Factors that hinder medical career aspirations: A nationwide questionnaire survey of teachers in charge of career guidance in Japanese high schools.

Despite concerns raised on the inequality in healthcare provision in Japan, little is known about the factors that hinder candidates' application to medical schools. A nationwide cross-sectional survey was conducted to identify the impact of economic factors and living place on students' choice of and preparation for medical school. The survey was administered to high school teachers with career advisory roles, as they support and likely influence students' choice and decision on this matter. Responses totaling 1,094 were obtained from 1,746 high schools across Japan. The ratio of high schools with two or more students enrolled in medical schools every year is higher in private schools, those with high tuition, and those located in big cities. Approximately 66.8% of the respondents agreed that "It is difficult for students in economically disadvantaged families to enroll in medical schools;" 42.0% agreed that "Some students gave up on aspiring to enter medical schools because they could not afford it," and 61.2% agreed that "Students living in urban areas are more likely to enroll in medical schools." When asked about the percentage of students attending prep school among those aspiring for a medical career, significantly more respondents from private versus public high schools answered "80% or more." When asked about the percentage of parents who are doctors or dentists among students aspiring for a medical career, significantly more respondents from private versus public high schools answered "50% or more." The results suggest that students from lower-income families and those living in rural areas are more likely to be disadvantaged when choosing a medical career (because of financial difficulties) than those who live in urban areas and come from wealthier families. The results imply that economic and geographical divides in medical admission are reflected in high school teachers' perception of and support provided to students.

How do case presentation teaching methods affect learning outcomes?--SNAPPS and the One-Minute preceptor.

BACKGROUND: Various techniques have been developed to enable preceptors to teach residents effectively in outpatient settings to promote active learning, including SNAPPS and the One-Minute Preceptor (OMP). This study aimed to ascertain the differences between SNAPPS and the OMP in case presentation content and learner evaluation when used to teach residents about case presentation. METHODS: From 2011 to 2013, participants were 71 junior clinical residents employed in two hospitals for clinical training. They were randomly allocated to two groups, one using SNAPPS and the other the OMP. From recorded discussions, the "differential diagnoses", "questions and uncertainties", "treatment plans", and "learning issues" were counted. Also, a self-evaluation form was distributed at the end of the study to evaluate the residents' satisfaction with the case presentation. RESULTS: Members of the SNAPPS group used significantly more meaning units related to questions and uncertainties compared with those of the OMP group (P < 0.001). Self-evaluation sheets revealed that members of the SNAPPS group had significantly higher positive responses than those of the OMP group in terms of the following evaluations: "It was easy to bring up questions and uncertainties" (P = 0.046), "It was easy to present the case efficiently" (P = 0.002), "It was easy to present the case in the sequence given" (P = 0.029), and "I was able to give an in-depth case presentation" (P = 0.005). CONCLUSIONS: SNAPPS may induce more meaning units related to questions and uncertainties and give more satisfaction to residents than the OMP.

Validity of direct ophthalmoscopy skill evaluation with ocular fundus examination simulators.

OBJECTIVE: We examined how direct ophthalmoscopy (DO) skills can be evaluated in a clinical setting using a simulator, and determined the appropriate assessment criteria for the DO skills in practical tests such as the Objective Structured Clinical Examination (OSCE). DESIGN: Cross-sectional study. PARTICIPANTS: Medical students, residents, and attending physicians (73 total participants). METHODS: We selected the following 3 factors that may indicate the ability to perform nonmydriatic direct funduscopy: (i) experience: total number of cases examined (without mydriasis); (ii) frequency: number of cases examined during the previous month; and (iii) range: viewable fundus field range. We used a fundus simulator with 3-level adjustable pupil sizes (2, 3.5, and 5 mm) and created original test slides for use in the simulator. We counted the number of correct answers of each participant for each pupil size using the simulator and test slides. RESULTS: There were significant differences in the median number of correct answers for pupil diameters of 2 (p = 0.008) and 3.5 mm (p = 0.007) among groups divided according to the total number of cases examined (without mydriasis). There were no significant differences among groups divided according to the viewable fundus field range (2 mm: p = 0.103, 3.5 mm: p = 0.083, 5 mm: p = 0.347). CONCLUSIONS: The results suggest a possible relation between the surrogate indicators "experience" and "range" and DO skills using a fundus simulator. The surrogate indicator experience showed a strong relation to DO skills using a fundus simulator.

The most requested factors in clinical skills exams for evaluating novice physicians: an internet-based survey of the general public in Japan.

BACKGROUND: Clinical skills tests have been added to the national medical licensure examinations in Canada, the U.S., Korea and Switzerland. Adding a clinical skills test to the Japanese national medical licensure examination should also be considered under the Medical Practitioners Act. On the other hand, such tests might be costly and represent an economic burden to the nation's citizens. Thus, it is appropriate to obtain the opinion of the general public for the introduction of such tests. Although a clinical skills test can measure various competencies, it remains uncertain as to what should be measured. In this study, we aimed to ascertain public opinion regarding the clinical skills demanded of novice physicians. METHODS: We conducted an internet-based survey of the general public in Japan. We randomly selected 7,213 people aged 20 to 69 years. The main topics surveyed included: whether the Japanese government should add a skills test to the existing national medical licensure examination; what kind of skills should be included in this test; and who should pay for the examination. RESULTS: Of 3,093 (1,531 men and 1,562 women) people who completed the questionnaire (completion rate 42.9%), 90.5% (n = 2,800) responded that a clinical skills test should be part of the national medical licensure examination. The main skills which respondents thought should be included were "explaining and discussing medical issues in an appropriate manner to patients" (n = 2,176, 70.4%), "accurately diagnosing problems by conducting a physical examination" (n = 1,984, 64.1%), and "carefully interviewing patients to make a diagnosis" (n = 1,663; 53.8%). Three-fifths of the respondents (n = 1,900; 61.4%) responded that more than half of the cost of the examination should be paid by the Japanese government. CONCLUSIONS: The majority of respondents indicated that a clinical skills test should be added to the national medical licensure examination. These respondents who represent the general public were requesting the verification of communication, diagnostic interview and diagnostic physical examination skills. Medical educators should incorporate these public requests, and teach and assess medical students accordingly.

Gender role stereotype and poor working condition pose obstacles for female doctors to stay in full-time employment: alumnae survey from two private medical schools in Japan.

The shortage of physicians has become a serious problem in Japan. It has been pointed out that an increase in the number of female doctors may contribute to the aggravation of this shortage because it is known that women work fewer hours than male doctors. Here, we investigated how many female doctors had ever resigned from a full-time position, and elucidated the reasons why female doctors find it difficult to stay in full-time employment. An alumnae survey of 2 private medical schools was conducted in 2007. A self-administered questionnaire was sent to 1423 graduates and 711 responded with informed consent (response rate, 50%; mean age, 39 years). Overall, 55% of the respondents had previously resigned from full-time employment, of which 90% resigned within 10 years of graduating from medical school. The difficulty in balancing work, childbirth and child rearing (45%) were the top 2 reasons for resignation, followed by physical problems (12%) and long working hours (8%). Among those who resigned, only 33% returned to full-time employment. Women who had at least 1 child were only 30% of those who had never resigned and 84% of those who had previously resigned. The majority of study subjects, regardless of experience of resignation (88%), agreed that women should continue to work even after childbirth. In conclusion, the results of this study suggested that many female doctors resigned from a full-time position within 10 years of graduating from medical school, largely because of the gender role stereotype and poor working conditions.

Experiences of alcohol-related harassment among medical students.

OBJECTIVES: Although fatal accidents caused by alcohol-related harassment occur frequently among college students, this issue has not been adequately examined. This study set out to investigate the prevalence of alcohol-related harassment among medical students in Japan. METHODS: A multi-institutional, cross-sectional survey was carried out across seven medical schools in Japan. A self-report anonymous questionnaire was distributed to 1152 medical students; 951 respondents (82.6%) satisfactorily completed it. From the responses, we determined the reported prevalences of the following types of alcohol-related harassment among medical students by senior medical students or doctors: (i) being coerced into drinking alcohol; (ii) being compelled to drink an alcoholic beverage all at once (the ikki drinking game); (iii) being deliberately forced to drink until unconscious, and (iv) being subjected to verbal abuse, physical abuse or sexual harassment in relation to alcohol. The prevalence of becoming a harasser among medical students was also measured. Multivariate regressions were used to assess the associations between experiences of alcohol-related harassment and student characteristics. RESULTS: A total of 821 respondents (86.3%) had experienced alcohol-related harassment and 686 (72.1%) had harassed others. Experiences of the ikki drinking game were frequently reported by both victims (n=686, 72.1% of all respondents) and harassers (n=595, 62.6% of all respondents). In multivariate regression, having an experience of alcohol-related harassment correlated with both being harassed (odds ratio [OR] 14.22, 95% confidence interval [CI] 8.73-23.98) and being a harasser (OR 13.19, 95% CI 8.05-22.34). The presence of senior members of medical college clubs who were regular drinkers also correlated with both being harassed (OR 2.96, 95% CI 1.88-4.67) and being a harasser (OR 2.97, 95% CI 2.06-4.27). CONCLUSIONS: Alcohol-related harassment among medical students is common and tends to occur at drinking parties with senior college club members. Hence, one of the most important strategies for preventing alcohol-related harassment may be to disrupt this vicious cycle.

Universal problems during residency: abuse and harassment.

OBJECTIVES: Perceived abuse or harassment during residency has a negative impact on residents' health and well-being. This issue pertains not only to Western countries, but also to those in Asia. In order to launch strong international preventive measures against this problem, it is necessary to establish the generality and cultural specificity of this problem in different countries. Therefore, we investigated mistreatment among resident doctors in Japan. METHODS: In 2007, a multi-institutional, cross-sectional survey was conducted at 37 hospitals. A total of 619 residents (409 men, 210 women) were recruited. Prevalence of mistreatment in six categories was evaluated: verbal abuse; physical abuse; academic abuse; sexual harassment; gender discrimination, and alcohol-associated harassment. In addition, alleged abusers, the emotional effects of abusive experiences, and reluctance to report the abuse to superiors were investigated. Male and female responses were statistically compared using chi-square analysis. RESULTS: A total of 355 respondents (228 men, 127 women) returned a completed questionnaire (response rate 57.4%). Mistreatment was reported by 84.8% of respondents (n = 301). Verbal abuse was the most frequently experienced form of mistreatment (n = 256, 72.1%), followed by alcohol-associated harassment (n = 184, 51.8%). Among women, sexual harassment was also often reported (n = 74, 58.3%). Doctors were most often reported as abusers (n = 124, 34.9%), followed by patients (n = 77, 21.7%) and nurses (n = 61, 17.2%). Abuse was reported to have occurred most frequently during surgical rotations (n = 98, 27.6%), followed by rotations in departments of internal medicine (n = 76, 21.4%), emergency medicine (n = 41, 11.5%) and anaesthesia (n = 40, 11.3%). Very few respondents reported their experiences of abuse to superiors (n = 36, 12.0%). The most frequent emotional response to experiences of abuse was anger (n = 84, 41.4%). CONCLUSIONS: Mistreatment during residency is a universal phenomenon. Deliberation on the occurrence of this universally wrong tradition in medical culture will lead to the establishment of strong preventive methods against it. Current results indicate that alcohol-associated harassment during residency is a Japanese culture-specific problem and effective preventive measures against this are also urgently required.

Involvement of free radicals followed by the activation of phospholipase A2 in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: comparison of the therapeutic potential of fullerene, mepacrine, and cooling.

An increase in polydrug abuse is a major problem worldwide. The coadministration of methamphetamine and morphine increased subacute toxicity or lethality in rodents. However, the underlying mechanisms by which lethality is increased by the coadministration of methamphetamine and morphine are not yet fully understood. Coadministered methamphetamine and morphine induced lethality by more than 80% in BALB/c mice, accompanied by the rupture of cells in the kidney and liver, and an increase in poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine was significantly attenuated by pretreatment with mepacrine (phospholipase A(2) inhibitor) or fullerene (a radical scavenger), or by cooling from 30 to 90 min after drug administration. Furthermore, based on the results of the electron spin resonance spin-trapping technique, hydroxyl radicals were increased by the administration of methamphetamine and morphine, and these increased hydroxyl radicals were potently attenuated by fullerene and cooling. These results suggest that hydroxyl radicals plays an important role in the increased lethality induced by the coadministration of methamphetamine plus morphine. The potency of cooling or drugs for decreasing the subacute toxicity or lethality induced by the coadministration of methamphetamine and morphine was in the order fullerene=cooling>mepacrine. These results indicate that fullerene and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine.

Cost-effectiveness of coronary artery disease screening in asymptomatic patients with type 2 diabetes and other atherogenic risk factors in Japan: factors influencing on international application of evidence-based guidelines.

BACKGROUND: Screening for coronary artery disease (CAD) in asymptomatic diabetic patients with atherogenic risk factors is recommended by the American College of Cardiology/American Diabetes Association. It is not clear whether these guidelines apply to the Japanese population with a different epidemiology of CAD. This study evaluates the applicability of the U.S. guidelines to Japan, taking account of cost-effectiveness. DESIGN: A cost-effectiveness analysis using a Markov model was performed to measure the clinical benefit and cost of CAD screening in asymptomatic patients with diabetes and additional atherogenic risk factors. We evaluated cohorts of patients stratified by age, gender, and atherogenic risks. The incremental cost-effectiveness of not screening, exercise electrocardiography, exercise echocardiography, and exercise single-photon emission-tomography (SPECT) was calculated. The data used were obtained from the literature. Outcomes are expressed as US dollars per quality-adjusted life year (QALY). RESULTS: Compared with not screening, the incremental cost-effectiveness ratio (ICER) of exercise electrocardiography was $31,400/QALY for 60-year-old asymptomatic diabetic men, and 46,600 for 65-year-old women with hypertension and smoking. The ICER of exercise echocardiography was $31,500/QALY and of SPECT was $326,000/QALY, compared with the next dominant strategy. Sensitivity analyses found that these results varied according to age, gender, the combination of additional atherogenic risk factors, and the frequency of screening. CONCLUSION: From a societal perspective the U.S. guidelines on screening for CAD in high risk diabetic patients are applicable to the Japanese population. However, the population subjected to screening should be carefully selected to obtain greatest benefit from screening.

[UVB-induced skin damage and the protection/treatment--effects of a novel, hydrophilic gamma-tocopherol derivative].

Ultraviolet radiation is the major environmental cause of skin damage. Although only 0.5% of ultraviolet B (UVB) radiation reaches the earth, it is the main cause of sunburn and inflammation and the most carcinogenic constituent of sunlight. We investigated whether the topical application of a novel, water-soluble gamma-tocopherol (gamma-Toc) derivative, gamma-tocopherol-N,N-dimethylglycinate hydrochloride (gamma-TDMG), could protect against UV-induced skin damage. Topical pre- or postapplication of gamma-TDMG solution significantly prevented sunburn cell formation, lipid peroxidation, and edema/inflammation that were induced by exposure to a single dose of UV irradiation. Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E(2) (PGE(2)) levels seen after UV exposure were significantly suppressed by pre- or posttreatment with gamma-TDMG. The increase in COX-2 activity was significantly inhibited by gamma-TDMG, suggesting that the reduction in PGE(2) concentration was due to the direct inhibition of COX-2 activity by gamma-TDMG. The derivative strongly inhibited inducible nitric oxide synthase mRNA expression and nitric oxide production. With the application of gamma-TDMG, the pigmentation in melanocytes was lightened and the increase melanin concentration was suppressed. Gamma-TDMG is converted to gamma-Toc in the skin and has higher bioavailability than gamma-Toc itself. These results suggest that gamma-TDMG-derived gamma-Toc acts as an antioxidant, antiinflammatory and antipigmentation agent. Our data further suggest that the topical application of gamma-TDMG may be efficacious in preventing and reducing UV-induced skin damage in humans.

NADH binding properties of rabbit lens lambda-crystallin.

PURPOSE: The present investigation aims to evaluate the NADH binding ability of lambda-crystallin, a taxon-specific enzyme-crystallin, in the rabbit lens. METHODS: A lambda/betaL1-crystallin fraction was separated from the rabbit lens soluble fraction by gel filtration and the enzyme-crystallin was partially purified by subsequent affinity column chromatography. Analysis of NADH bound to the lambda-crystallin preparation was performed using spectrophotometric and enzymological methods. Binding of added NADH to the enzyme-crystallin preparation was also analyzed using a simple ultrafiltration method, which was theoretically equivalent to equilibrium dialysis, to study additional NADH binding to the protein. RESULTS: The prepared lambda-crystallin samples clearly exhibited an absorption maximum at 340 nm, even though they were thoroughly dialyzed. This was due to the presence of nondialyzable NADH bound tightly to the protein. The bound NADH was removed by charcoal treatment, and extracted by 0.1% SDS or 70 degrees C heat treatment. A dissociation constant (Kd) of less than 5 nM indicated tight binding of NADH. The quantity of bound NADH in the 88% purified 33 kDa enzyme-crystallin was estimated to be 20.5 nmol/mg protein, suggesting a stoichiometry of 0.7 mol of the nucleotide/mol of the 33 kDa protein. Additional looser binding of added NADH to lambda-crystallin was observed in both the lambda/betaL1-crystallin fraction (including the full-length 33 kDa protein: 34%; 25-30 kDa proteins, most of which might be generated by cleavage of the 33 kDa protein: 64%) and the partially purified enzyme-crystallin. It was assumed from the analysis of binding titration that some (about 30%) of the 33 kDa protein and most of the lower molecular weight proteins still possessed the ability to loosely bind NADH. Kd values of their lower affinity binding were determined to be 2 or 6 microM. CONCLUSIONS: From the present study, we conclude that lambda-crystallin plays a sufficiently important role as a NADH binding protein to maintain high levels of this nucleotide in the rabbit lens.

Topical application of gamma-tocopherol derivative prevents UV-induced skin pigmentation.

We previously reported that a novel hydrophilic gamma-tocopherol (gamma-Toc) derivative, gamma-tocopheryl-N,N-dimethylglycinate hydrochloride (gamma-TDMG) gets converted to the antioxidant gamma-Toc in skin. We also found that this derivative displayed greater bioavailability than gamma-Toc itself. In the present study, we determined whether gamma-TDMG could reduce UV-induced skin pigmentation in brownish guinea pigs. gamma-TDMG (0.1 or 0.5%) was topically applied to the skin before and after it was exposed to UVB plus UVA (3 times/week for 1 week), and then 10 times/week for 4 weeks thereafter. Treatment with 0.5% gamma-TDMG resulted in significant skin lightening (70% of the pigmentation of irradiated controls). We also found that melanin synthesis was dose-dependently inhibited by gamma-TDMG in murine B16 melanoma cells. When gamma-TDMG or kojic acid (250 microM) were added to homogenates of B16 melanoma cells, their tyrosinase activity was significantly inhibited by approximately 40% and 75%, respectively. Mushroom tyrosinase activity was significantly inhibited by 200 microM gamma-Toc and kojic acid, but not gamma-TDMG. When B16 cells were incubated with 250 microM gamma-TDMG for 24 or 48 h, their intracellular gamma-Toc concentrations rose over 100 fold to 10.5 and 11.2 nmol/10(6) cells, respectively, suggesting that gamma-TDMG was rapidly converted to gamma-Toc in these cells and that their reduced melanin synthesis may have been due to the activity of gamma-Toc. Our data further suggest that the topical application of gamma-TDMG may be efficacious in preventing photo-induced skin pigmentation in humans.

Topical application of a novel, hydrophilic gamma-tocopherol derivative reduces photo-inflammation in mice skin.

We previously demonstrated that a novel hydrophilic gamma-tocopherol (gamma-Toc) derivative, gamma-tocopherol-N,N-dimethylglycinate hydrochloride (gamma-TDMG) converts to gamma-Toc in the mouse skin and has a higher bioavailability than gamma-Toc itself. In the present study, we determined whether gamma-TDMG could reduce photo-inflammation in mouse skin, and compared its effectiveness to that of alpha-Toc acetate (alpha-TA). Topical pre- or post-application of 5% gamma-TDMG significantly reduced the formation of edema and tempered the increase in cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E2 (PGE2) that were induced by a single dose of UV irradiation of 2 kJ/m2 (290-380 nm, maximum 312 nm). The pre-treatment of mouse skin with 10% alpha-TA had the same anti-inflammatory effect as did gamma-TDMG. In spite of same having the ability to reduce PGE2 levels, the effect of gamma-TDMG pre-treatment on the inhibition of COX-2 mRNA/protein expression was less than that seen with 10% alpha-TA. In contrast, the increase in COX-2 activity seen after UV exposure was reduced more by gamma-TDMG than by alpha-TA, suggesting that the reduction in PGE2 levels might have been due to the direct inhibition of COX-2 activity by gamma-TDMG-derived gamma-Toc. Both Toc derivatives strongly suppressed inducible nitric oxide synthase (iNOS) mRNA expression and nitric oxide (NO) production, both of which play important roles in UV-induced inflammation. Both derivatives also significantly reduced lipid peroxidation in response to UV exposure, though gamma-TDMG's ability in this regard was less than that seen with alpha-TA, which correlated with their abilities to suppress COX-2 expression. Thus, the gamma-TDMG-derived gamma-Toc acts as an antioxidant, suppresses iNOS expression and directly inhibits COX-2 activity, all of which likely play a role in mediating its suppressive effects on photo-inflammation. Our data further suggest that the topical application of gamma-TDMG, a novel hydrophilic gamma-Toc derivative, may be efficacious in preventing and reducing UV-induced inflammation in humans.

Medical student abuse during clinical clerkships in Japan.

OBJECTIVE: To assess the prevalence of medical student abuse during clinical clerkships in Japan. DESIGN: A cross-sectional questionnaire survey. SETTING: Six medical schools in Japan. PARTICIPANTS: Final year (sixth-year) and fifth-year medical students in the period from September 2003 to January 2004. From a total of 559 students solicited, 304 (54.4%) returned the questionnaire, and 276 (49.4%: 178 male and 98 female) completed it. MEASUREMENTS: Prevalence of medical student abuse in 5 categories: verbal abuse, physical abuse, academic abuse, sexual harassment, and gender discrimination; differences in abusive experience between male and female students; types of alleged abusers; reporting abusive experiences to authorities; and emotional effects of abusive experiences. RESULTS: Medical student abuse was reported by 68.5% of the respondents. Verbal abuse was the most frequently experienced abuse (male students 52.8%, female students 63.3%). Sexual harassment was experienced significantly more often (P<.001) by female students (54.1%) than by male students (14.6%). Faculty members were most often reported as abusers (45.2% of cases). Abuse occurred most frequently during surgical rotations (42.0% of cases), followed by internal medicine (25.1%) and anesthesia rotations (21.8%). Very few abused students reported their abusive experiences to authorities (8.5%). The most frequent emotional response to abuse was anger (27.1% of cases). CONCLUSIONS: Although experience of abuse during clinical clerkships is common among medical students in Japan, the concept of "medical student abuse" is not yet familiar to Japanese. To improve the learning environment, medical educators need to take action to resolve this serious issue.

Cost-effectiveness of pravastatin for primary prevention of coronary artery disease in Japan.

OBJECTIVE: This analysis was designed to estimate the cost-effectiveness of pravastatin for the primary prevention of coronary heart disease in Japan. METHODS: A state-transition model was used to compare the cost-effectiveness of pravastatin therapy with no intervention. Hypothetical cohorts were assumed according to patients' age, sex, initial serum total cholesterol (TC) levels, and other cardiac risk factors. For the baseline analysis, 20 mg/day of pravastatin was used for people aged 60 years who had an initial TC level of 240 mg/dl. Epidemiological, clinical, and economic data were collected from published articles. Incremental cost-effectiveness ratios (ICERs) in yen per quality-adjusted life year (QALY) were calculated. To confirm the effects of different variables, a sensitivity analysis was performed. The assumptions of our model were in accordance with the Japan Atherosclerosis Society Guidelines for the Diagnosis and Treatment of Atherosclerotic Cardiovascular disease. RESULTS: ICERs were respectively 44 million and 76 million yen/QALY for men and women at low cardiac risk (i.e., the risks of hypercholesterolemia and old age) and 7.5 million and 4.3 million yen/QALY for those at high cardiac risk (i.e., the risks of hypercholesterolemia, old age, cigarette smoking, hypertension, and hyperglycemia). CONCLUSIONS: The cost-effectiveness of pravastatin therapy differs substantially according to the level of cardiac risk. At present, pravastatin therapy is not cost-effective for persons at low cardiac risk.

A meta-analytic comparison of echocardiographic stressors.

BACKGROUND: The relative performance of alternative stressors for stress echocardiography for the diagnosis of coronary artery disease (CAD) is not well established. METHODS: All studies published between 1981 to December 2001 who met inclusion criteria were included in this analysis. We performed a summary receiver operator characteristic (SROC) analysis and calculated weighted mean of the likelihood ratio and sensitivity/specificity. A covariate analysis using meta-regression methods was also performed. RESULTS: Forty-four studies presented data on Exercise, 11 on Adenosine, 80 on Dobutamine, 40 on Dipyridamole, 16 on transatrial pacing transesophageal echocardiography (Tap-TEE), and 7 on transatrial pacing transthorasic echocardiography (Tap-TTE). SROC analysis showed that the following order of most discriminatory to least: Tap-TEE, Exercise, Dipyridamole, Dobutamine and Adenosine. Weighted means sensitivity/specificity were Exercise: 82.6/84.4%, Adenosine: 68.4/80.9%, Dobutamine: 79.6/85.1%, Dipyridamole: 71.0/92.2%, Tap-TTE: 90.7/86.1%, and Tap-TEE: 86.2/91.3%. Covariate analysis showed that the discriminatory power of Exercise decreased with increasing mean age. CONCLUSIONS: Tap-TEE is a very accurate test for both ruling in and ruling out CAD although its invasiveness may limit its clinical acceptability. Exercise is a well-balanced satisfactory test for both ruling in and ruling out but performance might be lower for the elderly. Dobutamine offers a reasonable compromise for Exercise. Dipyridamole might be good for ruling in but not for ruling out CAD. The incapability in ruling-out CAD was a major problem in clinical application of the stress. Adenosine was the least useful stressor in diagnosing CAD.

Production of the long and short forms of MFG-E8 by epidermal keratinocytes.

Mouse milk fat globule-EGF factor 8, MFG-E8, is the ortholog to the human mammary tumor marker, lactadherin, and comprises two spliced variants, the L and S forms. Recent studies have suggested that MFG-E8-L produced by macrophages and Langerhans cells in the skin serves as a linker between phagocytic cells and apoptotic cells, and that MFG-E8-S, also termed SED1, facilitates sperm-egg interaction for fertilization. However, Mfge8 gene expression occurs in various tissues apparently unrelated to these critical events. Our in situ hybridization study has revealed that Mfge8 is expressed in the periderm (the premature epidermis) on embryonic day-14, well before Langerhans cells begin to grow in the prenatal phase. Mfge8 transcript is detectable in the basal and spinous layers throughout skin development, whereas immunostaining has revealed MFG-E8 protein accumulation in the spinous layer. Cultured keratinocyte stem cells consistently express Mfge8-L and -S mRNAs and produce the L protein, which is primarily detectable in the culture supernatant, and the S protein, which is mostly associated with the cells. Upon Ca(2+)-stimulated differentiation, which is detected by a decrease in keratinocyte stem cell marker p63(p51) and the induction of keratin1, we have observed suppression of Mfge8, and the protein becomes localized to the cell-cell borders. Papillomas and carcinomas caused by chronic UV-B irradiation produce MFG-E8 as determined by immunostaining. Thus, undifferentiated and poorly differentiated keratinocytes produce the L and S forms of MFG-E8 during normal and pathological tissue development, probably to support an as yet unidentified membrane function.

Topical application of a novel, water-soluble gamma-tocopherol derivative prevents UV-induced skin damage in mice.

We investigated whether the topical application of a novel, water-soluble gamma-tocopherol (gamma-Toc) derivative, gamma-tocopherol-N,N-dimethylglycinate hydrochloride (gamma-TDMG), could protect against UV-induced skin damage in hairless mice. Topical pre- or post-application of a 5% (93 mM) gamma-TDMG solution in water/propylene glycol/ethanol (2:1:2) significantly prevented sunburn cell formation, lipid peroxidation and edema/inflammation that were induced by exposure to a single dose of UV irradiation of 5 kJ/m2 (290-380 nm, maximum 312 nm). This effect was greater than that seen with two alpha-Toc derivatives, alpha-tocopherol acetate (alpha-TA) and alpha-tocopherol-N,N-dimethylglycinate (alpha-TDMG). When a 5% solution of gamma-TDMG was applied to mouse skin for 1 h, cutaneous gamma-Toc increased by 25-fold after 24 h; levels of cutaneous alpha-Toc increased by only two- and eight-fold in alpha-TDMG and alpha-TA treated skins, respectively. These findings indicated that gamma-TDMG immediately converted to gamma-Toc in the skin and suggest that ability of gamma-TDMG to protect the skin from the damaging effects of irradiation was due to its conversion to gamma-Toc. When a 5% solution of gamma-Toc was applied to mouse skin for 1 h, cutaneous gamma-Toc rapidly increased by 25-fold, but fell to baseline levels by 24 h. In contrast, the concentration of gamma-Toc in skin that was treated with gamma-TDMG similarly increased, but these high levels were maintained after 24 h. These results suggest that gamma-TDMG may be a more effective source of gamma-Toc in skin. Thus, the topical application of gamma-TDMG may be efficacious for the prevention of UV-B-induced skin damage.