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The effect of a selective thromboxane synthetase inhibitor, OKY-046, and a selective 5-lipoxygenase inhibitor, AA-861, on bronchial responsiveness to acetylcholine was studied in 23 asthmatic subjects. The provocative concentration of acetylcholine producing a 20% fall in forced expiratory volume in one second (PC20 FEV1) was measured before and after oral administration of OKY-046 (3000 mg over four days) and AA-861 (1100 mg over four days) and inhalation of OKY-046 (30 mg) in 10, 10, and nine asthmatic subjects respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by oral OKY-046, oral AA-861, or inhaled OKY-046. The geometric mean value of PC20 FEV1 increased significantly from 0.55 to 2.24 mg/ml after oral OKY-046, but was unchanged after inhalation of OKY-046 and after oral administration of AA-861. These results suggest that thromboxane A2 may play a part in bronchial hyperresponsiveness to acetylcholine. [ABSTRACT FROM PUBLISHER]

To investigate the pathogenesis of acute myocardial infarction (AMI) and values of intracoronary aspiration thrombectomy (ICAT), we applied ICAT to reperfusion therapy using generally available intracoronary catheters to aspirate intracoronary occlusive tissues. We assigned ICAT or primary percutaneous transluminal coronary angioplasty (PTCA) to patients with evolving AMI (Thrombolysis In Myocardial Infarction (TIMI) trial grade 0), and investigated primary histopathologic, clinical, and angiographic outcomes in 43 patients treated with ICAT alone or followed by PTCA, and compared the outcomes with those in 48 patients treated with primary PTCA. No major complications (procedural death, emergent bypass graft surgery) occurred. Reconalization (TIMI grade 3 and 2) was achieved in 25 patients (58%) with ICAT alone and in 39 patients (91%) with ICAT alone or followed by PTCA. Aspirated thrombi were defined as recent thrombi in 21 cases (49%), atheroma in 6 (14%), no thrombi in 13 (30%), and organized thrombi in 1 case. In cases of recent thrombi, ICAT alone provided recanalization more frequently than in those of atheroma or no thrombi (18 of 21 [86%], 3 of 6 [50%], 4 of 13 [31%], respectively; p < 0.05; recent thrombi vs atheroma or no thrombi). There were no significant differences in primary recanalization rate (ICAT alone or followed by PTCA vs primary PTCA; 91% vs 92%) or incidence of complications between the 2 strategies. These results indicate that although the pathogenesis of AMI is heterogeneous in each individual case, intracoronary thrombus contributes little to the pathogenesis of average AMI, and therefore mechanical approaches may be feasible to maximize reperfusion therapies for AMI. [ABSTRACT FROM AUTHOR]

Macaque restricts hepatitis B virus (HBV) infection because its receptor homologue, NTCP (mNTCP), cannot bind preS1 on viral surface. To reveal how mNTCP loses the viral receptor function, we here solve the cryo-electron microscopy structure of mNTCP. Superposing on the human NTCP (hNTCP)-preS1 complex structure shows that Arg158 of mNTCP causes steric clash to prevent preS1 from embedding onto the bile acid tunnel of NTCP. Cell-based mutation analysis confirms that only Gly158 permitted preS1 binding, in contrast to robust bile acid transport among mutations. As the second determinant, Asn86 on the extracellular surface of mNTCP shows less capacity to restrain preS1 from dynamic fluctuation than Lys86 of hNTCP, resulting in unstable preS1 binding. Additionally, presence of long-chain conjugated-bile acids in the tunnel induces steric hindrance with preS1 through their tailed-chain. This study presents structural basis in which multiple sites in mNTCP constitute a molecular barrier to strictly restrict HBV., (© 2024. The Author(s).)

Hepatitis B virus (HBV), a leading cause of developing hepatocellular carcinoma affecting more than 290 million people worldwide, is an enveloped DNA virus specifically infecting hepatocytes. Myristoylated preS1 domain of the HBV large surface protein binds to the host receptor sodium-taurocholate cotransporting polypeptide (NTCP), a hepatocellular bile acid transporter, to initiate viral entry. Here, we report the cryogenic-electron microscopy structure of the myristoylated preS1 (residues 2-48) peptide bound to human NTCP. The unexpectedly folded N-terminal half of the peptide embeds deeply into the outward-facing tunnel of NTCP, whereas the C-terminal half formed extensive contacts on the extracellular surface. Our findings reveal an unprecedented induced-fit mechanism for establishing high-affinity virus-host attachment and provide a blueprint for the rational design of anti-HBV drugs targeting virus entry., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling., Methods: We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment., Results: Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations., Conclusions: These data suggest that atovaquone would be a potential candidate for treating mpox., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.026 to 0.89 μM) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the postentry step to reduce the intracellular production of virions. Knockdown of IMP dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. This evidence shows that IMPDH is a potential target for the development of anti-MPXV agents. IMPORTANCE Mpox is a zoonotic disease caused by infection with the mpox virus, and a worldwide outbreak occurred in May 2022. The smallpox vaccine has recently been approved for clinical use against mpox in the United States. Although brincidofovir and tecovirimat are drugs approved for the treatment of smallpox by the U.S. Food and Drug Administration, their efficacy against mpox has not been established. Moreover, these drugs may present negative side effects. Therefore, new anti-mpox virus agents are needed. This study revealed that gemcitabine, trifluridine, and mycophenolic acid inhibited mpox virus propagation and exhibited broad-spectrum anti-orthopoxvirus activities. We also suggested IMP dehydrogenase as a potential target for the development of anti-mpox virus agents. By targeting this molecule, we identified a series of compounds with stronger anti-mpox virus activity than mycophenolic acid., Competing Interests: The authors declare no conflict of interest.

Poly((R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate) [P(3HB-co-3HHx)], a flexible and practical kind of polyhydroxyalkanoates, is generally produced from plant oils and fatty acids by several wild and recombinant bacteria. This study established an improved artificial pathway for the biosynthesis of P(3HB-co-3HHx) with high 3HHx composition from structurally unrelated fructose in Ralstonia eutropha. Depression of (R)-specific reduction of acetoacetyl-CoA by the deletion of phaB1 was an effective modification for formation of the C6-monomer unit from fructose driven by crotonyl-CoA carboxylase/reductase (Ccr). Co-overexpression of phaJ4a, which encodes medium-chain-length (R)-enoyl-CoA hydratase, with ccr promoted the incorporation of both 3HB and 3HHx units. Further introduction of emdMm, a synthetic gene encoding ethylmalonyl-CoA decarboxylase derived from mouse, was remarkably effective for P(3HB-co-3HHx) biosynthesis, probably by converting ethylmalonyl-CoA generated by the reductive carboxylase activity of Ccr back into butyryl-CoA. A high cellular content of P(3HB-co-3HHx) composed of 22mol% 3HHx could be produced from fructose by the engineered strain of R. eutropha with ΔphaB1 genotype expressing ccr, phaJ4a, and emd., (Copyright © 2014 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

Ralstonia eutropha H16 is a useful platform for metabolic engineering aiming at efficient production of polyhydroxyalkanaotes being attracted as practical bioplastics. This study focused on bifunctional (S)-specific 2-enoyl-CoA hydratase/(S)-3-hydroxyacyl-CoA dehydrogenase encoded by fadB to obtain information regarding β-oxidation in this bacterium and to achieve compositional regulation of poly((R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate) [P(3HB-co-3HHx)] synthesized from soybean oil. In addition to two FadB homologs (FadB1 and FadB') encoded within the previously identified β-oxidation gene clusters on the chromosome 1, a gene of third homolog (FadB2) was found on chromosome 2 of R. eutropha. The fadB homologs were disrupted in R. eutropha strain NSDG expressing a mutant gene of PHA synthase from Aeromonas caviae. The gene disruptions affected neither growth nor PHA production on fructose. On soybean oil, fadB' deletion led to reduction of PHA quantity attributed to decrease of 3HB unit, while fadB1 deletion slightly increased 3HHx composition without serious negative impact on both cell growth and PHA biosynthesis. Double deletion of fadB1 and fadB' significantly impaired the cell growth and PHA biosynthesis, indicating the major roles of fadB1 and fadB' in β-oxidation. When fadB1 was deleted in several engineered strains of R. eutropha possessing additional (R)-enoyl-CoA hydratase gene(s), the net amounts of 3HHx unit in the PHA fractions showed 6-21% increase probably due to slightly enhanced supply of medium-chain-length 2-enoyl-CoAs through the partially impaired β-oxidation. These results demonstrated that modification of β-oxidation by fadB1 deletion was effective for increasing 3HHx composition in the copolyesters produced from soybean oil., (Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

A genome survey of polyhydroxyalkanoate (PHA)-producing Ralstonia eutropha H16 detected the presence of 16 orthologs of R-specific enoyl coenzyme A (enoyl-CoA) hydratase, among which three proteins shared high homologies with the enzyme specific to enoyl-CoAs of medium chain length encoded by phaJ4 from Pseudomonas aeruginosa (phaJ4(Pa)). The recombinant forms of the three proteins, termed PhaJ4a(Re) to PhaJ4c(Re), actually showed enoyl-CoA hydratase activity with R specificity, and the catalytic efficiencies were elevated as the substrate chain length increased from C(4) to C(8). PhaJ4a(Re) and PhaJ4b(Re) showed >10-fold-higher catalytic efficiency than PhaJ4c(Re). The functions of the new PhaJ4 proteins were investigated using previously engineered R. eutropha strains as host strains; these strains are capable of synthesizing poly((R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate) [P(3HB-co-3HHx)] from soybean oil. Deletion of phaJ4a(Re) from the chromosome resulted in significant decrease of 3HHx composition in the accumulated copolyester, whereas no change was observed with deletion of phaJ4b(Re) or phaJ4c(Re), indicating that only PhaJ4a(Re) was one of the major enzymes supplying the (R)-3HHx-CoA monomer through β-oxidation. Introduction of phaJ4a(Re) or phaJ4b(Re) into the R. eutropha strains using a broad-host-range vector enhanced the 3HHx composition of the copolyesters, but the introduction of phaJ4c(Re) did not. The two genes were then inserted into the pha operon on chromosome 1 of the engineered R. eutropha by homologous recombination. These modifications enabled the biosynthesis of P(3HB-co-3HHx) composed of a larger 3HHx fraction without a negative impact on cell growth and PHA production on soybean oil, especially when phaJ4a(Re) or phaJ4b(Re) was tandemly introduced with phaJ(Ac) from Aeromonas caviae.

New improved vaccines are needed for control of both bovine and human tuberculosis. Tuberculosis protein vaccines have advantages with regard to safety and ease of manufacture, but efficacy against tuberculosis has been difficult to achieve. Protective cellular immune responses can be preferentially induced when antigens are displayed on small particles. In this study, Escherichia coli and Lactococcus lactis were engineered to produce spherical polyhydroxybutyrate (PHB) inclusions which displayed a fusion protein of Mycobacterium tuberculosis, antigen 85A (Ag85A)-early secreted antigenic target 6-kDa protein (ESAT-6). L. lactis was chosen as a possible production host due its extensive use in the food industry and reduced risk of lipopolysaccharide contamination. Mice were vaccinated with PHB bead vaccines with or without displaying Ag85A-ESAT-6, recombinant Ag85A-ESAT-6, or M. bovis BCG. Separate groups of mice were used to measure immune responses and assess protection against an aerosol M. bovis challenge. Increased amounts of antigen-specific gamma interferon, interleukin-17A (IL-17A), IL-6, and tumor necrosis factor alpha were produced from splenocytes postvaccination, but no or minimal IL-4, IL-5, or IL-10 was produced, indicating Th1- and Th17-biased T cell responses. Decreased lung bacterial counts and less extensive foci of inflammation were observed in lungs of mice receiving BCG or PHB bead vaccines displaying Ag85A-ESAT-6 produced in either E. coli or L. lactis compared to those observed in the lungs of phosphate-buffered saline-treated control mice. No differences between those receiving wild-type PHB beads and those receiving recombinant Ag85A-ESAT-6 were observed. This versatile particulate vaccine delivery system incorporates a relatively simple production process using safe bacteria, and the results show that it is an effective delivery system for a tuberculosis protein vaccine.

Five kinds of promoters were evaluated as tools for regulated gene expression in the PHA-producing bacterium Cupriavidus necator. Several broad-host-range expression vectors were constructed by which expression of a reporter gene gfp was controlled by P(lac), P(tac), or P(BAD) derived from Escherichia coli, or promoter regions of phaC1 (P(phaC)) or phaP1 (P(phaP)) derived from C. necator. Then, the gfp-expression profiles were determined in C. necator strains harboring the constructed vectors when the cells were grown on fructose or soybean oil. P(lac), P(tac), P(phaC), and P(phaP ) mediated constitutive gene expression, among which P(tac) was the strongest promoter. lacI-P(tac) was not thoroughly functional even after addition of isopropyl-β-D-thiogalactopyranoside (IPTG), probably due to inability of C. necator to uptake IPTG. Gene expression by araC-P(BAD) could be regulated by varying L-arabinose concentration in the medium, although P(3HB) production rate was slightly decreased in the recombinant. phaR-P(phaP) exhibited an expression profile tightly coupled with P(3HB) accumulation, suggesting application of the vector harboring phaR-P(phaP ) for gene expression specific at the PHA-biosynthesis phase. The properties of these promoters were expected to be useful for effective engineering of PHA biosynthesis in C. necator.

Many bacteria are naturally capable of accumulating biopolyesters composed of 3-hydroxy fatty acids as intracellular inclusions, which serve as storage granules. Recently, these inclusions have been considered as nano-/microbeads with surface-attached proteins, which can be engineered to display various protein-based functions that are suitable for biotechnological and biomedical applications. In this study, the food-grade, generally-regarded-as-safe gram-positive organism Lactococcus lactis was engineered to recombinantly produce the biopolyester poly(3-hydroxybutyrate) and the respective intracellular inclusions. The codon-optimized polyhydroxybutyrate biosynthesis operon phaCAB from Cupriavidus necator was expressed using the nisin-controlled gene expression system. Recombinant L. lactis accumulated up to 6% (wt/wt) poly(3-hydroxybutyrate) of cellular dry weight. Poly(3-hydroxybutyrate) granules were isolated and analyzed with respect to bound proteins using biochemical methods and with respect to shape/size using transmission electron microscopy. The immunoglobulin G (IgG) binding ZZ domain of Staphylococcus aureus protein A was chosen as an exemplary functionality to be displayed at the granule surface by fusing it to the N terminus of the granule-associated poly(3-hydroxybutyrate) synthase. The presence of the fusion protein at the surface of isolated granules was confirmed by peptide fingerprinting using matrix-assisted laser desorption ionization-time of flight (mass spectrometry). The functionality of the ZZ domain-displaying granules was demonstrated by enzyme-linked immunosorbent assay and IgG affinity purification. In both assays, the ZZ beads from recombinant L. lactis performed at least equally to ZZ beads from Escherichia coli. Overall, in this study it was shown that recombinant L. lactis can be used to manufacture endotoxin-free poly(3-hydroxybutyrate) beads with surface functionalities that are suitable for biomedical applications.

We studied the effects of inhaled furosemide (40 mg) on bronchial responsiveness to acetylcholine (ACh) in patients with chronic congestive heart failure who had been premedicated with indomethacin (75 mg/day) for five days. The measurement of bronchial responsiveness was performed by inhaling doses of ACh and calculating the provocative concentration of ACh needed to cause a 20% fall in FEV1.0 (PC20-ACh). Inhaled furosemide (N = 11) had no effect on resting pulmonary function but did cause a significant increase in the median value of PC20-ACh, from 7.58 to 11.9 mg/ml (p < 0.01). Irrespective of premedication with indomethacin, inhaled furosemide reduces bronchial hyperresponsiveness to ACh in patients with chronic congestive heart failure. Therefore, we speculate that the mechanism of bronchial hyperresponsiveness noticed in our patients is not related to prostaglandins such as PGE2 or PGI2.

Study Objective: To investigate the similarity between coronary vasospasm and bronchial spasm., Design: Nonrandomized, case-control study., Setting: Referral-based clinics for cardiac and pulmonary disease at one secondary care center., Patients: Seventeen patients with vasospastic angina pectoris (VSAP) and 14 patients with chest pain syndrome (CPS)., Interventions: Medications prohibited: those with known effects on bronchial responsiveness., Measurement: Induction of coronary vasospasm: ergonovine maleate (10, 20, 40 micrograms) injection into coronary arteries during coronary angiography. Bronchial responsiveness to acetylcholine (ACh): acetylcholine chloride (0.08 to 20 mg/ml) inhalation and calculation of the provocative concentration of ACh (PC20-ACh) that revealed 20 percent fall in FEV1., Results: The median value for PC20-ACh in patients with VSAP, 7.80 mg/ml, was significantly lower than that in patients with CPS, > 20.0 mg/ml (p < 0.01 by Mann-Whitney U test). The PC20-ACh in patients with VSAP, however, was correlated neither with the responsive threshold of ergonovine maleate, which induced coronary vasospasm, nor with the duration from the latest angina attack., Conclusion: These results suggest that bronchial responsiveness was increased in most patients with VSAP, but not with CPS. We therefore speculate that patients with VSAP may also have hypercontractibility to ACh of noncoronary systemic smooth muscles.

Three patients showed ST elevation on precordial electrocardiogram and ST depression on intracoronary electrocardiogram during angioplasty of the left anterior descending coronary arteries (LAD). While none of the patients had spontaneously visible collaterals, all showed transient recruitable collaterals to the LAD. No evident collaterals into the diagonal branches were observed. Possibly, if the intracoronary electrocardiogram represents the potential changes of the epicardial surface in the vicinity of the guidewire tip, then endocardial ischemia may have developed even though epicardial ischemia was not observed, due to relatively sufficient blood flow through the recruitable collaterals to the LAD. ST elevation on the precordial electrocardiogram may have represented epicardial and endocardial ischemia of the diagonal branches, where the recruitable collaterals could not protect against transmural ischemia. These phenomena suggests that the recruitable collaterals are functionally limited during acute coronary occlusion, even though the collaterals are well developed.

To assess clinical significance of transient ischemic dilatation of the left ventricle (TID) on dipyridamole-stressed 201Tl myocardial scintigraphy, 110 patients suspected with coronary artery disease, including 13 with normal coronary, 48 with single vessel disease, 30 with 2 vessel disease, and 19 with 3 vessel disease were analyzed. TID was visually and quantitatively assessed calculating the ratio of the area within the left ventricular region on the initial and delayed image (TID ratio). TID was observed in 3 of 1 vessel disease (6%), 5 of 2 vessel disease (17%), and 8 of 3 vessel disease (42%). None of normal coronary artery showed TID. In patients with multivessel disease (MVD), TID was observed more frequently (27%) than in patients with 1 vessel disease (6%) (p < 0.025). Furthermore, the TID ratio tended to be higher (1.15 +/- 0.11) than those with single vessel disease (1.03 +/- 0.03). To identify patients with MVD, TID had a sensitivity of 27% and a specificity of 95%. ECG changes were observed more often in patients with TID than those without TID. Five patients showing TID underwent coronary artery bypass graft surgery, TID disappeared postoperatively in each patient. In conclusion, TID on dipyridamole 201Tl scan seems to be a specific although not sensitive marker for detecting MVD.

The reappearance of collateral vessels in patients with subtotal coronary artery occlusion or chronic total coronary artery occlusion was investigated. In all patients, the target vessels revealed restenosis after initial percutaneous transluminal coronary angioplasty (PTCA), so a 2nd PTCA was performed for the same lesions. Each collateral vessel was evaluated before, during, and after PTCA by contralateral contrast injection during balloon inflation. Grading of collateral filling was as follows: 0 = none, 1 = filling of side branches only, 2 = partial filling of the epicardial segment, 3 = complete filling of the epicardial segment. Before the 1st PTCA, group A (n = 11) had subtotal occlusions (75-95%) at the target vessels, and group B (n = 8) had chronic total occlusions. Collateral vessels reappeared in all patients (100%) in group A, with good images. Reappearance of collateral vessels was good in 6 patients (75%) and poor in 2 (25%) in group B. Both the latter patients suffered from acute myocardial infarction. These results suggest that reappearance of collateral vessels may be relatively poor in chronic total occlusion patients, who may suffer from acute myocardial infarction due to acute coronary occlusion.

Objectives: The purpose of this study was to test the hypothesis that the diameter of the recipient coronary artery of the well developed collateral circulation in patients with acute myocardial infarction increases because of the augmented intravascular pressure caused by subsequent collateral development., Background: It is well known that collateral circulation develops after acute myocardial infarction. However, some patients have a well developed collateral circulation at the onset of infarction, which may limit the angiographic evaluation of further development of collateral circulation., Methods: We measured the diameter of the donor and recipient arteries of the collateral circulation by means of a computer-assisted analysis system in seven patients with acute myocardial infarction who had a totally occluded infarct-related coronary artery during the acute and chronic stages of infarction. All coronary angiograms were obtained after the administration of sublingual nitroglycerin. The measurement was repeated immediately after (within 6 h) and late after (42 +/- 11 days) the onset of acute myocardial infarction., Results: The diameter of the donor artery remained unchanged (1.32 +/- 0.98 vs. 1.42 +/- 1.12 mm). In contrast, the diameter of the recipient artery increased from 1.25 +/- 0.63 to 1.55 +/- 0.61 mm (p < 0.01). These changes in coronary artery diameter were associated with an improvement in regional myocardial wall motion at rest in infarct areas (6.7 +/- 7.0% vs. 13.6 +/- 10.7%, p < 0.05)., Conclusions: These findings indicate that serial measurement of coronary artery diameter is useful for the evaluation of collateral development after acute myocardial infarction.

A 70-year-old woman was hospitalized for status asthmaticus. The level of CRP was high and chest roentgenogram showed infiltrative shadows in the left middle lung field. Artificial respiration and continuous infusion of methylprednisolone and aminophylline 750 mg/24 hr were performed. Eight hours after admission, seizures suddenly occurred. At this time, brain CT showed no abnormal findings. The seizures were thought to be induced by theophylline toxicity, since serum theophylline concentration was high at 69.9 micrograms/ml. Because theophylline clearance of the patient in a clinically stable condition was normal, it was speculated that theophylline clearance was reduced during status asthmaticus. It is thought that this rare case of theophylline toxicity occurred due to reduction of theophylline clearance during status asthmaticus associated with pneumonia.

We studied the effects of inhaled and intravenous furosemide (40 mg) on bronchial responsiveness to acetylcholine (ACh) in patients with chronic congestive heart failure. The measurement of bronchial responsiveness was performed by inhaling doses of ACh and calculating the provocative concentration of ACh needed to cause a 20% fall in FEV1.0 (PC20-ACh). Intravenous furosemide (N = 11) had a marked diuretic effect (urine output 1014 ml (SEM 156) in 2 hours), but had no effect on resting pulmonary function and PC20-ACh. In contrast, inhaled furosemide (N = 10) had no effect on urine output and resting pulmonary function, but caused significant increase in PC20-ACh from 2.74 (GSEM 1.28) to 8.47 (GSEM 1.22) mg/ml (p less than 0.05). We conclude that inhaled furosemide, but not intravenous furosemide reduces bronchial hyperresponsiveness to ACh in patients with chronic congestive heart failure. The mechanism of this effect appears to be related to the ion transport system of airway epithelium.

In patients with hypertrophic cardiomyopathy (HCM) and essential hypertension (HT), left ventricular dysfunction in early diastole which is associated with left atrial contraction plays an important role in left ventricular filling. To evaluate left atrial booster pump function, we analyzed left atrial preload (left atrial pressure at the end of diastasis; LAPd, left atrial volume index at the end of diastasis; LAVd), left atrial afterload (left ventricular end-diastolic pressure; LVEDP, left ventricular chamber stiffness constant; K), and left atrial ejection indices (left atrial ejection fraction during atrial contraction; LAEF, left atrial ejection volume index during atrial contraction; ACVI). The study subjects consisted of control subjects (n = 5), HT patients (n = 6), and HCM patients (n = 11). The left ventricular wall was significantly thicker in the HT and HCM groups. The left ventricular rapid filling volume index was less in the HT group, and significantly less in the HCM than in the control group. LAPd and LAVd were greater in the HT group than in the control group, and greater in the HCM group than in the HT group. LVEDP and K were greater in the HT group than in the control group, and significantly greater in the HCM group than in the other 2 groups. ACVI was greater in the HT group than in the control group, but in the HCM group, ACVI was significantly less than in the HT group and did not differ significantly from that in the control group. LAEF was significantly less in the HCM group than in the other 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a case of reversible collateral flow between the right coronary artery (RCA) and the left coronary artery (LCA). A 55 year-old woman was admitted to our hospital because of chest oppression. Cardiac catheterization revealed 99% stenosis to seg. 1. We found good collateral vessels from LCA to RCA. We performed PTCA (Percutaneous Transluminal Coronary Angioplasty) on this lesion. PTCA was successful and this lesion improved (99%----40%). After PTCA, collateral vessels had disappeared. After one year, the patient had chest oppression on effort again. We performed cardiac catheterization and found 90% stenosis to seg. 6. So we performed PTCA on the new lesion. During balloon inflation, we found good collateral vessels from RCA to LCA (reversible collateral flow). We considered that reversible collateral flow was important for myocardial protection.

Two hundred twenty five anginal symptomatic patients (37-75 years) undergoing selective coronary angiography were studied to clarify the importance of risk factors for coronary artery disease (CAD). Serum lipids, apolipoproteins, fasting blood glucose, hemoglobin A1 and A1c, serum insulin levels, hypertension, smoking and obesity were examined as coronary risk factors in 64 newly diagnosed non-insulin dependent diabetic patients (60 +/- 1 (+/- SE)yr), 88 impaired glucose tolerant (IGT) patients (58 +/- 1 yr) and 73 non-diabetic patients (62 +/- 1 yr). Diabetic and IGT patients showed significantly higher coronary atherosclerosis indices than non-diabetic patients (p less than 0.05). In the diabetic and IGT groups, the plasma triglyceride concentrations were significantly higher in the patients with coronary atherosclerosis (CAS) than in either patients without CAS (p less than 0.05) or non-diabetic patients with CAS (p less than 0.05). The prevalence of hypertension in the diabetic patients with CAS was higher than in the non-diabetic patients with CAS. These data suggest that hypertriglyceridemia and hypertension might be important as risk factors in the development of coronary atherosclerosis in persons with an abnormal glucose tolerance.

Bronchial hyperresponsiveness is one of the major clinical features of bronchial asthma. We previously reported that oral administration of a selective thromboxane synthetase inhibitor, OKY-046, reduced bronchial hyperresponsiveness to acetylcholine in asthmatic subjects. In this study, the effect of aerosol administration of OKY-046 on bronchial hyperresponsiveness was evaluated in ten inpatients with intrinsic asthma. Acetylcholine inhalation tests were performed before and after four days of inhalation of OKY-046 (100 mg/day). The provocative concentration of acetylcholine producing a 20 percent fall in forced expiratory volume in 1 s (PC20-FEV1) and that causing a 35 percent fall in respiratory conductance (PC35-Grs) were measured as indexes of bronchial responsiveness. There was a significant increase in PC20-FEV1 (p less than 0.001) and PC35-Grs (p less than 0.02) after inhalation of OKY-046 from 0.79 (GSEM, 1.41) Mg/ml and 0.96 (GSEM, 1.35) mg/ml to 1.20 (GSEM, 1.41) mg/ml and 1.74 (GSEM, 1.32) mg/ml, respectively. There was no significant difference in forced vital capacity (FVC), FEV1, or respiratory resistance (Rrs) baseline values before and after inhalation of OKY-046. Platelet aggregation was not inhibited by the treatment in other five inpatients. Thus, prophylactic administration of aerosol OKY-046 may be available for treatment of asthma by reduction of bronchial hyperresponsiveness. Further studies are needed to determine the optimum dose.

This study was performed to define the conditions present in chronic total occlusion of all three coronary vessels. Each left descending coronary artery (LAD), left circumflex branch (LCX) and right coronary artery (RCA) was totally occluded angiographically in 5 patients (mean age 64, male 3, female 2). Four of them had history of myocardial infarction. Anginal type was effort angina in all patients, and two cases showed unstable angina. Good collateral supply was found in the distal portions of occluded vessels from proximally located branches, such as Conus branch, Right ventricular branch, Septal branch and Left atrial circumflex branch. Almost all of the occlusions were located at mid portions (13/15: mid, 2/15: proximal). Ejection fractions (EF%) of the 5 patients were 70%, 69%, 60%, 28% and 22% respectively. EF was correlated with the degree of collateral supply and one of them (22%) ended in sudden death. These findings suggest that the mid portion occlusion, good collateral supply and a long history of angina pectoris are important factors involved in chronic total occlusion of the three coronary vessels.

To investigate the relationship between pulmonary congestion and bronchial responsiveness, we measured bronchial responsiveness to acetylcholine in 51 patients with left heart disorders. The measurement of bronchial responsiveness was performed by inhaling doses of acetylcholine chloride (0.08 to 20 mg/ml) and calculating the PC20-FEV1. The median value for PC20-FEV1 was above 20 mg/ml in the subjects without history of congestive heart failure (n = 18), was 5.29 mg/ml in the subjects with clinical evidence of congestive heart failure in the past days (n = 18; p less than 0.01), and was 5.74 mg/ml in the subjects with clinical evidence of congestive heart failure at the time of study (n = 15; p less than 0.01). The hemodynamic variables by cardiac catheterization and the clinical symptoms were not correlated with the grade of bronchial responsiveness. These results suggest that the bronchial responsiveness was increased in most of the patients with chronic congestive heart failure. We concluded that continuous pulmonary congestion may contribute to the pathogenesis of bronchial hyperresponsiveness.

A case of a 73-year-old man with variant angina who developed chest pain and shock following an injection of sodium bicarbonate and hydrocortisone is reported. The electrocardiogram (ECG) during the chest pain attack revealed ST elevation in leads II, III and aVF. It returned to a normal pattern 10 min later. Coronary angiography, performed 2 hours after the anginal attack, showed no significant coronary arterial stenosis. One month later, an injection of ergonovine (16 micrograms) into the right and left coronary arteries induced spasms in segments 4 and 13, with ischemic ECG changes. Possible causes of the anginal attack are a coronary arterial spasm induced by the allergic reaction to hydrocortisone and/or serum alkalosis due to the sodium bicarbonate injection triggered by hyperventilation.

Advances in echocardiography have made possible simple, noninvasive evaluation of the heart. We report the echocardiographic findings in a case of intrapericardial bronchogenic cyst. The patient, a 36-year-old woman, was hospitalized because of pericarditis. Echocardiography revealed a large unilocular cystic structure extending from behind the left atrium to the base of the left ventricle. Although the lesion was diagnosed as an intrapericardial bronchogenic cyst histopathologically, echocardiography was also of use in arriving at the correct diagnosis.

In order to assess the clinical effectiveness of an oral prostaglandin E1 derivative, OP-1206, five patients with chronic obstructive pulmonary disease and two with pulmonary fibrosis were studied from the standpoint of hemodynamics and nine others with chronic lung disease from the standpoint of respiratory function. Oral intake of OP-1206 resulted in a significant decrease in the pulmonary arterial pressure (p less than 0.01), total pulmonary vascular resistance (p less than 0.01), pulmonary arteriole resistance (p less than 0.01), and total systemic vascular resistance (p less than 0.05), and an increase in the cardiac index (p less than 0.05) and oxygen delivery (p less than 0.01) with insignificant changes of PaCO2, PaO2 and pH. There was no clinical improvement of lung function after OP-1206 intake. OP-1206 is a potent vasodilator, improving cardiac performance in patients with chronic lung disease and possibly preventing the progress of cor pulmonale in this kind of patient.

Twenty cases of left ventricular diverticula were gleaned from 4,300 consecutive angiocardiographic records (13 males and seven females whose age ranged from 17 to 78 years with a mean of 52 +/- 16 years). Their findings were compared with those of 16 patients with left ventricular aneurysms due to myocardial infarction. In only one patient was a diverticulum first detected by two-dimensional echocardiography before left ventriculography was performed. None of the patient had an associated midline thoracoabdominal defect. Five patients had premature ventricular beats, two of whom had ventricular tachycardia. Three patients complicated mitral valve prolapse and three atrial septal defect. Of the 20 patients, four each had two diverticula, as opposed to 16 others who each had a single diverticulum. The diameter of the diverticula ranged from eight to 70 mm. The sites of 14 diverticula were along the inferior wall; five in the anterior wall; four in the apex. Morphologically 15 diverticula were bulky outpouchings, six were tongue-like, and three hammocking. All diverticula exceeding 15 mm in diameter and originated near the mitral ring could always be detected in the short-axis view of two-dimensional echocardiography. However, those originating in the apex or of a tongue-like configuration could rarely by detected. Comparative two-dimensional echocardiographic analyses of 16 diverticula, 16 left ventricular aneurysms, and 16 normal left ventricular walls disclosed that the left ventricular aneurysmal wall had a higher echo intensity, but the diverticula had the same wall echo intensity as the normal left ventricular wall. Left ventricular end-diastolic wall thickness in an aneurysm (7.6 +/- 1.5 mm) was lower (p less than 0.01) than the normal left ventricular wall (11.1 +/- 1.3 mm), but it did not differ from the normal left ventricular wall in any case of diverticulum (10.2 +/- 1.5 mm). The percent wall thickening ratio in aneurysms (-3.6 +/- 10.7%) was lower (p less than 0.01) than the normal left ventricular wall (39.8 +/- 10.9%), but it did not differ from the normal left ventricular wall in diverticula (45.8 +/- 16.6%). Regional fractional shortening in the diverticula (41.3 +/- 9.2%) did not differ from that in the normal left ventricular wall (34.5 +/- 5.2%). In conclusion, a small diverticulum without a midline thoracoabdominal defect is not rare, and two-dimensional echocardiography is the diagnostic method of choice in many cases based on the echo features described above.

Sinus node function was analysed in 15 aged patients, including 8 with sick sinus syndrome and 7 without apparent sinus node dysfunction, by rapid artial pacing and premature atrial stimulation during sinus rhythm and 5 beats of atrial pacing. Three patterns of sinoatrial response were identified by premature atrial stimulation during atrial pacing. Type I response (3 cases) represented approximately constant return cycles and type II (2 cases) represented a markedly prolonged return cycles following premature stimulation. Type III response was characterized by a progressive shortening of return cycles as the prematurity of atrial extrastimuli was increased. Underlying mechanisms responsible for these responses were discussed in relation to the sinus node automaticity and sinoatrial conduction.

The incidence and pathologic features of cardiac lesions in 184 autopsied aged patients with disseminated intravascular coagulation (DIC) were reported. Coronary thrombosis was noted in 31 (16.8%), fresh myocardial necrosis in 60 (32.6%) and massive myocardial hemorrhage in 49 (26.6%) of these patients. Fresh myocardial infarction was present in 16 (8.7%) patients, 13 of whom manifested coronary thrombosis. The site of thrombi deposition was closely related to preexisting stenotic lesions of the coronary arteries. Only 3 of 16 patients with disseminated intravascular coagulation and acute myocardial infarction had typical cardiac symptoms. In most patients, the electrocardiographic changes were equivocal or not diagnostic for the diagnosis of acute myocardial infarction. We suggest the possibility that coronary thrombi in disseminated intravascular coagulation may gradually increase in extent and severity, leading to confluent areas of myocardial necrosis. The possibility of death due to heart failure, arrhythmia or cardiac rupture, points to the importance of recognizing the frequent cardiac involvement in aged patients with disseminated intravascular coagulation.

Although there are many reports on sudden cardiac arrest occurring outside the hospital, little is known about the precise prognostic factors that determine the outcome after cardiopulmonary resuscitation. Clinical information before and immediately after sudden cardiac arrest is frequently incomplete because the event occurs outside the hospital. We studied 90 consecutive patients with sudden and unexpected cardiac arrest who were resuscitated in the general ward of our hospital. Twenty-five (28%) were discharged from the hospital. Multivariate analysis revealed that the promptness of initiation of CPR, age, severity of cardiac dysfunction, time and the type of arrhythmia are of significance in relation to survival. To evaluate long-term survival after hospital cardiac arrest, we analyzed long-term follow-up data accumulated during a 16 year period. In the group of 25 patients in our study, there have been a total of 10 deaths (40%). Five of the 10 deaths resulted from recurrent cardiac arrest and 1 was a noncardiac death. There was a high rate of recurrence of cardiac arrest in the first year following resuscitation, especially among the cardiomyopathy patients.

Clinical and electrophysiologic studies were performed in 10 aged cases (50-82 years of age) with WPW syndrome and following results were obtained: 1) Episodes of paroxysm of supraventricular tachyarrhythmias were observed in 7 and complication of sinus node dysfunction was noted in 3. 2) P-delta intervals on electrocardiogram exceeding 0.12 sec were observed in 4 cases. 3) Patterns of normalization of QRS complex in 4 cases were characterized by tachycardia-dependent in 2 and bradycardia-dependent in 2. 4) Effective refractory period of the accessory pathway (AP) in antegrade direction exceeded that of A-V node in 5 cases and the former exceeding 500 msec was observed in 2 cases. The relations between the changes of the electrophysiologic properties of the AP and altered clinical manifestations of the WPW syndrome in aged cases were discussed.

As the efficacy of oral long-acting sympathomimetic drugs is not yet well established, we investigated the hemodynamic effects of orally administered salbutamol in eight heart failure patients. Cardiac index, heart rate, blood pressure, and left ventricular filling pressure were monitored for 6 hours after a single oral administration of 4 to 8 mg salbutamol and placebo. In patients who had received salbutamol, a 40% increase in the cardiac index (+0.75 L/min/m2, p less than 0.01) was noted 1 hour post administration; a 44% increase (peak effect) occurred at 2 hours (+0.84 L/min/m2, p less than 0.05); and a significant increase persisted for 6 hours. Changes in heart rate showed a similar time course; however, the increase was less pronounced (+27% at 2 hours). The changes in blood pressure were slight and none of the eight patients developed ventricular arrhythmia or other complications. After placebo administration, no consistent changes in the hemodynamic parameters were noted. The present study suggests that, due to its sustained positive action on cardiac output, the oral administration of salbutamol may be efficacious in ambulatory patients with low cardiac output due to heart failure.

Thirty patients (22 males and 8 females, aged 64 to 89 years) with chronic bifascicular block were studied electrophysiologically and prognosis was assessed. Three had RBBB with LPH, 17 had RBBB with LAH, and 10 had LBBB. AH interval was prolonged in 12 (43%) of 28 patients and HV interval was prolonged in 11 (37%) of 30 patients. Of 16 patients with first or second degree AV block, 11 (69%) had prolonged AH interval and 8 (50%) had prolonged HV interval. Effective refractory period of the right atrium was prolonged in 8 (50%) of 16 patients and that of atrioventricular node was prolonged in 9 (64%) of 14 patients. Second degree AV block was observed at lower rates of atrial pacing (130 beats/min or less) in 14 (74%) of 19 patients. Sinus node dysfunction was present in 16 (62%) of 26 patients. During the follow-up period (37.1 +/- 6.1 months), advanced or complete AV block developed in 2 of 27 patients (2.4% per year) and a patient died of acute myocardial infarction (1.1% per year). The present study showed that prolongation of AH interval was observed more frequently than that of HV interval, and the presence of widespread lesions in the conduction system was suggested in chronic bifascicular block, and in spite of these facts prognosis was not so unfavorable as reported previously.

The additive bronchodilating effect of isoproterenol-phenylephrine aerosol following ipratropium bromide was examined in seven intrinsic asthmatic patients and seven chronic bronchitic patients. FVC, FEV1 and Zrs were measured before and 30 min. after inhalation of ipratropium, 40 micrograms. Then inhalation of isoproterenol, 600 micrograms and phenylephrine, 570 micrograms was added and the pulmonary functions were measured 30 min. later. The age, baseline values of FVC and FEV1, and the increases in FEV1 and 1/Zrs with ipratropium did not differ between the two. Isoproterenol-phenylephrine aerosol following ipratropium produced further increases in FEV1 and 1/Zrs in asthmatic patients but no additive increases in bronchitic patients. These findings indicate that the role of autonomic nervous system, especially adrenergic system, on airway obstruction may be different between asthmatic and bronchitic patients and the method applied in this study may be helpful in differentiating these airway disorders.

Much remains unknown about the conditions surrounding the occurrence of prehospital sudden cardiac arrest. We have investigated the clinical characteristics and predictors of survival in a total of 90 consecutive patients in whom sudden cardiac arrest (SCA) happened to occur during their hospitalization in general wards over the past 19 years. The types of arrhythmia present at the time of SCA were ventricular fibrillation (in 46% of cases), ventricular tachycardia (19%), and bradyarrhythmia (35%). The underlying causes were coronary artery disease (45%), cardiomyopathy (20%), and valvular disease (14%). SCA showed a circadian pattern, with many cases during the day and few at night. Prodromal symptoms included chest pain (16% of patients), dyspnea (11%) and palpitations (2%). Of the total of 90 subjects, 26 (29%) were discharged from hospital alive, and SCA recurred in 24% of these. The 5-year survival rate was 52%. The most important predictors of survival examined were initiation of cardiopulmonary resuscitation, NYHA class, and time of SCA. Of those in whom cardiopulmonary resuscitation was initiated within 1 min, 52% were discharged alive, but all of those not receiving it within 10 min died.

Influence of vasodilator therapy on prognosis of acute myocardial infarction complicated by left heart failure (in Killip classes II and III) was studied in 22 aged patients (mean age; 75.7 years). The patients were retrospectively divided into 2 groups: Group I; 12 patients were treated with isosorbide dinitrate and/or chlorpromazine and Group II; 10 patients were treated with other conventional medical measures. Initial hemodynamic changes on admission were not significantly different between 2 groups. With these treatments mortality rate within 2 weeks of treatment was lower in Group I than in Group II (p less than 0.01), however, cumulative cardiac mortality rate within 18 months did not differ significantly. The present study demonstrated beneficial influence of vasodilator therapy on early prognosis in aged patients, but failed to show prolonged influence on later mortality.