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Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

Combination therapy with fluorouracil, platinum, and trastuzumab (Tmab) is the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, and there is currently no established second-line therapy. We evaluated the efficacy and safety of weekly paclitaxel plus Tmab as second-line chemotherapy for HER2-positive gastric cancer patients.Eligible patients were older than or equal to 20 years, had histologically confirmed gastric adenocarcinoma that was HER2 positive (immunohistochemistry 3+ or immunohistochemistry 2+ and fluorescence in-situ hybridization positive or dual color in-situ hybridization positive), and had been treated previously with chemotherapy (pretreated or not with Tmab). Patients received weekly paclitaxel plus Tmab as the second-line chemotherapy. The primary endpoint was the overall response rate (ORR; threshold ORR=20% and expected ORR=35%).Twenty-eight patients were enrolled. ORR was 21.4%. The median progression-free survival (PFS) was 4.6 months. The median overall survival (OS) was 9.6 months. No significant differences were observed in ORR, PFS, or OS between the Tmab beyond progression (TBP) group (n=20) and the non-TBP group (n=8). However, in the TBP group, a therapeutic effect was associated with the duration of PFS in the first-line Tmab treatment [≥6 months PFS in the first-line Tmab treatment (n=10) vs.6 months (n=10); ORR: 40 and 10%, P=0.303, PFS: 6.2 and 2.8 months, P=0.005, OS: 15.8 and 6.5 months, P=0.006, respectively].Weekly paclitaxel plus Tmab was not superior as second-line chemotherapy for HER2-positive gastric cancer patients, but may be effective for patients who showed better responses to Tmab-combined chemotherapy in the first-line treatment.

Background: Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. Although endothelial cell damage associated with vasculitis might lead to the hypercoagulability that is involved in coronary artery disease, the changes in coagulation after intravenous immunoglobulin therapy (IVIG) have not been well investigated in KD. The aims of this study were to address the changes in coagulation before and after IVIG in KD, and to further elucidate the coagulation-inflammation axis, with special attention to endothelial damage. Methods: We retrospectively collected the laboratory data before and after IVIG in 26 pediatric KD patients treated at the Nara Prefecture Western Medical Center between May 2010 and April 2012. Prothrombin time (PT), activated partial thromboplastin time (APTT) and levels of fibrin/fibrinogen degradation products (FDP) and D-dimer were assessed as coagulation markers. Fibrinogen, ferritin, serum amyloid A, procalcitonin and urine F2 microglobulin were assessed as inflammation markers. Thrombomodulin, antithrombin, factor VIII activity (FVIII:C), and von Willebrand factor antigen (VWF:Ag) were used to assess endothelial damage. Results: Prolonged PT and APTT before IVIG were significantly shortened after IVIG, and elevated levels of FDP and D-dimer were significantly decreased. Elevated levels of inflammation markers had decreased significantly after IVIG, but levels of FVIII:C and VWF:Ag remained high, even after IVIG. Conclusions: Ameliorated inflammation by IVIG might improve the hypercoagulable state. Nevertheless, our results suggest that endothelial damage might be prolonged in IVIG-treated patients. Control of endothelial damage in KD is critical. i 2014 S. Karger AG, Basel

Activity hydrolyzing both N omega-phosphoarginine and glucose-6-phosphate was detected in rat renal microsome but not in hepatic microsome. Renal microsome was solubilized with 1% n-octyl-beta-D-thioglucoside and purified with DEAE-Sepharose column chromatography. Fractions hydrolyzing both N omega-phosphoarginine or glucose-6-phosphate were subjected to 7.5%-polyacrylamide gel electrophoresis in the presence of 0.1% sodium dodecyl sulfate. Phosphatase activity in the gels was detected by a lead nitrate stain using N omega-phosphoarginine or glucose-6-phosphate as substrates. Both substrates produced a stain in the region of the gel corresponding to a protein with a mass of 150 kDa. Extracts of slices from this region of the gel also hydrolyzed phosphocreatine, inorganic pyrophosphate, and O-phosphotyrosine. Moreover, the phosphatase had its optimal pH in the alkaline range and was inhibited completely by 20 microM sodium vanadate, 1 mM cysteine, and 1 mM tetramisole. All these properties indicate that the microsomal phosphoamidase (EC 3.9.1.1) of rat kidney was identical with alkaline phosphatase (EC 3.1.3.1).

Polymorphism in MDR1 is associated with variation in the plasma level of a proton pump inhibitor.To investigate whether MDR1 polymorphism is associated with eradication rates of Helicobacter pylori by a triple therapy with lansoprazole, amoxicillin and clarithromycin in relation to CYP2C19 genotype status and bacterial susceptibility to clarithromycin.A total of 313 patients infected with H. pylori completed the treatment with lansoprazole 30 mg b.d., clarithromycin 200 mg b.d. and amoxicillin 750 mg b.d. for 1 week. MDR1 C3435T polymorphism and CYP2C19 genotypes of patients and sensitivity of H. pylori to clarithromycin were determined.Logistic regression analysis revealed that the MDR1 polymorphism as well as CYP2C19 genotypes of patients and clarithromycin-resistance of H. pylori were significantly associated with successful eradication. Eradication rates for H. pylori were 82% (83/101: 95% CI = 73-89), 81% (112/139: CI = 73-87), and 67% (44/73: CI = 48-72) in patients with the MDR1 3435 C/C, C/T and T/T genotype, respectively (P = 0.001).Polymorphism of MDR1 is one of the determinants of successful eradication of H. pylori by the triple therapy with lansoprazole, amoxicillin and clarithromycin, together with CYP2C19 genotype and bacterial susceptibility to clarithromycin.

Objectives: We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD). Patients and methods: Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom. Results: Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma. Conclusions: OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases. (Less)

A subchronic oral toxicity study of beta-carotene derived from Blakeslea trispora, a natural food colorant, was performed with groups of 10 male and 10 female F344 rats fed the agent at dietary levels of 0%, 0.2%, 1.0% and 5.0% for 90 days. There were no treatment-related adverse effects with regard to body weight, food and water consumption, urinalysis, ophthalmology, hematology, serum biochemistry, and organ weight data. On clinical observation, red coloring of fur was noted in both sexes of the 1.0% and 5.0% group rats, with red feces observed in all treated group animals, and necropsy revealed all rats of the treated groups to have reddish coloration of the contents of the gastro-intestinal tract, due to the pigmentation and thus lacking toxicological significance. On histopathological examination, sporadic spontaneous lesions known to occur in this strain of rats were the only findings, with no specific relation to the test substance. Thus, the no-observed-adverse-effect-level (NOAEL) was judged to be a dietary level of at least 5.0% (3127 mg/kg body weight/day for males, 3362 mg/kg body weight/day for females) for beta-carotene derived from B. trispora under the present experimental conditions.

A 50-year-old male presented with benign intracranial hypertension (BIH). He was admitted to our hospital for headache and papilledema. The diagnosis was BIH as continuous monitoring of lumbar cerebrospinal fluid pressure (CSFP) showed high basal pressure with intermittent plateau waves. Ten months after successful ventriculoperitoneal shunting, he presented with headache again due to shunt malfunction. CSFP monitoring showed the same findings as before. Regional cerebral blood flow (rCBF) was measured by positron emission tomography (PET) using the 15O-labeled water autoradiographic method with simultaneous recording of lumbar CSFP. The rCBF values of the cerebral cortex, white matter, thalamus, cerebellar cortex, and pons were evaluated during both the plateau waves and the intervals. In spite of severely reduced cerebral perfusion pressure, rCBF during the plateau waves was not reduced when compared with the rCBF of normal volunteers in all regions. This result might explain why patients with BIH show no impairment of consciousness or focal signs during the plateau waves.

Mutations in the hepatocyte nuclear factor-1beta (HNF-1beta) gene have been shown to be a cause of maturity-onset diabetes of the young (MODY). We studied the contribution of the HNF-1beta gene to susceptibility to common forms of Type 2 diabetes in the genetically homogeneous Japanese population, by investigating the allelic association of Type 2 diabetes with two markers in the HNF-1beta region. The frequency of a nonsense mutation, R177X, which was previously reported in a Japanese family, was also studied by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method using a mismatch primer. A total of 200 subjects were studied. There was no significant difference in allele frequencies of either of the two polymorphisms studied between patients with Type 2 diabetes and control subjects, or between subgroups of patients subdivided by the presence of mild or severe diabetic nephropathy. None of the subjects studied had R177X mutation, giving a frequency of less than 1.1% in common forms of Type 2 diabetes in Japan. These results suggest that mutations in the HNF-1beta gene derived from a limited number of founders are not a major cause of common forms of Type 2 diabetes, even in the genetically homogeneous Japanese population.

To investigate relationships between thyroid states and the cardiac endocrine system, we analyzed thyrotropin (TSH), thyroid hormone, plasma levels of interleukin-6 (IL-6) and brain natriuretic peptide (BNP) in 50 patients with chronic heart failure (CHF), in 30 patients with heart failure from acute myocardial infarction (AMI), and in 15 controls. Plasma levels of IL-6 and BNP in both CHF and AMI were significantly elevated, while free triiodothyronine (FT3) was significantly decreased compared to controls. FT3/free thyroxine (FT4) ratio was significantly decreased in CHF but not in AMI compared to controls. In CHF, diuretic treatment diminished circulating BNP but not IL-6, while diuretic treatment increased FT3/FT4 ratio. In AMI, FT3/FT4 ratio was significantly decreased 72 h compared to 12 h after the onset of AMI, while BNP and IL-6 were significantly increased 72 h compared to 12 h after the onset of AMI. In both CHF and AMI, BNP significantly correlated with FT4. On the other hand, significant correlations between IL-6 and FT3, and between IL-6 and FT3/FT4 ratio were detected in AMI but not in CHF. This preliminary study suggests that IL-6, BNP and thyroid hormone reflect ventricular dysfunction in both acute and chronic heart failure, and that IL-6 significantly relates to circulating thyroid hormone in AMI but not in CHF.

The aim of this study was to propose and validate a new method of making fused images from CT and FDG PET images for the upper abdominal area with no body surface marker. PET and CT were carried out in patients with pancreatic cancer (N = 5) and mass-forming pancreatitis (N = 2). First, we determined the midsagittal plane from PET and CT data. From the difference in location of the midsagittal planes, rotations of Y (from back to front) and Z axes (from foot to head) and X translation (from right to left) were calculated. An upper pole of the kidney was determined from PET and CT data. It showed Y and Z translations. The images of the three-dimensional data sets were fused on a workstation. Reproducibility was assessed with randomly misaligned PET and CT data sets. Pancreatic cancer and its lymph node metastases were identified easily on fused images. In reproducibility assessment, the average error of rotation was 0.77 degree. The average errors of translation were 3.43, 4.70, and 9.23 mm on the X, Y, and Z axes, respectively. In conclusion, this PET/CT image registration technique is feasible and practical. It allows precise anatomical assessment of normal and abnormal FDG accumulation.

The cementless femoral prostheses developed in Western countries have commonly been used for Japanese patients, but it has been noted that it is difficult to achieve a good fit between the cementless femoral prostheses and some femora. In Japan, there are many patients with secondary osteoarthrosis (OA) of the hip, but Western designed femoral prostheses seem to be mainly for use with primary OA of the hip. To design femoral prostheses better suited to Japanese patients, a new method to study the morphometry of the femur is required--one which can determine the particular features of the femur in Japanese patients. In this study, a new morphologic measurement technique of the femur is proposed and applied to a number of Japanese OA patients in order to demonstrate its efficacy. In this technique, a three-dimensional solid model based on the outer and inner borders of the femoral cortex is constructed from 3-D CT images and computer-aided design (CAD) software. The bone axis is defined as the line of best fit to the centers of gravity of the femur cross sections in each CT plane by using the least square method. A new femur coordinate system is considered based on this bone axis. The corrected outer borders of the cortex are reconstructed in sections perpendicular to the bone axis. The angle between the principal axis of inertia of the sections and a plane defined by the femur coordinate system is selected as providing a good measurement of the torsion value to characterize the femur morphology. The angles of principal axis were measured in 110 OA and 36 normal hips, and then compared with each other. A significant difference between the OA and normal group was observed especially in the proximal region above the section 6 mm below the level of the lesser trochanter. It is suggested that the anteversion of the femoral neck influences the torsion of the parts below the lesser trochanter. From the results, it is demonstrated that the proposed measurement technique is a reliable and efficient means of determining femur morphology.

To test whether a potent cGMP-specific phosphodiesterase inhibitor, E 4021, is a selective pulmonary vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects in conscious, chronically hypoxic pulmonary hypertensive rats. Chronically hypoxic pulmonary hypertension was induced by keeping adult Sprague-Dawley rats in a hypobaric chamber for 3 weeks. Two days after catheterization. E 4021 was injected intravenously at doses of 3, 10, 30, 100, 300, and 1,000 micrograms/kg at 10-min intervals. E 4021 caused significant decreases in mean pulmonary arterial pressure of 11 +/- 5, 12 +/- 6, and 18 +/- 5% at doses of 100, 300, and 1,000 micrograms/kg, respectively. In contrast to its depressor effect on mean pulmonary arterial pressure, E 4021 decreased mean systemic arterial pressure significantly (by 9 +/- 2%) at a dose of 1,000 micrograms/kg only. Heart rate and cardiac output were unchanged after the administration of E 4021. Tissue cGMP-specific phosphodiesterase activity was markedly higher in lung than in aorta. These results indicate that E 4021 is a relatively selective pulmonary vasodilator in chronically hypoxic pulmonary hypertensive rats. We conclude E 4021 may be useful for the treatment of pulmonary hypertension.

It is sometimes difficult to visualize the luminal borders of the vessel even by intracoronary ultrasound (ICUS), especially after coronary intervention. In this study, we evaluated the potential for improving visualization at intervention sites using contrast-enhanced ICUS and the suitable contrast agents for this procedure in humans. In 37 patients, ICUS (30 MHz) was performed with intracoronary injection (3 ml) of 7 different contrast preparations and without the contrast agents (control) after coronary intervention. The contrast agents used were as follows: saline solution, standard iomeprol, standard ioxaglate, sonicated iomeprol, sonicated ioxaglate, 50% Albunex, and 100% Albunex. Vessel wall delineation, contrast homogeneity (Grade 0-3), peak contrast intensity and shadowing were examined. Homogeneous and complete opacification of the vessel lumen and false lumen was observed with sonicated ioxaglate, 50% and 100% Albunex. Shadowing was not observed at all with sonicated ioxaglate and was uncommon with 50% Albunex, whereas 100% Albunex caused shadowing in all cases. The coronary delineation rate with the other contrast agents was only 50-70 %, and the homogeneity and peak intensity were relatively low. Thus, sonicated ioxaglate and 50 % Albunex both achieved good visualization, but the former is cheaper, stable and takes shorter to prepare. Large dissection in 5 patients were found by contrast-enhanced ICUS' whereas they were not detected by coronary angiography. All of them needed additional interventional therapy due to the results of contrast-enhanced ICUS. In conclusion, contrast-enhanced ICUS is useful for evaluation of the results by intervention therapy, and of the agents we studied sonicated ioxaglate is best for contrast-enhanced ICUS.

Although acetaminophen (APAP) method is widely used to evaluate the gastric emptying rates of liquids in Japan, patients need to take a large dose of APAP. A scintigraphic technique requires the gamma camera. In this present state we try to search for an alternative method, which is easy to perform and noninvasive for the patient. 13C-acetate breath test and APAP method were performed at the same time in 59 patients after overnight fasting. The liquid test meal OKUNOS-A (200 ml, 200 kcal), contained APAP (20 mg/kg) and 13C-acetate 100 mg was orally administered to the patient. Breath sampling for 13CO2 measurements was obtained every 5 min up to 20 min and every 10 min up to 90 min. Blood sampling for plasma APAP concentration was collected 15, 30, 45, and 60 min after oral administration of the test meal. The time of 13CO2 peak excretion in 13C-acetate breath test was ranged from 50 to 70 min in 37 out of 59 patients. Plasma APAP concentration at 45 min in over 80 min group was significantly lower than in 50-70 min group. In contrast, that in under 40 min group was significantly higher. 13CO2 breath excretion at 30-40 min correlated with plasma APAP concentration at 45 min significantly. These results suggest that optimal sampling time of breath test is 20-40 min. In conclusion, 13C-acetate breath test is reliable as a qualitative analysis, easy to perform, and a noninvasive method without taking blood and radiation exposure for a measurement of gastric emptying rates.

A 62-year-old man with a history of hereditary spherocytosis had an abnormal shadow on a chest X-ray film, but the shadow was not examined further. The patient was admitted to our hospital because of severe anemia, multiple gallstones, and splenomegaly. Acute cholecystitis developed due to gallstones. A smear of peripheral blood showed spherocytosis, and the osmotic fragility as measured by Parpart's method was abnormally high. These findings are consistent with hereditary spherocytosis. Splenectomy and cholecystectomy were done. The chest X-ray film, CT scan, and MRI revealed multiple well-demarcatd paravertebral masses. A biopsy of a mediastinal mass was done with an ultrasonically guided needle, and hyperplasic erythroid hemopoietic tissue was obtained. This finding led to the diagnosis of extramedullary hematopoeisis. We think extramedullary hematopoeisis should be included in the differential diagnosis of posterior mediastinal masses.

We encountered two cases in which pulmonary eosinophilic granuloma improved after cessation of smoking. The patient in case 1 was a 39-year-old woman. She smoked 10-15 cigarettes a day for 20 years. The patient in case 2 was a 19-year-old man. He smoked a pack of cigarettes a day for 5 years. CT revealed cystic lesions and small nodular lesions predominantly in the upper and middle lung fields. Diagnosis was made by thoracoscopic lung biopsy in case 1 and by transbronchial lung biopsy in case 2. After smoking cessation, symptoms, CT findings, and vital capacity of both patients improved remarkably. Smoking cessation may have been related to the improvement in these patients.

Left ventricular (LV) diastolic filling during isometric exercise was evaluated in patients with syndrome X using pulsed Doppler echocardiography. The handgrip exercise was performed by 12 normal subjects (group N), 14 patients with syndrome X (group X), and 20 patients with effort angina, who were divided into 13 patients with single vessel disease (group SVD) and seven patients with multiple vessel disease (group MVD). The transmitral inflow patterns before and at the end of exercise were recorded using Doppler flowmetry, to measure the peak velocity of early diastolic flow (E) and the peak velocity of atrial contraction flow (A). The A/E ratio and the % change in A/E (% A/E) at the end of exercise compared with those before were calculated. 1. Group N: E, A, and A/E did not change significantly. 2. Group X: E decreased, A increased, and A/E increased. 3. Group SVD: E did not change significantly. A increased, and A/E increased. 4. Group MVD: E decreased, A increased, and A/E increased. 5. % A/E in group X and group MVD were larger than in group SVD. 6. Systolic blood pressure (SBP) and heart rate (HR) increased during exercise to the same extent in each group. The impairment of LV diastolic filling in group X was more severe than in group SVD, possibly due to more extensive ischemic areas in group X than in group SVD. The extension of ischemic areas in syndrome X may be similar to that in group MVD.

Successful radiotherapy was performed for three post-operative hepatocellular carcinoma patients, two with bone metastases and one with lymph node metastasis. One patient had severe high back pain and paraplesia caused by spinal compression with bone metastasis on 5th thoracic vertebra. After a total of 45 Gy irradiations, the back pain was removed, and 9 months later the patient recovered from the paraplesia gradually and could start rehabilitation. A second patient with multiple bone metastases was very concerned about skull metastasis and severe headache. Radiation reduced the headache and the tumor vanished. A third patient with cervical lymph node metastasis was irradiated. The size of the lymph node was decreased but did not disappear. We concluded that radiotherapy for distant metastases (ie, bone, skin) in a hepatocellular carcinoma patient, can be an effective therapeutic procedure for patient complaints.

In this study of 10 patients with sick sinus syndrome, we examined the benefits of a single-chamber ventricular pacing system that utilizes a sensor to detect the QT interval and then adjusts the heart rate. Changes in exercise tolerance capacity and cardiac function were evaluated when the pacing mode was changed from rate-variable mode (VVIR) to fixed-rate mode (VVI). Anaerobic threshold (AT), peak VO2 and cardiac output were measured in VVIR, during short-term VVI(VVI-S), which occurred two hours after the pacing mode was changed, and during long-term VVI (VVI-L), which occurred one month after the pacing mode was changed. 8 of 10 cases (80%) had their own beats during exercise. The AT and peak VO2 during VVI-S were not different from those during VVIR. However, AT and peak VO2 during VVI-L were significantly lower than those during VVIR pacing. (Respectively, 11.7 +/- 2.4 vs. 16.4 +/- 3.3, p0.01; 21.5 +/- 5.9 vs. 24.6 +/- 6.2, p0.01). At AT and peak VO2, there were no differences in cardiac output between VVIR and VVI-S, or between VVIR and VVI-L(NS). Physiologic changes in heart rate and cardiac output after exercise during VVIR were greater than those during VVI pacing. The present study suggests the above-mentioned changes after exercise effect, oxygen consumption in the peripheral circulation, which might lower exercise tolerance capacity in the chronic phase. The rate-variable pacing mode might improve exercise tolerance capacity and may be of benefit for patients with sick sinus syndrome.

The clinical and pathological features of siblings with infantile neuroaxonal dystrophy were reported. Early clinical symptoms were marked hypotonia in legs, mental regression and poor vision. Laboratory data were normal except for the mild elevation of GOT and LDH in serum and cerebrospinal fluid. MRI showed progressive atrophy of cerebellar vermis and brainstem. EEG showed a progressive increase in the amount and amplitude of the fast activities over the age of 3 years. Auditory brainstem response (ABR) showed progressive worsening with no response by 2 years and 6 months. Somatosensory evoked potentials (SEP) showed no cortical response by 4 years. Nerve conduction velocity (NCV) of both motor and sensory nerves was within normal limits. Pathologically, spheroid bodies were found in the axons of central and peripheral nerves, remarkably in brainstem and dorsal column. MRI, ABR and SEP findings were clinically useful, suggestive of the degeneration of brainstem.

Primary coronary artery dissection occurring as a spontaneous event and not associated with trauma due to catheter manipulation is rare. We recently experienced (a case of) a 52-year-old man with primary artery dissection. He was admitted to our hospital with severe chest pain as his chief complaint on September 6, 1988. Electrocardiography and laboratory data showed acute inferior myocardial infarction. He was treated with medication and underwent coronary angiograms on October 3, 1988. Right coronary angiogram revealed an intimal flap and false lumen. But right coronary angiograms 6 months after the onset of myocardial infarction revealed progression of stenosis but no intimal flap, and coronary spasm was not evoked after acetylcholine administration. Primary coronary artery dissection has been reported since Pretty's first description of it in 1931. The majority of earlier cases were diagnosed at autopsy, but recently reports of survivors have been increasing due to the progress in and popularization of coronary angiographic technics. This case is the 46th case of primary coronary dissection found by coronary angiography. So it is not extremely rare. In our case the involved artery was the right coronary artery. In survivors, right coronary artery dissection is more frequent than left, because the area supplied by the right coronary artery is smaller than the area supplied by the left one. Although in our case coronary artery stenosis progressed, after a long term resolution of dissection may occur. There are a few cases in which resolution of dissection occurred naturally.(ABSTRACT TRUNCATED AT 250 WORDS)

To study the functional change of masticatory muscles during growth and development, frequency analyses of surface electromyogram (EMG) power spectra were carried out. The subjects were six children (five males and one female), aged 4.5 +/- 0.2 years, having full deciduous dentition (Hellman's dental age IIA) and six adults (four males and two females), aged 27.7 +/- 3.8 years, having full permanent dentition. EMG signals were recorded bilaterally by using bipolar silver-surface electrodes from the anterior temporal and masseter muscles while the subjects were chewing gum and while performing maximum clenching in the intercuspal position. A fast Fourier transform algorithm was used to obtain the power-spectral density function and the power spectra of the EMG signals. Since the total power value from 62.5 to 1000 Hz was 100 percent, the frequencies at 25, 50, 75, and 90 percent of the cumulative power were calculated. The results showed that the frequencies at every percent of the cumulative power were age-dependent and that the EMG power spectra patterns in adult muscles were shifted to significantly lower frequencies than those in child muscles. The shift was probably caused by differences in the proportion of fiber type and fiber size between muscles of children and adults.

A significantly lower incidence of DDS, hypotension, and impending shock was found during and after hemofiltration as compared with conventional hemodialysis. Hemofiltration, in contrast to hemodialysis, showed less decrease of circulating plasma volume, mild change in plasma osmolality without red cell swelling, better compensation of acidosis despite less uptake of acetate, more stable PCO2 during the procedure, less paradoxical acidosis in cerebrospinal fluid, and a lower urea concentration gradient between cerebrospinal fluid and plasma. These phenomena might be explained by better mass transfer between compartments bithin the body during hemofiltration. Mass transfer from the intracellular as well as the extracellular space to circulating plasma occurred more rapidly and smoothly during HF than during HD. HF is preferable to HD in patients with severe cardiovascular complications such as hypertension, as well as hypotension and cardiac failure, and in those subject to DDS during HD. Accordingly, hemofiltration therapy promises patients more comfortable and more stable treatment of chronic uremia.

An enzyme system that catalyzes the conversion of L-tryptophan to 5-hydroxy-L-tryptophan was studied in the 5,000 × g supernatant fraction of 0.25 M sucrose homogenate of the rat small intestine. The reaction proceeded in the presence of ascorbic acid under aerobic conditions. The enzyme did not require cupric ion.

The value and change with time of the impedance of surface EMG electrodes and the effects of their difference between the bipolar electrodes on the electromyographic activity from the anterior temporal muscle and the masseter muscle in six adult male subjects with normal occlusion were studied. The results were as follows: 1. In the anterior temporal muscle, if the impedance of the electrode was under 20 k omega it was stable from just after the electrode disc was applied to the skin. In the masseter muscle, if the impedance was under 30 k omega it became stable within two minutes after the electrode was applied. 2. The difference of impedance between the bipolar EMG electrodes did not correlate with EMG activity.

The factor IX genes in four Japanese families with haemophilia B were analysed for the restriction fragment length polymorphisms (RFLPs) ofTaqI,XmnI andDdeI, using subcloned intragenic DNA fragments as probes (probes VIII and XIII). The factor IX genes in 12 patients with haemophilia B and three high-responder-inhibitor cases showed no size difference using a cDNA probe (cVII) when restricted byTaqI,EcoRI andHindIII. Complete gene deletions were observed in two other high-responder-inhibitor cases.

For the investigation of the functional change of the masticatory muscles along with growth and development, the frequency analysis of the EMG power spectrum was carried out. The subjects were 6 children (5 males and 1 female) with full deciduous dentition (Hellman's dental age IIA) aged 4.5 +/- 0.2 years and 6 adults (4 males and 2 females) with full permanent dentition aged 27.7 +/- 3.8 years. EMG signals were recorded bilaterally by means of bipolar silver surface electrodes from the anterior temporal and masseter muscles when the subjects were chewing chewing gum or performing maximum clenches in the intercuspal position. A fast Fourier transform (FFT) algorithm was used to obtain the power spectrum of the EMG signal. As the total power value from 62.5 to 1000 Hz was 100 per cent, the mean frequencies at 25, 50, 75 and 90 per cent of the cumulative power were calculated. The results were as follows: 1. The mean frequencies at each ratio of the cumulative power were age-dependent and EMG power spectrum patterns significantly shifted to lower frequencies in the muscles of the adults. 2. No statistically significant differences between the chewing and clenching, the anterior temporal and masseter muscle and the left and right side were observed in each group.

Carriers of haemophilia A were detected in 20 Japanese families with using the factor VIII gene probe (F8A) and the gene-linked ST 14-1 probe. Polymorphism by the use of theBclI and F8A probe detected the smaller allele (0.9 kb) in 86% and the larger allele (1.2 kb) in 14% of the 65 normal X chromosomes. The frequency ofBclI polymorphism was 30% in 30 normal fameles. In six out of 20 haemophilia A families, the haemophilia gene was identified byBclI allele polymorphism. The use ofTaqI and the ST 14-1 probe detected 11 carriers in 20 haemophilia A families. In 14 families (70%), either theBclI polymorphism in the factor VIII locus orTaqI polymorphisms in the ST 14 locus was useful for carrier detection.

Disappearance of an inhibitor to factor IX in an 11-year-old boy with haemophilia B is described. He had been given a total of 14,200 units of a prothrombin complex concentrate (PCC) before an inhibitor to factor IX developed. He subsequently received four separate infusions of PCC and his inhibitor titre rose in response to the treatment for the following 4 years. No inhibitor is presently detected despite repeated administration of PCC. Immunological characterization of the inhibitor by inhibitor neutralization assays, modified crossed-immunoelectrophoresis and enzyme-linked immunosorbent assay demonstrated that it contained IgG2 and IgG4 heavy chains and kappa and lambda light chains. No large deletion of the factor IX gene in the patient was observed using cDNA (cVII).

Mastication has attracted considerable attention in recent years for its effects on the postnatal growth and development of the mandible, brain, salivary glands and other organs in children. In this study, the relationship between mastication and growth and development of the salivary glands was examined, because the salivary glands are rich in growth factors and many kinds of biological polypeptides, and have endocrine and exocrine actions and effects, on the growth and metabolic rates in developing animals. The experiment utilized two groups of male mice, a control group fed a solid diet, and an experimental group receiving the paste diet ad lib. In the experimental group fed the paste diet, the increase of the tissue weights and the contents of DNA and RNA in the parotid and submandibular glands were lower than those of the control group. Also the rise of amylase activity in the parotid glands was depressed. Next, the polyamine metabolism in the parotid and submandibular glands was examined. The activities of the late limiting enzymes in polyamine syntheses, ornithine decarboxylase and S-adenosylmethionine decarboxylase and the lev- putrescine and spermidine in both parotid and submandibular glands were in the experimental group. These results suggest that mastication plays an important roles in the growth development of the parotid and submandibular glands in mice.

For the investigation of the functional change of the masticatory muscles along with growth and development, electromyographic evaluation was carried out. The subjects were 6 children (5 males and 1 female) with full deciduous dentition (Hellman's dental age IIA) aged 4.5 +/- 0.2 years and 6 adults (4 males and 2 females) with full permanent dentition aged 27.7 +/- 3.8 years. EMG signals were recorded bilaterally by means of bipolar silver surface electrodes from the anterior temporal and masseter muscles when the subjects were chewing chewing gum or performing maximum clenches in intercuspal position. The cumulative power values from 62.5 to 1000 Hz in the EMG power spectrum during chewing or clenching were calculated as the muscle action potential. The ratio of the action potential of each muscle to the total action potential of four muscles were analyzed. Masticatory rhythm during chewing was analyzed by means of the time parameter (duration, interval and cycle) and their coefficients of variation. The results were as follows: 1. In children the temporal muscles predominated in chewing and clenching, whereas in adults there were three types with Temporal muscles predominating, Masseter muscles predominating and both muscles sharing equally. 2. No statistically significant differences between children and adults were observed in the duration, interval and cycle. 3. In adults the coefficients of variation of the duration, interval and cycle were smaller and the masticatory rhythm was more stable than in children.

A new variant of von Willebrand disease (vWD) was identified by a new analytic method which characterizes the ability of plasma von Willebrand Factor (vWF) to bind to purified factor VIII (F.VIII). vWF was isolated from small amounts of plasma by immunoadsorption with a selected monoclonal antibody to vWF previously coated onto wells of microtitration plates. Plasma F.VIII was removed from immobilized vWF by washing with 0.4 mol/L CaCl2; purified F.VIII was then added to the well. The amount of bound F.VIII was estimated directly in the wells by a chromogenic assay and immobilized vWF was estimated by an immunologic a pool of normal plasma, ten control individuals, 13 with hemophilia A and five with type I vWD. In all cases, the dose-response curves were linear and the slopes of the regression lines were essentially the same. The method was then applied to investigate the binding of vWF to F.VIII in two vWD patients (sister and brother) who demonstrated significantly lower activity of F.VIII than of vWF. The first patient, with a long history of epistaxis, bruising, and hematomas, showed a slightly prolonged bleeding time (10 minutes); 15% VIII:C and 39% of vWF:Ag and vWFRCo. Her brother, who has a bleeding syndrome but no hematomas, showed similar data (bleeding time 9 minutes, 20% VIII:C, 53% vWF:Ag and vWFRCo). Similar levels of F.VIII were observed in the two propositi by four different methods (one- and two-stage clotting and chromogenic and immunologic assays). Sodium dodecyl sulfate (SDS) 1.4% agarose gel electrophoresis showed that all multimers of vWF were present in both patients. vWF binding to F.VIII was markedly decreased in the two propositi. The abnormal binding of vWF to F.VIII was not corrected during pregnancy or after infusion of 1-deamino (8-D-arginine) vasopressin despite an increase in vWF levels. The qualitative abnormality of vWF in both patients was associated with a subtle alteration of the multimeric structure by SDS 3% agarose gel electrophoresis in which the two central subbands of the quintuplet of individual oligomers were undetectable or poorly visible. SDS-polyacrylamide gel electrophoresis under reducing conditions demonstrated a single band of 275 Kd in the plasma of both patients, and there was no evidence of a second band corresponding to pro-vWF, the precursor of the mature vWF subunit, suggesting that proteolytic processing of vWF was normal.(ABSTRACT TRUNCATED AT 400 WORDS)