Search

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

Summary Background & aims The associations between dietary magnesium intake and stroke and coronary heart disease (CHD) incidences are inconsistent and not established in Asian. We aimed to determine the association between dietary magnesium intake and the risk of stroke and CHD in a Japanese population. Subjects/Methods We studied 85,293 Japanese subjects by questionnaire at baseline (age 45–74 years, without cardiovascular disease or cancer in 1995 and 1998 for Cohorts I and II, respectively). The participants were followed until the end of 2009 and 2010 in Cohorts I and II, respectively. Dietary magnesium intake was estimated from a self-administered 138-item food-frequency questionnaire. Results After 1,305,738 person-years of follow-up, 4110 strokes and 1283 cases of CHD were documented. The multivariable-adjusted hazard ratios (HRs, 95% confidence intervals, 95%CIs) of CHD for the fourth and fifth quintiles of dietary magnesium intake were 0.70 (0.50–0.99) and 0.66 (0.44–0.97) in men (P for trend = 0.036), respectively, and third quintile of dietary magnesium intake was 0.61 (0.39–0.96) in women (P for trend = 0.241), compared with the lowest quintile in men and women. We observed no decreased risks of incident stroke in men or women with higher dietary magnesium intakes. Conclusions Higher dietary magnesium intake was associated with a reduced risk of CHD in Japanese men.

The biological behaviour and prognostic factors of Merkel cell carcinoma (MCC) in 20 cats were studied. The tumours were surgically removed and histopathologically examined. The animals were 8 to 20 years old (median age: 14 years), and the tumours were predominantly located in the neck and head. Follow-up data were available in 17 cases, and 12 cats died within a year of surgery. The overall median survival time after resection was 243 days (range 16-360 days). Recurrence occurred in 11 cases, although 6 of them (55%) were found to be margin-negative. Possible metastasis occurred after the surgery in 10 cases, although 6 of them (60%) were found to be margin-negative. The histopathological features of MCC included tumour necrosis in 16 cases (80%), vascular invasion in 6 cases (38%) and high mitotic counts (median: 28.5 per high-power field). Irregular acanthosis was noted adjacent to the tumours in 9 cases (60%). Immunohistochemically, the tumour cells were positive for cytokeratin (CK) 20 and p63 in all cases, synaptophysin in 19 (95%) cases, and CK18 in 16 cases (80%). The study shows that feline MCC is associated with a poor prognosis and exhibited a strong tendency towards local recurrence, regional lymph node metastasis and distant spread.

A finding between dietary pattern and cancer may provide visions beyond the assessment of individual foods or nutrients. We examined the influence of dietary pattern with colorectal cancer (CRC) among a Japanese population.A total of 93,062 subjects (43,591 men, 49,471 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995-1998 to the end of 2012, during which 2482 cases of CRC (1514 men, 968 women) were newly identified. Dietary data was obtained from a validated food-frequency questionnaire between 1995 and 1998.Three dietary pattern was derived from principal components factor: prudent, westernized, and traditional pattern. After controlled for potential confounders, the prudent pattern showed a decreased association of CRC risk in men (HR for highest quintile vs lowest: 0.85; 95% CI: 0.72-1.00; P trend0.05), slightly more strongly with distal colon cancer (P trend0.05); but an increased risk of rectal cancer in women (P trend0.05). The westernized pattern showed a significant positive linear trend for colon (P trend0.05) and distal cancer (P trend0.05) in women. There was no apparent association of traditional Japanese dietary pattern on the overall or any specific sites risk of CRC.A prudent dietary pattern showed an inverse association with CRC risk in men, and a westernized pattern was related with a higher risk of colon and distal cancer in women.

Afidopyropen is an insecticide that acts as a transient receptor potential vanilloid subtype (TRPV) channel modulator in chordotonal organs of target insects and has been assessed for a wide range of toxicity endpoints including chronic toxicity and carcinogenicity in rats and mice. The current study evaluates the toxicokinetic properties of afidopyropen and its plasma metabolites in rats at dose levels where the pharmacokinetics (PK) are linear and nonlinear in an attempt to identify a point of inflection. Based on the results of this study and depending on the analysis method used, the kinetically derived maximum dose (KMD) is estimated to be between 2.5 and 12.5 mg/kg bw/d with linearity observed at doses below 2.5 mg/kg bw/d. A defined point of inflection could not be determined. These data demonstrate that consideration of PK is critical for improving the dose-selection in toxicity studies as well as to enhance human relevance of the interpretation of animal toxicity studies. The study also demonstrates the technical difficulty in obtaining a defined point of inflection from in vivo PK data.

First impressions based on practitioner appearance often form the basis for preliminary assumptions regarding trust, confidence, and competence, especially in situations where patients or family members do not have an established relationship with the physician. Given their growing prevalence, we strove to further investigate whether visible tattoos or piercings on a medical provider affects a patient’s perception of the provider’s capabilities and their trust in the care that would be provided. A survey using photographs of simulated practitioners was administered to 314 participants split between rural and urban locations. Study volunteers rated tattooed practitioners with lower confidence ratings when compared with nontattooed practitioners and reported greater degrees of discomfort with greater degrees of facial piercing. We concluded that these factors adversely affect the clinical confidence ratings of practitioners, regardless of the gender, age group, or location of participants.

Aims Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. Methods and results The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000–04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50–79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality. The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73–1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55–0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64–0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01–4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07–11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03–1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40–0.99), respectively. Conclusion An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

Introduction Low back pain and vertebral endplate abnormalities are common conditions within the population. Subclinical infection caused by indolent pathogens can potentially lead to these findings, with differentiation between them notably challenging from a clinical perspective. Progressive infection of the intervertebral disc has been extensively associated with increasing low back pain, with Propionibacterium acnes specifically implicated with in relation to sciatica. The main purpose of this study is to identify if the presence of an infective pathogen within the intervertebral disc is primary or is a result of intraoperative contamination, and whether this correlates to low back pain. Methods and analysis An open prospective cohort study will be performed. Subjects included within the study will be between the ages of 18 and 65 years and have a diagnosis of lumbar disc herniation requiring open decompression surgery. Excised herniated disc fragments, muscle and ligamentum flavum samples will be collected during surgery and sent to microbiology for tissue culture and pathogen identification. Score questionnaires for pain, functionality and quality of life will be given preoperatively and at 1, 3, 6 and 12 months postoperatively. A MRI will be performed 12 months after surgery for analysis of Modic changes and baseline comparison. The primary endpoint is the rate of disc infection in patients with symptomatic degenerative disc disease. The secondary endpoints will be performance scores, Modic incidence and volume. Ethics and dissemination This study was approved by our Institutional Review Board and was only initiated after it (CAAE 65102617.2.0000.0071). Patients agreeing to participate will sign an informed consent form before entering the study. Results will be published in a peer reviewed medical journal irrespective of study findings. If shown to be the case, this would have profound effects on the way physicians treat chronic low back pain, even impacting health costs. Trials registration number NCT0315876; Pre-results.

Background and aims Higher intake of fish or n-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of coronary heart disease (CHD). However, it is unclear whether increased blood levels of n-3 PUFAs are associated with reduced risk of CHD in the Japanese population. Methods The relationship between circulating levels of n-3 PUFAs (eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid) and risk of CHD was examined in a nested case-control study among participants in the Japan Public Health Center (JPHC)-based Study Cohort. Plasma n-3 PUFA phospholipid levels were measured at baseline by gas chromatography in 209 cases with CHD and 418 controls matched for sex, age, date of blood draw, time elapsed since last meal before blood collection, and study location. The CHD cases (n = 209) comprised 168 cases of myocardial infarction and 41 of sudden cardiac death, otherwise classified as 157 non-fatal and 52 fatal coronary events, respectively. Mean duration of follow-up was 13.5 years. Results Multivariate conditional logistic analysis showed no significant association between n-3 PUFAs and risk of total CHD. The odds ratio (OR) for the highest versus lowest quartiles of plasma n-3 PUFAs was 0.79 (95% confidence interval [95% CI]: 0.41–1.51, p for trend = 0.51). Subtype analysis of CHD revealed that the multivariate ORs for the highest versus lowest quartiles for n-3 PUFAs were 0.91 (95% CI: 0.43–1.89, p for trend = 0.90) for myocardial infarction, 0.08 (95% CI: 0.01–0.88, p for trend = 0.04) for sudden cardiac death, 0.89 (95% CI: 0.42–1.89, p for trend = 0.97) for nonfatal coronary events, and 0.12 (95% CI: 0.02–0.75, p for trend = 0.03) for fatal coronary events. Conclusions Plasma n-3 PUFA levels were not associated with risk of total CHD but were inversely associated with risks of sudden cardiac death and fatal coronary events among middle-aged Japanese individuals.

Seafood/fish intake has been regarded as a protective factor for coronary heart disease (CHD), while smoking is a strong risk factor. To examine whether associations between smoking and risk of CHD are modified by seafood/fish intake, we studied 72,012 Japanese men and women aged 45-74 years who completed 2 food frequency questionnaires, 5 years apart, during the period 1995-2009. After 878,163 person-years of follow-up, 584 incident cases of CHD (101 fatal and 483 nonfatal), including 516 myocardial infarctions, were documented. There was a clear dose-response association between smoking and CHD risk among subjects with a low seafood/fish intake (

Widespread human exposure to multifunctional acrylates is of concern, due to their inherent reactivity and irritating properties. Trimethylolpropane triacrylate (TMPTA) and pentaerythritol triacrylate (PETA) are industrially important representatives of multifunctional acrylates. The current studies characterized the toxicity of 3-month topical administration of technical grade TMPTA and PETA in F344/N rats and B6C3F1 mice, and evaluated the carcinogenic potential of TMPTA and PETA in hemizygous Tg.AC (v-Ha-ras) transgenic mice. Administration of 0.75, 1.5, 3, 6, and 12 mg/kg TMPTA and PETA for 3 months resulted in hyperplastic, degenerative, and necrotic lesions, accompanied by chronic inflammation of the skin, with severities generally increasing with dose. Lesions were slightly more severe in rats, when compared with mice, and illustrate the irritant potential of TMPTA and PETA. A similar dosage regimen was used for the 6-month study with Tg.AC mice. Topical application of TMPTA and PETA to Tg.AC mice showed dose-dependent increases in squamous cell papillomas at the site of application, with decreases in the latency of their appearance in mice receiving 3 mg/kg or greater. Papillomas, the reporter phenotype in Tg.AC mice, were accompanied by a few squamous cell carcinomas, along with hyperplastic and inflammatory lesions. Although chronic inflammation might have contributed to the development of the skin lesions, the dose-related nature of the induction of the skin papillomas in Tg.AC mice by TMPTA and PETA may reflect a potential for carcinogenicity.

Stoddard solvent IIC is widely used as a solvent in paints and varnishes, and for dry cleaning and other grease removal applications. Because concern exists regarding the long-term effects of occupational exposure in industrial settings, the toxicity and carcinogenicity of Stoddard solvent IIC were evaluated in male and female F344/N rats and B6C3F1 mice. Rats and mice were exposed to 0, 138, 275, 550, 1100, or 2200 mg/m3 Stoddard solvent IIC by whole-body inhalation for 3 mo, and to 0, 138 (male rats), 550, 1100, or 2200 (female rats and male and female mice) mg/m3 for 2 yr. The kidney, liver, and adrenal medulla were targets of Stoddard solvent IIC toxicity in rats. After 3 mo of exposure, male rats developed lesions characteristic of alpha2u-globulin nephropathy. Male and female rats displayed increased liver weights and/or clinical pathology changes suggestive of hepatic injury, although no accompanying histopathologic changes were observed. After 2 yr, increased incidences of adrenal medullary pheochromocytomas provided some evidence of carcinogenicity in male rats. Renal tubule adenomas were slightly increased in male rats after 2 yr, and may have been related to exposure. In mice, there was no chemical-related toxicity after 3 mo, with the exception of increased liver weights in male mice exposed to 2200 mg/m3. After 2 yr, the incidences of hepatocellular adenomas were increased in female mice exposed to 2200 mg/m3; however, these increases were marginal and associated with increases in body weight. There was no evidence of Stoddard solvent IIC carcinogenicity in female rats or male mice. In summary, inhalation exposures of Stoddard solvent IIC resulted in renal toxicity and adrenal medullary pheochromocytomas in male rats. The liver also appeared to be a site of toxicity in male and female rats and mice.

Studies of transplacental transfer of aflatoxin B(1) (AFB(1)) suggest that the developing human fetus may be a sensitive target for AFB(1) injury. Because AFB(1) requires metabolic activation to the reactive AFB(1)-8,9-exo-epoxide (AFBO) to exert its carcinogenic effects, ontogenic and interindividual differences in AFB(1) biotransformation enzymes may underlie susceptibility to AFB(1)-induced cell injury. The present study was initiated to compare the rates of in vitro AFB(1)-DNA and AFB(1)-protein adduct formation among a panel of 10 adult and 10 second-trimester prenatal livers and to examine the relationship among AFB(1) metabolizing enzyme expression and AFB(1) binding. Mixtures of cytosolic and microsomal proteins from prenatal and adult livers catalyzed the formation of AFB(1)-DNA and AFB(1)-protein adducts at relatively similar rates, although greater individual variability in AFB(1) adduct formation was observed in adult tissues. Extensive interindividual variation among adult tissues was observed in the expression of the AFB(1) activation enzymes cytochrome P4501A2 (CYP1A2), CYP3A4/5, and lipoxygenase (LO). Prenatal CYP3A7 expression was also highly variable. LO expression was eightfold higher in prenatal liver tissues than adults, whereas the expression of the AFBO detoxification enzyme microsomal epoxide hydrolase was twofold higher in adult liver. The levels of the polymorphic glutathione S-transferase M1 (hGSTM1-1), which may potentially protect against AFBO injury, were higher in the hGSTM1-1-expressing tissues of adults in relation to prenatal livers. In general, there was not a strong relationship among AFB(1)-DNA or AFB(1)-protein adduct formation and expression levels of individual AFB(1) metabolizing enzymes. In summary, despite the presence of marked individual and ontogenic differences in the expression of AFB(1) metabolizing enzymes, human second trimester prenatal liver tissues compared to adults do not exhibit a marked sensitivity to the in vitro formation of macromolecular AFB(1) adducts.

We examined the association between green tea consumption and mortality due to all causes, cancer, heart disease, cerebrovascular disease, respiratory disease, injuries, and other causes of death in a large-scale population-based cohort study in Japan.We studied 90,914 Japanese (aged between 40 and 69 years) recruited between 1990 and 1994. After 18.7 years of follow-up, 12,874 deaths were reported. The association between green tea consumption and risk of all causes and major causes of mortality was assessed using the Cox proportional hazards regression model with adjustment for potential confounders.Hazard ratios for all-cause mortality among men who consumed green tea compared with those who drank less than 1 cup/day were 0.96 (0.89-1.03) for 1-2 cups/day, 0.88 (0.82-0.95) for 3-4 cups/day, and 0.87 (0.81-0.94) for more than 5 cups/day (P for trend.001). Corresponding hazard ratios for women were 0.90 (0.81-1.00), 0.87 (0.79-0.96), and 0.83 (0.75-0.91; P for trend.001). Green tea was inversely associated with mortality from heart disease in both men and women and mortality from cerebrovascular disease and respiratory disease in men. No association was found between green tea and total cancer mortality.This prospective study suggests that the consumption of green tea may reduce the risk of all-cause mortality and the three leading causes of death in Japan.

Xenotransplantation with porcine islets is a promising approach to overcome the shortage of human donors. This is the first report of phase 1/2a xenotransplantation study of encapsulated neonatal porcine islets under the current framework of regulations for xenotransplantation in New Zealand.Newborn piglets were anesthetized and bled, and the pancreata were removed with the use of sterile technique and processed. Encapsulated neonatal porcine islets were implanted with the use of laparoscopy into the peritoneal cavity of 14 patients with unstable type 1 diabetes without any immunosuppressive drugs. The patients received encapsulated islets of 5,000 (n = 4; group 1), 10,000 (n = 4; group 2), 15,000 (n = 4; group 3), or 20,000 (n = 2; group 4) islet equivalents per kg body weight. Outcome was determined from adverse event reports, HbA1c, total daily insulin dose, and frequency of unaware hypoglycemic events. To assess graft function, transplant estimated function (TEF) scores were calculated. Sufficient or marginal numbers of encapsulated neonatal porcine islets were transplanted into streptozotocin-induced diabetic B6 mice as an in vivo functional assay.There were 4 serious adverse events, of which 3 were considered to be possibly related to the procedure. Tests for porcine endogenous retrovirus DNA and RNA were all negative. The numbers of unaware hypoglycemia events were reduced after transplantation in all groups. Four of 14 patients attained HbA1c 7% compared with 1 at baseline. The average TEF scores were 0.17, 0.02, -0.01, and 0.08 in groups 1, 2, 3, and 4 respectively. The in vivo study demonstrated that a sufficient number of the transplanted group reversed diabetes with positive porcine C-peptide.Transplantation of encapsulated neonatal porcine islets was safe and was followed by a reduction in unaware hypoglycemia events in unstable type 1 diabetic patients. The mouse in vivo assessment data demonstrated certain graft function.

Concurrent relationships among measures of naming speed, phonological awareness, orthographic skill, and other reading subskills were explored in a representative sample of second graders. Hierarchical regression analyses revealed that naming speed, as measured by the the rapid automatized naming (RAN) task, accounted for a sizable amount of unique variance in reading with vocabulary and phonemic awareness partialled out. The unique contribution of naming speed to reading was relatively stronger for orthographic skills, whereas the contribution of phonemic skills was stronger for nonword decoding. In further analyses, marked difficulties on a range of reading tasks, including orthographic processing, were seen in a subgroup with a double deficit (slow naming speed and low phonemic awareness) but not in groups with only a single deficit. These findings are broadly consistent with Bowers and Wolf's (1993a, 1993b; Wolf & Bowers, 1999) double-deficit hypothesis of reading disability.

Moccasin-type tinea pedis(MTTP) is a hardly curable superficial dermatomycosis primarily characterized by hyperkeratosis of the sole. In this study, we compared the usefulness of combination therapy of bifonazole (Mycospor cream) + 10% urea ointment (Urepearl) (overlapping application group = group I) with occlusive dressing therapy with the same agents (group II) in the treatment of MTTP, and obtained the following results. (1) The clinical improvement rate (percentage of "marked improvement" and "moderate improvement") was 60.4% in group I and 83.3% in group II. (2) The mycological eradication rate was 48.7% in group I and 82.1% in group II after 4 weeks of treatment and 90.9 and 96.9%, after 12 weeks of treatment, respectively. (3) The clinical utility rate (percentage of "very beneficial" and "beneficial") was 83.3% in group I and 93.8% in group II. These results indicate the superiority of both combination therapy of bifonazole + 10% urea ointment (overlapping application group) and occlusive dressing therapy with the same agents in terms of efficacy and safety for the treatment of MTTP, and suggest that they can be recommended for treatment of patients for whom it is difficult to use oral antimycotic agents or for patients who fail to respond to oral medications alone.

We have compared the auditory evoked potential index (AEPIndex) and bispectral index (BIS) for monitoring depth of anaesthesia in spontaneously breathing surgical patients. Twenty patients (aged 17-49 yr) undergoing day surgery were anaesthetized with computer-controlled infusions of propofol. The mean (SD and range) of each measurement was determined during consciousness and unconsciousness and at specific times during the perioperative period. Mean values for AEPIndex during consciousness and unconsciousness were 74.5 (SD 14.7) 36.7 (7.1), respectively. BIS had mean values of 89.5 (SD 4.6) during consciousness and 48.8 (16.4) during unconsciousness. AEPIndex and BIS were greater during consciousness compared with during unconsciousness. The average awake values of AEPIndex were significantly higher than all average values during unconsciousness but this was not the case for BIS. BIS increased gradually during emergence from anaesthesia and may therefore be able to predict recovery of consciousness at the end of anaesthesia. AEPIndex was more able to detect the transition from unconsciousness to consciousness.

In this study, in addition to studying the efficacy and safety of the once-daily administration of 100-mg capsules of fluconazole over an 8-week administration period with six patients with hyperkeratotic-type tinea pedis, we also measured the serum and horny layer concentrations of fluconazole to study the mobility into the horny layer in diseased areas of the sole skin. The final overall efficacy and overall safety were both 100% (six out of six), and no side-effects, including abnormal laboratory changes, were observed in any of the patients. The drug mobility study revealed that in the horny layer of the skin a steady state was reached after 4 weeks of administration, with the mean concentration being 12.8 micrograms g-1. This concentration was a high concentration that was no less than 13 times the geometric mean MIC (0.972 microgram ml-1) for fresh clinical isolates of Trichophyton rubrum. Based on the above results, fluconazole is considered to be highly useful for treating various kinds of dermatomycosis, including hyperkeratotic-type tinea pedis.

Changes in intracranial pressure (ICP) resulting from head-down tilt (HDT) were studied in rabbits, and a possible role of edema formation in the change of ICP was examined. Animals were anesthetized with pentobarbital sodium and artificially ventilated. ICP was continuously monitored through a catheter inserted into the subarachnoid space. It increased depending on the tilt angle and decreased when the tilt angle was reduced. ICP elevated from 4.6 +/- 0.7 mmHg (mean +/- standard error of the mean) at horizontal prone position to 13.7 +/- 1.0 mmHg immediately after the onset of 45 degrees HDT and gradually reduced toward the pre-HDT baseline in the next 8 h. ICP decreased below the pre-HDT baseline value immediately after returning to the horizontal prone position, and gradually increased toward the baseline during the 2 h of recovery period. Histological examination (HE stain) demonstrated that exposure to 8 h of HDT did not cause remarkable edema in either the gray matter or the white matter in rabbits. Water content and specific gravity of brain tissues both were increased in the HDT group in comparison with the control group. These results suggest that edema formation plays little role in the elevation of ICP during the acute phase of HDT in rabbits.

We studied the effects of hypothermia and cardiopulmonary bypass (CPB) on four depth of anaesthesia monitors; spectral edge frequency (SEF), median frequency (MF), bispectral index (BIS) and auditory evoked potential index (AEPIndex) in 12 patients during uneventful cardiac anaesthesia. Each variable was recorded simultaneously at 10 periods during anaesthesia. All four variables were not affected by the transition to CPB. During hypothermia, values of AEPIndex, MF and SEF were tightly distributed but values of BIS were very variable and overlapped with those before induction of anaesthesia. The variability decreased during rewarming. The values of AEPIndex throughout the anaesthesia never overlapped with those before induction of anaesthesia. The AEPIndex was the most stable and reliable as a depth of anaesthesia monitor among the four variables in cardiac bypass surgery.

PURPOSE: Low intraocular pressure (IOP) measured by Goldmann applanation tonometry (GAT) is one of the ocular manifestations of Steinert's myotonic dystrophy. The goal of this study was to evaluate the corneal-compensated IOP as well as corneal properties (central corneal thickness and corneal hysteresis) in patients with myotonic dystrophy. METHODS: A total of 12 eyes of 6 patients with Steinert's myotonic dystrophy (dystrophy group) and 12 eyes of 6 age-, race-, and gender-matched healthy volunteers (control group) were included in the study. GAT, Dynamic Contour Tonometry (DCT-Pascal) and Ocular Response Analyzer (ORA) were used to assess the IOP. Central corneal thickness was obtained by ultrasound pachymetry, and corneal hysteresis was analyzed using the ORA device. In light of the multiplicity of tests performed, the significance level was set at 0.01 rather than 0.05. RESULTS: The mean (standard deviation [SD]) GAT, DCT, and corneal-compensated ORA IOP in the dystrophy group were 5.4 (1.4) mmHg, 9.7 (1.5) mmHg, and 10.1 (2.6) mmHg, respectively. The mean (SD) GAT, DCT, and corneal-compensated ORA IOP in the control group was 12.6 (2.9) mmHg, 15.5 (2.7) mmHg, and 15.8 (3.4) mmHg, respectively. There were significant differences in IOP values between dystrophy and control groups obtained by GAT (mean, -7.2 mmHg; 99% confidence interval [CI], -10.5 to -3.9 mmHg; P

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Purpose: To compare the effect on intraocular pressure (IOP) of the silicone Ahmed glaucoma valve with and without an intravitreal injection of triamcinolone acetonide.Patients and Methods: Forty-nine patients with clinically uncontrolled neovascular glaucoma were included in the study; 22 were randomly assigned to the study group (silicone Ahmed glaucoma valve implant with intravitreal triamcinolone acetonide) and 27 to the control group (silicone Ahmed glaucoma valve). IOP was the primary outcome measure in this study. the secondary outcome measure was success, defined by IOP lower than 22 mm Hg and higher than 5 mm Hg, and no serious complications. Success rates in both the groups were compared using Kaplan-Meier survival curves and the log-rank test. IOP levels were compared using mixed linear model analysis to correct for repeated measures correlation.Results: Forty-three patients, 18 in the study group and 25 in the control group, completed the study (follow-up of 12 mo). the mean IOP was significantly lower after 1 year in both the groups (P < 0.001). the mean IOP in the first month of follow-up was lower in the study group (control; 20.4 +/- 9.7, study; 13.6 +/- 6.5, P < 0.01). the success rate at 1 year was 78% for the study group and 76% for the control group (P = 0.82). Complication rates were not different between the groups.Conclusions: Intravitreal injection of triamcinolone acetonide in neovascular glaucoma did not affect the intermediate-term success of the silicone Ahmed valve nor reduce the incidence of complications. the mean IOP spike in the first month was lower in the triamcinolone group. Universidade Federal de São Paulo, Dept Ophthalmol, São Paulo, Brazil Hosp Israelita Albert Einstein, São Paulo, Brazil HORP, Sao Jose Do Rio Preto, SP, Brazil Univ Fed Triangulo Mineiro, Uberaba, MG, Brazil Universidade Federal de São Paulo, Dept Ophthalmol, São Paulo, Brazil Web of Science

Chemically induced renal neoplasms in male rats, developed coincident with α2u-globulin nephropathy, are not considered predictive of risk to humans by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency. Criteria have been defined to establish the role of α2u-globulin nephropathy in renal carcinogenesis, based on a proposed mode of action involving sustained tubular cell proliferation resulting from α2u-induced nephropathy, with consequent development of neoplastic lesions. Recent NTP studies demonstrated inconsistencies with this proposed mechanism, including in some cases, far weaker kidney tumor responses than expected based on the extent of α2u-globulin nephropathy. NTP studies with decalin, propylene glycol mono-t-butyl ether and Stoddard solvent IIC included extended evaluations of α2u-related nephropathy, and were thus used in assessing the linkage between key events in 90-day studies with renal tumors in 2-year studies. This review revealed no or at best weak associations of tumor responses with renal α2u-globulin concentrations, indices of cell turnover, or microscopic evidence of α2u-associated nephropathy in prechronic studies. While tumor responses corresponded somewhat with a measure of cumulative α2u-associated nephropathy (linear mineralization of the papilla) at the end of the 2-year studies, the severity of chronic nephropathy was generally in best agreement with the pattern of tumor response. These results suggest that while α2u-globulin nephropathy may contribute to the renal tumor response, the critical component(s) of the nephropathy most closely associated with the development of tumors could not be clearly identified in this review.

Surgery for pituitary tumours at our institution was performed by rhinosurgical route by combined procedure by otolaryngologist and neurosurgeons. A retrospective review of case records of patients who had endonasal endoscopic transphenoidal approach for pituitary tumours from September 1998 to December 2004 was performed. A total of 81 trans-sphenoidal surgeries were performed during this study period. Only 68 case records with adequate information were available for review, 56 patients were included in the study and 12 were excluded. There were 24 males (42%) and 32 females (58%). The ethnic distribution, were 29 Malays, 24 Chinese, 2 Indian and 1 others. The age ranged from 16 years to 76 years, with a mean of 46 years. The majority of our patients presented with visual symptoms (38), headache (28), menstrual cycle disturbance or impotence (14) and acromegalic features (16). Forty patients had macroadenoma (71%) and 16 had microadenomas (29%). Thirty-six patients out of 40 macro-adenomas had suprasellar extensions (90%). Only eleven patients had lumbar drain inserted prior to commencement of the surgery and the majority of these were macroadenomas. The common complications encountered were diabetes insipidus (4), cerebrospinal fluid leak (2), meningitis (3), epistaxis (2), septal perforation (2), intercavernous sinus haemorrhage (3) and anterior pituitary insufficiency (2). Our study reveals that endonasal trans-sphenoidal approach is a safe and effective method of management of pituitary adenomas.

Aims: To evaluate the effect of the combination of bimatoprost and latanoprost on intraocular pressure (IOP) in primary open angle glaucoma (POAG). Methods: An open label randomised clinical trial was conducted, which included 18 glaucomatous patients (36 eyes). In the first 4 weeks, latanoprost 0.005% was prescribed for both eyes of the patients and any other antiglaucoma medication was discontinued. In the next 4 weeks (phase 1), bimatoprost 0.03% was combined with latanoprost in one randomly assigned eye (case eye) of each patient. In the next 4 weeks (phase 2), bimatoprost was discontinued in the case eyes, while bimatoprost was substituted for latanoprost in the fellow eye (control eye). The IOP was measured at the end of the first 4 weeks (baseline measurement) and weekly during phases 1 and 2. Results: In the case eyes, the mean IOP increased along the first phase (1.8 mm Hg; p = 0.006) when compared to baseline measurements. The IOP returned to previous values after discontinuation of bimatoprost in phase 2. In the control eyes, the mean IOP did not change throughout the study. Conclusion: The combination of bimatoprost and latanoprost in POAG increases the IOP and should not be considered as a therapeutic option.

Propylene glycol mono-t-butyl ether (PGMBE) is used as a solvent in a variety of commercial applications. Male and female F344/N rats and B6C3F(1) mice were exposed to PGMBE by whole-body inhalation for 2 or 14 weeks (0, 75, 150, 300, 600, or 1200 ppm) or 2 years (0, 75, 300, or 1200 ppm); male NBR rats were exposed for 2 weeks. The kidney and the liver were targets of PGMBE toxicity in rats. Renal lesions suggestive of alpha(2u)-globulin nephropathy were observed in male F344/N, in the 2 and 14-week studies, no kidney lesions were seen in NBR rats. In the 2-year study, male rats displayed exposure-related nonneoplastic lesions in the kidney, and may have shown marginal increases in tubular neoplasms. In the liver, the incidences of hepatocellular adenomas occurred with a positive trend in male rats, and may have been related to PGMBE exposure. In mice of both sexes, the major target of PGMBE toxicity was the liver. In the 2-week study, liver weights and in the 14-week study, liver weights and the incidences of centrilobular hypertrophy were increased. In the 2-year study, the incidences of exposure-related hepatocellular adenoma, adenoma or carcinoma combined, and hepatoblastoma occurred with a positive trend, and were significantly increased in 1200 ppm groups. In summary, exposure to PGMBE resulted in nonneoplastic lesions of the kidney characteristic of alpha(2u)-globulin nephropathy, and may have increased renal tubular neoplasms in male rats. Exposure to PGMBE also produced increases in hepatic tumors in male and female mice.

The present study examined the inhibitory effects of N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016) on the renal metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes. HET0016 exhibited a high degree of selectivity in inhibiting the formation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in rat renal microsomes. The IC(50) value averaged 35+/-4 nM, whereas the IC(50) value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800+/-300 nM. In human renal microsomes, HET0016 potently inhibited the formation of 20-HETE with an IC(50) value of 8.9+/-2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4-catalysed substrates oxidation with IC(50) values of 3300, 83,900 and 71,000 nM. The IC(50) value for HET0016 on cyclo-oxygenase activity was 2300 nM. These results indicate that HET0016 is a potent and selective inhibitor of CYP enzymes responsible for the formation of 20-HETE in man and rat.

99mTc-ethylcysteinate dimer (99mTc-ECD) SPECT imaging reportedly fails to show reflow hyperemia in patients with subacute stroke. This study attempts to determine the clinical usefulness of dynamic 99mTc-ECD SPECT in evaluating regional blood flow in subacute cerebral infarction and the kinetic behavior of 99mTc-ECD in infarct areas.133Xe and consecutive dynamic and static 99mTc-ECD SPECT studies were performed on 24 patients with cortical infarction in the middle cerebral artery territory 13-15 d after the onset of a stroke. Image contrast between infarct and contralateral control areas on 99mTc-ECD tomograms (ECD uptake ratio) was compared with that on cerebral blood flow (CBF) images obtained using 133Xe inhalation (CBF ratio).In all cases, ECD uptake ratios from static images were lower than CBF ratios. This tendency was obvious when CBF in the infarct area increased above the normal control value, and no significant correlation was found between ECD uptake ratios from static images and CBF ratios. Only in the infarct areas with CBF below the normal control value, however, was a significant correlation between the two maintained (r = 0.795; P = 0.0011). A very strong correlation was found between CBF ratios and ECD uptake ratios on both the first dynamic scan (36 s after injection) (r = 0.991; P0.0001) and the second dynamic scan (72 s after injection) (r = 0.945; P0.0001). The correlation coefficient decreased in a time-dependent manner, with no significant correlation observed after the fourth dynamic scan (144 s after injection). On the other hand, significant correlations were observed on all dynamic scans only in the infarct areas with CBF below the control value.Super-early images of dynamic 99mTc-ECD SPECT provide a close imaging contrast with CBF and reveal reflow hyperemia in areas with irreversible changes produced by subacute stroke, which static 99mTc-ECD SPECT images fail to show. Decreased retention of the tracer in the infarct areas with hyperperfusion causes an underestimation of CBF on static 99mTc-ECD SPECT images. Given these results, we believe that dynamic 99mTc-ECD SPECT is an effective clinical tool to evaluate regional blood flow in subacute cerebral infarction.

The usefulness of 1% terbinafine HCl (Lamisil) cream for hyperkeratotic-type tinea pedis and its transfer into the horny layer were evaluated. Of the 36 patients enrolled in the study, 35 were retained for analysis and one was excluded due to inappropriate drug application. Hyperkeratotic-type tinea pedis was classified into three types: true hyperkeratotic-type, partial hyperkeratotic-type, and quasi-hyperkeratotic type. The overall clinical improvement rate was 95.5% (100% for true-, 80% for partial- and 96.2% for quasi-hyperkeratotic type). The overall fungal eradication rate was 88.6% (75% for true-, 100% for partial- and 88.5% for quasi-hyperkeratotic type). The overall efficacy rate was 88.6% (75% for true-, 100% for partial- and 88.5% for quasi-hyperkeratotic type). No adverse reactions were reported. Drug concentrations in the horny layer were 170.3, 228.5 and 249.2 ng mg-1, respectively, 2, 4 and 12 weeks after starting the treatment. These concentrations are more than 50,000 times higher than the minimum inhibitory concentrations of terbinafine for dermatophytes. These findings indicate that terbinafine HCl (Lamisil) cream is very useful for refractory hyperkeratotic-type tinea pedis when administered alone. The pharmacokinetic data also support the clinical and mycological findings.

A 42-year-old man without family history of neurologic disease developed muscle weakness, and wasting associated with tremor and choreiform movement. He died at age 75 with 33 years of total duration of illness. Autopsy revealed neuronal loss and gliosis in the anterior horns of the spinal cord, hypoglossal nuclei, caudate nuclei, putamen, globus pallidus, and substantia nigra. Bunina bodies or Lewy bodies were not seen. Several similar cases with motor neuron disease, dementia and parkinsonism have been reported in the literature. However, this pattern of chronic spinal neostriato-pallido-nigral degeneration has not been reported.

The patient was a 53-year-old man whose chief complaint was a dry cough and hemoptysis. Chest X-ray films and computed tomographic scans revealed a hazy shadow with unclear margins in the left middle lobe. A diagnosis of inflammatory pseudotumor was made because transbronchial lung biopsy specimens showed proliferation of plasma cells and lymphocytes. Initially, in response to steroid therapy, his clinical condition and pulmonary infiltration improved, but about 30 days after the start of steroid therapy, hemoptysis occurred and the shadow increased, and therefore left segmentectomy was performed. Histology revealed not only proliferation of acute and chronic inflammatory cells but also changes in the vessels. These pathologic findings were considered to be related to the infiltration shadows and the hemoptysis.

The role of thrombin as a spasmogen after subarachnoid hemorrhage was evaluated using the intrathecally administered thrombin inhibitor hirudin, released from a drug delivery system (DDS) based on collagen in a canine vasospasm model. The DDS was implanted into the cisterna magna with autologous blood in the hirudin-treated group. The reduction in the angiographical diameter of the basilar artery was only 19% in the hirudin-treated group on day 7, showing a significant difference between hirudin-treated and nontreated groups (p0.01). These results suggest that thrombin is an important cause of vasospasm. The collagen DDS has great potential for treatment in the cerebrospinal fluid milieu.

We undertook a retrospective study of elderly patients with stage III non-small cell lung cancer who had been treated solely with radiotherapy during the period 1986 to 1995. Our study was designed to assess the influence of age on survival and malnutrition in patients aged 75 years or older (elderly group) and patients aged 74 years or younger (younger group). Radiotherapy alone resulted in a median survival period of 11.5 months in the younger group and 6.3 months in the elderly group (p = 0.0043). With the Cox multivariate model, good performance status, age less than 75 years, and good response were significant favorable independent predictors. Furthermore, the elderly group patients more frequently died of respiratory infections and had lower prognostic nutritional indexes than the younger group patients before and after radiotherapy. These findings suggested elderly patients with stage III non-small cell lung cancer who had been treated with radiotherapy alone had a poor prognosis and that malnutrition caused by radiotherapy was a factor contributing to the risk of death from respiratory infection in such patients.

Hematomyelia usually has an acute onset and rapid progression, which results in a poor prognosis. However, there have been a few cases in which the clinical symptoms have progressed chronically, with a good prognosis. These two different clinical courses should be analyzed separately. The differential diagnosis of spinal tumor and other chronic progressive diseases due to the similarity of the clinical courses is also important.Two cases of hematomyelia with slowly progressive symptoms are reported. Unlike the acute onset and rapid progression or recurrent episodic deterioration usually seen in hematomyelia, the symptoms of chronic hematomyelia progressed over months and resulted in a better clinical prognosis than the acute course. The cases of "chronic progressive hematomyelia" from the literature are briefly summarized.Chronic progressive hematomyelia should be considered as a different clinical entity from the acute version because of its slowly progressive clinical course and good outcome. Magnetic resonance imaging is the procedure of choice to exclude spinal tumors or other slowly progressive intraspinal diseases.

The central nervous system involvement in chronic graft versus host disease (GVHD) has been suggested. Chronic GVHD resembles auto immune connective tissue disorders. In order to investigate the immunoglobulin intra blood brain barrier (BBB) synthesis during chronic GVHD, and contribute to understanding the pathophysiology of the disease, we studied 33 patients who underwent allogeneic bone marrow transplants (BMT) from HLA identical related donors. Immunoglobulin intra BBB synthesis was investigated quantitative and qualitatively. The samples were collected pre BMT, pos BMT and during chronic GVHD. There were no evidence of immunoglobulin intra BBB synthesis, and no oligoclonal bands were found. Only isolated cases suggested IgO and IgA intra BBB synthesis, and in one case IgM during GVHD.

The blood-brain barrier (BBB) contributes to the central nervous system (CNS) immunological isolation. BBB has never been studied in patients who developed chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplants (BMT), from HLA identical related donors. BBB disruption was investigated through the cerebrospinal fluid (CSF) proteins, quantitative and graphically, in order to detect the incidence and possible pathophysiology of the CNS involvement in chronic GVHD. Thirty three CSF and matched serum samples from chronic myeloid leukemia patients were collected pre BMT pos BMT and during chronic GVHD. There was no evidence of BBB disruption in any patient studied.

Terbinafine was remarkably effective in tinea barbae due to Trichophyton rubrum on the cheek in front of the right ear in a 75-year-old man. This patient also showed tinea pedis and unguium, but these were due to Trichophyton mentagrophytes and were unrelated to the tinea in the cheek. This patient showed an atypical clinical picture slightly different from that during the initial visit, requiring histological differentiation from trichophytic granuloma.

To examine whether pulmonary neuroendocrine cells (PNEC) is associated with sudden infant death syndrome (SIDS), distribution and function of PNEC were investigated in infants from one to twelve months of age, including 19 cases with SIDS and 18 control cases without congenital heart disease and premature birth. In this study, lung tissue sections were immunostained with antibodies against chromogranin A (CGA) and calcitonin gene-related peptide (CGRP). Although the positivity of CGA in SIDS cases was not significantly different from that in control, the positivity of CGRP in SIDS cases was lower than that in control cases among one to four months old (p0.05). Our results suggest that respiratory and/or circulatory regulation of cases with SIDS is disturbed by reduction of CGRP expression, because CGRP is well known to be a vasodilator, a neurotransmitter and a promoter for proliferation of epithelium in airways.

We devised a new physical training program on the basis of anaerobic threshold for rehabilitation in the early phase of acute myocardial infarction. Forty-four patients were divided into two groups, control and training. We measured the left ventricular ejection fraction using nuclear stethoscopy during the treadmill test and calculating radioactive cardiac output. In the training group, anaerobic threshold and exercise time to the anaerobic threshold point were significantly increased, and stroke volume at rest measured by the dye dilution method increased significantly. Radioactive cardiac output during exercise also increased after the exercise therapy. These results indicate that the rehabilitation program consisting of physical training based on the anaerobic threshold is effective.

Phonological awareness and phoneme identification tasks were administered to dyslexic children and both chronological age (CA) and reading-level (RL) comparison groups. Dyslexic children showed less sharply defined categorical perception of a bath-path continuum varying voice onset time when compared to the CA but not the RL group. The dyslexic children were divided into two subgroups based on phoneme awareness. Dyslexics with low phonemic awareness made poorer /b/-/p/ distinctions than both CA and RL groups, but dyslexics with normal phonemic awareness did not. Examination of individual profiles revealed that the majority of subjects in each group exhibited normal categorical perception. However, 7 of 25 dyslexics had abnormal identification functions, compared to 1 subject in the CA group and 3 in the RL group. The results suggest that some dyslexic children have a perceptual deficit that may interfere with processing of phonological information. Speech perception difficulties may also be partially related to reading experience.

The authors proposed a new application of helical CT, namely, CT-ventriculography that can obtain 2D and 3D images of different cardiac phases. CT-ventriculography could assess wall motion, systolic thickening and chamber volume. From a single breath hold helical CT 50-rotation), about 500 transaxial slices were obtained by applying overlapping reconstruction (0.1 pitch, 0.08 sec = 0.2 mm interval). All transaxial slices were recordered to separate different cardiac phases. Then, long and short axial 2D tomograms and 3D images in different cardiac phases were reformatted. CT-ventriculography is a promising new application for the assessment of heart function.

A 28-year-old male patient with both IgA nephropathy and an unusual case of Fabry's disease has been followed for 10 years. Diagnosis of both these diseases was made by histological examination of renal biopsy tissues and the enzyme activities of alpha-galactosidase A. Serial biopsies revealed the hithertofore unrecognized process of glomerular glycolipid accumulation peculiar to Fabry's disease at the initial stages of the disease. Physical examinations and routine laboratory analyses failed to show significant signs of Fabry's disease throughout the 10-year period. While alpha-galactosidase A activity is markedly decreased in the plasma of this patient as in classical Fabry hemizygotes, the activity in leukocytes and culture fibroblasts showed a considerable residual activity. Fabry's disease associated with IgA nephropathy apparently is extremely rare, and the present subclinical case is unique in that the early stages of substrate accumulation are demonstrable.

The acute occlusion of cerebral artery by embolism causes severe cerebral infarction. In cases with poor colateral circulation, cerebral infarction develops more severely. In these cases, quick recanalization of the occluded cerebral artery is necessary to prevent severe hemorrhagic infarction and brain edema. We report a case where interventional techniques were used to bring about quick recanalization of occluded cerebral artery. We encountered a case of a sixty-year-old male who experienced complete occlusion of the left middle cerebral artery due to an embolus. It was very hard to pass a guide wire through the embolic lesion. At first, we tried mild local fibrinolysis therapy using tissue plasminogen activator, but we could not get any recanalization. However, after mild local fibrinolysis therapy, the guide wire could be passed through the occlusion point. Secondly, we tried percutaneous transluminal angioplasty (PTA) with 2.0mm diameter angioplastic balloon using up to five atomic pressures, after which we obtained partial recanalization. Finally we achieved total recanalization of the middle cerebral artery by PTA with a 2.5mm diameter angioplastic balloon. We crushed this embolus using the angioplastic balloon with up to six atomic pressures. The point of the techniques is to press the embolus against the arterial wall. After this angioplasty, there was an occlusion of the common trunk of the posterior parietal artery and the angular artery. However there was neither massive hemorrhagic infarction nor massive brain edema on follow up CT. In the treatment of acute occlusion of the cerebral artery due to embolism, we found PTA is very effective against the embolus. In the future, we need to develop a retrieving device and a balloon that will prevent the production of small emboli during the crush process involved when bringing about recanalization using PTA.

In two patients with pulmonary alveolar proteinosis, PaO2 was normalized by massive bronchoalveolar lavage (BAL). Patient 1: A 29-year-old man presented with exertional dyspnea and a PaO2 of 57.8 mmHg. After four BALs, the PaO2 was 106.4 mmHg. For ten years thereafter he has been doing well. Patient 2: A 58-year-old women presented with extertional dyspnea and a PaO2 of 64.4 mmHg. The PaO2 increased to 110.6 mmHg after four BALs. BAL required much skill, but it is one of the most effective methods for the treatment of pulmonary alveolar proteinosis. Because this condition is related to an interstitial process, these two patients need to be followed carefully.

This study examined whether there are different subtypes of developmental dyslexia. The subjects were 51 dyslexic children (reading below the 30th percentile in isolated word recognition), 51 age-matched normal readers, and 27 younger normal readers who scored in the same range as the dyslexics on word recognition. Using methods developed by Castles and Coltheart (1993), we identified two subgroups who fit the profiles commonly termed "surface" and "phonological" dyslexia. Surface subjects were relatively poorer in reading exception words compared to nonwords; phonological dyslexics showed the opposite pattern. However, most dyslexics were impaired on reading both exception words and nonwords compared to same-aged normal readers. Whereas the surface dyslexics' performance was very similar to that of younger normal readers, the phonological dyslexics' was not. The two dyslexic groups also exhibited a double dissociation on two validation tasks: surface subjects were impaired on a task involving orthographic knowledge but not one involving phonology; phonological dyslexics showed the opposite pattern. The data support the conclusion that there are at least two subtypes of developmental dyslexia. Although these patterns have been taken as evidence for the dual-route model, we provide an alternative account of them within the Seidenberg and McClelland (1989) connectionist model. The connectionist model accounts for why dyslexics tend to be impaired on both exception words and nonwords; it also suggests that the subtypes may arise from multiple underlying deficits. We conclude that performance on exception words and nonwords is not sufficient to identify the basis of dyslexic behavior; rather, information about children's performance on other tasks, their remediation experiences, and the computational mechanisms that give rise to impairments must be taken into account as well.

Histamine and recombinant granulocyte colony-stimulating factor (rG-CSF) stimulated the differentiation of murine myeloblasts and promyelocytes to mature neutrophils. In connection with this, myeloperoxidase activity of these progenitor cells was decreased by either histamine or rG-CSF treatment. After pretreatment with histamine at 1 microM, both differentiation and the decrease in myeloperoxidase activity of myeloblasts and promyelocytes induced by rG-CSF were significantly augmented. Binding assays using 125I-labeled rG-CSF showed that the number of rG-CSF binding sites on the surface of neutrophil progenitor cells increased after histamine treatment. The histamine-induced increase in rG-CSF binding appeared to be definitely through H2 receptors. Furthermore, the increase in rG-CSF binding sites due to histamine treatment seemed to take place in association with the externalization of G-CSF receptors, because 1) the binding increase was observed in the presence of cycloheximide, 2) no concomitant increase in [3H]leucine uptake was elicited, and 3) colchicine and cytochalasin D effectively prevented the increase in rG-CSF binding due to histamine. In neutrophil progenitors, cAMP contents increased very rapidly and significantly after either histamine or rG-CSF treatment. Moreover, dibutyryl-cAMP increased rG-CSF binding to neutrophil progenitor cells in a dose-dependent fashion. However, when progenitor cells were pretreated with protein kinase A inhibitors, the histamine-induced increase in rG-CSF binding was remarkably decreased. This result seems to indicate that the stimulatory effects of histamine on rG-CSF binding to progenitor cells are intimately related to the cAMP-protein kinase A system in neutrophil progenitors. Moreover, c-myc mRNA expression in neutrophil progenitors was markedly reduced by either histamine or rG-CSF treatment. It was concluded that rG-CSF-induced differentiation of murine neutrophil progenitors was augmented by histamine pretreatment mainly due to an increase in rG-CSF receptors on these cells and this increase might be related to the externalization of rG-CSF receptors.

Kochi Prefecture had a higher admission rate for patients with cardiovascular disease, particularly for stroke, than Shimane Prefecture which has a similar socio-economic level. Kochi Prefecture had a smaller average number of persons in a household, a lower proportion of three generation households, and a lower proportion of households with six persons or more than Shimane Prefecture. The decline in number of persons in a household was greater in Kochi Prefecture than in Shimane Prefecture from 1960 to 1985, especially between 1970 and 1975. The association between family make-up and hospital discharge one year after stroke was examined in a rural community in Kochi Prefecture. Two hundred forty nine patients aged 40 years and older who were admitted immediately after stroke events were registered between 1969 and 1988, and they were followed for one year. According to family make-up, the subjects were divided into four groups: 1) persons who lived with spouse and daughter-in-law, 2) persons who lived with spouse, 3) persons who lived with daughter-in-law, 4) persons who lived without spouse and daughter-in-law. Although mean age and the proportion of serious cases were not different between group 1 and group 4, the proportion of admitted patients of group 1 was significantly lower than that of group 4. About 60% of group 1 had households with six persons or more. Group 2 had the lowest proportion of admitted patients, but this group was significantly younger than other groups. Within group 3, the proportion of admitted patients was higher in households in which the daughter-in-law had a job than in households in which she did not. These results suggest that the high admission rate in Kochi Prefecture is attributable to households which are short of personnel for home care.

Eleven patients with pheochromocytoma were divided into two groups; epinephrine predominant group (n = 4) and norepinephrine predominant group (n = 7). In each case, anesthesia was given using only inhalational anesthetics and adenosine triphosphate (ATP); and the same strategy was used to control cardiovascular variables. If arterial blood pressure, pulmonary artery pressure, central venous pressure or heart rate failed to be controlled with the strategy before the tumor resection, phentolamine, trinitroglycerine or propranolol was used. After the tumor resection, if decreasing the anesthetic concentration, cessation of ATP infusion and rapid intravenous infusion could not maintain the systolic arterial blood pressure above 80 mmHg, norepinephrine was infused. Maximum heart rate and arterial blood pressure during the tumor exploration were similar in both groups. No ventricular arrhythmias were recognized in any case. The frequency of usage of the cardiovascular depressants was not different between the two groups. In the norepinephrine predominant group, five cases required norepinephrine infusion after the tumor resection, but in the epinephrine predominant group, none required the norepinephrine infusion. Desensitization of alpha 1 adrenergic receptor induced by continuous high plasma norepinephrine concentration, was considered to decrease vascular resistance. In conclusion, except for the hypotension after the tumor resection in the norepinephrine predominant pheochromocytoma, both epinephrine predominant and norepinephrine predominant pheochromocytoma could be managed with similar anesthetic risks.