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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.

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.

Background and purpose To confirm the feasibility of accelerator-based BNCT (AB-BNCT) for treatment of multiple liver tumors and malignant pleural mesothelioma (MPM), we compared dose distribution and irradiation time between AB-BNCT and reactor-based BNCT (RB-BNCT). Material and methods We constructed treatment plans for AB-BNCT and RB-BNCT of four multiple liver tumors and six MPM. The neutron beam data on RB-BNCT were those from the research reactor at Kyoto University Research Reactor Institute (KURRI). The irradiation time and dose–volume histogram data were assessed for each BNCT system. Results In BNCT for multiple liver tumors, when the 5 Gy-Eq dose was delivered as the mean dose to the healthy liver tissues, the mean dose delivered to the liver tumors by AB-BNCT and RB-BNCT was 68.1 and 65.1 Gy-Eq, respectively. In BNCT for MPM, when the mean lung dose to the normal ipsilateral lung was 5 Gy-Eq, the mean dose delivered to the MPM tumor by AB-BNCT and RB-BNCT was 20.2 and 19.9 Gy-Eq, respectively. Dose distribution analysis revealed that AB-BNCT is superior to RB-BNCT for treatment of deep-seated tumors. Conclusions The feasibility of the AB-BNCT system constructed at our institute was confirmed from a clinical viewpoint in BNCT for multiple liver tumors and MPM.

It is possible to accurately recognize the shape of an object or to grip it by setting soft tactile sensors on a robot's hands. We studied a multichannel soft tactile sensor as an artificial hand and evaluated the pressure's response performance from several directions and the slipping and sliding responses. The tactile sensor consisted of multiple pneumatic sensors and a soft cap with a fingerprint structure that was made of silicone gum and was separated from multiple spaces. Evaluation tests showed that the multiple soft tactile sensors estimate both an object's contact force and its contact location. Our tactile sensor also measured the object's roughness by the slide on surface texture.

We developed a robot hand with three fingers and controlled them using underactuated control to obtain a more flexible grip. With underactuated control, we can flexibly operate an artificial robot hand and reduce the number of actuators. The robot fingers had three joints to imitate human fingers. One finger was driven by one wire and one servo motor for bending and by three torsion springs for extension. We also developed a soft tactile sensor having three pneumatic sensors and mounted it on front of each robot fingers. We obtained the following information from our experimental examinations of the robot hand. It adaptively grasped an object by underactuated control. The soft tactile sensor deftly touched an object, and the data showed the contact position with. By analyzing the data from tactile sensors, we obtained the rough information of the object's shape.

The aim of this study was to establish and confirm the safety of administering 1110MBq of 131I to outpatients.Total radiation exposure from patients to household members was hypothesized from the measured dose rate at 1 m when the patient is released. Actually we also measured the effective dose to household members who assisted outpatients during the first 7 days after the administration of 131I by personal dosimeter. A list of radiation safety precautions is given to the patient and household members. Behavioral reports about the distances and times of close contact throughout the 7 days are requested of each household member.The effective dose measured using the personal dosimeter to all household members employing several safety precautions was confirmed to be lower than the hypothesized dose calculated using our formula. And the mean whole-body effective dose rate over the 7 days in household members was 0.05±0.08 (range, 0.05 to 0.43) mSv, which specify that radiation exposure to household members of the outpatients who have just received ablative radiation therapy must be below 5.0 mSv/event.Remnant thyroid ablation with 1110MBq for outpatients showed that the radiation doses to household members were within the recommended constraint dose according to several safety precautions. The method of returning home after remnant thyroid ablation is thought to be the most important factor that determines the effective dose to household members of outpatients.

Pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV) treatment fails to achieve a sustained virological response (SVR) in approximately 20-50% of patients with chronic hepatitis C virus (HCV) infection. We assessed the contribution of an anti-IFN-α neutralizing antibody (NAb) on the nonresponse to treatment. NAbs were detected using an antiviral assay that assessed the neutralizing effects of serum samples against IFN. Serum samples were obtained at the end of the treatment and evaluated for the presence of NAbs using recombinant IFN-α as a standard. We studied 129 PEG-IFN-α/RBV-treated patients. In the 82 end-of-treatment responders, no NAbs were detected. Of the 47 patients who did not respond, seven (15%) were positive for NAbs. We also examined an additional 83 patients who had not responded to PEG-IFN-α treatment, and detected 12 with NAbs. Patients with good IFN-responsive characteristics, including HCV genotype 2/3 and major allele homozygotes for interleukin-28B, were included in the 19 patients with NAbs. No NAbs interfered with the antiviral activity of natural human IFN-β (nIFN-β) and re-treatement of patients with NAbs with nIFN-β/RBV achieved SVR. Our analyses revealed that the emergence of anti-IFN-α NAbs was a candidate causal factor of PEG-IFN-α-treatment failure. Therefore, these antibodies should be assayed in patients who do not respond to PEG-IFN-α therapy, and if detected, other effective treatments, i.e., medications that are not neutralized by anti-IFN-α NAbs, should be considered.

In order to generate epithermal neutrons for boron neutron capture therapy (BNCT), we proposed the method of filtering and moderating fast neutrons, which are emitted from the reaction between a beryllium target and 30 MeV protons accelerated by a cyclotron, using an optimum moderator system composed of iron, lead, aluminum, calcium fluoride, and enriched (6)LiF ceramic filter. At present, the epithermal-neutron source is under construction since June 2008 at Kyoto University Research Reactor Institute. This system consists of a cyclotron to supply a proton beam of about 1 mA at 30 MeV, a beam transport system, a beam scanner system for heat reduction on the beryllium target, a target cooling system, a beam shaping assembly, and an irradiation bed for patients. In this article, an overview of the cyclotron-based neutron source (CBNS) and the properties of the treatment neutron beam optimized by using the MCNPX Monte Carlo code are presented. The distribution of the RBE (relative biological effectiveness) dose in a phantom shows that, assuming a (10)B concentration of 13 ppm for normal tissue, this beam could be employed to treat a patient with an irradiation time less than 30 min and a dose less than 12.5 Gy-eq to normal tissue. The CBNS might be an alternative to the reactor-based neutron sources for BNCT treatments.

Coronary artery disease is one of the major causes of morbidity and mortality in industrialized countries, including Japan. Increasing numbers of patients have been treated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), but there is little information in Japan concerning the use of revascularization therapy and the facilities. The Japanese Coronary Intervention Study (JCIS) Group conducted a nationwide survey on coronary revascularization procedures and facilities during 1997. A questionnaire was mailed to the presidents or designated delegates of 8,253 laboratories in 7,986 hospitals that had departments of internal medicine and/or cardiovascular medicine and to 578 facilities in 558 hospitals identified by the PCI survey as performing CABG and/or registered in the annual survey carried out by the Japanese Association for Thoracic Surgery. A total of 109,788 PCIs were performed at 1,023 laboratories, and 17,667 CABGs at 477 facilities. PCI and CABG numbers per 10(6) population were 870 and 140, respectively. The ratio of PCI to CABG was 6.2. The numbers of PCI laboratories and CABG facilities per 10(6) population were 8.1 and 3.8, respectively. The majority of PCI laboratories and CABG facilities had a small annual volume: 44% of PCI laboratories and 77% of CABG facilities had annual volumes of 50 or less. Only half of the PCI laboratories had surgical backup on-site. Despite the small volume for each facility, coronary revascularization, especially PCI, is highly utilized in Japan.

A nation-wide survey on the procedures and facilities of coronary revascularization, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) conducted by the Japanese Coronary Intervention Study (JCIS) group during 1997 revealed that PCI is more often used than CABG and is mainly carried out in low-volume facilities without surgical backup. The present study aimed to investigate the temporal changes in the usage of revascularization therapies and facilities from 1997 to 1999. A questionnaire was mailed in 1998 to the delegates of 1,086 PCI and 582 CABG facilities identified by the previous survey, and 89% of PCIs surveyed and 94% of CABGs surveyed reported back. The number of PCI procedures had increased by 19% from 97,831 to 116,479 and that of CABG procedures also increased by 21% from 16,374 to 19,846. The ratio of PCI to CABG was 5.9 in 1999, showing no significant change from 6.0 in 1997. In parallel, the number of PCI and CABG facilities increased from 888 to 941 and from 442 to 453, respectively. The use of coronary stents and other interventional devices increased during these 2 years. Coronary stents were used regardless of the annual procedural volume of the facilities, whereas other interventional devices, directional and rotational coronary atherectomy, were used mainly in the high-volume laboratories (p0.01). Beating-heart, off-pump CABG had increased from 2% to 11% of total cases. Continued monitoring of trends in PCI and CABG facilities and procedures will be needed for nation-wide assessment of the use of new technology.

Although the distribution of atherosclerosis at the curved coronary segments has implications for atherogenesis and interventional procedures, few data exist regarding the plaque distribution in these sites. Therefore, we prospectively analyzed the intravascular ultrasound images of 55 coronary sites from 37 patients where the atherosclerotic plaque and pericardium were simultaneously demonstrated by intravascular ultrasound. The pericardial images were defined as a high-intensity linear echo image moving during cardiac cycles outside the vessel wall. By the line that was parallel to the pericardial image, the vessel area was divided into 2 semicircles with the same area, namely myocardial and pericardial sides. In each side, the maximal thickness, area, and percent area of plaque were measured. The plaque thickness and area of the myocardial side were significantly greater (1.5 +/- 0.5 mm, 4.9 +/- 2.1 mm or 66%, mean +/- SD) than those of the pericardial side (1.1 +/- 0.4 mm, 3.5 +/- 2.1 mm2 or 45%, p0.01). The maximal plaque thickness was positioned at the point with a mean angle of 139 +/- 37 degrees from the point just facing the pericardial image, indicating that atherosclerosis was eccentrically located on the opposite side of the pericardium in these coronary segments, and suggesting that the side of the pericardial image represents the outer curvature of the coronary artery. These results indicate that the pericardial images can be seen by intravascular ultrasound, facilitating the recognition of the disease distribution in situ. The eccentric plaque located on the inner wall at the curved coronary segments, probably due to uneven local shear stress, may have implications for the interventional procedures for these segments.

Regional vessel wall distensibility was determined by measuring luminal area and pressure, using intravascular ultrasound (Sonicath; Boston-Scientific, Watertown, MA, USA; 3.5 Fr, 30 MHz) in 45 left coronary sites from 40 patients. Luminal area in diastole (A) and in systole was measured at the diseased sites. With the ratio of luminal area changes (dA) to coronary pressure changes (dP) during a cardiac cycle, the total distensibility index was calculated by the formula: [(dA/A)/dP] x 10(3). At sites with non-circumferential disease, perimeters in diastole (L) and in systole were measured at the normal and diseased portions, and the changes in perimeters (dL) during a cardiac cycle were calculated. The regional distensibility index was obtained by the formula: [(dL/L)/dP] x 10(3). In 22 sites with circumferential disease, the total distensibility index was 1.03 +/- 0.61/mmHg, significantly lower than that for 23 sites with non-circumferential disease (1.45 +/- 0.89/mmHg; P0.05). In non-circumferential disease, the regional distensibility index at the diseased portion was significantly lower (0.33 +/- 0.47/mmHg) than that at the normal portion (1.11 +/- 0.75/mmHg; P0.01). Coronary sites with residual non-circumferential disease after angioplasty also exhibited heterogeneity of regional distensibility (0.73 +/- 0.76 at disease sites versus 1.58 +/- 0.95/mmHg at normal sites, n = 10, P0.05). These results indicate that heterogeneous regional wall distensibility exists at sites with non-circumferential disease where the total vessel distensibility is preserved by the presence of compliant normal portion. This heterogeneity of regional wall distensibility may represent a biomechanical factor that explains the mechanism of plaque rupture that occurs mainly at the shoulder of the non-circumferential disease.

Myocardial uptake of iodine-123 meta-iodobenzylguanidine (123I-MIBG) was measured using scintigrams at rest in 12 patients with isolated, nonischemic mitral regurgitation (MR; regurgitant fraction 64% +/- 7%) and was related to the left ventricular (LV) function assessed by cardiac catheterization. Iodine-123 meta-iodobenzylguanidine activity in the upper mediastinum, liver, and lung was comparable between MR and control (n = 8) patients. The heart-to-mediastinum 123I-MIBG activity ratio 4 hours after injection was significantly (p0.01) decreased in MR (2.0 +/- 0.1, mean +/- SE) compared with control (2.7 +/- 0.1) with the increased clearance of MIBG. In addition, MR patients had significantly greater heterogeneity in the 123I-MIBG distribution within the myocardial images (26.1% +/- 2.1% intraimage variability for MR versus 15.6% +/- 0.8% for control, p0.01). Myocardial 123I-MIBG activity correlated positively with cardiac index and negatively with pulmonary capillary wedge pressure and LV volume indexes. Thus, 123I-MIBG scintigrams can be a noninvasive method for assessing the contractile dysfunction in MR.

The purpose of this study was to assess feasibility and safety in the diagnosis of coronary artery in the diagnosis of coronary artery disease and myocardial ischemia using adenosine triphosphate (ATP) stress echocardiography. ATP, a product of human myocardial tissue, is more potent than adenosine in increasing coronary blood flow. Like adenosine, ATP also has a short half-life (10 s). Left ventricular echocardiograms were recorded during step-wise infusions of ATP in 86 patients who underwent coronary angiography and stress thallium 201 scintigraphy. No serious complications occurred with ATP infusion and most of the side effects were mild and transient. Significant coronary artery disease (75% diameter stenosis) was present in 34 of 48 patients who had normal echocardiograms at rest. The sensitivity and specificity of ATP-induced wall motion abnormalities for coronary artery disease was 65% (22 of 34) and 100% (14 of 14), respectively. The sensitivity was 50% (10 of 20) in those with one-vessel disease and 86% (12 of 14) in those with multivessel disease (P.05). In patients with normal echocardiograms at rest and without prior myocardial infarction, the sensitivity of ATP stress echocardiography for the detection of myocardial ischemia assessed by 201Tl single proton emission computed tomography was 58%, with a specificity of 76%, and a diagnostic accuracy of 66%. The sensitivity was 43% in those with one-vessel disease, and 86% in those with multivessel disease (P = .05). In patients with prior myocardial infarction, the sensitivity of ATP stress echocardiography for the detection of viable but jeopardized myocardium was 81%, with a specificity of 91%. The patients with well-developed collateral circulation had a higher incidence of developing wall motion abnormality than those without collaterals (70% v 40%, P.01). ATP stress echocardiography is valuable for the assessment of coronary artery disease in patients with multivessel disease, coronary collaterals, and with prior myocardial infarction.

In order to evaluate the effect of recombinant human erythropoietin (rHuEPO) on autologous blood transfusion in patients with rheumatoid arthritis (RA), we performed a phase II clinical trial in 65 RA patients undergoing elective surgery. rHuEPO was administered subcutaneously once a week and after observing erythropoiesis, autologous blood was collected. Fifty-seven of the 58 patients who completed treatment responded to rHuEPO and could donate more than 400 ml of autologous blood. Among them, 23 out of 28 patients undergoing total hip arthroplasty, 27 out of 28 undergoing total knee arthroplasty and 1 out of 1 undergoing spinal surgery did not need homologous blood transfusion perioperatively. During rHuEPO treatment, no significant changes of clinical parameters of RA activity were observed. Two patients discontinued the treatment because of mild and transient side effects. These results indicate that subcutaneous rHuEPO is safe and effective in eliminate the need for homologous blood transfusion, even in anemic RA patients undergoing elective orthopedic surgery.

Preoperative blood reservation for autologous blood transfusion generally causes anemia. We performed a double blind controlled study to determine the optimal dose of subcutaneous rHuEPO (recombinant human erythropoietin, KRN5702) for preventing preoperative anemia due to blood reservation. Patients received KRN5702 subcutaneously once a week in a doses of 12000, 24000 or 36000 IU by a double blind technique. After storage of 1200 ml of their own blood right before surgery, their hemoglobin (Hb) averaged about 1 and was about 0.5 g/dl lower than the level before administration of KRN5702 in doses of 12000 and 24000 IU, respectively. This fall was significant. In patients receiving KRN5702 in a dose of 36000 IU, the level of Hb rose instead of a fall; Hb immediately before surgery was 1.1% higher than that before administration which, however, was not significant. This elevation indicates a possibility of abnormal elevation of Hb at this dose. The mean Hb value right before surgery was significantly lower in patients receiving 12000 IU KRN5702 than in patients of the other two groups. The recovery rate of Hb was an indicator to reflect improvement of anemic conditions, and increased as the dose increased after the blood reservation. The rate in the 12000 IU group was significantly lower than that in the other two groups; there was not much difference between the other two rates. We estimated that to reserve 1200 ml of autologous blood, 24000 IU of KRN5702 is adequate but not excessive. One patient receiving 24000 IU showed side effects including an elevation of body temperature, rash, and edema.

The Kupffer cells are sessile macrophages residing in the hepatic sinusoids. The Kupffer cells are well known as the first line of defence against pathogenic agents derived from not-self substances, in some cases even from self proteins. Indeed, Kupffer cells play an important roles in such a defence system: they act as an antigen presenting cells, and also produce various kinds of cytokines and chemical mediators such as prostaglandins, leukotrienes and platelet activating factor. In this article, we introduce these functions of Kupffer cells and discuss the possible pathway of the signal transduction.

Drug-induced allergic hepatitis is a tissue-specific inflammatory disease caused by hypersensitivity to a particular drug. Although the frequency of drug-induced allergic hepatitis appears to increase in proportion to the medicine, the mechanism by which tissue specificity is determined is still to be elucidated. In this study, we established CD4+ T cell clones specific for particular drugs from patients with drug-induced allergic hepatitis accompanied with mild blood eosinophilia and analyzed the possible role of liver protein as a directing factor of liver-specific inflammatory reactions. All CD4+ T cell clones obtained from two patients with this disease proliferated in response to a combination of the particular drug plus liver specific protein (LSP), which consists of over 30 proteins. Some T cell clones were responsive to an antigenic conformation consisting of the 200-kDa glycoprotein (partly purified LSP), a component of LSP, plus the causal drug. In contrast, all CD4+ T cell clones from a patient with simple drug-induced eosinophilia responded to the causal drug in the absence of LSP and partly purified LSP. These data suggested that LSP or partly purified LSP of the appropriate Ag is the target that leads to liver-specific inflammation in drug-induced allergic hepatitis. Furthermore, T cell lines derived from patients with drug-induced allergic hepatitis and simple drug-induced eosinophilia produced large amounts of IL-5 after the appropriate antigenic stimulation, whereas CD4+ T cell clones from donors with a normal amount of peripheral blood eosinophils secreted a much less IL-5. Taken together, these results indicate that overproduction of IL-5 by the allergen-sensitized T cells may result in blood eosinophilia.

To study the long-term effects of pharmacological combination therapy, a comparison was made of the haemodynamic changes in patients with cirrhosis and portal hypertension following a 4-week treatment of propranolol or nipradilol, a new nonselective beta-blocker with nitrovasodilating effect. Nipradilol (12 mg/dag, n = 12) significantly diminished wedged hepatic venous pressure (WHVP, 25 +/- 16%), the hepatic venous pressure gradient (HVPG, 20 +/- 12%), and estimated hepatic blood flow (EHBF, 18 +/- 16%). Propranolol (30 mg/day, n = 11) also caused a significant reduction in WHVP (22 +/- 21%) and HVPG (24 +/- 21%), but not in EHBF. The percentage of portal pressure reduction and the frequency of nonresponders did not differ between the nipradilol and propranolol groups. Both agents reduced heart rate by approx. 20%. Nipradilol, however, did not cause a significant reduction in cardiac index (CI) versus a 14% reduction by propranolol. Pulmonary capillary wedge pressure and central venous pressure, an index of preload, were decreased slightly in the nipradilol group. When nonresponders were excluded, there was a significant correlation of the percentage of reduction between WHVP and CI or systemic vascular resistance, in the nipradilol group. These results indicate that nipradilol may have potent hypotensive effects on portal hypertension, similar but not superior to propranolol. Nipradilol, at the dosage used in the present study, did not appear to exert a nitrovasodilating effect to enhance the portal pressure reduction induced by beta-blocking action.

Diffuse panbronchiolitis in two brothers is reported. The elder brother aged 46, was admitted in May 1983 due to severe dyspnea and productive cough, which had gradually worsened over several years. He had severe hypoxemia and hypercapnia. He died at age 47 of respiratory failure due to pseudomonas infection despite antibiotic therapy. The younger brother, at age 41, was admitted in March 1983 due to fever, productive cough, and abnormal shadows on chest X-ray films. He showed mild hypoxemia and his symptoms improved with antibiotic treatment. Since then he has been followed as an outpatient for over 7 years while taking 400 mg of Erythromycin per day, and he has had no exacerbation. These two cases had different clinical courses despite the facts that both had similar conditions of chronic sinusitis and appeared to be exposed to no special environmental or occupational hazards. These facts suggest that not only intrinsic factors, such as defenselessness of airways, but extrinsic factors such as viral, mycoplasmal, or bacterial infection may act together on the mechanisms of the onset and progression of diffuse panbronchiolitis.

The effect of plasma volume contraction induced by a 4-wk administration of spironolactone or furosemide on the hepatic venous pressure gradient was evaluated in consecutively allocated patients with cirrhosis and no ascites. In the spironolactone group (n = 15), the hepatic venous pressure gradient decreased significantly (p less than 0.005), by 21.8%, with a significant contraction of circulating plasma volume (p less than 0.01). Although there were no statistically significant correlations between the change in hepatic venous pressure gradient and changes in circulating plasma volume or in simultaneously determined systemic hemodynamics, a significant negative correlation (r = -0.74, p less than 0.01, n = 12) between the hepatic venous pressure gradient change and the post-treatment plasma aldosterone levels was found. However, in the furosemide group (n = 10), the hepatic venous pressure gradient and circulating plasma volume did not significantly decrease. Our data demonstrated a significant reduction in the hepatic venous pressure gradient on a chronic administration of spironolactone, which may have been due to volume contractions in patients with cirrhosis and no ascites.

A case of SLE with moderately deteriorated renal function due to lupus nephritis developed cryptococcal meningitis. Long term administration of amphotericin B (cumulative dose 5 g) combined with 5-flucytosine eradicated this fungal infection. Throughout amphotericin B administration urinary excretions of Na and K, as well as plasma HCO3 concentration were monitored, and, Na, K and HCO3 were supplemented orally and intravenously so much as to replace their urinary losses. Neither prominent water-electrolyte disturbance nor severe azotemia, which are the most serious side effects of amphotericin B, did not ensue. This case study indicates that sufficient water.electrolytes supplementation is important to prevent the nephrotoxicity of amphotericin B.

An intracellular membrane-free, trypsinlike protease was isolated from cells of Bacteroides gingivalis 381. The protease was extracted from the cells by ultrasonic treatment and was purified about 250-fold with a recovery of 2% by sequential procedures. The properties of the protease were as follows: its optimal pH was 8.5; its activity was almost completely lost on incubation at 50 degrees C for 15 min; its activity was inhibited by diisopropylfluorophosphate, p-toluenesulfonyl-L-lysine chloromethyl ketone hydrochloride, leupeptin, Mn2+, Cu2+, and Zn2+; it hydrolyzed casein, azocasein, N-alpha-benzoyl-DL-arginine-p-nitroanilide (BAPNA), bovine serum albumin, azocoll, and gelatin, but not N-alpha-benzoyl-DL-lysine-p-nitroanilide or human serum immunoglobulin A; its molecular weight was estimated as 45,000 by gel filtration and 50,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis; and its Km values for azocasein and BAPNA were 1.11% and 0.19 mM, respectively.

The double contrast hysterography, which was performed by the continuous CO2 insufflation with the ordinary HSG, was applied to 162 infertile patients. Forty-nine of 162 patients showed the abnormal findings by this method. Hysteroscopic or histological examinations revealed that 26 of these patients had hyperplasia, 15 had polyp, 2 had myoma and 1 had intrauterine foreign body. When these results were compared with those obtained by ordinary HSG, it was found that the double contrast hysterography would be more useful to investigate the detailed intrauterine changes such as hyperplasia or polyp than the ordinary HSG, and, therefore, would be a useful aid in the clinical care.

Identification of mutagenic factors in foods is of concern because they may represent carcinogens to man. Cooked foods, especially their basic fractions containing heterocyclic amines, have high mutagenicity; the neutral fractions containing mutagenic nitropyrenes, however, have not been studied in detail. The mutagenicity of various grilled foods--10 vegetables, 4 fish, and 4 kinds of meat with and without sauce--was studied. The concentration of 1-nitropyrene was measured after reduction by a specific nitroreductase purified from Bacteroides fragilis. 1-Nitropyrene was detected in grilled corn, horse-mackerel, and mackerel, and accounted for less than 10% of the total mutagenicity of the crude extracts in the Salmonella mutation test using strain TA98 in the absence of S9 mix. The mutagenicity of the diethyl ether-soluble basic fractions of meat grilled without a marinating sauce was very high. However, the sauce decreased the mutagenicity of the basic fractions and increased the mutagenicity of the neutral fractions. Moreover, considerable amounts of 1-nitropyrene were detected in pork and yakitori (grilled chicken) grilled with the sauce. The neutral fractions of yakitori grilled for 3, 5, and 7 min contained 3.8, 19, and 43 ng, respectively, of 1-nitropyrene per gram of yakitori, accounting for 3.0, 2.7, and 1.3%, respectively, of the total extract mutagenicity. We conclude that formation of 1-nitropyrene in the yakitori is due to pyrene produced by incomplete combustion of fat in the chicken, its nitration at acidic pH by nitrogen dioxide emitted by burning of cooking gas, and some components of the marinating sauce. Antimutagenic activity of edible mushrooms against 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indol (Trp-P-1) was also studied.

The purpose of this paper is to apply selective angiography to the shoulder joint based on anatomical quantitative study. Prior to the selective angiography, I made the arterial casts of adult cadavers (30 joints) to investigate the vascular distribution of the rotator cuff, and the arterial specimen of fetus cadavers (60 joints) using a modification of Teichmann's technique with cold injection medium to observe the types of origin of the main arteries roentgenographically. Results of these anatomical studies showed the rotator cuff to have 4 main arteries, and each tendon of the rotator cuff to have 2 or more arteries from the scapular side and the humeral side, forming a vascular network on the tendon. The critical zone of the vascular network was in the subacromial part of the rotator cuff where the selective angiogram showed a variety of abnormal vasculature in clinical cases with lesions at the supraspinatus tendon.

Despite a large number of papers concerning coronary spasm, its mechanism still remains unsolved. Several cases have been reported in which coronary spasm was triggered by allergy. Since histamine is one of the causative substances released in allergic reactions, we speculated on some involvement of an allergic mechanism in the pathogenesis of coronary spasm. We retrospectively examined by questionnaire the incidence of allergic history in patients with variant angina (n = 47) and compared it with that in patients with non-ischemic heart diseases (n = 83). We could not find any relationship between coronary spasm and allergy. Furthermore, we have not experienced any case in which myocardial ischemia was provoked by an allergic reaction. Accordingly, allergy could not be a major cause of coronary spasm in our present experience.

The effects of long-term aprindine administration on cardiac function were clinically investigated in seven patients with supraventricular or ventricular arrhythmias associated with organic heart disease. Three patients had normal cardiac function and four had various degrees of cardiac dysfunction before treatment with aprindine. The drug was administered orally in doses of 25 to 75 mg daily (mean +/- SD, 54 +/- 14 mg/day). The duration of follow-up ranged from six to 23 months (mean +/- SD, 14 +/- 6 months). An antiarrhythmic effect was achieved in five cases. No worsening or newly acquired symptoms or signs of cardiac dysfunction were recognized. No significant changes in end-diastolic dimension or ejection fraction were observed echocardiographically. Results of this study suggest that aprindine, which has been reported to have a negative inotropic action, does not cause significant deterioration of cardiac function even when given as long-term antiarrhythmic therapy to patients with cardiac dysfunction.