Biomedical subjects

Hiroshi Inoue

Publications and source records attributed to Hiroshi Inoue.

At least 73 records · Page 4Linked to original sources

PubMed2006

[Predicted vales of respiratory function tests in young Japanese aged from 10 to 20 years].

To find predicted values of respiratory function tests in young persons in Japan, we measured slow vital capacity and forced vital capacity in 1,141 subjects aged from 10 to 20 years. The values obtained from 636 persons (363 males and 273 females) who were not smokers or had no suspected rhinitis or asthma were analyzed. Although FEV1% by the Gaensler and Tiffeneau methods were almost constant regardless of age, all other values of respiratory function tests increased with age and then reached a plateau level in late teens. Excluding the Gaensler and Tiffeneau FEV1%, in a single regression analysis using gender, age, and height, both the contribution ratio and regression coefficient were the highest using height, followed by age. In addition, the result was similar with multiple regression analysis. Therefore, for a young person aged from 10 to 20 years, body height is the most important predictor variable of respiratory function tests, compared to gender and age. For each respiratory function test, we showed the prediction relation according to gender obtained from multiple linear regression analysis using 2 variables of height and age.

Adolescent↗

PubMed2005

Inactivation of PTEN is associated with a low p27Kip1 protein expression in breast carcinoma.

BACKGROUND: It was previously demonstrated that PTEN protein expression is reduced in 67 of 236 (28%) breast carcinomas. Recent experimental studies suggested that the cell cycle inhibitor p27Kip1 (p27) is a downstream mediator through which PTEN negatively regulates cell cycle progression. METHODS: The immunohistochemic expression of p27 and PTEN protein expression was evaluated in a series of 228 invasive ductal carcinomas of the breast. RESULTS: PTEN protein expression was found to have decreased in 65 of 228 (29%) cases, while the nuclear accumulation of p27 protein was low in 99 of 228 (43%) cases. A reduced PTEN protein expression correlated significantly (P = 0.0214) with a low p27 protein expression. Univariate analysis indicated that the patients demonstrating a combined decrease in PTEN and p27 protein expression have a significantly (P = 0.0044) worse disease-free survival (DFS) than those with other combinations of these two protein expression patterns, while multivariate analysis indicated that the lymph node status, MIB-1 counts, and the combination of PTEN/p27 protein expression (P = 0.0452) are independently significant prognostic factors for DFS. CONCLUSIONS: A reduced PTEN protein expression correlated significantly with a low p27 protein expression in breast carcinoma. The finding that the patients with a combined decrease in both protein expressions had a poor prognosis thus suggests that a combined loss of PTEN and p27 function is associated with an aggressive phenotype in breast carcinoma.

Biomarkers, Tumor↗

PubMed2005

The alpha 2 type IX collagen gene tryptophan polymorphism is not associated with rheumatoid arthritis in the Japanese population.

The aim of this study was to investigate whether the alpha 2 type IX collagen (COL9A2) polymorphism that introduces tryptophan residue into the collagen triple-helix is a marker of susceptibility to, or severity of, rheumatoid arthritis (RA). The study included 749 Japanese patients with RA. One hundred twenty-four unrelated healthy individuals served as the control subjects. The relationship between the COL9A2 gene polymorphism and clinical manifestations of RA was evaluated. For the number of subjects positive for COL9A2 tryptophan polymorphism, there was no statistically significant difference between RA patients and normal controls. Furthermore, we did not detect any association of COL9A2 tryptophan polymorphism with disease status, least erosive subset, more erosive subset, or mutilating disease. The lack of association of COL9A2 tryptophan polymorphism with RA and the clinical findings in our study implies that the polymorphism may not function as a candidate gene marker for screening RA patients.

Adolescent↗

PubMed2005

Characterization of a side population of cancer cells from human gastrointestinal system.

A subset of stem cells, termed "side population" (SP) cells, has been identified and characterized in several mammalian tissues and cell lines. However, SP cells have never been identified or isolated from gastrointestinal cancers. We used flow cytometry and the DNA-binding dye Hoechst 33342 to isolate SP cells from various human gastrointestinal system cancer cell lines. Fifteen of sixteen cancer cell lines from the gastrointestinal system contained 0.3%-2.2% SP cells. Next, we used an oligonucleotide microarray to analyze differentially expressed genes between SP and non-SP cells of hepatoma HuH7. The expression of GATA6, which is associated with embryonic development and hepatocytic differentiation, was significantly upregulated in HuH7 SP cells. The expression of ABCG2, ABCB1, and CEACAM6, which are associated with chemoresistance, was also significantly increased in SP cells. In addition, some epithelial markers and mesenchymal markers were overexpressed in SP cells. Reverse transcription-polymerase chain reaction and immunocytochemical staining validated these results and suggested a multilineage potential for HuH7 SP cells. In hepatoma HuH7 and colorectal SW480 cell lines, SP cells showed evidence for self-renewal, generating both SP and non-SP cells. Finally, chemoresistance to anticancer agents, including doxorubicin, 5-fluorouracil, and gemcitabine, were compared between HuH7 SP and non-SP cells using an ATP bioluminescence assay. The HuH7 SP cells expressed a higher resistance to doxorubicin, 5-fluorouracil, and gemcitabine compared with non-SP cells. These findings demonstrate that cancers of the gastrointestinal system do contain SP cells that show some characteristics of so-called stem cells.

Antigens, Differentiation↗

PubMed2005

Clinicopathologic and prognostic values of apolipoprotein D alterations in hepatocellular carcinoma.

We previously identified apolipoprotein D (Apo D) as a novel tumor suppressor gene based on the pharmacological unmasking of epigenetic silencing. We analyzed Apo D expression using real-time reverse transcription-PCR and evaluated its expression status based on the clinicopathological parameters of 70 patients with hepatocellular carcinoma (HCC). Immunohistochemical staining was also performed. We determined the methylation status of Apo D gene promoter by methylation-specific PCR (MSP). The Apo D gene-expression in tumor tissue was significantly lower than that in nontumor tissue (p = 0.011). A low Apo D expression significantly correlated with less-differentiated HCC (p = 0.019). Immunohistochemical studies confirmed a decreased Apo D expression in poorly differentiated tumors. The prognosis of patients with a lower Apo D gene-expression was significantly worse than that in those with a higher expression (p = 0.028). The Apo D gene-expression was an independent prognostic factor (relative risk: 2.36, p = 0.018). An MSP assay showed a low-level of methylation in well differentiated HCC and a high-level of methylation in less differentiated tumors. Apo D may be a novel tumor suppressor gene of HCC, and its expression status may be a useful biomarker for predicting the patient outcome.

Aged↗

PubMed2005

Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast.

OBJECTIVE: The PTEN tumor suppressor gene has been demonstrated to be inactivated in a variety of human tumors. In breast cancer, the PTEN gene mutation is not commonly found whereas loss of heterozygosity affecting the PTEN locus is frequently found. The aim of this study was to analyze PTEN protein expression in breast cancer and to evaluate the prognostic significance of PTEN protein expression. METHODS: Paraffin-embedded sections ofinvasive ductal carcinoma of the breast were immunohistochemically stained for PTEN protein expression in 236 breast cancers. The immunohistochemical expression of breast cancer cells was judged to be either normal or reduced compared with the PTEN protein expression of the normal mammary gland. RESULTS: The expression of PTEN protein was found to have decreased in 67 (28%) of 236 breast cancers. The reduced expression correlated with lymph node metastasis (p = 0.0371), but not with tumor size, nuclear grade, MIB-1 counts or p53 protein expression. Univariate analysis indicated that patients with a reduced PTEN expression had a shorter disease-free survival (DFS) than those with a normal PTEN expression (p = 0.0174). Univariate analyses also determined tumor size, lymph node metastases, nuclear grade, MIB-1 counts, p53 protein as well as PTEN protein expression to be significant factors for DFS, while multivariate analysis determined lymph node metastases and the MIB-1 counts to be independent significant factors for DFS. CONCLUSIONS: The inactivation of PTEN, demonstrated by a reduced expression of PTEN protein by immunohistochemistry, was found in about one third of all breast cancers. The reduced expression of PTEN protein correlated with lymph node metastases and a worse prognosis in the patients with breast cancer.

Adult↗

PubMed2005

D-dimer level influences thromboembolic events in patients with atrial fibrillation.

BACKGROUND: Elevated coagulative molecular markers could reflect the prothrombotic state in the cardiovascular system of patients with non-valvular atrial fibrillation (NVAF). A prospective, cooperative study was conducted to determine whether levels of coagulative markers alone or in combination with clinical risk factors could predict subsequent thromboembolic events in patients with NVAF. METHODS: Coagulative markers of prothrombin fragment 1+2, D-dimer, platelet factor 4, and beta-thromboglobulin were determined at the enrollment in the prospective study. RESULTS: Of 509 patients with NVAF (mean age, 66.6 +/- 10.3 years), 263 patients were treated with warfarin (mean international normalized ratio, 1.86), and 163 patients, with antiplatelet drugs. During an average follow-up period of 2.0 years, 31 thromboembolic events occurred. Event-free survival was significantly better in patients with D-dimer level < 150 ng/ml than in those with D-dimer level>or==150 ng/ml. Other coagulative markers, however, did not predict thromboembolic events. Age (>or==75 years), cardiomyopathies, and prior stroke or transient ischemic attack were independent, clinical risk factors for thromboembolism. Thromboembolic risk in patients without the clinical risk factors was quite low (0.7%/year) when D-dimer was < 150 ng/ml, but not low (3.8%/year) when D-dimer was >or==150 ng/ml. It was >5%/year in patients with the risk factors regardless of D-dimer levels. This was also true when analyses were confined to patients treated with warfarin. CONCLUSIONS: D-dimer level in combination with clinical risk factors could effectively predict subsequent thromboembolic events in patients with NVAF even when treated with warfarin.

Aged↗

PubMed2005

Molecular cloning and characterization of the murine gnathodiaphyseal dysplasia gene GDD1.

Mutations in the GDD1 gene cause gnathodiaphyseal dysplasia, a rare human skeletal syndrome with autosomal dominant inheritance. The biochemical function(s) of GDD1 protein and the molecular pathophysiology of GDD1 mutations leading to GDD have not yet been elucidated. In this study, we characterized the complete cDNA sequence and genomic organization of the mouse GDD1 gene. Analysis of GDD1 mRNA revealed a complex alternative splicing pattern, involving five exons of the GDD1 gene. GDD1 isoforms lacking conserved amino acids at the N-terminus cytoplasmic tails, and with changes in transmembrane topology, are presumably associated with changes in protein functions and subcellular localizations of GDD1. We found GDD1 expression to be up-regulated during the course of myogenic differentiation in the murine pluripotent mesenchymal precursor cell line C2C12, whereas its expression was diminished during osteoblastic differentiation. These observations suggest diverse cellular roles of GDD1 protein.

Alternative Splicing↗

PubMed2005

Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice.

BACKGROUND/AIMS: Liver regeneration following hepatectomy is complicated and involves a variety of interacting factors. The present study was designed to study the roles of proliferation and hypertrophy of hepatocytes in liver regeneration following hepatectomy in liver-specific STAT3-knockout (LS3-KO) mice lacking mitogenic activity. METHODS: Partial hepatectomy was performed in LS3-KO and control mice. Liver regeneration was estimated by the liver weight, cell proliferation and cell size, and the related cellular signals were analyzed. RESULTS: Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Analysis of hepatocellular growth revealed that cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70S6K, mTOR and GSK-3beta in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy. CONCLUSIONS: PI3-K/Akt-mediated responsive hepatocellular hypertrophy may be essential for liver regeneration following hepatectomy and sufficiently compensated liver regeneration even in STAT3-deficient liver, in which cell proliferation is impaired.

Animals↗

PubMed2005

Lead tolerance and accumulation in the gametophytes of the fern Athyrium yokoscense.

The fern Athyrium yokoscense is known to be highly tolerant to lead toxicity, and is a lead hyperaccumulator that can accumulate over 1,000 microg g(-1) of lead in its dry matter. In this work, we examined whether the gametophytic generation of A. yokoscense also resists lead toxicity like the sporophytic generation. Spore germination in A. yokoscense was more tolerant to Pb2+, compared to that in other fern species, such as Pteridium aquilinum, Lygodium japonicum and Pteris vittata. In addition, the early gametophyte development of A. yokoscense was not much affected by 10 microM Pb2+, as evaluated from the prothallial growth and rhizoid development. We also showed that Athyrium gametophytes could accumulate more than 10,000 microg g(-1) of lead, and that the lead was localized in the cytosol and vacuole of rhizoidal cells, as determined by a transmission electron micrograph. These results indicate that Athyrium gametophytes have the ability to accumulate lead in the rhizoids. Furthermore, the gametophytes were found to include a large amount of proanthocyanidins (condensed tannins). Because proanthocyanidins have a latent ability to complex with lead ions, the possible roles of proanthocyanidins in the lead tolerance and accumulation of Athyrium gametophytes are discussed.

Biological Transport↗

PubMed2005

Clinical significance of human kallikrein gene 6 messenger RNA expression in colorectal cancer.

PURPOSE: Human kallikrein gene 6 (KLK6) is a member of the human kallikrein gene family, and recent studies have found that many kallikreins have altered expression patterns in various malignancies. The purpose of the current study was to quantify the expression of KLK6 in malignant and benign colorectal tissues and to statistically analyze whether KLK6 expression levels correlate with clinicopathologic variables and prognosis in patients with colorectal cancer. EXPERIMENTAL DESIGNS: Paired colorectal tissue samples from cancerous and corresponding noncancerous tissues were obtained from 63 patients with colorectal cancer who underwent surgical resection. Quantitative analyses of KLK6 mRNA expression were done using real-time quantitative reverse transcription-PCR. RESULTS: KLK6 mRNA overexpression in cancerous tissues compared with normal counterparts was observed in 57 of 63 (90%) patients. The mean expression level of KLK6 mRNA in cancerous tissues was significantly higher than that in noncancerous tissues (P < 0.0001). Elevated KLK6 expression was significantly correlated with serosal invasion (P < 0.05), liver metastasis (P < 0.05), and advanced Duke's stage (P < 0.01). Furthermore, patients with high KLK6 expression had a significantly poorer actuarial overall survival than patients with low KLK6 expression (5-year overall survival rates: 54% and 73%, respectively, P < 0.05). CONCLUSIONS: The results of this study indicated that KLK6 mRNA expression was significantly higher in cancerous than in noncancerous colorectal tissues, and high expression of KLK6 mRNA correlated with serosal invasion, liver metastasis, advanced Duke's stage, and a poor prognosis for patients with colorectal cancer.

Aged↗

PubMed2005

Essential roles of angiotensin II in vascular endothelial growth factor expression in sleep apnea syndrome.

BACKGROUND: Hypoxia-induced endothelial cell dysfunction has been implicated in increased cardiovascular disease associated with obstructive sleep apnea syndrome (OSAS). OSAS mediates hypertension by stimulating angiotensin II (Ang II) production. Hypoxia and Ang II are the major stimuli of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine and also contributes to the atherogenic process itself. METHODS AND RESULTS: We observed serum Ang II and VEGF levels and peripheral blood mononuclear cell (PBMC) and neutrophil VEGF expression. Compared to controls, subjects with OSAS had significantly increased levels of serum Ang II and VEGF and VEGF mRNA expression in their leukocytes. To examine whether Ang II stimulates VEGF expression in OSAS, we treated PBMCs obtained from control subjects with Ang II and with an Ang II receptor type 1 (AT(1)) blocker, olmesartan. We observed an increased expression of VEGF in the Ang II-stimulated PBMCs and decreased in VEGF mRNA and protein expression in the PBMCs treated with olmesartan. CONCLUSIONS: These findings suggest that the Ang II-AT(1) receptors pathway potentially are involved in OSAS and VEGF-induced vascularity and that endothelial dysfunction might be linked to this change in Ang II activity within leukocytes of OSAS patients.

Adult↗

PubMed2005

Role of Krüppel-like factor 15 in PEPCK gene expression in the liver.

Regulation of hepatic gene expression is important for energy homeostasis. We now show that hepatic expression of the gene for the transcription factor Kruppel-like factor 15 (KLF15) is increased by food deprivation and reduced by feeding in mice. Expression of the KLF15 gene in mouse liver was also down-regulated by a euglycemic-hyperinsulinemic clamp and was increased by inhibition of phosphatidylinositol 3-kinase. In cultured rat hepatocytes, KLF15 gene expression was induced by dexamethasone and a non-hydrolyzing analog of cAMP, and this effect was inhibited by insulin in a manner dependent on phosphatidylinositol 3-kinase signaling. Forced expression of KLF15 in cultured hepatocytes increased both the expression and the promoter activity of the gene for phosphoenolpyruvate carboxykinase (PEPCK). These results suggest that insulin and its counteracting hormones regulate the hepatic expression of KLF15, and that this transcription factor contributes to the regulation of PEPCK gene expression in the liver.

Animals↗

PubMed2005

Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.

In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 10l and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 microM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 microM, respectively.

Cell Line↗

PubMed2005

Somatic mutations of epidermal growth factor receptor in colorectal carcinoma.

PURPOSE: Somatic mutations of the epidermal growth factor receptor (EGFR) gene may predict the sensitivity of non-small cell lung carcinoma to gefitinib. However, no mutations have been reported for colorectal carcinoma. We therefore analyzed EGFR mutations in colorectal adenocarcinomas by the combined use of laser microdissection and sequencing of genomic DNA. EXPERIMENTAL DESIGN: We examined 11 representative colorectal adenocarcinoma cell lines and 33 clinical samples of colorectal carcinoma. In the clinical cases, we carefully dissected only carcinoma cells from frozen sections by laser microdissection. After DNA extraction and PCR, we examined EGFR mutations by sequencing genomic DNA. RESULTS: None of 11 colorectal carcinoma cell lines exhibited somatic mutations, but 4 of 33 clinical tumors (12%) exhibited mutations in the EGFR kinase domain. This may be the first report of somatic mutations in colorectal adenocarcinoma. CONCLUSIONS: Our findings suggest that a distinct minority of colorectal adenocarcinomas exhibit somatic mutations of EGFR, and these tumors may be susceptible to gefitinib treatment.

Base Sequence↗

PubMed2005

Global analysis of altered gene expressions during the process of esophageal squamous cell carcinogenesis in the rat: a study combined with a laser microdissection and a cDNA microarray.

The genetic alterations that occur during esophageal tumorigenesis have yet to be determined. We previously established a Wister rat carcinogenesis model of esophageal squamous cell carcinoma. To understand more about the molecular mechanisms during carcinogenesis, we produced esophageal neoplastic lesions by administering N-amyl-N-methylnitrosamine and 12-O-tetradecanoylphorbol-13-acetate to rats. We used laser microdissection to specifically isolate the cells from the normal epithelium, papilloma, dysplasia, and invasive carcinoma. Using a cDNA microarray representing 14,815 clones, we then analyzed the gene expression profiles for each esophageal lesion. The number of differentially expressed genes compared with the normal control dramatically increased in a step-by-step fashion from normal epithelium (1,151 +/- 119 genes) to papilloma (1,899 +/- 543 genes), dysplasia (1,991 +/- 193 genes), and invasive carcinoma (2,756 +/- 87 genes). A hierarchical clustering analysis showed that the three stages of normal epithelium, dysplasia (papilloma), and invasive carcinoma could be clearly classified, whereas the gene expression patterns of papilloma and dysplasia were indistinguishable. Using the Fisher criterion, we also identified 50 genes whose expression level had either significantly increased or decreased in a step-by-step manner from the normal epithelium to dysplasia and then finally to invasive carcinoma. Many of these genes were not previously known to be associated with esophageal carcinogenesis. The present findings in our rat model thus seem to provide us with a better understanding of the molecular alterations that occur during esophageal carcinogenesis and hopefully will also help lead to the development of novel diagnostic and therapeutic targets.

Animals↗

PubMed2005

Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population.

OBJECTIVE: To identify rheumatoid arthritis (RA) susceptibility genes in a Japanese population by conducting a large-scale case-control association analysis and linkage disequilibrium (LD) mapping on chromosome 7q31-34, a candidate susceptibility locus identified in a preliminary genome-wide scan in 53 Japanese families, using single-nucleotide polymorphisms (SNPs). METHODS: We prepared 728 dense, evenly spaced SNPs with a minor allele frequency >0.15 in each gene locus on chromosome 7q31-34. Using these SNPs, a 2-stage case-control analysis was performed on 760 RA patients (157 men and 603 women) and 806 non-RA controls (189 men and 617 women). Haplotypes and LD mapping results were assessed based on SNP genotypes in 380 controls. RESULTS: Forty-eight SNPs showed allele associations (P < 0.05) in the first set of DNA samples (380 RA cases and 380 non-RA controls; first-stage analysis). For 4 of the SNPs in the SEC8L1 gene, the association was replicated (P < 0.05) in the second, independent set of DNA samples (an additional 380 RA cases and 380 non-RA controls; second-stage analysis). When data from the 2 groups were combined, the most significant allele association was observed with SNP 441, an intronic SNP of the SEC8L1 gene (P = 0.000059). The SEC8L1 SNPs with significant allele associations were all located in a single conserved LD block (block 4). Haplotype analysis revealed the disease-risk (P = 0.0015) and disease-protective (P = 0.0000062) haplotypes. Resequencing of coding exons within block 4 did not identify any nonsynonymous SNPs. Real-time quantitative polymerase chain reaction revealed that SEC8L1 was expressed ubiquitously in human tissues, including fibroblast-like synoviocytes from RA patients. CONCLUSION: Our locus-wide association and LD analyses identified intronic SNPs and haplotypes in the SEC8L1 gene that are strongly associated with RA. We propose that SEC8L1, which encodes a component of the exocyst complex, is a candidate susceptibility gene for RA in the Japanese population.

Adult↗

PubMed2005

Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide.

The electrocardiographic parameters relating occurrence of ventricular fibrillation (VF) episodes in patients with idiopathic VF (IVF) are still unknown. The aim of this study was to clarify efficacy of pharmacological therapy in patients with IVF with respect to repolarization dynamics. The study group consisted of 8 men (age 43.6 +/- 9.1 years) with IVF (Brugada type 5 patients, prominent J wave in the inferior leads 3 patients) who had documented spontaneous episodes of VF, 7 of whom had implantable cardioverter defibrillators. The relation between QT and RR interval was analyzed from 24-hour Holter ECG using an automatic analyzing system before and after pharmacological therapy (bepridil 5 and disopyramide 3). From QT-RR linear regression lines, QT intervals were determined at RR intervals of 0.6 second [QT(0.6)], 1.0 second [QT(1.0)], and 1.2 seconds [QT(1.2)]. Pharmacological therapy increased the slope of QT-RR regression line from 0.105 +/- 0.020 to 0.144 +/- 0.037 (P < 0.05). Accordingly, QT(1.0) and QT(1.2) became longer after drug therapy [QT(1.0), 0.382 +/- 0.016 seconds vs 0.414 +/- 0.016 seconds (P < 0.01); QT(1.2), 0.403 +/- 0.017 seconds vs 0.442 +/- 0.021 seconds (P < 0.01)]. However, QT(0.6) did not change after drug administration. Before drug therapy the average episodes of VF were 5.5 +/- 5.8 (range 1 to 17) during the observation period of 19.3 +/- 17.6 months (range 6 to 60 months). After drug therapy, 6 patients had no episode of VF for 24 to 120 months (66.0 +/- 38.5 months). Two patients had a single episode of VF for 12- and 96-month follow-ups. Pharmacological therapy decreased the frequency of VF episodes in association with prolongation of QT intervals at slower heart rates. Not only J wave and ST elevation but also shorter QT intervals at slower heart rates may represent an electrophysiological substrate for development of VF episodes in these specific IVF patients.

Adult↗