Low-dose hyperthermia enhances the antitumor effects of chemotherapy in squamous cell carcinoma.

Esophageal squamous cell carcinoma is a highly aggressive neoplasm and the sixth leading cause of global cancer-related death; the 5-year survival rate for esophageal cancer is only about 20%-25% for all stages. Therefore, improving the therapeutic effect is important. This study assessed whether low-dose hyperthermia (LDH) enhances the antitumor effects of chemotherapy. The antitumor effect of chemotherapy with/without LDH in the squamous cell carcinoma cell line SCCVII was evaluated. A comprehensive analysis was performed with real-time polymerase chain reaction (PCR) to study the hyperthermia-induced changes in the gene expression of SCCVII cell lines. In addition, the cytotoxic and apoptotic changes in the cells treated with LDH combined with/without 5-fluorouracil (5-FU) were measured. LDH combined with 5-FU (10 nM) strongly inhibited the cell growth of SCCVII, with flow cytometry showing an increased population of apoptotic cells. PCR showed that LDH promoted a 25.22-fold increase of p53 mRNA and 18.08-fold increase of Bax mRNA in vitro. MDR1 expression was decreased to 28.7% after LDH. This treatment can result in much higher efficacy of antitumor drugs. After LDH, the expressions of TS decreased to 12.06%, OPRT increased by 4.17-fold, and DPD did not change (1.03-fold). This transformations will induce susceptibility to 5-FU. LDH may be a useful enhancer of chemotherapy drugs for squamous cell carcinoma.

MicroRNA-133a regulates the mRNAs of two invadopodia-related proteins, FSCN1 and MMP14, in esophageal cancer.

BACKGROUND: FSCN1 and matrix metalloproteinase 14 (MMP14) are both invadopodia-related proteins. We herein elucidate the tumourigenicity of these proteins and identify novel therapeutic agents in esophageal squamous cell carcinoma (ESCC). METHODS: FSCN1 and MMP14 were evaluated by immunohistochemistry and quantitative PCR, and microRNA (miR)-133a was also evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells. RESULTS: The expression of FSCN1 or MMP14 was an independent poor prognostic factor according to a multivariate analysis of immunohistochemistry, and their co-expression correlated with the poorest overall survival (OS) out of all the examined factors. Additionally, their mRNAs significantly correlated and both inversely correlated with miR-133a in surgical specimens. Transfection of a miR-133a mimic decreased the mRNA and protein levels of both FSCN1 and MMP14 in ESCC cells. The knockdown of FSCN1 or MMP14 and transfection of a miR-133a mimic inhibited the proliferation and invasion of ESCC cells. Patients with a lower miR-133a expression have a significantly poorer OS than those with a higher expression. CONCLUSION: The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.

Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma.

BACKGROUND: Recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in blood and can serve as useful biomarkers for cancer. METHODS: We performed an miRNA array using serum samples obtained from oesophageal squamous cell carcinoma (ESCC) patients or healthy controls. MiR-1246 was the most markedly elevated in ESCC patients. Therefore, miR-1246 was selected as a candidate for further analysis. The serum miR-1246 level in 46 healthy controls and 101 ESCC patients was evaluated and compared among various clinicopathological characteristics. MiR-1246 expressions in tissue, exosomal, and cellular samples were also examined. RESULTS: Serum miR-1246 alone yielded an receiver-operating characteristic curve area of 0.754, with 71.3% sensitivity and 73.9% specificity for distinguishing ESCC patients from healthy controls. Serum miR-1246 was significantly correlated with the TNM stage and showed to be the strongest independent risk factor for poor survival (HR, 4.032; P=0.017). Unlike the tendency shown in previous reports, miR-1246 was not upregulated in ESCC tissue samples. Furthermore, exosomal miR-1246 did not reflect the abundance in the cell of origin. CONCLUSION: These data support our contention that serum miR-1246 has strong potential as a novel diagnostic and prognostic biomarker in ESCC, and its releasing mechanism is selective and independent of tissue miRNA abundance.

Prothrombotic and inflammatory effects of intravenous administration of human immunoglobulin G in dogs.

BACKGROUND: Intravenous administration of human immunoglobulin G (hIVIgG) has been suggested to potentiate thromboembolism in dogs, but supportive scientific reports are lacking. OBJECTIVES: To determine if hIVIgG therapy promotes hypercoagulability and inflammation in dogs. ANIMALS: Twelve healthy Beagle dogs. METHODS: Prospective, experimental trial. An hIVIgG/saline solution was infused IV at 1 g/kg BW over 8 hours to 6 dogs, and physiological saline was infused to the other 6 dogs. Blood samples were drawn before, during, and after infusion for serial measurement of indicators of coagulation and inflammation. Data were analyzed by 2-way repeated measures analysis of variance. RESULTS: Dogs administered hIVIgG developed mildly decreased blood platelet concentrations without thrombocytopenia (median, 200 x 10(3)/microL; range, 150-302 x 10(3)/microL; P < .01), leukopenia (median, 3.5 x 10(3)/microL; range, 20-62 x 10(3)/microL; P < .001), and mildly increased plasma total protein concentrations (median, 6.3 g/dL; range, 5.6-6.7 g/dL; P < .001). Administration of hIVIgG was also associated with increases in fibrin/fibrinogen degradation products in all dogs (either 5 microg/mL or 10 microg/dL), thrombin-antithrombin III complexes (median, 7.2 ng/mL; range, 4.9-14.2 ng/mL; P < .001), and C-reactive protein concentrations (median, 2.5 mg/dL; range, 0.5-4.3 mg/dL; P < .01). CONCLUSION AND CLINICAL IMPORTANCE: Administration of hIVIgG to dogs promotes hypercoagulability and an inflammatory state. This should be further evaluated and considered when using hIVIgG in dogs with IMHA or other prothrombotic conditions.

Development and characterization of a mouse monoclonal antibody, MoAb HMSA-1, against a melanosomal fraction of human malignant melanoma.

To characterize the biological property unique to melanocytes and to utilize this property to establish laboratory diagnostic tools for malignant melanoma, monoclonal antibody (MoAb) human melanosome-associated antigen-1 (HMSA-1), a mouse monoclonal antibody, was developed against purified melanosomal fractions of human melanoma. MoAb HMSA-1 belongs to an IgG1 (kappa) subclass. Fractionation of cell organelles combined with enzyme linked immunosorbent assay analysis indicated that the antigen(s) reactive with MoAb HMSA-1 is localized in melanosome and endoplasmic reticulum fractions and that it is related to melanosomal protein and its precursor forms. The localization of the antigen in the melanosome and endoplasmic reticulum was also confirmed by immunoelectron microscopy. Characteristically, MoAb HMSA-1 reacted with formalin-fixed and paraffin-processed tissues of melanocytic nevi and malignant melanoma, including amelanotic lesions. It did not react with normal melanocytes, normal tissues and organs from fetuses and adults, or most non-melanocytic tumors. Thus MoAb HMSA-1 identifies the differentiation antigen for the melanosome-associated property in neoplastic melanocytes and is a useful adjunct for immunohistological diagnosis of melanocytic lesions on routine paraffin sections.

Antitumor cytotoxicity mediated by ligand-activated human V alpha24 NKT cells.

Human V alpha24 NKT cells bearing an invariant V alpha24J alphaQ antigen receptor, the counterpart of the murine V alpha14 NKT cells, are activated by the specific ligand, alpha-galactosylceramide (alpha-GalCer) in a CD1d-dependent manner. Here, we demonstrate that the alpha-GalCer-activated V alpha24 NKT cells exert a potent perforin-dependent cytotoxic activity against a wide variety of human tumor cell lines. In addition, we demonstrate that V alpha24 NKT cells and dendritic cells (DCs) from melanoma patients are functionally normal, even in the tumor-bearing status. The potential use of alpha-GalCer-activated V alpha24 NKT cells and/or DCs from patients for cancer immunotherapy is discussed.

Immunoelectron microscopic demonstration of human melanosome associated antigens (HMSA) on melanoma cells: comparison with tyrosinase distribution.

Previously, we have developed a mouse monoclonal antibody (MoAb) HMSA-1 (human melanosome-associated antigen-1) against the melanosome fraction of human malignant melanoma, and demonstrated the selective distribution of the HMSA-1 in neoplastic melanocytes on routine paraffin sections. This study examined, by using enzyme linked immunosorbent assay (ELISA) and immunoelectron microscopy, the subcellular distribution of the HMSA-1 in malignant melanocytes. Fractionation of cell organelles and ELISA assay indicated that the HMSA-1 is rich in fractions of large granule, melanosome and endoplasmic reticulum (ER) in melanoma cells. Immunoelectron microscopic study showed that the HMSA-1 is localized in the melanosomes of various developmental stages and vacuolar structures, which appeared to be the stage I melanosomes and which contained the matrix protein. Dopa cytochemistry revealed that the distribution of MoAb HMSA-1 reaction product is localized in the area different from that of tyrosinase, indicating that the synthetic processes of melanosomal matrix protein and tyrosinase are different. Furthermore, the reaction product with MoAb HMSA-1 was seen in the rough ER, indicating that the melanosomal matrix protein is synthesized by membrane-bound ribosomes and processed through the channel of ER.

Fine structural and immunohistochemical properties of dysplastic melanocytic nevi: comparison with malignant melanoma.

This study will review the clinical features of dysplastic melanocytic nevi (DMN) in Japanese cases, and then show the fine structure of melanosomes/melanogenesis in the dysplastic melanocytes and the immunohistochemical property of DMN as identified by monoclonal antibodies against human melanosome specific antigen (HMSA). The incidence of DMN is quite low in the Japanese. It is indicated that this fact may partly explain the low incidence of malignant melanoma in Japanese; in particular, low incidence in sun-exposed areas. The patients with DMN were largely males. They were different from ordinary Japanese in that they usually burn and tan poorly after sun exposure. In addition, the synthesis of melanosomes in the dysplastic melanocytes was found to be abnormal and characterized by a significant alteration in the fine structure of the melanosomal matrix and the pattern of melanization. These abnormal melanosomes reacted positively with MoAb HMSA-1 and HMSA-2, which identify the structural matrix protein of melanosomes unique to neoplastic melanocytes. Importantly, HMSA was present in both dysplastic melanocytes and melanoma cells, but not in epidermal melanocytes (nevus cells) of common melanocytic nevi.

Comparison of the antinociceptive effects of intracerebroventricular injection of kyotorphin, cyclo (N-methyl-Tyr-Arg) and Met-enkephalin in mice.

Intracerebroventricular (i.c.v.) administration of kyotorphin (L-Tyrosine-L-Arginine) or Metenkephalin (Met-ENK) to conscious mice resulted in a dose-dependent antinociceptive effect as measured by three pain tests. Cyclo(N-methyl-L-Tyrosine-L-Arginine) (cyclo NMTA), an analogue of kyotorphin, increased the reaction time in the tail-pressure and tail-flick tests. Both dipeptides also decreased writhing induced by acetic acid. However, the antinociceptive activity of cyclo NMTA was substantially greater than that of kyotorphin or Met-enkephalin. At the maximum effective dose of 62.7 nmol/mouse, this cyclic dipeptide produced a more long-lasting antinociceptive effect than did kyotorphin or Met-enkephalin. Antinociception induced by cyclo NMTA or kyotorphin was significantly reversed by pretreatment with naloxone (2 or 8 mg/kg, i.p.), though naloxone was not as effective an antagonist of the antinociceptive action of these peptides as it was against Met-enkephalin. The results indicate that the antinociceptive effect induced by cyclo NMTA may in part involve the endogenous opioid system in mice.

Relation between exercise-induced myocardial ischemia as assessed by nitrogen-13 ammonia positron emission tomography and QT interval behavior in patients with right bundle branch block.

Exercise-induced myocardial ischemia is difficult to detect with ST-T changes in patients with right bundle branch block (RBBB). We sought to predict exercise-induced myocardial ischemia with QT interval behavior during exercise in patients with RBBB. Twenty-two patients with angiographically proven coronary artery disease and RBBB and 9 healthy volunteers underwent nitrogen-13 ammonia positron emission tomography with bicycle ergometer exercise at a fixed workload of 25 W. Regional myocardial blood flow (RMBF) and electrocardiographic changes were measured both at rest and after 5 minutes of exercise. The QT interval was measured from the onset of the QRS complex to the offset of the T wave in lead V5. The deltaQT and deltaRMBF, which indicated values after 5 minutes of exercise minus values at rest, were negatively correlated (r = -0.74, p <0.001). Exercise-induced shortening of the QT interval (422 +/- 27 to 381 +/- 38 ms, p = 0.0020) was observed in 15 patients (group 1) and no change or prolongation (411 +/- 45 to 420 +/- 37 ms, p = NS) was observed in 7 patients (group 2). Multivessel disease was significantly more frequent but collateral circulation was significantly less in group 2 than in group 1 (p <0.01, p <0.05, respectively). Cardiac output at rest was significantly lower in groups 1 and 2 than in healthy volunteers (4.52 +/- 0.83 and 4.51 +/- 0.84 vs 6.20 +/- 0.83 L/min; p = 0.0014, p = 0.0003). Although RMBF at rest did not differ significantly among groups 1 and 2 and healthy volunteers (0.63 +/- 0.20 vs 0.69 +/- 0.13 and vs 0.77 +/- 0.14 ml/min/g), RMBF after 5 minutes of exercise was significantly lower in group 2 than in group 1 and healthy volunteers (0.78 +/- 0.11 vs 0.96 +/- 0.20 and vs 1.20 +/- 0.18 ml/min/g; p = 0.0289, p <0.0001). The number of regions of critical coronary artery disease was significantly greater in group 2 than in group 1 (4.0 +/- 1.2 vs 2.1 +/- 1.3, p = 0.0039). Our results suggest that the absence of QT interval shortening during exercise may indicate severe myocardial ischemia induced by exercise in patients with RBBB and coronary artery disease.

Immunochemical characterization of a cytochrome P450 isozyme and a protein purified from liver microsomes of male guinea pigs and their roles in the oxidative metabolism of delta 9-tetrahydrocannabinol by guinea pig liver microsomes.

A protein (designated as protein-B) was purified from liver microsomes of adult male guinea pigs by an affinity chromatography with omega-aminooctyl Sepharose 4B, followed by HPLC using DEAE-5PW and hydroxyapatite columns which had been used to purify a cytochrome P450 (P450) isozyme (P450-A) from the same subcellular fraction (Narimatsu et al., Biochem Biophys Res Commun 172: 607-613, 1990). Protein-B had a molecular mass of 49 kDa in SDS-PAGE, but did not show absorbance at 417 nm for heme. Further, it did not show any oxidative activities towards aniline (AN), d-benzphetamine (d-BP), p-nitroanisole (p-NA) or delta 9-tetrahydrocannabinol (delta 9-THC) in a reconstituted system including dilauroylphosphatidylcholine, NADPH-P450 reductase, and cytochrome b5. However, antiserum against protein-B raised in rabbits suppressed liver microsomal oxidative activities towards d-BP and p-NA dose-dependently. The antibody decreased delta 9-THC oxidative activity most effectively, but did not decrease AN hydroxylation activity. Antiserum against P450-A suppressed all the activities towards these four substrates, especially towards delta 9-THC, in liver microsomes of male guinea pigs. Moreover, reconstitution with hemin made it possible for protein-B to produce some oxidative activity toward delta 9-THC. These results suggest that protein-B is also a cytochrome P450 isozyme which has lost a heme moiety during purification steps. Both P450-A and protein-B could have a role as cytochrome P450 isozymes in the oxidative metabolism of drugs, especially that of delta 9-THC by the liver microsomes of adult male guinea pigs.

Actions of intracerebroventricular administration of kyotorphin and an analog on thermoregulation in the mouse.

Intracerebroventricular (ICV) administration of kyotorphin (L-Tyr-L-Arg) and cyclo (N-methyl-L-Tyr-L-Arg), its analog, produced significant dose-dependent hypothermic responses in mice at an ambient temperature of 24 degrees C. The hypothermic action of kyotorphin was much greater than that of Met-enkephalin (Met-ENK) but less than that of cyclo NMTA. This action was slightly but not significantly reversed by intraperitoneally administered naloxone (8 mg/kg), an opioid receptor antagonist. Met-ENK utilized as a control peptide in this study also produced a dose-dependent hypothermia which was slightly antagonized by naloxone (8 mg/kg, IP). Thyrotropin releasing hormone (TRH) injected ICV produced hyperthermia dose-dependently. The hypothermia induced by kyotorphin, its cyclic analog and Met-ENK was prevented by a small dose of TRH (0.18 microgram = 0.5 nmol/animal) which by itself had little effect on body temperature. A TRH neuronal system in the brain may explain the mechanism of kyotorphin-induced hypothermia. However, there was little evidence of involvement of opioid receptors. The present study demonstrates a potent action of kyotorphin and its analog on thermoregulation.

Properties of a bacterium which degrades solid poly(tetramethylene succinate)-co-adipate, a biodegradable plastic.

Various microorganisms were screened for their ability to degrade poly(tetramethylene succinate)-co-(tetramethylene adipate) (PBSA). Strain BS-3, which was newly isolated from a soil sample, was selected as the best strain. From taxonomical studies, the strain was tentatively ascribed to belong to the genus Acidovorax, most probably to the species A. delafieldii. Strain BS-3 could degrade both solid and emulsified PBSA, and also emulsified poly(tetramethylene succinate). During the degradation, a lipase activity was observed in the culture broth. This lipase activity was induced more strongly by PBSA than by tributyrin or triolein which are typical substrates of lipase. These observations strongly suggest that this lipase was involved in the PBSA biodegradation in strain BS-3.

Antinociceptive effect of centrally administered cyclo(N-methyl-L-Tyr-L-Arg) in the rat.

The tail-flick test was used to test cyclo(N-methyl-L-Tyr-L-Arg) (C.NMTA), kyotorphin (L-Tyr-L-Arg) and morphine for antinociceptive effects following injection into the cerebroventricles (lateral ventricle (VL), third ventricle (V3) and fourth ventricle (V4)) and into the spinal subarachnoid space in the rat. When injected into the VL, V3 and V4, but not into the spinal subarachnoid space, C.NMTA produced a dose-dependent inhibition of the tail-flick response to thermal stimulation. The ED50 values for each site were 61.0 (48.0-77.5), 40.0 (27.4-58.4) and 163.0 (86.7-306.4) nmol/rat, respectively. Behavioral sedation was seen when C.NMTA was injected into the VL, V3 and V4, but not into the spinal subarachnoid space. Kyotorphin was without antinociceptive effect when given by all routes. However, weak sedation was seen after injection into the cerebroventricles. Naloxone (2, 4 and 20 mg/kg), an opiate antagonist, injected intraperitoneally (i.p.) 20 min before C.NMTA injection, did not significantly alter the C.NMTA-induced antinociceptive effect. Additionally, naloxone (2, 4 and 20 mg/kg i.p.) did not abolish the sedative effect of this peptide. It is suggested that C.NMTA produced a naloxone-resistant antinociceptive effect mainly on the upper brain stem.

Radical formation from the reaction of combustion smoke with diphenylamine.

We have attempted to examine the effects of radical scavengers, such as amines and phenols, to trap gas-phase radicals produced from the combustion of Poly (methyl methacrylate)(PMMA), which might cause damage to a living body, using an electron spin resonance (ESR) spin-trapping technique. As a result, diphenylamine did not decrease the amount of radicals but rather increased it. It indicates that under the conditions of this study, gas-phase radicals were hardly trapped by radical scavengers and that the precursors to produce other kinds of radicals can exist. It was suggested that from the experiments using several peroxides, the precursors should be diacylperoxides produced from the combustion of PMMA.

Functional role of coronary collaterals with exercise in infarct-related myocardium.

We evaluated the regional myocardial blood flow in collateral dependent infarct-related areas to examine the functional role of coronary collaterals. Regional myocardial blood flow was measured by positron emission tomography with 13N-ammonia at rest and during low-grade exercise (bicycle ergometer fixed at 25 W for 6.5 min). The study was performed in 24 subjects, consisting of 19 patients with prior myocardial infarction, and five normal individuals. Regional myocardial blood flow was calculated using the radioactivity in myocardial tissue measured by positron emission tomography and the radioactivity in arterial blood. Concerning the infarct related area, the exercise caused myocardial blood flow to decrease by 18.4% (P < 0.01) in the collateral-dependent areas (n = 8) of angiographically positive collaterals, and to increase by 14.4% (P = not significant) in the areas (n = 10) of negative collaterals. Four patients in whom the myocardial blood flow in all walls, including the normal areas, decreased with exercise were excluded from this evaluation. Myocardial blood flow in collateral-dependent infarct-related areas appeared to decrease transiently by low-grade exercise. Our results suggest that collaterals increase the incidence of exercise-induced ischemia, but may protect the infarct related but viable myocardium from necrosis.

IgA nephritis in Behçet's disease: case report and review of the literature.

We describe a 13-year-old girl with the incomplete type of Behçet's disease who had recurrent oral and genital ulcers, folliculitis, proteinuria and hematuria. Renal biopsy specimens revealed diffuse proliferative glomerulonephritis with strongly positive IgA deposits in the glomerular mesangial area, which is histologically indistinguishable from primary IgA nephritis. Further studies of the IgA subclasses showed that IgA1 deposits were predominant in the glomerular mesangium. Primary IgA nephritis is thought to be associated with polymeric IgA1. So it appears that there may be a common underlying disease or mechanism involved in both primary IgA nephritis and the IgA nephritis in Behçet's disease.

Vertical density matrix algorithm: a higher-dimensional numerical renormalization scheme based on the tensor product state ansatz.

We present a new algorithm to calculate the thermodynamic quantities of three-dimensional (3D) classical statistical systems, based on the ideas of the tensor product state and the density matrix renormalization group. We represent the maximum-eigenvalue eigenstate of the transfer matrix as the product of local tensors that are iteratively optimized by the use of the "vertical density matrix" formed by cutting the system along the transfer direction. This algorithm, which we call vertical density matrix algorithm (VDMA), is successfully applied to the 3D Ising model. Using the Suzuki-Trotter transformation, we can also apply the VDMA to 2D quantum systems, which we demonstrate for the 2D transverse field Ising model.

Potentiation of cyclo (N-methyl-Tyr-Arg)-induced antinociceptive activity by thyrotropin-releasing hormone in mice.

The effect of thyrotropin-releasing hormone (TRH) and its metabolite, cyclo(His-Pro) (C.HP), on cyclo(N-methyl-Tyr-Arg) (C.NMTA)-induced antinociception as measured by the tail-pressure test in mice has been examined. C.NMTA-induced antinociception was significantly potentiated by simultaneously intracerebroventricular or intraperitoneal injection of TRH (approximately 20-50%) in a dose-dependent manner, whereas the effect of morphine was not influenced significantly by TRH. C.HP had no significant effect on the antinociceptive response induced by C.NMTA or morphine. It is concluded that the mechanism of C.NMTA-induced antinociception may be involved in TRH neuronal system in the brain.

Exercise-induced QTc-interval changes for predicting improvement in regional blood flow in ischemic myocardium and cardiac output after coronary angioplasty in patients with right bundle-branch block.

BACKGROUND: We have previously shown that QT-interval changes are more useful than ST-T changes in evaluating the severity of exercise-induced myocardial ischemia in patients with right bundle-branch block (RBBB). HYPOTHESIS: The purpose of this study was to evaluate whether the improvement in regional myocardial blood flow (RMBF) in ischemic areas and cardiac output after percutaneous transluminal coronary angioplasty (PTCA) can be predicted by exercise-induced QT-interval changes prior to PTCA. METHODS: The RMBF and cardiac output were quantified with nitrogen-13 ammonia positron emission tomography at rest and during exercise in 20 patients with RBBB and ischemic heart disease before and 6 months after PTCA, and in 9 healthy volunteers. RESULTS: Before PTCA, exercise-induced prolongation by < 20 ms or shortening of the Bazett-corrected QT (QTc) interval (454 +/- 38 to 451 +/- 41 ms, p = NS) was observed in 13 patients (Group 1) and prolongation by > or = 20 ms (429 +/- 44 to 466 +/- 50 ms, p < 0.002) was observed in 7 (Group 2). The number of regions of exercise-induced ischemia was significantly greater in Group 2 than in Group 1 (4.0 +/- 1.2 vs. 2.1 +/- 1.2, p < 0.01). The RMBF in regions of exercise-induced ischemia and cardiac output at rest was not significantly different between Groups 1 and 2, whereas during exercise both the parameters were significantly lower in Group 2 than in Group 1 (both p < 0.05). After successful PTCA, RMBF both at rest and during exercise improved significantly in Group 1 (0.67 +/- 0.04 to 0.71 +/- 0.06 ml/min/g, 0.74 +/- 0.05 to 0.84 +/- 0.08 ml/min/g; both p < 0.0001), but did not improve significantly in Group 2 (0.63 +/- 0.05 to 0.65 +/- 0.07 ml/min/g, 0.65 +/- 0.04 to 0.69 +/- 0.11 ml/ min/g; both p = NS). Cardiac output during exercise improved significantly in Group 1 (6.4 +/- 0.7 to 7.4 +/- 0.9 l/min; p < 0.002) but not in Group 2 (5.7 +/- 0.6 to 5.9 +/- 0.6 l/min; p = NS). CONCLUSIONS: Our results suggest that the marked prolongation of the QTc interval induced by pre-PTCA exercise may predict a lack of improvement in RMBF in ischemic areas and cardiac output after PTCA in patients with RBBB and ischemic heart disease.