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Recently in the field of oncology, immune checkpoint inhibitors (ICI) are being increasingly utilized both in clinical trials and in clinical practice. It is a form of biological therapy that targets tumors by activating the immune system, which in turn eliminates proliferating cancer cells. These have numerous immune-related adverse events (irAEs), one of which is myocarditis, which has high rates of mortality. This article was a narrative review of myocarditis related to ICI use.  Studies from the PubMed, Cochrane, and American Society of Clinical Oncology (ASCO) databases were used in writing this review. The databases were searched for original publications for adverse effects related to ICI use and myocarditis specifically. There are numerous published instances of cancer immunotherapy causing myocarditis. ICI therapy has numerous benefits, as it upregulates the immune system to target cancer cells, utilizing the body's own defense mechanisms to target proliferating cells. Myocarditis is a serious side effect, however. Therefore, on balance, these monotherapies are worth using. While this literature review primarily identifies cross-reaction as the main mechanism of myocarditis, there are other possible mechanisms. One proposed mechanism involves a shared antigen between the myocardial tissue and the tumor. This mechanism is called molecular mimicry, where the monoclonal antibody attacks both the myocardial tissue and the tumor cell. Management of ICI-induced myocarditis has not been studied by randomized controlled trials or prospective studies, but based on previous case reports and case series it is mostly treated with steroids initially. An ICI rechallenge after temporary discontinuation appears conceivable in many cases, especially given its therapeutic effects, but only limited data are available on the safety of a rechallenge after an irAE. The lack of RCTs regarding rechallenge with an ICI after irAE, more so specifically about myocarditis, along with the overall results and the complexity involved in such cases once again emphasize the need to make decisions on an individual basis by a multidisciplinary expert working group. At the same time, the focus should also be on publishing more data as the need will grow along with the indications for ICI therapies.

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Black rot caused by Xanthomonas campestris pv. campestris was found in 28 sampled cabbage fields in five major cabbage-growing districts in Nepal in 2001 and in four cauliflower fields in two districts and a leaf mustard seed bed in 2003. Pathogenic X. campestris pv. campestris strains were obtained from 39 cabbage plants, 4 cauliflower plants, and 1 leaf mustard plant with typical lesions. Repetitive DNA polymerase chain reaction-based fingerprinting (rep-PCR) using repetitive extragenic palindromic, enterobacterial repetitive intergenic consensus, and BOX primers was used to assess the genetic diversity. Strains were also race typed using a differential series of Brassica spp. Cabbage strains belonged to five races (races 1, 4, 5, 6, and 7), with races 4, 1, and 6 the most common. All cauliflower strains were race 4 and the leaf mustard strain was race 6. A dendrogram derived from the combined rep-PCR profiles showed that the Nepalese X. campestris pv. campestris strains clustered separately from other Xanthomonas spp. and pathovars. Race 1 strains clustered together and strains of races 4, 5, and 6 were each split into at least two clusters. The presence of different races and the genetic variability of the pathogen should be considered when resistant cultivars are bred and introduced into regions in Nepal to control black rot of brassicas.

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The fungus Fusarium graminearum (sexual stage Gibberella zeae) causes ear rot of maize (Zea mays) and contamination with the 8-ketotrichothecenes nivalenol (1) or 4-deoxynivalenol (2), depending on diversity of the fungal population for the 4-oxygenase gene (TRI13). To determine the importance of 1 and 2 in maize ear rot, a survey of naturally contaminated maize in Nepal was combined with experiments in the field and in a plant growth room. In the survey, 1 contamination was 4-fold more frequent than 2 contamination and 1-producers (TRI13) were isolated more than twice as frequently as 2-producers (Psi TRI13). In maize ear rot experiments, genetically diverse 1-producers and 2-producers caused ear rot and trichothecene contamination. Among strains with the same genetic background, however, 1-producers caused less ear rot and trichothecene contamination than did 2-producers. The high frequency of 1 contamination and the high virulence of many 1-producers are of concern because maize is a staple food of rural populations in Nepal and because 1 has proven to be more toxic than 2 to animals.

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The prevalence of systemic lupus erythematosus (SLE) is far higher in females than in males, and numerous investigations of this gender bias have been performed from several perspectives. Sex hormones, particularly estrogens, may be significant in causing the gender discrepancy. This article discusses the possible importance of estrogens in regulating the expression of and responsivity to autoantigens in SLE and in atopic disorders, which are associated with hyperreactivity to exogenous antigens. Estrogens seem to play an important role in the overexpression of endogenous autoantigens, such as human endogenous retroviruses (HERV), and this may be related to the existence of a gender bias in the incidence of SLE but not atopy.

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BACKGROUND: Providing patients with disease- and treatment-related information is an important role of medical staff and is now reimbursed in Japan by the national health insurance system under the rubric 'patient education'. Evaluation of the effectiveness of patient education programs is necessary to ensure that limited health care resources are used efficiently. OBJECTIVE: The objective is to determine whether educating patients with Parkinson's disease (PD) is related to better health-related quality of life (HRQOL). DESIGN: A cross-sectional study was conducted. SETTING: Members of the Japan Association of Patients with Parkinson's disease were randomly selected. PARTICIPANTS: A total of 1200 patients with PD were asked to fill in written questionnaires and replies from 762 (63.5%) were analyzed. MEASUREMENTS: The questionnaire inquired about clinical characteristics, comorbidity, symptoms of PD, complications of therapy, HRQOL, and patient education. SF-36 was used to assess HRQOL. The section on patient education comprised one question each on patient-perceived satisfaction with information provided on (1) disease condition and pathophysiology, (2) effectiveness of drug therapy, (3) adverse drug reactions, (4) publicly available financial and social resources, and (5) rehabilitation and daily activities. Patient education score was defined as the sum of the individual scores for these five questions. The relationships between scores on the SF-36 subscales and the patient education score were examined. RESULTS: More satisfaction with patient education was associated with higher scores in all SF-36 subscales except physical functioning and bodily pain. The difference in score between the most satisfied and the least satisfied patients ranged from 8.4 points on the subscales of general health and 16.7 points on the subscale of role limitation due to emotional problems. CONCLUSION: The conclusion that patient education is associated with better HRQOL in patients with PD is drawn.

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OBJECTIVE: To estimate the cost of treating a tuberculosis (TB) case and to analyse TB-related medical service utilisation, a cost-of-illness study was conducted for all patients with a primary diagnosis of TB admitted to a public hospital in Japan. METHODS: Retrospective analysis by abstracting in- and out-patient medical records of 57 paediatric patients diagnosed with TB during 1993-1998 at a public hospital in Osaka prefecture. Costs were estimated based on third party's payer perspectives according to the service utilisation pattern. In addition to cost data, sociodemographic information and service utilisation pattern were also extracted from the medical records. Cost of preventing a case of TB was abstracted from the published literature. RESULTS: The average cost of treatment was 8384 US dollars (95%CI 5667-11,099), while the average length of hospitalisation was 63 days (95%CI 43-84). Based on 20-80% vaccine efficacy, the cost of preventing a case of TB was 35,950-175,862 US dollars. In univariate analysis, site of TB (P = 0.04) was significantly associated with TB treatment cost, while case-finding method (contact tracing, symptoms, etc.) was associated with length of hospitalisation (P = 0.03). Multivariate regression analysis, however, showed none of the factors to be significant predictors of TB treatment cost and length of hospital stay. CONCLUSION: The cost of treating a case of paediatric TB is much lower than that of preventing one. Japan's universal BCG vaccination policy should be re-examined in the light of economic, social and political issues.

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A 59-year-old Japanese man presented with a slightly elevated, pruritic, erythematous plaque on his left buttock measuring 5 x 5 cm in diameter. The man had a history of chromomycosis, dating 6 years prior to the current consultation, for which he had been treated with oral terbinafine. Diagnosis of a recurrence of chromomycosis of the skin due to infection by Foncecaea pedrosoi was made after careful analysis of the clinical features, skin biopsy, KOH mounts, and fungal culture results. We administered topical heat therapy followed by treatment with CO2 laser to eradicate the unresponsive remnants of the lesion. The operative site re-epithelized within 10 weeks, and 1 year after the treatment there was no evidence of recurrence. For a recalcitrant case of chromomycosis, as in this case, the use of CO2 laser combined with topical heat therapy may be a new therapeutic modality.

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Low incidence of bystander-initiated cardiopulmonary resuscitation (CPR) is allegedly responsible for poor survival from out-of-hospital cardiac arrest (OHCA) in Japan. This study was conducted to determine significant predictors for survival after collapse-witnessed OHCA of presumed cardiac etiology to investigate the impact of bystander-initiated CPR. Logistic regression analysis of OHCA of presumed cardiac etiology was performed on retrospective data sets from three Japanese suburban communities. All arrest incidents were witnessed and occurred prior to the arrival of EMS personnel. Outcome measure was survival to discharge. Initial electrocardiogram (ECG) rhythm (ventricular fibrillation (VF) or not), interval from collapse to CPR (within 5 min or not), and initial ECG rhythm/collapse-to-CPR interval interaction were significantly associated with survival. Patient age (70 years or less/over 70 years), interval from collapse to EMS response, and bystander-initiated CPR were significantly associated with VF in an initial ECG. The effectiveness of bystander-initiated CPR for OHCA can be successfully predicted based on the interval from collapse to CPR and initial ECG rhythm. The increase in the proportion of bystander-initiated CPR from the present level of 20-50% would be expected to rescue another 1800 victims of OHCA per year in Japan.

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BACKGROUND: Dopamine agonists such as bromocriptine or pergolide are often used in Japan to treat Parkinson's disease. Dopamine agonists are relatively expensive drugs; economic evaluations are required. OBJECTIVE: To evaluate the cost effectiveness of dopamine agonists for the treatment of Parkinson's disease in Japan. DESIGN AND SETTING: We used a Markov model to simulate the course of Parkinson's disease and to compare the cost effectiveness of dopamine agonists added to levodopa with that of levodopa alone in Japan. The model assumed that 60-year-old men with Parkinson's disease in Hoehn-Yahr (HY) stages 2 to 5 using levodopa were administered dopamine agonists or continued on levodopa alone. The incremental cost effectiveness of dopamine agonists used for 10 years was then estimated. STUDY PERSPECTIVE: Societal. MAIN OUTCOME MEASURES AND RESULTS: In the patients in HY stage 2, the incremental cost effectiveness of dopamine agonists was 18,610,000 to 19,320,000 yen per quality-adjusted life-year (QALY) [$US 172,300 to $US 178,900/QALY; 1998 values] . In patients in HY stage 3 or higher, the use of dopamine agonists was dominant over levodopa alone mainly due to reduced cost for care. In sensitivity analyses, costs and effectiveness of dopamine agonists significantly influenced the results. The use of a generic formulation of bromocriptine was dominant over levodopa alone even in the patients with HY stage 2 disease. CONCLUSIONS: Dopamine agonists appear to be cost effective in advanced Parkinson's disease, although their use is sensitive to the costs and effectiveness of dopamine agonists. If factors discouraging the prescription of generic drugs in Japan were removed, the treatment of Parkinson's disease would become more cost effective.

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Because hyperkalaemia above a certain level is life-threatening, erroneous interpretation of serum potassium concentration may misguide and complicate diagnostic procedures. We investigated a number of cases with pseudohyperkalaemia, which was assumed to have been caused by the recentrifugation of blood samples after storage in gel separator tubes. The time trend of serum potassium concentration was explored before (January-March 1997) and after (May-July 1997) ceasing the practice of recentrifuging blood samples after overnight storage. Next, we conducted an experiment on a volunteer's serum. The sample was divided into two groups and centrifuged once (control group) or twice (recentrifugation group). For both groups, serum potassium concentrations were measured immediately, and at 24, 48 and 72 h. For the recentrifugation group, the second centrifugation was done just before the measurement. The time series study showed that the mean serum potassium concentrations measured after overnight storage were 4.68 (95% CI: 4.60-4.76) mmol/L before and 4.14 (4.07-4.20) mmol/L after ceasing the practice of recentrifugation. The experiment showed that the mean serum potassium concentrations in the control group versus the recentrifugation group were 3.95 (95% CI: 3.89-4.01) mmol/L versus 4.05 (3.92-4.17) immediately (P=0.0979), 3.95 (3.89-4.01) versus 5.95 (5.61-6.29) at 24 h (P=0.0001), 4.13 (4.05-4.22) versus 6.90 (6.46-7.34) at 48 h (P=0.0001), and 4.22 (3.85-4.58) versus 7.61 (6.94-8.30) at 72 h (P<0.0001). Recentrifugation of blood samples after storage causes a spurious rise in serum potassium concentration to the degree of clinical significance. Clinicians and biochemists should take appropriate measures to stop this practice.

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A cell line, termed NCJ, was established from the bone marrow-derived mast cells (BMMCs) of NC/Nga mice that are mouse models for atopic dermatitis. NCJ cells expressed FcepsilonRI and c-kit and showed a metachromasia of the granules with a toluidine blue-positive and safranin-negative staining pattern that is characteristic for immature-type mast cells. Interestingly, NCJ cells showed proliferation independent of IL-3, which was associated with constitutive phosphorylation of Raf-1 and Erk kinases. Although NCJ cells had several characteristics of mast cells, we failed to detect FcepsilonRI-mediated beta-hexosaminidase release and its histamine content. These findings indicated that NCJ cells represented a mast cell line with an immature phenotype and the ability to proliferate in the absence of mast cell growth factors. NCJ cells might thus be useful to study the molecular basis of mast cell proliferation.

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BACKGROUND: The international controversy surrounding the use and effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine and the low incidence of tuberculosis (TB) among Japanese children prompted this study. METHODS: We compared 'universal BCG vaccination' with 'no vaccination at all' using a cost-effectiveness analysis. The study population was a hypothetical cohort comprising a total of 1.2 million infants born in 1996 at locations all over Japan. A model was developed to calculate the number of TB cases prevented by the vaccination programme. Assuming 40-80% overall vaccine efficacy (64-86% for TB-meningitis) and 10 years of protection, we calculated the cost and number of immunizations required to prevent one child from developing TB, the total number of TB cases averted by vaccination and total costs required for the programme. RESULTS: Based on an assumption of flexible vaccine efficacy (40-80%), we estimated that 111-542 TB cases including 10-27 of TB-meningitis would be prevented during the 10 years after BCG vaccination among the cohort of infants born in 1996. About US$35 950-175 862 or 2125-10 399 immunizations would be required to prevent one child from developing TB. Sensitivity analyses covering a wide duration of protection, incidence of TB, vaccine coverage and discount rate, revealed that other than vaccine efficacy, the cost of preventing a single case of TB is highly sensitive to the duration of BCG protection and TB incidence. CONCLUSION: The cost per case of TB prevented is heavily dependent on vaccine efficacy and the duration of protection, and is high compared with the cost of treating one child who has developed TB.

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OBJECTIVE: To ascertain the differences among hospitals in Japan in the management patterns and outcomes of patients with acute myocardial infarction (AMI). DESIGN: Retrospective cohort study by means of patient chart review. SETTING: Four tertiary-care teaching hospitals in Japan observed over a 1-year period. STUDY PARTICIPANTS: Consecutive patients (N=482) admitted for AMI. MAIN OUTCOME MEASURES: Clinical characteristics, rates of diagnostic and therapeutic procedures performed, cardiac complications, and length of stay. RESULTS: Patients' clinical characteristics differed significantly among the four hospitals in terms of age, gender, and prior cardiac history, but not in terms of comorbidity or infarct location. The frequency and type of diagnostic and therapeutic procedures were different, and in-hospital mortality varied (4-14%, P=0.022). Average length of hospital stay ranged from 15.8+/-12.6 days to 41.0+/-19.4 days (P=0.0001). After adjustment for the clinical characteristics, these differences remained significant among hospitals. CONCLUSION: Considerable differences in the management and outcomes of patients with AMI exist in Japan.

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Although seven years have passed after basic emergency medical technician (EMT) defibrillation system was introduced in Japan, the overall survival for out-of-hospital cardiac arrest (OHCA) remains poor. We investigated factors leading to such an unanticipated result in Japan by comparing the data of OHCA in Japan with those in other countries. We obtained population-based OHCA data from three communities in Japan. We also performed a comprehensive literature and manual search to identify reports that included rates for incidence and survival or provided sufficient data for the calculation of these rates of OHCA. Statistical analysis was performed to compare survival and incidence rates between the communities. We identified 36 articles from 16 countries by a comprehensive literature search. There was no significant difference in incidence and survival rates among communities in Japan. Although the incidence rate of collapse-witnessed OHCA with ventricular fibrillation (VF) was much lower in Japan than western countries, the proportions of survival from it were comparable to those. Basic-EMT defibrillation system in Japan has yielded excellent result in terms of the survival of VF cases. However, much lower proportion of VF to all cases is responsible for lower overall rates of survival from OHCA in Japan.

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During postischemic reperfusion, free radicals are produced and have deleterious effects in isolated rat hearts. We investigated whether melatonin (MEL) reduces the production of hydroxyl radical (*OH) in the effluent and aids in recovery of left ventricular (LV) function. Hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. Salicylic acid (SAL) was used as the probe for *OH, and its derivatives 2,5- and 2,3-dihydroxybenzoic acid (DHBA) were quantified using HPLC. In addition, thiobarbituric acid reactive substances (TBARS) in the myocardium was measured. Plateaus in the measurement of 2,5- and 2,3-DHBA were seen from 3 to 8 min after reperfusion in each group. The group that received 100 microM MEL+ SAL had significantly reduced amounts of 2,5- and 2,3-DHBA by multiple folds, compared to the SAL group. TBARS was significantly decreased in the 100 microM MEL group (1.20+/-0.36 vs 1.85+/-0.10 micromol/g of drug-free group, p<0.001). More importantly, the 100 microM MEL group significantly recovered in LV function (LV developed pressure, +dp/dt, and -dp/dt; 63.0%, 60.3%, and 59.4% in the 100 microM MEL group; 30.2%, 29.7%, and 31.5% in the drug-free group, respectively; p<0.05). Duration of ventricular tachycardia or ventricular fibrillation significantly decreased in the 100 microM MEL group (100 microM MEL, 159+/-67 sec; drug-free, 1244+/-233 sec; p<0.05). As a result of scavenging *OH and reducing the extent of lipid peroxidation, MEL is an effective agent for protection against postischemic reperfusion injury.

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BACKGROUND: In addition to cigarettes, bidi, made of unprocessed and low-grade tobacco, is being smoked widely in Bangladesh and in other south Asian countries. The cause-and-effect relationship is established between thromboangiitis obliterans (TAO) and smoking. However, type of smoking material(s) most strongly related to TAO is not yet determined. METHODS: We conducted a hospital-based case-control study in Rajshahi, Bangladesh, to examine the relationship of type of smoking materials (cigarette versus bidi) with TAO on 103 pairs of cases and controls matched by age and sex during the period 1995 to 1996. The inclusion criteria for cases were newly diagnosed TAO and current smoker, while those for controls were current smokers admitted to the hospital due to non-cardiovascular diseases. RESULTS: Among the cases 35.0% and 65.0% were cigarette and bidi smokers, while among the controls 69.9% and 30.1%, respectively. Using logistic regression approach, considering cigarette smoking approximately 10 per day as reference, bidi smoking >20 per day (odds ratio [OR] = 34.76, 95% CI: 6.11-197.67) and 11-20 per day (OR = 7.12, 95% CI: 2.35-21.63) had greater risk of TAO after adjusting confounding factors. Respective OR for bidi smoking approximately 10 per day, cigarette smoking 11-20 per day and cigarette smoking >20 per day, were 2.18 (95% CI: 0.64-7.51), 3.81 (95% CI: 1.37-10.57) and 6.88 (95% CI: 1.87-25.30). CONCLUSION: Within the limits inherent to case-control study, our findings suggest that bidi smoking may well play a more important role in causing TAO than cigarettes. It leads to the speculation that unprocessed and low-grade tobacco used for producing bidi might play a more potent role to initiate TAO than cigarettes.

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A dose of 300 mg/day of suplatast tosilate was administered to one hundred one cases of atopic dermatitis for eight weeks, and the severity scores, peripheral blood eosinophil count, total serum IgE levels, plasma eosinophil cationic protein (ECP) levels, and other immunological parameters before and after the trial were observed and comparatively examined. The results are as follows: 1) Temporary improvements were found in the scores of severity and itchiness on all evaluated skin regions (face, limbs, and trunk). These scores decreased significantly for all observation periods at two, four, six and eight weeks after administration of suplatast tosilate compared with those before the administration (p < 0.01). 2) There was no sign of adverse effects on the drug. In the blood tests, one patient displayed elevated levels of GPT and another showed elevated total bilirubin. In the urine test (qualitative test), one case with positive urinary protein was observed. 3) Clinical examinations including assessment of the immunologic parameters were conducted at an average of 8.68 +/- 0.36th week. The peripheral blood eosinophil count, the percentage of eosinophil, and plasma ECP levels significantly diminished compared with those before administration, but no significant difference was found in total serum IgE levels and LDH levels. 4) The subjects were divided into two groups, one in which the clinical scores were improved by more than five and another with scores of less than five (including worsening), and the fluctuation of the immunological parameters (values before and after administration of the drug) of the two groups were compared. As a result, a significant difference was observed in the plasma ECP levels (p = 0.02) and peripheral blood eosinophil count (p = 0.091), but no difference was observed in total serum IgE levels and LDH levels. From the above mentioned results, the high efficacy and safety of suplatast tosilate in the treatment of severe atopic dermatitis were confirmed. At the same time, a decrease in the peripheral blood eosinophil count and the serum ECP levels were observed, suggesting the possibility that these values could be used as indices of the severity of atopic dermatitis.

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Atopic dermatitis (AD) is a common pruritic disease that occurs primarily in infancy and childhood. AD is characterized by itching and the patient having an individual or family history of atopic diseases. Although AD is also frequently associated with elevated serum IgE levels and with common environmental factors contributing to its pathogenesis, the etiology of AD is still unknown. We examined NC/Nga mice (NC mice) that showed AD-like skin lesions with aging as a possible mouse model for AD. NC mice were maintained under conventional (Conv) or specific pathogen-free (SPF) conditions. Clinical symptoms, serum IgE levels and histopathology of the skin were compared between these 2 groups, and we explored their application as a model of human AD. It was found that the skin lesions of inbred NC mice were clinically and histologically very similar to human AD when the mice were raised under Conv conditions, but not under SPF conditions, and we assumed that some kinds of environmental factors might trigger AD-like signs and symptoms in NC mice. To further investigate the pathophysiology and treatment of AD, a suitable animal model is absolutely required, and NC mice are very useful for this purpose.

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OBJECTIVES: To determine the influence of superstition about Taian (a lucky day)-Butsumetsu (an unlucky day) on decision to leave hospital. To estimate the costs of the effect of this superstition. DESIGN: Retrospective and descriptive study. SETTING: University hospital in Kyoto, Japan. SUBJECTS: Patients who were discharged alive from Kyoto University Hospital from 1 April 1992 to 31 March 1995. MAIN OUTCOME MEASURES: Mean number, age, and hospital stay of patients discharged on each day of six day cycle. RESULTS: The mean number, age, and hospital stay of discharged patients were highest on Taian and lowest on Butsumetsu (25.8 v 19.3 patients/day, P=0.0001; 43.9 v 41.4 years, P=0.0001; and 43.1 v 33.3 days, P=0.0001 respectively). The effect of this difference on the hospital's costs was estimated to be 7.4 million yen (¿31 000). CONCLUSION: The superstition influenced the decision to leave hospital, contributing to higher medical care costs in Japan. Although hospital stays need to be kept as short as possible to minimise costs, doctors should not ignore the possible psychological effects on patients' health caused by dismissing the superstition.

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