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Introduction Alglucosidase alfa received marketing approval for the treatment of Pompe disease in Japan in 2007. We conducted a post-marketing surveillance study to monitor the long-term safety and efficacy of alglucosidase alfa therapy among Japanese patients with Pompe disease. Methods The safety and efficacy outcomes were collected as real-world data for up to 9 years following the initiation of treatment with alglucosidase alfa, without any intervention to treatment strategies. The safety of the drug was assessed in 73 patients in terms of the rate of drug-related adverse events, infusion-associated reactions, and antibody titers. The efficacy was evaluated in 72 patients on the basis of subjective evaluation of their general condition after treatment, pulmonary function, 6-min walk test, and survival rate. Results Drug-related adverse events were observed in 29 of 73 (39.7%) cases, and the cumulative adverse event rate during the 9 years of the study was 45.7%. Immunoglobulin G antibodies against alglucosidase alfa were positive in 59 of 61 cases in which the titers were not correlated with drug-related adverse events or infusion-associated reactions. After the final dosing, the treating physicians determined that the disease was at least stabilized in 62 of 72 cases (86.1%), while the results of the physical function tests suggested that disease progression was actually not stopped completely. Survival of infantile-onset cases was sustained for 9 years. Conclusion The drug was generally well tolerated, and treatment with alglucosidase alfa was able to suppress disease progression in the majority of Japanese patients with Pompe disease included in this study. Funding Sanofi Electronic supplementary material The online version of this article (10.1007/s40120-019-00157-4) contains supplementary material, which is available to authorized users.

Enzyme replacement therapy in Fabry disease has been available in Japan since 2004. Two post-authorization safety studies were conducted to evaluate agalsidase beta in Japanese patients with Fabry disease in real-world practice. The Special Drug Use Investigation monitored the long-term safety and efficacy of agalsidase beta, and the Drug Use Investigation monitored safety in patients not participating in the Special Drug Use Investigation. Safety and efficacy evaluations included adverse drug reactions (ADRs), infusion-associated reactions and hypersensitivity reactions, and change in blood GL-3 level over time. Of 396 patients in the aggregated data set, safety and efficacy analysis sets comprised 307 and 196 patients, respectively. ADRs occurred in 93 (30.3%) patients and serious ADRs occurred in 25 (8.1%) patients, with general disorders and administration site conditions (n=55, 17.9%), nervous system disorders (n=30, 9.8%) and skin and subcutaneous tissue disorders (n=23, 7.5%) the most common. Reductions in blood GL-3 levels occurred over the study, irrespective of age or disease phenotype. Agalsidase beta demonstrated acceptable safety and tolerability, with sustained reductions in blood GL-3 levelsin Japanese patients with Fabry disease in real-world clinical practice NCT00233870/AGAL03004 (Special Drug Use Investigation of Agalsidase beta)

Enzyme replacement therapy with idursulfase has been shown to improve somatic signs and symptoms of mucopolysaccharidosis type II (MPS II). Idursulfase is available in Japan (since 2007), based on the outcome of clinical trials conducted in the United States, but data from Japanese patients are limited.This was a postmarketing study of Japanese MPS II patients treated with 0.5 mg/kg intravenous idursulfase weekly, conducted over a period of 8 years after initial administration. Assessments included the safety profile, survival rate, degree of clinical improvement, change in urinary uronic acid (UA) concentration, and 6-minute walk test (6MWT).The safety and efficacy analysis populations included 145 and 143 patients, respectively. The incidence of serious adverse events was 42.8% and the incidence of adverse drug reactions was 48.3%. The 7-year survival rate was 82.7%. Improvements in the clinical features of hepatosplenomegaly, skin, joint, and respiratory disorders were reported (per investigator's assessment). The mean change in urinary UA concentration was -128.39 mg/g creatinine, and that of 6MWT walking distance was +31.8 m.Long-term idursulfase treatment was well tolerated, and effective in improving clinical features, reducing urinary UA, and slowing disease progression in Japanese MPS II patients.

Our hospital was introduced in the media as the hospital at which the first patient who died of COVID-19 infection in Japan was hospitalized Patients with pneumonia associated with COVID-19 sometimes show rapid deterioration of the respiratory status, with a poor prognosis The cases encountered by us that we report here also needed intensive long-term respiratory management ARDS is an important pathological condition complicating COVID-19 pneumonia From the perspective of the continuing pathology of ARDS, we treated the patients with a steroid and sivelestat However, it became clear that the respiratory pathology in the patients could not be adequately addressed by the uniform treatment protocol for ARDS In conclusion, inpatient treatment in a local community-based small hospital without an ICU can be extremely difficult

This chapter explores and focuses on aspects to consider when companies face risk and crisis (i.e., natural disaster and many kinds of business risk), particularly how they manage risk, how they grasp the situation, and how they overcome it. Upon analyzing such companies, this research aims to understand the thinking and methods behind these concepts to make useful guidelines regarding employee satisfaction, spiritual growth, corporate life, and corporate management that ultimately fosters business resilience.

A set of experiments was performed to make a cross-language comparison of intelligibility of locally time-reversed speech, employing a total of 117 native listeners of English, German, Japanese, and Mandarin Chinese. The experiments enabled to examine whether the languages of three types of timing—stress-, syllable-, and mora-timed languages—exhibit different trends in intelligibility, depending on the duration of the segments that were temporally reversed. The results showed a strikingly similar trend across languages, especially when the time axis of segment duration was normalised with respect to the deviation of a talker’s speech rate from the average in each language. This similarity is somewhat surprising given the systematic differences in vocalic proportions characterising the languages studied which had been shown in previous research and were largely replicated with the present speech material. These findings suggest that a universal temporal window shorter than 20–40 ms plays a crucial role in perceiving locally time-reversed speech by working as a buffer in which temporal reorganisation can take place with regard to lexical and semantic processing.

Acoustic analyses of eight different languages/dialects had revealed a language universal: Three spectral factors consistently appeared in analyses of power fluctuations of spoken sentences divided by critical-band filters into narrow frequency bands. Examining linguistic implications of these factors seems important to understand how speech sounds carry linguistic information. Here we show the three general categories of the English phonemes, i.e., vowels, sonorant consonants, and obstruents, to be discriminable in the Cartesian space constructed by these factors: A factor related to frequency components above 3,300 Hz was associated only with obstruents (e.g., /k/ or /z/), and another factor related to frequency components around 1,100 Hz only with vowels (e.g., /a/ or /i/) and sonorant consonants (e.g., /w/, /r/, or /m/). The latter factor highly correlated with the hypothetical concept of sonority or aperture in phonology. These factors turned out to connect the linguistic and acoustic aspects of speech sounds systematically.

The second of two consecutively presented sounds may be perceived as being longer than if that sound had been presented in isolation. We performed five experiments using heterophonic patterns in which a sine tone was preceded by a frequency-band noise. We observed significant overestimations of sine-tone duration, the size of which depended on intensity and frequency differences between the band noise and the sine tone (Experiments 1 and 2). Band noises that were considerably shorter than the sine tone still caused significant overestimations (Experiment 3). A short silent gap between the band noise and the sine tone strongly reduced the amount of overestimation (Experiment 4). Both frozen and nonfrozen band noises yielded overestimations (Experiment 5). Our explanation for the overestimation is that the onset of the sine tone is blurred by the band noise and that such a blurred onset is restored at the level of perceptual organization following rules of a simple auditory grammar. This restoration takes mental processing time, which adds to the perceived duration of the sine tone. We call this illusion time stretching and discuss the notion that subsequent temporal assimilation and/or contrast effects can dilate or compress the amount of stretching.

Time relation among clothing pressure developed at waistband, respiratory movement, and girth of abdomen were investigated. The time constants of 3 sensors to monitor these waves in this measuring system were examined, and were 0.016s, 268.9ms, and 57.0ms corresponded to that order. Therefore, this measuring system for the clothing pressure could sufficiently follow the changes of waistband-pressure which might be caused by either respiratory movements or changes in posture, and the most suitable method to measure the clothing pressure. Subjects were 10 women aged from 20 to 22 years old, and 3 waves measured under 3 conditions : non waistband, wearing waistband with a perfect fitting length and a tight fitting length in free respiration. These waves analyzed by Fourier transform to examine these constitutional frequencies which were 3.85 +/- 0.99s, 3.85 +/- 0.92s, 3.72 +/- 0.85s and nearly equal. By the way, the time lags of peak in girth of abdomen and in respiratory movement were calculated from their cross spectra, the time became significantly late. So, the timing of air flowed into the body became significantly late, because of worn waistband. We distinguish whether the body region influenced by respiratory movement, and have to investigate a permissible limit of the pressure including a change of a respiratory function in the future., Article, SEN-I GAKKAISHI. 66(1):26-33 (2010)

Bradycardia is a trigger of ventricular arrhythmias in patients with arrhythmia including Brugada syndrome and long QT syndrome. The HCN4 channel controls the heart rate, and its mutations predispose to inherited sick sinus syndrome and long QT syndrome associated with bradycardia. We found a 4 base-insertion at the splice donor site of the HCN4 gene in a patient with idiopathic ventricular tachycardia, which was supposed to generate a truncated channel. To investigate the role of the HCN4 channel in ventricular arrhythmia, we introduced a ventricular action potential of I(f) channel produced by HCN4 in a computer simulation model and found that the I(f) channel generated a leaky outward current during the plateau phase of ventricular action potential. Currents through the I(f) channel were suggested to contribute to the shortening of the action potential duration and the prevention of early after-depolarization in bradycardia. These observations suggested that the HCN4 channel played a preventive role in triggering bradycardia-induced ventricular arrhythmias.

To compare the clinical features of aortic stiffness and its contributors between hemodialysis (HD) patients with and those without diabetes, we performed a cross-sectional study of stably treated HD patients (n = 242). Aortic stiffness was assessed by measuring carotid-femoral pulse wave velocity (cfPWV). Annual laboratory data, comorbid conditions, and contributors to cfPWV were compared between HD patients with and those without diabetes. Of the 242 patients, 94 had diabetes. The comparison showed that patients with diabetes had a shorter duration of HD; higher systolic blood pressure (SBP), cfPWV, and rate of macrovascular complications; and lower ankle-brachial blood pressure index and concentrations of serum albumin and calcium. Stepwise multiple regression analysis identified age, duration of HD, SBP, heart rate (HR), and HbA1c as independent determinants of cfPWV in nondiabetic HD patients, while only SBP, HbA1c, and duration of diabetes were independent contributors of cfPWV in HD patients with diabetes. Our results indicate that glucose metabolism plays an important role in the promotion of aortic stiffness in both diabetic and nondiabetic HD patients. In particular, hyperglycemia's effect on aortic compliance in HD patients with diabetes is so strong that it negates the effects of the uremic milieu and aging. Follow-up studies are needed to ascertain whether or not strict diabetes management could improve aortic compliance.

Background— Autopsy-negative sudden unexplained death, including sudden infant death syndrome, can be caused by cardiac channelopathies such as Brugada syndrome (BrS). Type 1 BrS, caused by mutations in the SCN5A -encoded sodium channel, accounts for ≈20% of BrS. Recently, a novel mutation in the glycerol-3-phosphate dehydrogenase 1–like gene ( GPD1-L ) disrupted trafficking of SCN5A in a multigenerational family with BrS. We hypothesized that mutations in GPD1-L may be responsible for some cases of sudden unexplained death/sudden infant death syndrome. Methods and Results— Using denaturing high-performance liquid chromatography and direct DNA sequencing, we performed comprehensive open-reading frame/splice site mutational analysis of GPD1-L on genomic DNA extracted from necropsy tissue of 83 unrelated cases of sudden unexplained death (26 females, 57 males; average age, 14.6±10.7 years; range, 1 month to 48 years). A putative, sudden unexplained death–associated GPD1-L missense mutation, E83K, was discovered in a 3-month-old white boy. Further mutational analysis was then performed on genomic DNA derived from a population-based cohort of 221 anonymous cases of sudden infant death syndrome (84 females, 137 males; average age, 3±2 months; range, 3 days to 12 months), revealing 2 additional mutations, I124V and R273C, in a 5-week-old white girl and a 1-month-old white boy, respectively. All mutations occurred in highly conserved residues and were absent in 600 reference alleles. Compared with wild-type GPD1-L, GPD1-L mutations coexpressed with SCN5A in heterologous HEK cells produced a significantly reduced sodium current ( P P Conclusions— The present study is the first to report mutations in GPD1-L as a pathogenic cause for a small subset of sudden infant death syndrome via a secondary loss-of-function mechanism whereby perturbations in GPD1-L precipitate a marked decrease in the peak sodium current and a potentially lethal BrS-like proarrhythmic substrate.

Aortic pulse wave velocity (Ao-PWV) and ankle-brachial blood pressure index (ABPI) are significant prognostic factors in patients with end-stage renal disease (ESRD). Diabetes mellitus (DM) promotes changes in arterial walls, including marked increases in Ao-PWV and decreases in ABPI. To determine the prevalence of peripheral arterial occlusive disease (PAOD) as well as the clinical variables useful in predicting these changes in nondiabetic patients with ESRD undergoing hemodialysis (HD), we performed a cross-sectional study in a cohort of 143 patients. Ao-PWV and ABPI were measured simultaneously and compared with several annual biochemical measurements and other clinical variables. The prevalence of PAOD in our cohort was 30.5%. In univariate regression analysis, Ao-PWV correlated positively with age, heart rate (HR), blood pressure (BP), pulse pressure (PP) and HbA1c, and negatively with serum albumin and ABPI. ABPI correlated negatively with age, HD duration, systolic BP, PP, low-density lipoprotein (LDL) cholesterol and hypersensitive C-reactive protein (hs-CRP), and positively with serum albumin and bone mineral density. In a step-down multiple regression analysis, HbA1c was identified as an independent determinant of Ao-PWV along with age, HD duration, HR and mean BP, while hs-CRP was an independent contributor to ABPI along with age, HD duration, PP and LDL cholesterol. Our results suggest that HD promotes aortic wall stiffness and PAOD progression. We recommend the monitoring of HbA1c to allow the prediction of aortic wall stiffness in nondiabetic ESRD patients. Our results did not confirm the influence of insulin resistance on the development of arterial sclerosis lesions.

Fitz-Hugh-Curtis症候群は,性感染症を原因とする肝周囲炎である.クラミジア・トラコマティス感染症による本症候群の3例を報告する.年齢は25～36歳の女性で,いずれも右上腹部痛を主訴に来院した.全例ともに血清クラミジアIgA, IgG抗体が上昇していた.腹部超音波検査では, 2症例で肝右葉表面に腹水と思われる低エコー域を認めたが, Morison窩には認めなかった.また,超音波プローブで肝表面を圧迫すると全例に圧痛が増強した.腹部CT検査では,全例に肝右葉表面に腹水が確認されたが,やはりMorison窩には認めなかった.さらに,造影CT検査を施行した1例では,肝被膜の濃染像を認めた.以上の所見は,クラミジア肝周囲炎を診断する上で重要な所見と考えられた.なお,全例ともに抗生剤により軽快した.最近,クラミジア感染症は増加傾向にあり,若い女性の右上腹部痛の診断には,本症候群を念頭に置くことが重要と考えられる.

Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.

We investigated the temperature-dependent Hall resistance and magnetization of the semiconductor/ferromagnetic hybrid structure of GaAs:MnAs granular films under dark and laser irradiated conditions. Under the laser irradiation with the energy above the band gap energy of GaAs, negative large Hall resistance due to the anomalous Hall effect was observed below the blocking temperature T b of the MnAs clusters. The intrinsic photo-induced magnetization of the MnAs clusters was, however, hardly observed. These results indicate that the blocking phenomena correlate with the photo-induced anomalous Hall resistance of the GaAs:MnAs granular films. Therefore, the magnetic interaction between the photo-induced carriers and the blocked magnetization of the MnAs clusters plays an important role in the photo-induced phenomena in the GaAs:MnAs granular films.

The objectives of the study were to clarify the relationship between blood pressure and mortality from stroke, heart disease, cardiovascular diseases and all causes of death among representative population of Japanese and to estimate category-specific excess mortality from stroke due to blood pressure (BP) level. The study design comprised a retrospective cohort study using the 1980 National Survey on Cardiovascular Diseases and identification of underlying causes of death using national vital statistics data. In 1994, a 14-year follow-up cohort study was conducted among participants of the National Survey on Cardiovascular Diseases in 1980, randomly selected from the Japanese population. With a collaboration of 300 public health centres, which had conducted the original survey in 1980, 91.4% of the participants of the original survey could be followed up. Total observed person-years were 53948 for men and 70932 for women. During follow-up, 1327 deaths were observed. BP levels were significantly related to mortality from strokes, cardiovascular diseases and all causes of death for both sexes (P

The purpose of this paper is to present the concept and design of Technical Listening Training, a systematic education program designed to allow prospective acoustic engineers and sound designers to enhance their auditory sensitivity. Sound professionals should have the ability to express auditory differences using appropriate technical terms for the physical properties of sounds. Furthermore, they should be able to imagine the sounds when given the acoustic properties of the sounds. Training starts with a discrimination task for pitch, loudness, and timbre in order to increase sensitivity to auditory differences. This is followed by instruction on sound property identification to improve students’ ability to correlate auditory impressions with the physical properties of the sound, thereby allowing them to imagine the sound. Through Technical Listening Training, students improve their sound sensitivity and understanding of the relationship between acoustic properties and auditory impression.

There have been many studies investigating the association between gene polymorphisms and coronary artery disease (CAD) including myocardial infarction (MI), and some studies have shown that certain gene polymorphisms are associated with CAD/MI. However, the results of the association have sometimes been controversial. The reason may be that the contribution of genetic risk factors to CAD/MI varies depending on the ethnic, environmental, and habitual backgrounds, and differs between males and females. In this study, we analyzed 17 polymorphisms in 12 candidate genes for MI in 136 patients and 200 to 235 controls, and found that there is a significant association of MI with the polymorphisms in the genes for E-selectin and CD14 receptor. To further explore the association, we investigated the C-260 T polymorphism in the promoter region of the CD14 gene in 502 MI patients and 527 control subjects. The genotype distributions of the CD14 polymorphism were as follows: patients; T/T 32.5%, C/T 48.2%, C/C 19.3%, and controls; T/T 25.4%, C/T 52.8%, C/C 21.8%. The frequencies of the T/T homozygotes were significantly higher in the patients (OR = 1.41, P = 0.013) than in the control group, confirming the association of CD14 polymorphism with MI in Japanese. Stratification analyses further demonstrated that the association was more prominent in females and in patients with a relatively low body mass index, suggesting that the contribution of the CD14-linked genetic risk to MI differs with respect to gender and habitual background.

Mutations in the human cardiac Na+ channel α subunit gene (SCN5A) are responsible for Brugada syndrome, an idiopathic ventricular fibrillation (IVF) subgroup characterized by right bundle branch block and ST elevation on an electrocardiogram (ECG). However, the molecular basis of IVF in subgroups lacking these ECG findings has not been elucidated. We performed genetic screenings of Japanese IVF patients and found a novel SCN5A missense mutation (S1710L) in one symptomatic IVF patient that did not exhibit the typical Brugada ECG. Heterologously expressed S1710L channels showed marked acceleration in the current decay together with a large hyperpolarizing shift of steady-state inactivation and depolarizing shift of activation. These findings suggest that SCN5A is one of the responsible genes for IVF patients who do not show typical ECG manifestations of the Brugada syndrome.

We report a case of pseudomembranous colitis that developed in a patient with liver cirrhosis during anti-tuberculosis therapy with rifampicin and isoniazid. The association between rifampicin and pseudomembranous colitis has been controversial; this report, however, supports the association. Colonoscopy performed 3 days after the onset of the pseudomembranous colitis revealed only reddish patches and a few aphthoid lesions, but 4 days later pseudomembranes were apparent. The pseudomembranous colitis was successfully controlled by discontinuation of the anti-tuberculosis agents, along with the administration of lactic acid bacteria, without vancomycin or metronidazole. Possible predisposing factors for the development of pseudomembranous colitis in this patient are also discussed.

Using a sample of 561 Japanese manufacturing firms, we test whether or not their Keiretsu affiliation characteristics affect their import behavior. After controlling for the effects of other economic determinants of imports, we find that Keiretsu firms import as much as non-Keiretsu firms do. Thus, we do not find evidence to support the claim that Keiretsu relationships are an important non-tariff barrier to imports at the firm level.

The purpose of this study is to observe the disease-disability association through a cross-sectional study. Between 1994 and 1995, we conducted a questionnaire survey in 5 towns in Japan. Among the items included in the questionnaire, 5 related to ADL (bathing, feeding, dressing/undressing, toileting, and going out socially) were treated as purpose variables; and 5 related to the history of medical treatment received over the past year (diabetes, heart disease, cerebrovascular disease, neuralgia, and bone fractures) were used as explanatory variables. Multiple logistic models were applied to observe the relationship. The history of medical treatment for cerebrovascular disease greatly and unavoidably affects disability related to ADL. Bone fractures, diabetes, and heart diseases contributed to specific ADL disabilities.

In order to investigate the effect of body mass index (BMI, kg/m2) on life expectancy, 2053 Hisayama residents, aged 40 years or older were studied for 13 years from 1974. During the follow-up period, 419 subjects died; of these, 39 deaths due to accident or suicide were excluded from further analysis. On initial examination, male subjects with BMI > or = 27 had significantly higher age-adjusted prevalence rates of hypertension, glucose intolerance, hypercholesterolemia, electrocardiogram abnormalities and proteinuria, as compared with those with 23-25 BMI. In contrast, the frequency of male smokers was inversely associated with BMI levels. Female prevalence rates of glucose intolerance, hypercholesterolemia and proteinuria were significantly higher in 25-27 BMI than in 23-25. Body Mass Index showed a U-shaped relationship with all cause mortality rates with the lowest rate in 23-27 BMI for men and in 23-25 BMI for women. These associations remained substantially unchanged, even after controlling for age, systolic blood pressure, glucose intolerance, serum cholesterol, proteinuria, electrocardiogram abnormalities, alcohol consumption, and smoking habits. When analyzing the BMI mortality relationship by cause of death, age- and sex-adjusted mortality rates from myocardial infarction and stroke significantly increased in subjects with BMI > or = 27 compared with those with 23-25 BMI. In contrast, there was a decreasing risk of death from malignant neoplasms with rising BMI levels, but the relationship was not significant. Mortality from pneumonia and other causes showed a U-shaped relationship with significantly higher rates seen in BMI < 19 than in 23-25 BMI. These data indicate that BMI has a U-shaped relationship with total mortality in the general Japanese population, which results from various associations between BMI and cause-specific mortality rates.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an autosomal dominant inherited disorder characterized by adrenergic induced polymorphic ventricular tachycardias and associated with sudden cardiac death. The human cardiac ryanodine receptor gene (RyR2) was linked to CPVT. A 20-year-old male was referred to our hospital because of recurrent syncope after physical and emotional stress. Routine cardiac examinations including catheterization revealed no structural abnormality. Exercise on treadmill induced premature ventricular contraction in bigeminy and bidirectional ventricular tachycardia was induced during isoproterenol infusion. β-Blocking drug was effective in suppressing the arrhythmias. We performed genetic screening by PCR–SSCP method followed by DNA sequencing, and a novel missense mutation R2401H in RyR2 located in FKBP12.6 binding region was identified. This mutation was not detected in 190 healthy controls. Since FKBP12.6 plays a critical role in Ca channel gating, the R2401H mutation can be expected to alter Ca-induced Ca release and E–C coupling resulting in CPVT. This is the first report of RyR2 mutation in CPVT patient from Asia including Japan.

A 75-year-old woman was admitted to our hospital because of proteinuria, pitting edema on the foot, and renal impairment. She had undergone total hip replacement (THR) for femoral neck fracture at the age of 66. Nine years later, she met with an accident during farming and was treated at an emergency hospital for severe general trauma. On the basis of systemic symptoms, she was diagnosed with nephrotic syndrome. Renal biopsy by Congo-red staining and electron microscopy revealed amyloid deposition on glomeruli, interstitium, and interlobar arteries. The amyloid was immunohistochemically identified as AA amyloidosis. The patient eventually required maintenance hemodialysis because of impaired renal function. AA amyloidosis is an unusual complication of intractable inflammation. Chronic infection with abscess occurred around the artificial hip joint following THR and possibly induced secondary amyloidosis. THR is a common and necessary procedure adopted for femoral neck fracture. Orthopedic surgeons should, however, carefully monitor the occurrence of chronic infection after THR because such an infection could lead to renal dysfunction and/or failure via AA amyloidosis in rare cases.

This paper analyzes the performance of the Reconstruction Finance Bank (RFB) in order to shed light on the role of development banks in fostering economic growth. The RFB played a large role in Japan′s transition from war-time command economy to a market economy in the early post-war period. We use individual firm level data on sales, profits, and loans from the RFB, and find that, initially, the RFB was making loans to firms with below-average performance. We then find that this was partly a result of political interventions into the loan policy of the RFB. In fact, we also find evidence of improvements in the performance of the RFB after its loan policy became more independent. Implications for developing economies are also discussed. J. Japan. Int. Econ ., Dec. 1995, 9 (4), pp. 486-504. Faculty of Economics, The University of Tokyo, Bunkyo-ku, Tokyo 13, Japan.

Background and Purpose The purpose of this study was to assess the prevalence and characteristics of silent cerebral infarction in a population-based consecutive autopsy series of residents of Hisayama, Kyushu, Japan. Methods Autopsy records, cerebral pathological findings, and clinical charts of 966 Hisayama residents recorded during the 26 years from 1961 to 1987 were examined (autopsy rate, 82.4%). The subjects were divided into three groups: those with both clinically apparent strokes and pathologically verified cerebral infarcts (stroke group), those having pathological evidence of cerebral infarction in the brain but without clinical stroke episodes (silent infarction group), and those with neither infarction nor stroke episode (noninfarction group). Risk factors and brain pathology in the three groups were compared. Results Silent cerebral infarction was found in 12.9% of the 966 subjects who had undergone autopsy, and its frequency increased with age. The subjects with silent infarcts were older, had higher systolic or diastolic blood pressure, and had atrial fibrillation more frequently than subjects in the noninfarction group. There were no significant differences in the locations of infarcts between the stroke and silent infarction groups, although infarcts tended to be located in the deeper area of the brain in the latter. The number and size of infarcts were smaller in the silent infarction group than in the stroke group. Conclusions Diastolic blood pressure and atrial fibrillation appear to be strong predictors of silent cerebral infarction in the Japanese general population. Stroke becomes clinically apparent as infarct volume increases.

近年, 小腸虚血・再灌流障害の発生因子として, 活性酸素が注目されている.著者らは, 血小板活性化因子 (PAF), ロイコトリエン (LTB4-C4) などのchemical mediatorも重要な因子と考え報告してきた.これらは再灌流後に活性酸素とともに粘膜障害を引き起こすが, 虚血中にも出現し何らかの障害を誘発すると考えている.そこで小腸虚血・再灌流犬を作製し, 内視鏡を用い虚血中より粘膜を経時的に観察するとともに, PAF, LTB4・C4を測定し検討した.小腸虚血中にPAFが組織中に増量し, 再灌流後門脈血中にPAF, LTB4・C4が出現した.内視鏡的観察では, 小腸虚血・再灌流障害は虚血とともにその準備状態が始まり, 再灌流によりさらに顕著なものとなった.一方, 高濃度酸素投与下虚血・再灌流では虚血中PAFの増量はなく粘膜障害も軽度であった.小腸虚血・再灌流の全経過を通じPAFの果たす役割は重要であることを強調したい.

To elucidate the risk factors for initiating glucose intolerance, the relevant factors were explored in a cross-sectional survey conducted in a sample population aged 40–79 years old selected from a Japanese community, Hisayama, Japan in 1988. A 75-g oral glucose tolerance test was used to classify 1,073 men (72.5% of the entire population in the same age range) and 1,407 women (80.5%) into normal, impaired glucose tolerance and diabetes mellitus groups. In all age and sex groups with normal glucose tolerance, the sum of fasting and 2-h post-load insulin values varied widely and demonstrated significant positive correlations with triglycerides, body mass index, waist-hip ratio, systolic and diastolic blood pressure, while it negatively correlated to HDL cholesterol (p

The authors studied mortality from major causes of death and risk factors in the elderly in a long-term prospective survey conducted in a Japanese suburban community, Hisayama. In the baseline survey in 1961, we scrutinized 1658 residents of the town aged 40 years or older accounting for 92% of the total population in this age range. Of those, 591 residents (245 men and 346 women) aged 60 years or older, who were free from major cardiovascular disease, were selected for the present study. They were followed-up for 26 years from 1961 to 1987. The average age was 67 years for men and 70 years for women, being significantly higher for women than for men. During the follow-up period, 529 subjects (89.5%) died, and 448 were autopsied (autopsy rate 84.7%). The all-cause mortality (per 1,000 person-years) after adjustment for age was 89.9 for men and 56.7 for women, the former being significantly higher than the latter (p0.01). The age-adjusted mortality from cerebrovascular disease was estimated to be 21.4 for men and 9.9 for women, i.e. 8.9 and 8.8 from heart disease, and 19.9 and 10.6 from neoplasm, and 18.1 and 12.2 from-pneumonia, respectively. There was significant sex difference in mortality from cerebrovascular disease, neoplasm and pneumonia (p0.01) but not from heart disease (p0.1). Multiple Cox's proportional hazards regression analysis showed systolic blood pressure and male sex to be significant risk factors for death by cerebrovascular disease. Systolic blood pressure was also a predictor for death by heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

We reviewed the characteristics of stroke epidemiology in Japan mainly based on the 30-year experience of the Hisayama study which is a prospective and autopsy-based population survey conducted since 1961 in a Japanese subrural area. The most frequent type of cerebral stroke was cerebral infarction, sequentially followed by intracerebral hemorrhage and subarachnoid hemorrhage for men, while subarachnoid hemorrhage was more frequent than intracerebral hemorrhage for women. Among subtypes of cerebral infarction, lacunar infarction was a major type for the Hisayama residents. Hypertension was the most powerful risk factor for both intracerebral hemorrhage and cerebral infarction, and diabetes mellitus contributed to the occurrence of cerebral infarction through conferring an excess risk of hypertension to the ictus. Hypertension and diabetes could play an important role as an accerelating factor for brain small arteriolar lesions. The incidence of both intracerebral hemorrhage and cerebral infarction decreased in the recent Hisayama residents, and this could be related to the decreased prevalence of hypertension. However, the type of cerebral stroke will change into that more related to atherosclerosis in the future, since the prevalence of metabolic disorders such as hypercholesterolemia, obesity or glucose intolerance has much more increased among the recent Hisayama population. (Hypertens Res 1994; 17 Suppl. I: S11-S21)

Hyperinsulinemia has been closely associated with hypertension in several epidemiological studies, but little is known about this condition in the elderly. The authors studied the relationship between serum insulin and blood pressure levels, and the prevalence of hypertension according to insulin levels in the elderly in a Japanese rural community, Hisayama. In 1988, 75 g oral glucose tolerance test was performed on 426 male and 567 female Hisayama residents aged 60 to 79 years. Fasting and 2 hr serum insulin values were measured by radioimmunoassay. In the subjects, excluding those receiving antihypertensive drugs, the sum of fasting and 2 hr postload insulin (sigma IRI) significantly correlated with systolic (r = 0.15 and 0.25 for males and females, respectively) and diastolic blood pressure (r = 0.20, 0.16). In multiple regression analyses, the correlation with systolic blood pressure remained significant in females after controlling for age, body mass index, alcohol intake, smoking habits, serum total cholesterol, HDL-cholesterol, triglycerides, and fasting plasma glucose. In contrast, sigma IRI did not remain as an independent variable relevant to blood pressure among males. The age-adjusted prevalence rates of hypertension (> or = 160/95 mmHg or receiving drug treatment) significantly increased with increasing quartiles of sigma IRI in females. The prevalence of hypertension which was not treated with drugs also increased significantly with increasing sigma IRI in females. However, no significant association was observed in males. In conclusion, the present study suggests that hyperinsulinemia can be related to hypertension in the female elderly in the general population of Japan.

Increased aortic stiffness is an independent predictor of death from cardiovascular disease in patients with end-stage renal disease (ESRD). Various factors that contribute to carotid-femoral pulse wave velocity (cfPWV) as a surrogate of aortic stiffness have been identified, but determinants of long-term worsening of aortic stiffness remain to be elucidated. To clarify the factors that accelerate aortic stiffness in hemodialysis patients, 148 patients with ESRD on hemodialysis were evaluated. At baseline, cfPWV and ankle-brachial blood pressure index (ABPI) were measured and clinical status including biochemical parameters, with or without hepatitis c virus (HCV) infection, diabetes mellitus (DM), cardiovascular disease, cerebrovascular disease and peripheral arterial disease at baseline, were evaluated. The cfPWV was measured again after a 3-year follow up and the annual change in cfPWV was calculated. The cfPWV decreased in 54 patients, worsened slowly in 47 (annual change in cfPWV ranged from 0 to 0.33 ms(-1) per year), and worsened rapidly in 47 patients (annual change in cfPWV was more than 0.33 ms(-1) per year). The prevalences of DM, HCV infection and peripheral arterial disease were the highest in the rapid progression group. Univariate analysis showed that age, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio, HCV infection, ABPI and number of vasculopathies were significantly associated with annual change in cfPWV. Stepwise regression analysis identified ABPI, LDL-C/HDL-C ratio and HCV infection as independent determinants of worsening of cfPWV. Further studies are needed to investigate the mechanism of HCV-related enhancement of aortic stiffness in ESRD patients.

Incidence and risk factors for cerebral stroke and its changing pattern with time were studied in a prospective population survey which has been conducted in a Japanese rural community, Hisayama. Cerebral infarction was more frequent than intracerebral hemorrhage among Hisayama residents, however, the incidence of intracerebral hemorrhage would actually have been higher in Hisayama residents than in western populations especially in 1960's or 1970's. Incidence of both intracerebral hemorrhage and cerebral infarction decreased in the recent Hisayama population, and among the types of cerebral infarction perforating infarcts most prominently decreased. The reduced prevalence of hypertension and successful management of hypertension were considered to contribute to the reduction in cerebral stroke. It is expected, however, that characteristics or patterns of cerebral stroke would change in the future with increasing prevalence of atherogenic factors among the.Japanese population.

We investigated seasonal variation in the incidence of cerebral stroke among the general population aged greater than or equal to 40 years in November of 1961 in Hisayama, Japan. During the 24-year follow-up period, 311 cases of cerebrovascular diseases occurred. The date or month of onset was determined in 308 cases, of which 51 were classified as intracerebral hemorrhage, 223 as cerebral infarction, and 27 as subarachnoid hemorrhage. We observed a significant seasonality in the incidence of all stroke (p less than 0.01), of intracerebral hemorrhage (p less than 0.05), and of cerebral infarction (p less than 0.01), whereas subarachnoid hemorrhage had no significant seasonal pattern. Subjects less than 64 years of age showed a significant seasonal variation in the incidence of both intracerebral hemorrhage (p less than 0.05) and cerebral infarction (p less than 0.01). A significant seasonal pattern for the incidence of intracerebral hemorrhage was also noted among persons with hypertension (p less than 0.05) or a high serum cholesterol level (p less than 0.05), whereas such a pattern for cerebral infarction was documented among normotensive persons (p less than 0.05) and those with a low serum cholesterol level (p less than 0.01). In addition, the incidences of intracerebral hemorrhage and cerebral infarction were negatively correlated with mean ambient temperature (p less than 0.01 and p less than 0.05, respectively), and all stroke and intracerebral hemorrhage in men were significantly related to intradiurnal temperature change (p less than 0.05 and p less than 0.01, respectively). The significance of the seasonal occurrence of stroke is discussed in relation to relevant risk factors.

A mass screening for prostatic cancer was conducted in Hisayama town, Fukuoka Prefecture, Japan from 1988 to 1989. As the primary screening questionnaire survey about urination and measurement of serum prostate specific antigen (PSA) were performed in 789 of the 1025 male residents over 50 years old (77.0%). For the second screening with digital rectal examination and transrectal ultrasonography, 184 subjects (23.3%) were picked up. Prostatic cancer was suspected in 33 (4.2%) of the 134 subjects who actually underwent the second screening examination. Prostatic biopsy and other examinations such as measurement of prostatic acid phosphatase and gamma-seminoprotein, urinalysis and radiographic examination were performed in 26 as the third screening, and prostatic cancer was detected in 5 (0.63%); 3 in stage B and 2 in stage C. Four of the 5 subjects with prostatic cancer had complained no urinary symptoms on questionnaire. Serum PSA was useful for detecting early stage prostatic cancer.

Background— Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming α-subunit associated with 1 or more auxiliary β-subunits. Four different β-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. Methods and Results— We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na vβ -subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A -encoded sodium channel α-subunit (hNa V 1.5). Compared with the wild-type, L179F-β4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-β4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. Conclusions— We provide the seminal report of SCN4B -encoded Na vβ 4 as a novel LQT3-susceptibility gene.

In Japan, cohort studies on stroke have been mainly conducted in rural areas, with few studies comparing stroke mortality between urban and rural areas. We aimed to explore urban-rural difference in stroke mortality throughout Japan using a representative sample of the general Japanese population, the NIPPON DATA80. This study included 9309 subjects (4080 men and 5229 women) aged 30 years or older who were residents of 294 areas in 211 municipalities of Japan in 1980 and followed-up until 1999. Population size of the municipality in which the aforementioned areas were located was used to distinguish between urban and rural areas, because municipalities in Japan are classified as village, town or city principally by population size. We applied a multilevel logistic regression model to take into account the hierarchical data structure of individuals (subjects) (level 1) nested within areas (level 2), and then calculated odds ratios and 95% confidence intervals (CIs) of deaths from total stroke. Statistically significant variance between areas was not observed in men but was in women. Age-adjusted odds ratios of the areas in the medium (populationor = 30,000 and300,000) and small municipalities (30,000) compared with the areas in the large municipalities (or = 300,000) were 1.31 and 1.40 in men, and 1.32 and 1.62 in women, respectively. Multivariate-adjusted odds ratios (adjusted for age, body mass index, total cholesterol, diabetes, hypertension, current smoking, and daily alcohol consumption) of the areas in the medium and small municipalities compared with the areas in the large municipalities were 1.29 and 1.36 in men, and 1.34 and 1.68 in women, respectively. In conclusion, stroke mortality tended to be higher in rural areas than in urban areas in Japan, especially among women.

This paper provides an empirical investigation of monetary policy in Japan in the zero interest rate environment that has held sway since 1999. In particular, we focus on the effects of the zero interest rate commitment and of quantitative monetary easing on medium- to long-term interest rates in Japan. In the study we apply a version of the macro-finance approach, involving a combination of estimation of a structural macro-model and calibration of time-variant parameters to the yield curve observed in the market. This enables us to decompose interest rates into expectations and risk premium components and simultaneously to extract the market's perception of the Bank of Japan's (BOJ's) willingness to carry on its zero interest rate policy. In the analysis we make clear the counterfactual policy that would have been practiced in the absence of the actual policies followed by the BOJ since 1999. From this analysis, we tentatively conclude that the BOJ's monetary policy since 1999 has functioned mainly through the zero interest rate commitment, which has led to declines in medium- to long-term interest rates. We also find some evidence that, up until the end of 2003, raising the reserve target may have been perceived as a signal indicating the BOJ's accommodative policy stance although the size of the effect is not large. The portfolio rebalancing effect -- either by the BOJ's supplying ample liquidity or by its purchases of long-term government bonds -- has not been found to be significant.