Effect of coronary risk factors on arterial compensatory enlargement in japanese middle-aged patients with de novo single-vessel disease--an intravascular ultrasound study.

BACKGROUND: Compensatory enlargement (CE) of atherosclerotic human arteries has been reported; however, the pattern of arterial remodeling in response to plaque formation is not unique. HYPOTHESIS: The study was undertaken to determine the extent of coronary artery compensatory enlargement at stenotic lesions and to correlate the arterial compensatory enlargement with risk factors. METHODS: We studied 62 patients with stable angina and de novo single-vessel disease using intravascular ultrasound and obtained good images in 42 patients (68%). The vessel cross-sectional area (VA), lumen cross-sectional area (LA), and plaque cross-sectional area (PA) were measured at the lesion site and at proximal and distal reference sites. Positive CE was defined as increase in VA of lesion site > 10% compared with that of proximal reference site (CE group, n = 15); shrinkage was defined as reduction in VA of lesion site > 10% compared with that of proximal reference site (S group, n = 14); inadequate CE was defined as intermediate between CE and S (IE group, n = 13). All subjects had coronary risk factors measured before this study. RESULTS: There was no difference in VA, LA, or PA among the three groups at the proximal and distal reference sites, nor in LA at the lesion site; however, VA and PA were significantly smaller in the S group than in the other groups (p < 0.01). Of coronary risk factors, increased systolic blood pressure (SBP), increased diastolic blood pressure (DBP), and decreased high-density lipoprotein cholesterol (HDL-c) levels had the strongest association with shrinkage (p < 0.05). CONCLUSION: Hypertension and decreased HDL level may contribute to the shrinkage response in middle-aged patients with stable angina.

Myocardial hypertrophy in transgenic mice overexpressing human interleukin 1alpha.

BACKGROUND: Interleukin (IL)-1 has profound effects on nonimmune cells and organs, including the heart. The effects of IL-1 on transgenic hearts have not yet been described. METHODS AND RESULTS: We generated transgenic mice overexpressing the human IL-1 gene under control of the cytomegalovirus enhancer/chicken beta-actin promoter. Heart weight-body weight ratio increased 1.4- to 2.2-fold in transgenic mice compared with wild-type mice. Lung weight-body weight ratio also increased in transgenic mice, all of which died within 14 days of birth. Light microscopy revealed concentric hypertrophy with cardiomyocyte hypertrophy in all transgenic mice and pulmonary edema in some of them. Electron microscopy showed myofilament loss and an increased number of giant mitochondria, but no sarcomere disarray. Northern blotting showed that gene expression had been reprogrammed in the left ventricle of transgenic mice. Expression of fetal-type genes such as prepro-atrial natriuretic factor and beta-myosin heavy chain were increased, but voltage-dependent calcium channel messenger RNA expression was decreased in the left ventricle of transgenic mice compared with that of wild-type mice. CONCLUSIONS: IL-1 may cause structural and functional alterations in cardiac myocytes.

Inhibition of IL-12 synthesis of peripheral blood mononuclear cells (PBMC) stimulated with a bacterial superantigen by pooled human immunoglobulin: implications for its effect on Kawasaki disease (KD).

The aim of this study was to further assess the role of pooled human immunoglobulin (PHIG) on cytokine production from PBMC stimulated with a bacterial superantigen. Human PBMC were cultured with Streptococcus pyrogenic exotoxin A (SPE-A) with or without PHIG and several proinflammatory cytokine levels of culture supernatants were measured. Serum cytokine levels of KD patients before and after PHIG therapy were also examined. PHIG greatly reduced the production of IL-12, interferon-gamma (IFN-gamma) and other cytokines from SPE-A-stimulated PBMC, while exogenous IL-12, but neither IL-1 nor tumour necrosis factor-alpha (TNF-alpha), restored IFN-gamma production inhibited by PHIG. Although PHIG partially adsorbed SPE-A, its inhibitory effect on cytokine production was not played by anti-SPE-A antibody. Although purified CD4+ T cells cultured with human HLA-DR-transfected mouse L cells and SPE-A could not effectively produce IFN-gamma, they produced large amounts of IFN-gamma if exogenous IL-12 was introduced. KD patients in the acute phase had higher levels of serum IFN-gamma than did controls and patients with bacterial infection. Although IL-12 levels of children with or without KD were not significantly different, IL-12 levels of children were much higher than those of adults. However, serum levels of IL-12 of KD patients were transiently but significantly decreased by PHIG therapy and IFN-gamma amounts subsequently reverted to basal levels thereafter. These findings indicate that PHIG inhibits IL-12 production of SPE-A-activated monocytes and thereby decreases IFN-gamma synthesis by T cells and suggest that inhibition of IL-12 and IFN-gamma production is an important part of the mechanisms underlying PHIG therapy on KD.

Streptococcal mitogenic exotoxin Z, a novel acidic superantigenic toxin produced by a T1 strain of Streptococcus pyogenes.

Streptococcus pyogenes T1 was previously found to produce an acidic mitogenic exotoxin, designated A beta, antigenically distinct from erythrogenic toxin type A (ETA) of strains T1 and NY5. Following chemical analysis and biological characterization, we have renamed this toxin streptococcal mitogenic exotoxin Z (SMEZ). Physicochemical separation of SMEZ from ETA was successfully performed on a hydrophobic chromatograph. The isoelectric point was pH 5.3, and the molecular size was estimated to be 28 kDa. These values were similar to those of ETA, but the amino acid composition and the NH2-terminal sequence of SMEZ were distinct from those of any mitogenic exotoxins hitherto described. Its mitogenic activity was found to be more potent than that of ETA in rabbit lymphocyte cultures. A specific antiserum raised against SMEZ did not cross-react with ETA, ETB, or ETC in the neutralization tests of mitogenic and erythrogenic activities. Its superantigenic nature was evident from the reverse transcriptase PCR findings of the T-cell receptor Vbeta profiles of rabbit lymphocytes stimulated in vitro. The Vbeta 8 subfamily was unique to SMEZ, while the Vbeta 2 and 6 subfamilies were found to be common among lymphocytes stimulated with ETA, ETB, ETC, or SMEZ. The results from this study provide an additional example of the diversity that exists among mitogenic or superantigenic exotoxins of streptococcal origin.

A case of acute massive pulmonary thromboembolism treated by mechanical clot fragmentation using a percutaneous transluminal angioplasty balloon.

Large, bilateral central pulmonary thromboemboli (PTE) led to cor pulmonale and severe hypoxemia in a patient who had undergone Hardy's operation. After several unsuccessful efforts (thrombolysis using a percutaneous catheter and aspiration of the emboli), mechanical clot fragmentation using a percutaneous transluminal angioplasty (PTA) balloon was attempted. This procedure was successful, resulting in a decrease in pulmonary artery pressure from 58/22 (mean 34) mmHg to 20/10 (mean 13) mmHg together with an increase in aortic pressure from 64/36 (mean 45) mmHg to 112/60 (mean 77) mmHg. Thus, mechanical clot fragmentation using a PTA balloon is a promising method for reducing pulmonary artery pressure and increasing aortic pressure in patients with acute PTE.

In vitro glucuronidation of 25-hydroxyvitamin D3 and its pro-form.

In vitro glucuronidation of 25-hydroxyvitamin D3 and its pro-form has been investigated by means of HPLC with UV detection. Although both substrates gave 3- and 25-glucuronides in the presence of the rat liver microsomal fraction and uridine-5'-diphosphoglucuronic acid, 25-hydroxyvitamin D3 and its pro-form yielded 3- and 25-glucuronide as the main product, respectively. The latter glucuronide is the one in which the tert-hydroxy group is conjugated. Each glucuromide was identified by its chromatographic behavior in comparison with an authentic sample and data obtained from liquid chromatography/mass spectrometry (LC/MS) using atmospheric pressure chemical ionization.

Nonneutralizing antibody to erythrogenic toxin A alpha(NY5ETA) in human sera.

A solid phase adsorption experiment was performed to detect anti-ETA alpha(NY5 strain ETA) nonneutralizing antibody. Toxin was applied to the Protein A-Sepharose column retaining IgG bound after pretreatment with test serum. Mitogenic activity recovered in the effluent and in the eluate containing the IgG was measured separately in rabbit lymphocyte culture. A significantly increased recovery in the eluate was found in combination with decreased recovery in the effluent of three sera from Kawasaki disease and one from Streptococcus pyogenes infection among 13 ELISA-positive, antimitogen assay (AMA)-negative sera tested. The nonneutralizing antibody may play an important role in the immune protection against ETA by binding to nonmitogenic epitope(s) on ETA and enabling to handle the toxin not as a superantigen but as a conventional peptide antigen.

Increased vascular permeability, erythema, and leukocyte emigration induced in rabbit skin by streptococcal erythrogenic toxin type A.

A highly purified streptococcal erythrogenic toxin type-A (SET-A) caused increased vascular permeability, erythema, and leukocyte emigration when injected into the skin of rabbits. A blueing reaction indicating increased vascular permeability appeared at 1 h, reaching the highest intensity between 4 and 5 h, decreasing thereafter and completely disappearing at 12 h after toxin injection. The intensity of the increase in permeability was found to be dose dependent. The erythematous reaction began later and persisted longer than the blueing. The time course of leukocyte emigration was found roughly to parallel that of the blueing reaction. The skin reaction to SET-A in rabbits can be characterized as having an acute non-specific exudative inflammatory nature.

Detection of serum antibody by the antimitogen assay against streptococcal erythrogenic toxins. Age distribution in children and the relation to Kawasaki disease.

We describe a new method to measure human serum antibody against streptococcal erythrogenic toxins that uses inhibition of lymphocyte mitogenicity of the toxins as the indicator. Sera from 53% of 53 Kawasaki disease patients contained specific inhibitory activity against A toxin, whereas only 15% had serum inhibitory activity against B toxin. The specific anti-A toxin serum inhibitor was found in 10% of 118 age-matched control patients suffering from various infections and allergic diseases (p = 0.001, compared to Kawasaki disease patients). Serum inhibitory activity was detected in a small number of patients with beta-hemolytic streptococcal infection (3/19) and in none of the age-matched healthy children (0/17). However, four of seven cord blood sera samples and five of 13 sera samples from healthy neonates contained the inhibitor, a result suggesting passive transfer from mothers. Most of the antimitogen-positive sera were also positive by ELISA of IgG antibody against A toxin, and IgG fractions of the positive sera remained positive in both assays. Thus, it is possible that the specific serum inhibitor detected by the antimitogen assay represents anti-A toxin antibody. The role of toxin-producing bacteria in the pathogenesis of Kawasaki disease remains to be investigated.

Purification and characterization of streptococcal erythrogenic toxin type A produced by Streptococcus pyogenes strain NY-5 cultured in the synthetic medium NCTC-135. Comparison with the dialyzed medium (TP medium)-derived toxin.

Streptococcal erythrogenic toxin type A (ET-A) was purified from culture filtrate of Streptococcus pyogenes strain NY-5 grown in a chemically defined synthetic medium NCTC-135. We succeeded in simplifying the purification procedure, and obtained a highly purified preparation of ET-A. The purification procedure was the combination of ultrafiltration with Amicon PM-10 and YM-10 membranes, chromatofocusing with PBE-94 exchanger (pH 4.0-6.0), and gel filtration through Sephacryl S-200. The purified toxin protein showed a single band with Mr 28,000 on SDS-PAGE and had pI 5.2 on agarose IEF. HPLC chromatography pattern of the toxin revealed one symmetric peak. The result of amino acid analysis of the toxin was in accordance with that of Gerlach et al and with Weeks and Ferretti who reported the nucleotide sequence of the spe A gene. Biological activities of the purified toxin were remarkably potent. The mitogenic activity for rabbit lymphocytes and one skin test dose in rabbit were found at the lower dose of 10 pg and 1 ng of the toxin, respectively.