKGROUND: It has been argued that the best method of acquiring clinical reasoning is through seeing new out-patients. The purpose of this interventional study was to establish a clinical clerkship course for Japanese medical students in an out-patient care setting, with multiple opportunities for reflective practice and improving the clinical reasoning abilities of the students. The effectiveness of the course was also examined. METHODS: Students performed examinations of new patients and made diagnostic decisions in 20 minutes. They presented their case using the SNAPPS (Summarize the case, Narrow the differential, Analyze the differential, Probe the preceptor, Plan management, and Select an issue for self directed learning) method, and this was followed by feedback from faculty members using the 1-minute preceptor method and a mini clinical evaluation exercise (mini-CEX). Students' clinical reasoning abilities were assessed by the objective structured clinical examination (OSCE) and the script concordance test (SCT). Students' written comments and responses to an interview about the course were also analysed. Cross-sectional data were examined by comparing individual OSCE and SCT scores, and the multiple-choice question examination (MCQ) completed by students who did and did not participate in this project. RESULTS: Students in the programme had higher scores on the mini-CEX in all areas. The SCT and OSCE scores were also significantly higher than the scores for the control group. Students' comments about the course, which provided an opportunity for daily reflection, were positive. DISCUSSION: Students rapidly acquired clinical reasoning skills through reflective practice. Students also demonstrated motivation to learn through the examination of new patients. The clinical clerkship programme with multiple opportunities for reflective practice in an out-patient care setting substantially improved the clinical reasoning abilities of medical students.

[International accreditation of medical school towards quality assurance of medical education].

An internationalization of practical medicine evoked international migrations of medical professionals. Since basic medical education is different among countries, the internationalization required international quality assurance of medical education. Global trend moves toward establishment of international accreditation system based on international standards. The World Federation for Medical Education proposed Global Standards for Quality Improvement as the international standards. Medical schools in Japan have started to establish program evaluation system. The standards which incorporated international standards have been published. The system for accreditation is being considered. An accreditation body, Japan Accreditation Council for Medical Education, is under construction. The accreditation is expected to enhance quality of education in Japan.

Team-based learning, a learning strategy for clinical reasoning, in students with problem-based learning tutorial experiences.

Acquiring clinical reasoning skills in lectures may be difficult, but it can be learnt through problem-solving in the context of clinical practice. Problem finding and solving are skills required for clinical reasoning; however, students who underwent problem-based learning (PBL) still have difficulty in acquiring clinical reasoning skills. We hypothesized that team-based learning (TBL), a learning strategy that provides the opportunity to solve problems by repeatedly taking tests, can enhance the clinical reasoning ability in medical students with PBL experiences during the pre-clinical years. TBL courses were designed for 4(th) year students in a 6-year program in 2008, 2009, and 2010. TBL individual scores, consisting of a combination of individual and group tests, were compared with scores of several examinations including computer-based testing (CBT), an original examination assessing clinical reasoning ability (problem-solving ability test; P-SAT), term examinations, and Objective Structured Clinical Examination (OSCE). CBT, OSCE and P-SAT scores were compared with those of students who learned clinical reasoning only through PBL tutorials in 2005, 2006, and 2007 (non-TBL students). Individual TBL scores of students did not correlate with scores of any other examination. Assessments on clinical reasoning ability, such as CBT, OSCE, and P-SAT scores, were significantly higher in TBL students compared with non-TBL students. Students found TBL to be effective, particularly in areas of problem solving by both individuals and teams, and feedback from specialists. In conclusion, TBL for clinical reasoning is useful in improving clinical reasoning ability in students with PBL experiences with limited clinical exposure.

Characteristics of medical school graduates who underwent problem-based learning.

INTRODUCTION: In this study, we compared the choice of medical specialty and subspecialty interest among problem-based-learning (PBL) graduates and non-PBL graduates. MATERIALS AND METHODS: Questionnaires were mailed to a total of 1398 female doctors who graduated from Tokyo Women's Medical University (TWMU) between 1989 and 2003. The response rate was over 30%, giving 248 respondents who had undergone a PBL curriculum (PBL+) and 220 subjects who had not (PBL-). Current specialty of the graduates were compared between the PBL+ and PBL-, and also compared with the general Japanese female doctors (Control 1 and 2) of similar age groups. Respondents were analysed in terms of their interests in subspecialty medical care or general medical practise, which includes comprehensive medical care, primary care and basic medicine. Internal medicine doctors working in the university hospitals were compared with those working outside the university hospitals. Internal medicine doctors were also compared with specialists in ophthalmology, otolaryngology, dermatology and psychiatry. Subjects were compared by odds ratio (OR) to examine group difference in the field of interest. OR >2.0 was considered statistically significant. RESULTS: Most doctors in all groups chose internal medicine. More PBL+ internal medicine doctors showed interests in comprehensive medical care and primary care; more PBL+ internal medicine doctors working outside university hospitals showed interest in comprehensive medical care and primary care when compared with those who were working in the university hospitals. The PBL- graduates did not show such a characteristic. CONCLUSIONS: More PBL+ graduates who chose internal medicine showed interest in holistic medical practices such as primary care and community medicine and more PBL+ specialists showed sustained interest in their respective fields.

Facilitation of problem finding among first year medical school students undergoing problem-based learning.

BACKGROUND: Adaptation to problem-based learning (PBL) is a difficult process for high school graduates who are not used to self-directed learning, especially in the freshmen year of medical school. The difficulty includes finding problems from a given case. PURPOSE: Evaluate the effect of an intervention to facilitate case-based problem finding among medical school freshmen undergoing a PBL tutorial. METHODS: Medical school freshmen in 2000 (nonintervened group) and 2001 (intervened group) participated in the study. The intervened group received the modified problem-based program by (a) having briefings on the importance of problem finding, (b) encouragement by the tutors in problem finding, and (c) reinforcement using a self-assessment sheet. At the end of the year, the ability of students to extract problems from a short case was evaluated and compared with the nonintervened students. RESULTS: The intervened group extracted a significantly greater number of problems than the nonintervened group. When extracted problems were categorized, the intervened group was able to generate more questions in a greater number of specified categories. CONCLUSIONS: Interventions to foster problem finding significantly facilitated acquisition of problem extraction skills among young medical students.

Suppression by 17beta-estradiol of monocyte adhesion to vascular endothelial cells is mediated by estrogen receptors.

Several observational studies have shown that estrogen replacement therapy decreases cardiovascular mortality and morbidity in postmenopausal women. However, The Women's Health Initiative (WHI) study has found that women receiving estrogen plus progestin had a significantly higher risk of breast cancer, coronary heart disease, stroke, and pulmonary embolus. In the present study, we examined whether estrogen prevents mechanisms that relate to plaque formation by inhibiting monocyte adhesion to endothelial cells. ECV304 cells, an endothelial cell line that normally expresses minimal estrogen receptor (ER)alpha, were transfected with an ERalpha expression plasmid. Treatment with tumor necrosis factor (TNF)-alpha increased expression of vascular cell adhesion molecule (VCAM)-1 mRNA, activation of nuclear factor-kappaB (NF-kappaB), and U937 cell adhesion in ECV304 cells. These effects of TNF-alpha were not significantly inhibited by pretreatment of native ECV304 cells with 17beta-estradiol (E(2)). In ECV304 cells overexpressing ERalpha, E(2) significantly inhibited the effects of TNF-alpha on NF-kappaB activation, VCAM-1 expression, and U937 cell adhesion. These findings suggest E(2) suppresses inflammatory cell adhesion to vascular endothelial cells that possess functional estrogen receptors. The mechanism of suppression may involve inhibition of NF-kappaB-mediated up-regulation of VCAM-1 expression induced by atherogenic stimuli. E(2) may prevent plaque formation, as first stage of atheroscrelosis through inhibiting adhesion monocytes to endothelial cell. Actions of estrogen replacement therapy can be assessed in terms of densities of functional ERalpha.

Regulation of nuclear retention of glucocorticoid receptor by nuclear Hsp90.

Heat shock protein 90 (Hsp90) has been demonstrated in both cytoplasm and nucleus, and regulates cytoplasmic retention of glucocorticoid receptor (GR). However, the role of nuclear Hsp90 in GR trafficking is less characterized. The present study examined the role of Hsp90 in nuclear retention of GR after ligand withdrawal. Hsp90 inhibitors; geldanamycin (GA) and radicicol (Rad), significantly accelerated nuclear export of GR after withdrawal of ligands including dexamethasone, corticosterone and RU486. GA accelerated relocalization of GR in the cytoplasm even when reimport of GR into the nucleus was inhibited by okadaic acid or when novel GR synthesis was inhibited by cycloheximide. Overexpression of wild type or nuclear-targeted Hsp90 attenuated Hsp90 inhibitor-induced acceleration of GR nuclear export, although nuclear Hsp90 showed higher activity than the wild type. Only nuclear-targeted Hsp90 prolonged basal nuclear retention of GR after withdrawal of dexamethasone and corticosterone. These results suggest that nuclear Hsp90 regulates the nuclear retention of GR.

Hsp90 inhibitors attenuate effect of dexamethasone on activated NF-kappaB and AP-1.

Heat shock protein 90 (Hsp90) regulates the functions of glucocorticoid receptor (GR). Hsp90 inhibitors geldanamycin (GA) and radicicol (Rad) have been studied as anti-inflammatory agents; however, their effects on glucocorticoid-mediated anti-inflammatory mechanism are not known. In the present study, we examined the effects of dexamethasone (Dex) and Hsp90 inhibitors, alone and in combination, on the activation of GR and proinflammatory transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In cell-based reporter assay, Hsp90 inhibitors inhibited Dex-induced nuclear import and transcriptional activity of GR. Both tumor necrosis factor-alpha-activated NF-kappaB and phorbol ester-activated AP-1 were inhibited by Dex and Hsp90 inhibitors alone. When the cells were treated with a combination of these drugs, the inhibitory effect of Dex was significantly attenuated by Hsp90 inhibitors. We further examined the effects of Dex and Rad on lipopolysaccharide-induced gene expressions of the proinflammatory cytokine interleukin (IL)-1beta in macrophages. Dex, but not Rad, inhibited IL-1beta expression. Rad concentration-dependently attenuated the inhibitory effect of Dex. These results suggest that Hsp90 inhibitor itself inhibits the activation of NF-kappaB and AP-1, however, impedes Dex-induced inhibition of IL-1beta induction by attenuating Dex-mediated activation of GR and inhibition of the proinflammatory transcription factors.

Cellular carbonyl stress enhances the expression of plasminogen activator inhibitor-1 in rat white adipocytes via reactive oxygen species-dependent pathway.

Carbonyl stress is one of the important mechanisms of tissue damage in vascular complications of diabetes. In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes. To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress. Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels. The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mm, 48 h). The stimulatory effects by AGE or high glucose were inhibited by antioxidant, pyrrolidine dithiocarbamate, and reactive oxygen scavenger, probucol, suggesting a pivotal role of oxidative stress in white adipocytes. We also found that the effect by HNE was inhibited by antioxidant, N-acetylcysteine and that a specific inhibitor of glutathione biosynthesis, l-buthionine-S,R-sulfoximine, augmented the effect of subthreshold effect of HNE. Bioimaging of reactive oxygen species (ROS) by a fluorescent indicator, 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, revealed ROS production in white adipocytes treated with AGE or HNE. These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation.

Uremic toxins overload accelerates renal damage in a rat model of chronic renal failure.

Uremic toxins have been suggested to promote progression of chronic renal failure by damaging tubular cells. Previous in vitro studies have indicated that some uremic toxins induce oxidative stress and activate NF-kappaB to upregulate plasminogen activator inhibitor-1 in tubular cells. These mechanisms may promote tubulointerstitial fibrosis. The present study examined whether uremic toxins induce glomerular and tubulointerstitial damage in vivo. Two uremic toxins, hippuric acid (HA) or indoleacetic acid (IAA), were tested in two independent experiments (HA-treated rats vs. non-HA-treated controls, IAA-treated rats vs. non-IAA-treated controls). The uremic toxins were administered to subtotally nephrectomized rats. Renal functions were measured periodically and glomerular sclerosis and interstitial fibrosis were examined at the end of the experimental period (18 and 24 weeks, respectively, after subtotal nephrectomy for HA and IAA treatments). Glomerular filtration rate (inulin clearance) at the end of the study period was significantly lower in uremic toxin-treated rats than in control rats (HA-treated rats: 0.090 +/- 0.004 ml/min/100 g body weight vs. non-HA-treated controls: 0.125 +/- 0.013, IAA-treated rats: 0.068 +/- 0.006 versus non-IAA-treated controls: 0.100 +/- 0.013; both p < 0.05). Beta-N-acetyl-glucoseamidase excretion was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.55 +/- 0.05 U/day vs. control: 0.39 +/- 0.04 at week 18, IAA-treated: 0.35 +/- 0.02 vs. control: 0.26 +/- 0.07 at week 16; both p < 0.05). Glomerular sclerosis index was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.85 +/- 0.16 versus control: 0.48 +/- 0.10, IAA-treated: 1.13 +/- 0.25 vs. control: 0.57 +/- 0.10; both p < 0.05). Significant enlargement of interstitial fibrosis was observed in indoleacetic acid-treated rats. These results indicate that overload of uremic toxins accelerates the loss of kidney function, glomerular sclerosis and tubulointerstitial injury in a rat model of chronic renal failure. The present study suggests the potential benefit of early intervention to remove various uremic toxins in delaying the onset of end-stage renal failure in patients with progressive renal disease.

[Pharmacological education under the Medical Education Model Core Curriculum].

The objectives of undergraduate medical education have been shifted drastically during the last decades. As the world standard, basic medical knowledge, skill, and attitude to practice patient-centered medical care became main objectives in undergraduate medical education. In response to these changes in the environment of medical practice and education, the Medical Education Model Core Curriculum (MEMCC), was published in 2001. MEMCC describes general and specific behavioral objectives in an integrated form to be used in the practice of medicine. The achievement of MEMCC will be evaluated by the Nationwide Common Achievement Test. The test examines knowledge, skill, and attitude that is required for clinical clerkship. Pharmacological teachers in medical schools should discuss, study, and evaluate MEMCC based on their experience in the use of the curriculum. MEMCC and the Nationwide Common Achievement Test will enhance intra- and inter-disciplinary, as well as inter-institutional informational exchange in the context and strategies in pharmacological education.

Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells.

BACKGROUND: Uremic toxins have been suggested to promote progression of chronic renal failure. We have shown that organic anion transporter-mediated uptake of uremic toxins induces oxidative stress in opossum kidney renal tubular cells overexpressing the transporter. Plasminogen activator inhibitor-1 (PAI-1) and nuclear factor-kappa B (NF-kappaB) are major factors known to promote tubulointerstitial fibrosis. The present study examined the signaling pathway that is activated by uremic toxins to induce PAI-1 and activate NF-kappaB in human renal proximal tubular cells (HK-2). METHODS: Uremic toxins in the form of organic anion were examined their ability to induce oxidative stress, PAI-1 gene expression, and NF-kappaB activation in HK-2. PAI-1 expression was measured by enzyme-linked immunosorbent assay (ELISA) and the Northern blotting. Human PAI-1 promoter activity was estimated by luciferase reporter gene (NKkappaB-luc) assay. NF-kappaB activation was measured by the pNFkappaB-luc reporter gene and electrophretic gel mobility shift assay. RESULTS: Among organic anion species tested, indoxyl sulfate and indoleacetic acid induced free radical production in HK-2. A nonspecific transporter inhibitor (probenecid) suppressed the IS-stimulated radical production. Indoxyl sulfate and indoleacetic acid dose dependently increased the expressions of PAI-1 mRNA and protein in these cells. The luciferase reporter gene assay revealed that indoxyl sulfate and indoleacetic acid dose dependently activated NF-kappaB and PAI-1 promoter. Activation of NF-kappaB was also confirmed by an electrophoretic gel mobility shift assay. Both antioxidant and NF-kappaB inhibitors dose dependently inhibited the activation of PAI-1 promoter by indoxyl sulfate. CONCLUSION: Uremic toxins induce free radical production by renal tubular cells and activate NF-kappaB which, in turn, up-regulates PAI-1 expression. Thus, progression of chronic renal failure may be promoted by PAI-1 up-regulation induced by uremic toxins.

Format of cases affects learning outcomes in first year medical students.

CONTEXT: Longitudinal problem-based learning (PBL) tutorials are practiced at the Tokyo Women's Medical University. First year medical school students - most of whom are high school graduates with no medical background - often encounter difficulty identifying problems while solving PBL cases in basic science. The format of PBL case presentation may affect learning. OBJECTIVES: This study compares the learning outcomes of two cohorts of first year students who learned basic human biology through PBL cases presented in clinical vs. non-clinical formats. METHODS: All first year students in 1995 and 2000 undertook PBL tutorials. The 1995 case was presented in a non-clinical format; the 2000 case was presented in a clinical format. Both cases had five identical pre-set learning objectives in basic science. By examining all written materials generated during the tutorial sessions, learning outcomes were categorized and the accomplishment of preset objectives was analysed. FINDINGS: In 2000, the number of learning outcomes for clinical medicine was more than double compared to 1995, whereas the numbers of total and basic science learning outcomes were not significantly different. The number of preset objectives accomplished by the students was significantly higher in 2000. Thus, PBL case format affected the learning outcomes, enabling these first year students to achieve basic science objectives, while enhancing their interest in the clinical aspects of human biology. CONCLUSION: Learning outcomes in first year medical students may be enhanced when PBL cases designed to learn basic science contain relevant clinical elements.

Effect of heat stress on lipopolysaccharide-induced vascular permeability change in mice.

The effect of heat shock protein (hsp) induction on lipopolysaccharide (LPS)-induced increase in vascular permeability was studied in mice as a model of inflammatory mediator-induced inflammatory response. Mice were exposed to an ambient temperature of 43 degrees C for 1 h and then returned to 23 degrees C to recover up to 24 h. Dermal contents of hsp70 and hsp90 but not heat shock cognate protein (hsc)70 increased at 6 h after heat exposure and returned to the basal level at 24 h. LPS was injected subcutaneously at 0, 2, 4, 6, or 24 h after heat exposure. Two hours after LPS injection, vascular permeability was assessed by dermal accumulation of intravenously injected dye. LPS-induced dye leakage was reduced by 42 and 49% in heat-exposed mice after recovery for 4 and 6 h, respectively. Increases in dermal tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) contents induced by LPS were significantly reduced in the heat-stressed mice recovered for 6 h. LPS-induced increase in cyclooxygenase-2 but not TNF-alpha mRNA was attenuated in heat-stressed mice. Deoxyspergualin, an inhibitor of hsc70 and hsp90, and geldanamycin, a specific hsp90 inhibitor, dose dependently reversed the inhibitory effect of heat stress on LPS-induced dye leakage and dermal TNF-alpha content but not PGE(2) content. These results suggest that heat stress attenuated LPS-induced vascular permeability change by inducing hsp90, leading to inhibition of TNF-alpha production.

Anti-inflammatory potency of FR167653, a p38 mitogen-activated protein kinase inhibitor, in mouse models of acute inflammation.

The anti-inflammatory effect of FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate), a p38 mitogen-activated protein (MAP) kinase inhibitor, was examined in two mouse models of acute inflammation. Carrageenan-induced paw edema was inhibited by pretreatment with FR167653, anti-tumor necrosis factor (TNF)-alpha antibody, and NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide), a selective cyclooxygenase-2 inhibitor. Carrageenan increased TNF-alpha and prostaglandin E(2) levels in the paw, both of which were suppressed by FR167653. Subcutaneous injection of lipopolysaccharide at the back of mouse caused local increase in vascular permeability determined by leakage of Pontamine sky blue. FR167653 dose-dependently inhibited the lipopolysaccharide-induced plasma leakage. FR167653 also inhibited lipopolysaccharide-induced increases in serum TNF-alpha level, and skin TNF-alpha and prostaglandin E(2) levels at the injection site. On the other hand, FR167653 did not reduce arachidonic acid-induced plasma leakage which is not mediated by cyclooxygenase-2. FR167653 exhibits anti-inflammatory effects against both carrageenan-induced paw edema and lipopolysaccharide-induced plasma leakage through inhibiting the synthesis of inflammatory mediators that are regulated by p38 MAP kinase.

Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake.

A direct effect of uraemic toxins in promoting progression of chronic renal disease has not been established. In this study, we investigated the toxic effects of organic anions which characteristically appeared in the patients with progressive renal disease on renal proximal tubular cells expressing human organic anion transporter (hOAT) 1. A renal proximal tubular cell line, opossum kidney (OK) cells, was transformed with hOAT1. Among the organic anions examined, hippuric acid, para-hydroxyhippuric acid, ortho-hydroxyhippuric acid, indoxyl sulphate and indoleacetic acid showed a high affinity for hOAT1 expressed in the OK cells. Indoxyl sulphate and indoleacetic acid concentration-dependently inhibited proliferation of the hOAT1-transformed cells. The h.p.l.c. analysis demonstrated that cellular uptake of these organic anions was significantly elevated in hOAT1-transformed cells. These organic anions also concentration-dependently stimulated cellular free radical production. The degrees of inhibition of cell proliferation and the stimulation of free radical production induced by the organic anions were significantly higher in the hOAT1-transformed cells than vector-transformed cells. The stimulatory effect of indoxyl sulphate on free radical production was abolished by anti-oxidants and probenecid. Less free radical production was observed in the hOAT1-transformed cells treated with p-hydroxyhippuric acid, o-hydroxyhippuric acid compared with indoxyl sulphate and indoleacetic acid. Hippuric acid had little effect on free radical production. Organic anions present in the serum of patients with progressive renal disease may cause proximal tubular injury via hOAT1-mediated uptake. The mechanism of cellular toxicity by these uraemic toxins involves free radical production. Thus, some uraemic toxins may directly promote progression of chronic renal disease.