Assessment of Residual Vasospasm in Patients with Plaque Rupture or Plaque Erosion using Optical Coherence Tomography.

AIMS: Coronary vasospasm is associated with acute coronary syndrome (ACS) and may persist during primary percutaneous coronary intervention (PCI). We aimed to elucidate the incidence, morphological characteristics, and prognostic impact of residual vasospasm in plaque rupture (PR) and plaque erosion (PE) lesions using optical coherence tomography (OCT). METHODS: We enrolled 142 patients with ACS who underwent OCT-guided primary PCI. All patients received intracoronary vasodilators before OCT examination. Residual vasospasm was identified as intimal gathering and categorised as polygonal- or wavy- patterned depending on the luminal shape. A wavy pattern was defined as a curved intimal surface line. A polygonal pattern was defined as a lumen with multiple angles. The incidence of major cardiovascular events, defined as death, non-fatal myocardial infarction, stroke, and any revascularization, within 1-year of PCI was identified. RESULTS: The prevalence of residual vasospasm in PR and PE was 15.1% (13 of 86) and 21.4% (12 of 56), respectively. Wavy pattern was the major shape of the residual vasospasm. Polygonal-patterned lumen was more frequently observed in PR than in PE (38.5 vs. 8.3 %). The polygonal-patterned lumens had significantly larger lipid arcs (257.9 vs. 78.0 °; P＜0.01), and significantly smaller areas (1.27 vs. 1.88 mm2; P=0.05) than wavy patterned lumens. Residual vasospasm had a prognostic impact on PR but not PE at 1-year of successful primary PCI. CONCLUSION: Considerable proportion of ACS including both PR and PE had residual vasospasm with variable morphological feature and different prognostic impact.

Model-based meta-analysis of ethnic differences and their variabilities in clearance of oral drugs classified by clearance mechanism.

In this study, the ethnic ratios (ERs) of oral clearance between Japanese and Western populations were subjected to model-based meta-analysis (MBMA) for 81 drugs evaluated in 673 clinical studies. The drugs were classified into eight groups according to the clearance mechanism, and the ER for each group was inferred together with interindividual variability (IIV), interstudy variability (ISV), and inter-drug variability within a group (IDV) using the Markov chain Monte Carlo (MCMC) method. The ER, IIV, ISV, and IDV were dependent on the clearance mechanism, and, except for particular groups such as drugs metabolized by polymorphic enzymes or their clearance mechanism is not confirmative, the ethnic difference was found to be generally small. The IIV was well-matched across ethnicities, and the ISV was approximately half of the IIV as the coefficient of variation. To adequately assess ethnic differences in oral clearance without false detections, phase I studies should be designed with full consideration of the mechanism of clearance. This study suggests that the methodology of classifying drugs based on the mechanism that causes ethnic differences and performing MBMA with statistical techniques such as MCMC analysis is helpful for a rational understanding of ethnic differences and for strategic drug development.

Lifecycle management of orphan drugs approved in Japan.

BACKGROUND: The development of orphan drugs (ODs) is challenging from both development and business perspectives because of their small patient populations. To overcome such business challenges, lifecycle management (LCM), which maximizes profits by increasing sales and extending product lifetimes, is important to overcome the business challenges arising from their small patient populations. To clarify the activities of the LCM of ODs, we investigated additional indications that contribute to market expansion and marketing exclusivity using the patent extension and re-examination system of ODs approved in Japan between 2004 and 2019. RESULTS: The 203 ODs consisting of 173 active ingredients were approved in Japan between 2004 and 2019. Sixty-eight (39%) of the 173 active ingredients have additional indications, of which 57 have at least one non-OD indication. Three-fourths of the 203 ODs had patent rights, and most of them included substance or use claims. Although the re-examination period for most ODs was 10 years after the approval, most patents had a longer duration than the re-examination period. CONCLUSIONS: Pharmaceutical companies were actively adding non-OD indications and were emphasizing the use of patent rights by registering extensions of substance or use patents for exclusive marketing periods. These results indicate that LCM through the addition of indications and registration of patent extensions is carried out as a strategy for many ODs in Japan, similar to the LCM of general non-ODs.

Assessment of Screening for Nasal Obstruction among Sleep Dentistry Outpatients with Obstructive Sleep Apnea.

Oral appliances (OA), a common treatment modality for obstructive sleep apnea (OSA), are not suitable for patients with nasal obstruction. Rhinomanometry, the gold standard technique to assess nasal airway resistance, is not readily available in sleep dentistry clinics. We demonstrate the use of a portable lightweight peak nasal inspiratory flow (PNIF) rate meter to objectively assess nasal airflow and utilized the Nasal Obstruction Symptom Evaluation (NOSE) scale to subjectively assess nasal obstruction in 97 patients with OSA and 105 healthy controls. We examined the correlations between the following variables between the groups: demographics, body mass index, PNIF, NOSE scale scores, apnea-hypopnea index (AHI), minimum SpO2 (SpO2min), Mallampati classification, and Epworth Sleepiness Scale (ESS) scores. Patients with OSA had significantly lower PNIF values and higher NOSE scores than controls. In the patient group, PNIF was not significantly correlated with AHI, SpO2min, Mallampati classification, or NOSE or ESS scores. Lower PNIF values and higher NOSE scores suggested impaired nasal airflow in the OSA group. As daytime PNIF measurement bears no relationship to AHI, this cannot be used alone in predicting the suitability of treatment for OSA with OA but can be used as an adjunct for making clinical decisions.

Initial hazard assessment of 1,4-dichlorobutane: Genotoxicity tests, 28-day repeated-dose toxicity test, and reproductive/developmental toxicity screening test in rats.

1,4-Dichlorobutane (1,4-DCB) is used as raw materials for drugs, pesticides, fragrances, and chemical fibers, and being used as a solvent. Its toxicity data was insufficient for screening assessment under the Japanese Chemical Substances Control Law. We conducted toxicity tests and hazard classification for screening assessment 1,4-DCB showed negative in the Ames test, positive in the in vitro chromosomal aberrations test with metabolic activation, and negative in the in vivo mouse bone-marrow micronucleus test. The 28-day repeated-dose toxicity study, where male and female rats were administered 1,4-DCB by gavage at 0, 12, 60, and 300 mg/kg/day, showed significant effects on the liver and pancreas from 12 mg/kg/day and kidney at 300 mg/kg/day. Based on periportal hepatocellular hypertrophy and decreased zymogen granules in pancreas, the lowest observed adverse effect level (LOAEL) of 12 mg/kg/day was obtained. The reproductive/developmental toxicity screening study, in which male and female rats were administered 1,4-DCB by gavage at dose of 0, 2.4, 12, and 60 mg/kg/day for 42-46 days, showed that the delivery index was decreased at 60 mg/kg/day without maternal toxicity. Based on the general toxicity, we classified this chemical as hazard class 2, with a D-value (Derived No Effect Level) of 0.002 mg/kg/day.

Initial hazard assessment of benzyl salicylate: In vitro genotoxicity test and combined repeated-dose and reproductive/developmental toxicity screening test in rats.

Benzyl salicylate is used as a fragrance ingredient and an ultraviolet light absorber, but its toxicity is unknown. Therefore, toxicity tests and hazard classification were conducted for screening assessment under the Japanese Chemical Substances Control Law. Benzyl salicylate was found to be non-genotoxic in vitro based on the chromosomal aberration test using Chinese hamster lung cells. However, the combined repeated-dose and reproductive/developmental screening toxicity test, in which male and female rats were administered benzyl salicylate by gavage at 0, 30, 100, or 300 mg/kg/day for 42 and 41-46 days, respectively, from 14 days before mating until postnatal Day 4, showed that repeated doses had major effects on the thymus, liver, epididymis, and femur at 100 and/or 300 mg/kg/day. Furthermore, although benzyl salicylate had no effect on the estrus cycle, fertility, corpus lutea, or implantation rate, embryonic resorption, offspring mortality, and neural tube defects were observed at 300 mg/kg/day, and the offspring had lower body weights at 30 and 100 mg/kg/day, suggesting teratogenicity similar to other salicylates. Based on the developmental toxicity, this chemical was classified as hazard class 2, with a lowest observed adverse effect level (LOAEL) of 30 mg/kg/day and a D-value of 0.003 mg/kg/day.

Initial hazard assessment of 4-benzylphenol, a structural analog of bisphenol F: Genotoxicity tests in vitro and a 28-day repeated-dose toxicity study in rats.

4-Benzylphenol (CAS No. 101-53-1), a structural analog of bisphenol F, has estrogenic activity in vitro and in vivo, as is the case with bisphenol F. 4-Benzylphenol is used in plastics and during organic synthesis. Since its safety is largely unknown, we conducted toxicity tests as part of screening risk assessment in an existing chemical safety survey program. Based on results of the Ames test and the chromosomal aberration test using Chinese hamster lung cells (OECD TG 471 and 473), 4-benzylphenol was determined to be non-genotoxic in vitro. In a 28-day repeated-dose toxicity study, Crl:CD (SD) rats were administrated 4-benzylphenol by gavage at 0, 30, 150, or 750 mg/kg/day (OECD TG 407). Consequently, body weight was lower in males at 750 mg/kg/day. In the liver, relative organ weights were increased in both sexes at 750 mg/kg/day, and centrilobular hepatocellular hypertrophy was observed in males at 150 and 750 mg/kg/day. In the forestomach, hyperkeratosis and hyperplasia of squamous cells were observed in males at 150 and 750 mg/kg/day, and in females at 750 mg/kg/day. Based on these results, we identified the NOAEL for 4-benzylphenol as 30 mg/kg/day, with a hazard assessment value (D-value) of 0.05 mg/kg/day corresponding to hazard class 3.

Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether Pioglitazone Protects DM Patients Against Re-Infarction (PPAR Study).

BACKGROUND: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. METHODS: In this multicentre, prospective, randomised, open, blinded-endpoint trial, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. FINDINGS: HbA1C levels were 5·9 and 5·8% (p = 0·71) at baseline and 6·0 and 5·8% (p < 0·01) at 2 years for the control and pioglitazone groups, respectively.The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662-1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786-32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051-3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618-1·237, p = 0·45). INTERPRETATION: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.

Assessment of Drug-Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy.

Aprepitant is a known inducer of CYP2C9, the main warfarin-metabolizing enzyme. Consequently, co-administration of these two drugs may result in reduction of the anticoagulation activity of warfarin. However, the nature and degree of time-dependent changes in prothrombin time international normalized ratio (PT-INR) after aprepitant and warfarin co-treatment in patients receiving anticancer chemotherapy has not been elucidated. We retrospectively examined the changes in warfarin dose, PT-INR, and warfarin sensitivity index (WSI; average of PT-INR value/average of daily warfarin dose) during four weeks, i.e., one week before and three weeks after aprepitant administration. The mean and standard deviation values of WSI for one week before and one, two, and three weeks after the beginning of aprepitant administration were 0.51±0.22 (1.00, n=34), 0.74±0.30 (1.53±0.59, n=30), 0.38±0.15 (0.82±0.22, n=28), and 0.46±0.29 (0.87±0.23, n=24), respectively. Values in parentheses represent relative changes versus WSI of one week before and number of subjects. Although the mean value of WSI significantly increased one week after aprepitant administration compared to that at one week before the administration, it in turn significantly decreased two weeks after compared to one week before (paired t-test, p<0.05 after Bonferoni correction). In patients taking warfarin, PT-INR should be carefully monitored for at least two weeks after the beginning of aprepitant administration because it may fluctuate with both aprepitant and chemotherapy during this period.

Assessment of intestinal availability (FG) of substrate drugs of cytochrome p450s by analyzing changes in pharmacokinetic properties caused by drug-drug interactions.

In this study, we developed the drug-drug interaction (DDI) method as a new assessment technique of intestinal availability (F(G), the fraction of drug transferred from the intestinal enterocytes into the liver, escaping from intestinal metabolism) based on the clearance theory. This method evaluates F(G) from changes caused by DDIs in the area under the blood concentration-time curve and in the elimination half-life of victim drugs. Application of the DDI method to data from the literature revealed that the mean and S.D. of F(G) values for 20 substrate drugs of CYP3A was 0.56 ± 0.29, whereas that for 8 substrate drugs of CYP2C9, CYP2C19, and CYP2D6 was 0.86 ± 0.11. These results were consistent with the fact that intestinal metabolism is mediated predominantly by CYP3A. The DDI method showed reasonable correlations with the conventional i.v./p.o. method and the grape fruit juice (GFJ) method (coefficients of determination of 0.41 and 0.81, respectively). The i.v./p.o. method was more susceptible to fluctuations in the hepatic blood flow rate compared with the DDI and GFJ methods. The DDI method evaluates F(G) separating from the absorption ratio (F(A)) although it requires approximation of F(A). Since preciseness of approximation of F(A) does not greatly affect the evaluation of F(G) by the DDI method, we proposed a reasonable approximation method of F(A) for the evaluation of F(G) in the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable.

Underweight/overweight and the risk of long-term care: follow-up study using data of the Japanese long-term care insurance system.

AIM: Both being underweight and overweight can lead to reduced activity of daily living, which subsequently can require long-term care. The aim of the present study was to clarify the association between underweight/overweight and the subsequent risk of long-term care introduction. METHODS: We tracked the data of long-term care insurance for 1580 men and women aged ≥65 years who had participated in the official population-based health check-up program in 2001 in Tsunan town and Sekikawa village, Japan. The health check-up data and medical expenditure data for the fiscal year 2001 were used as baseline data. Participants were classified into underweight (body mass index (BMI) <18.5 kg/m(2) ), normal range (BMI = 18.5 to <25.0 kg/m(2) ) and overweight (BMI ≥25.0 kg/m(2) ); the normal range was used as a reference category in Cox proportional hazards models. RESULTS: During the average 5.8 years of follow up, 156 participants were identified to start using long-term care services. Among the young-old elderly (65-74 years-of-age), underweight was significantly associated with the risk of long-term care introduction (multivariable-adjusted HR 4.26, 95% CI 1.69-10.72), whereas overweight was not (multivariable-adjusted HR 1.45, 95% CI 0.69-3.06). Neither underweight nor overweight were significantly associated with long-term care introduction among the old-old elderly (≥75 years-of-age). CONCLUSIONS: Underweight could be a good predictor of long-term care introduction in the young-old elderly. We should pay attention to underweight in the elderly, as it might be a manifestation of some physical or mental problems related to future long-term care introduction.

[Longer working hours of pharmacists in the ward resulted in lower medication-related errors--survey of national university hospitals in Japan].

It is obvious that pharmacists play a critical role as risk managers in the healthcare system, especially in medication treatment. Hitherto, there is not a single multicenter-survey report describing the effectiveness of clinical pharmacists in preventing medical errors from occurring in the wards in Japan. Thus, we conducted a 1-month survey to elucidate the relationship between the number of errors and working hours of pharmacists in the ward, and verified whether the assignment of clinical pharmacists to the ward would prevent medical errors between October 1-31, 2009. Questionnaire items for the pharmacists at 42 national university hospitals and a medical institute included the total and the respective numbers of medication-related errors, beds and working hours of pharmacist in 2 internal medicine and 2 surgical departments in each hospital. Regardless of severity, errors were consecutively reported to the Medical Security and Safety Management Section in each hospital. The analysis of errors revealed that longer working hours of pharmacists in the ward resulted in less medication-related errors; this was especially significant in the internal medicine ward (where a variety of drugs were used) compared with the surgical ward. However, the nurse assignment mode (nurse/inpatients ratio: 1 : 7-10) did not influence the error frequency. The results of this survey strongly indicate that assignment of clinical pharmacists to the ward is critically essential in promoting medication safety and efficacy.

The impact of community-based outreach immunisation services on immunisation coverage with GIS network accessibility analysis in peri-urban areas, Zambia.

BACKGROUND: Accessibility to health services is a critical determinant for health outcome. OBJECTIVES: To examine the association between immunisation coverage and distance to an immunisation service as well as socio-demographic and economic factors before and after the introduction of outreach immunisation services, and to identify optimal locations for outreach immunisation service points in a peri-urban area in Zambia. METHODS: Repeated cross-sectional surveys were conducted for two groups of children born between 1999 and 2001, and between 2003 and 2005.The association between immunisation coverage for DPT3 and measles, and access distance, child sex, female headed households, and monthly household income were assessed using logistic regression analysis. Optimal locations for outreach service points were identified using GIS network analysis and genetic algorithms. RESULTS: Before the introduction of outreach services, longer distances to the service points were associated with lower DPT3 and measles immunisation coverage (OR=0.24, 95% CI 0.10 to 0.56, p<0.01 for DPT3; and OR=0.38, 95% CI 0.17 to 0.83, p<0.05 for measles). However, access distances were not an impediment to immunisation coverage once the outreach services were introduced. The average distance to immunisation services could be decreased from 232.3 to 168.4 metres if the current 12 outreach service points were repositioned at optimal locations. CONCLUSION: Access distance to immunisation services was a critical determinant of immunisation coverage in a peri-urban area. Intervention via outreach services played an important role in averting the risk of missing out on immunisation. Optimal location analysis has the potential to contribute to efficient decision making regarding the delivery of immunisation services.

The impact of an immunization programme administered through the Growth Monitoring Programme Plus as an alternative way of implementing Integrated Management of Childhood Illnesses in urban-slum areas of Lusaka, Zambia.

A time-lag study design was used to examine the effects of an immunization programme implemented through an integrated community-based child health approach called the Growth Monitoring Programme Plus (GMP+) in peri-urban areas of Lusaka, Zambia. The immunization coverage and sociodemographic data of eligible children and households were obtained from three repeated surveys in two intervention areas. Logistic regression analysis was performed to explore the factors affecting immunization coverage. For assessing the timeliness of immunization, a Computerised Immunization Coverage Calculation System (CICCS) was used. Full immunization coverage significantly increased in both the primary intervention (P<0.001) and lagged intervention (P = 0.011) areas after the initiation of the GMP+. Frequent attendance to GMP+ sessions played a significant role in the improvement of immunization coverage (P<0.001 for the final survey in the primary intervention area), whereas other sociodemographic characteristics of the child and caretaker were not associated with immunization coverage. Analysis of the timeliness of three doses of diphtheria, pertussis and tetanus DPT3 immunization by CICCS showed that coverage in the primary intervention area had significantly improved compared to the lagged intervention area. Our study indicated that immunization coverage was improved effectively with the intervention of the GMP+ as a model of an integrated immunization programme for child health in line with the Integrated Management of Childhood Illnesses (IMCI) and the Global Immunization Vision and Strategy (GIVS).

Access to a health facility and care-seeking for danger signs in children: before and after a community-based intervention in Lusaka, Zambia.

OBJECTIVE: To assess the association of accessibility to a health facility with caregivers' care-seeking practices for children with danger signs before and after community-based intervention in Lusaka, Zambia. METHOD: Health education on childhood danger signs was started in September 2003 at the monthly Growth Monitoring Program Plus (GMP+) service through various channels of health talk and one-on-one communication in a peri-urban area of Lusaka. Two repeated surveys were conducted: in 2003 to collect baseline data before the intervention and in 2006 for 3-year follow-up data. Caregivers who had perceived one or more danger signs in their children within 2 months of the surveys were eligible for the analysis. The association between appropriate and timely care-seeking practices and socio-demographic and socio-economic factors, attendance at community-based intervention and the distance to a health facility was examined with logistic regression analysis. RESULTS: The percentage of caregivers immediately seeking care from health professionals increased from 56.1% (106/189) at baseline to 65.8% (148/225) at follow-up 3 years later (OR = 1.51, P < 0.05). Long distance to the health facility and low-household income negatively influenced caregivers' appropriate and timely care-seeking practices at baseline, but 3 years later, after the implementation of a community-based intervention, distance and household income were not significantly related to caregivers' care-seeking practices. CONCLUSION: Poor accessibility to health facilities was a significant barrier to care-seeking in a peri-urban area. However, when caregivers are properly educated about danger signs and appropriate responses through community-based intervention, this barrier can be overcome through behavioural change in caregivers.

Risk assessment by post-challenge plasma glucose, insulin response ratio, and other indices of insulin resistance and/or secretion for predicting the development of type 2 diabetes.

OBJECTIVE: To find useful indices to identify subjects at high risk for developing diabetes. METHODS: We retrospectively reviewed 75-g oral glucose tolerance test (OGTT) surveys conducted during 1980 to 2001 in a Japanese community. Using personal charts of the surveys, 230 non-diabetics were followed for progression to type 2 diabetes. The usefulness of HbA(1C), fasting (Glucose(0)) and 1-hour (Glucose(60)) glucose levels during OGTT, and indices for insulin resistance and/or secretion to identify high risk subjects for diabetes were then analyzed. MATERIALS: Data described in personal charts of the OGTT program for residents of Nishikawa Town, Niigata Prefecture, Japan. RESULTS: During the 4.3+/-2.7 years of follow-up, 52 subjects progressed to type 2 diabetes. Assessing glucose and insulin levels during OGTT, Glucose(0), Glucose(60), "Insulin Response Ratio" (IRR(30), Insulin at 30 minutes / Fasting insulin; IRR(60), insulin at 60 minutes / fasting insulin), and insulin secretion / insulin resistance index (ISIRI(30)) were significantly associated with progression to type 2 diabetes even after the result for OGTT, body mass index, and familial history of diabetes were adjusted. These were also able to identify still higher risk subjects for type 2 diabetes from those with impaired glucose tolerance (IGT) although other indices for insulin resistance or secretion and hemoglobin A(1C) were less contributable for this purpose. CONCLUSION: A combination of Glucose(0) and Glucose(60) can most cost effectively identify high risk subjects for type 2 diabetes from IGT. IRR(30), IRR(60) and ISIRI(30) can also be used for such identification. However, further studies are needed to clarify whether these indices are superior to Glucose(0) and Glucose(60).

Resovist-enhanced MRI for preoperative assessment of colorectal hepatic metastases: a case of multiple bile duct hamartomas associated with colon cancer.

Extensive preoperative assessment of hepatic metastases is required in colon cancer patients. We report a case in whom the preoperative investigation by ultrasound scan and contrast-enhanced computed tomography revealed numerous cystic lesions of the liver, suspicious of von Meyenburg complex. Magnetic resonance and magnetic resonance cholangiographic images demonstrated typical features of von Meyenburg complex. Further Resovist-enhanced magnetic resonance imaging detected two hemangiomas in addition to the multiple cystic lesions. So-called Kupffer cell imaging strongly helped the detection of these hemangiomas, and a combination of various magnetic resonance pulse sequences was of great value for the differential diagnosis of cystic lesions and hemangiomas. In cases in whom conventional imaging studies fail to give a definite diagnosis, such as in the present case, superparamagnetic iron oxide-enhanced magnetic resonance imaging is meaningful for adequate preoperative staging.

Targeted deletion of class A macrophage scavenger receptor increases the risk of cardiac rupture after experimental myocardial infarction.

BACKGROUND: Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A-deficient (SR-A(-/-)) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction. METHODS AND RESULTS: Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A(-/-) and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A(-/-) mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A(-/-) mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A(-/-) mice compared with WT mice. Real-time reverse transcription-polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A(-/-) mice compared with WT mice. Furthermore, SR-A(-/-) mice showed augmented expression of tumor necrosis factor-alpha and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor-alpha and decreased interleukin-10 expression in activated SR-A(-/-) macrophages. CONCLUSIONS: The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor-alpha and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.

Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta.

The aim of the present study was to assess the contribution of polymorphisms in the breast cancer resistance protein/ATP-binding cassette transporter G2 (BCRP/ABCG2) gene to the placental expression from a new perspective, allelic imbalance. Polymorphisms were screened by polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis followed by sequencing with DNA extracted from 100 placentas. To examine whether polymorphisms of the BCRP gene correlate with the placental BCRP expression, we determined mRNA and protein levels by quantitative real-time PCR and Western blotting, respectively. In placentas, G34A (Val(12)Met) and C421A (Gln(141)Lys) were frequently observed (18-36%), but C376T, which creates a stop codon (Gln(126) stop codon), was found with an allelic frequency of 1%. The mean of the BCRP protein level was significantly lower (p < 0.05) in homozygotes for the A421 allele than in those for the C421 allele, and heterozygotes had an intermediate value. To evaluate whether the C421A polymorphism acts as a cis-element in BCRP transcription, allelic imbalance was determined using informative lymphoblasts and 56 samples of placental cDNA. In most of the placental samples we tested, the difference in expression levels between the two alleles was small, and only two samples indicated a monoallelic expression (i.e., preferential expression of one allele). These results suggest that 1) the predominant allelic expression pattern of BCRP in placental samples is biallelic, and 2) the mutation C421A is not a genetic variant acting in cis, but is considered to influence the translation efficiency.

[Patient assessment for zanamivir therapy (second report) -- a survey of patients with influenza who were prescribed zanamivir during the 2001/2002 season in Japan].

Patients diagnosed as influenza who were prescribed zanamivir were surveyed from December 2001 to April 2002 in Japan as the same 2000/2001 influenza season. A total of 751 survey questionnaires were returned. We analyzed the efficacy of zanamivir against 367 patients who were diagnosed as influenza by rapid diagnosed kit and took zanamivir within 48 hours after onset of symptoms. Following the first zanamivir treatment, symptom relief was reported by 24.0% of the patients within 12 hours, 52.6% within 24 hours and 79.6% within 48 hours. The patients reported that the severest influenza symptom was fever, 28.4% of the patients started to feel reduction of fever within 12 hours, 62.2% within 24 hours. All of the 751 patients, 98.8% reported that the Diskhaler could be used as instructed by the doctor or pharmacist and 91.3% found the device easy or very easy to use. These results showed that the effect of zanamivir started very fast and the diskhaer was well accepted. This was the same as the previous results.