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ABSTRACT Aim Visceral adipose tissue ( VAT) and liver fat ( LF) are strongly associated with type 2 diabetes. It is not known, however, how diabetes treatment and/or risk factor management modulates the association between VAT, LF and diabetes. The aim was to determine the level of VAT and LF in patients with type 2 diabetes according to their treatment status and achievement of the American Diabetes Association's ( ADA) diabetes management goals. Methods We performed a cross-sectional analysis of the baseline data of the International Study of the Prediction of Intra-Abdominal Adiposity and its Relationship with Cardiometabolic risk/Intra-Abdominal Adiposity ( INSPIRE ME IAA), a 3-year prospective cardiometabolic imaging study conducted in 29 countries. Patients (n = 3991) were divided into four groups: (i) those without type 2 diabetes ( noT2D n = 1003 men, n = 1027 women); (ii) those with type 2 diabetes but not treated with diabetes medications ( T2Dnomeds n = 248 men, n = 198 women); (iii) those with type 2 diabetes and treated with diabetes medications but not yet using insulin ( T2Dmeds-ins n = 591 men, n = 484 women) and (iv) those with type 2 diabetes and treated with insulin ( T2Dmeds+ins n = 233 men, n = 207 women). Abdominal and liver adiposity were measured by computed tomography. Results Fewer patients with high VAT or LF achieved the ADA's goals for high-density lipoprotein cholesterol ( HDL-C) or triglycerides compared to patients with low VAT or LF. Visceral adiposity (p = 0.02 men, p = 0.003 women) and LF (p = 0.0002 men, p = 0.0004 women) increased among patients who met fewer of the ADA treatment criteria, regardless of type 2 diabetes treatment. Conclusion Residual cardiometabolic risk exists among patients with type 2 diabetes characterized by elevated VAT and LF. [ABSTRACT FROM AUTHOR]

Abstract Somatic hybrids were produced between Moricandia arvensis (MaMa, 2n = 28) and Brassica oleracea (CC, 2n = 18) through cell fusion and then characterized by analysing their morphology, cytology, DNA constitution, leaf anatomy and seed fertility. Cell fusion was carried out between greenish protoplasts isolated from the mesophyll of M. arvensis and colourless ones from hypocotyls of B. oleracea . Three plants were generated from one shoot via cuttings and acclimatized in vivo . They closely resembled each other in morphology, exhibiting traits intermediate between the parental species. They were confirmed to be amphidiploids by mitotic and meiotic analyses, being 2n = 46 (MaMaCC), with pollen fertility of about 50%, which was enough to develop the subsequent progenies. Anatomical analysis of the for leaf tissue showed that the bundle sheath cells of the somatic hybrids contained some centripetally arranged organelles, like those of M. arvensis . The hybridity was also confirmed by random amplified polymorphic DNA analysis. Both chloroplast DNA and mitochondrial DNA of the somatic hybrids were estimated to be derived from M. arvensis . In leaf anatomy, the somatic hybrid showed the C3 -C4 intermediate trait as in M. arvensis . Many progenies resulted from backcrossing with parental species. The somatic hybrids are expected to be used as bridging plant material to introduce the C3 -C4 intermediate trait into Brassica crop species. [ABSTRACT FROM AUTHOR]

The genetic stability and maintenance of Raphanus sativus-Brassica rapa monosomic chromosome addition lines (a-h-types MALs, 2n = 19, BC[SUB2]), developed by backcrossing the synthesized amphidiploid Raphanobrassica (Raphanus sativus × Brassica rapa, 2n = 38, RRAA) with R. sativus cv. 'Shogoin' (2n = 18, RR), was investigated. Transmission of the added alien chromosome through selected smaller seeds (SSS) and the inheritance of morphological traits and random amplified polymorphic DNA (RAPD)-specific markers together with meiotic chromosome configuration and seed fertility were also investigated for three successive generations (BC[SUB3] to BC[SUB5]). The distinctive traits and the RAPD-specific markers of the eight types of MAL were substantially inherited and stably maintained throughout three generations, although a few variant plants (2n = 18) resembling MALs (2n = 19) and hyperploidal plants (2n = 26 and 2n = 37) were generated in the earlier generations of BC[SUB3] and BC[SUB4] in comparison with BC[SUB5]. The average transmission rates for three generations ranged from 26% for both the b-type and the d-type to 44% for the e-type through SSS. On the other hand, the transmission rates through randomly selected seeds (RSS) were lower, ranging from 6.5% for the f-type to 23.5% for the b-type. In meiosis, more than 90% of PMCs showed the 9II + 1I pairing configuration at metaphase I throughout three generations. For seed fertility, when backcrossed with the radish cv. 'Shogoin', the values were approximately 180% to 500% with the mode around 300% with the seed harvested from a pod increasing with the advancing generations. Genetic recombination between the radish chromosomes and the added chromosome is probably rare, suggesting that the added chromosome is mostly maintained unaltered in the background of the radish genome. [ABSTRACT FROM AUTHOR]

Abstract Background Patients with lipoprotein lipase (LPL) deficiency had been generally thought to be spared accelerated atherosclerosis in spite of a marked elevation of plasma triglyceride levels. However, it has been recently reported that some heterozygous and homozygous LPL-deficient patients are associated with premature atherosclerosis. In this paper, we report a 55-year-old type I hyperlipidaemic patient with a novel missense mutation in the LPL gene. Patient and results The patient had suffered from coronary artery disease, abdominal aortic aneurysm, and stenoses of the bilateral renal arteries and superficial femoral arteries. Sequencing of the genomic DNA revealed that the patient was a homozygote for the mutation, a G to C transition at nucleotide position 1069 in the exon 6, resulting in an amino acid substitution of Phe for Leu303 (L303F). Approximately ∼6% and ∼40% of normal LPL activity and LPL mass, respectively, were detected in the patient's postheparin plasma. An in vitro expression study demonstrated that COS7 cells transfected with L303F mutant cDNA produced a 40% amount of LPL protein in cell lysates compared with normal cDNA, but no protein was detected in the media. Lipoprotein lipase activity was completely absent in both lysates and media of the cells transfected with the mutant cDNA, suggesting that this mutation in the LPL gene results in the production of a functionally inactive protein. Conclusion This case suggests that the LPL missense mutation (L303F), which impairs lipolysis but preserves the LPL mass, is proatherogenic. [ABSTRACT FROM AUTHOR]

Cardiac sarcoidosis occurs in 1-5% of sarcoidosis patients. We previously reported a significant increase of the uncommon TNFA (tumor necrosis factor α) allele, TNFA2 with cardiac sarcoidosis in Japanese. In order to precisely localize the susceptible locus for cardiac sarcoidosis within the HLA region, genetic polymorphisms of classical HLA genes, non-classical HLA class II genes such as HLA-DMA and -DMB genes and several genes involved in the class I-mediated antigen presentation pathway (TAP1, TAP2, LMP2 and LMP7) were investigated. Further, association analyses using four polymorphic microsatellite markers located around the TAP1 and TNFA genes were also carried out. As a result, HLA-DQB1*0601 was found to be the most significantly associated allele, being more significantly increased than TNFA2. No significant increase of the DR52-associated DRB1 alleles (DRB1*03, 05, 06 and 08), which was suggested to be primarily associated with lung sarcoidosis, was observed in cardiac sarcoidosis. A primary role of DQB1*0601 in determination of the susceptibility to cardiac sarcoidosis was supported by association analysis using four polymorphic microsatellite markers, in which only the TAP1 microsatellite locus, the nearest marker to the DQB1 gene among the microsatellites tested, displayed a significant posi-tive association with cardiac sarcoidosis. On the other hand, the HLA-DQB1* 0501-DQA1*0101-DRB1*0101-B7 haplotype showed a negative association with the disease, as similarly observed in lung sarcoidosis. Thus, molecular mechanism for controlling the development of the disease related to HLA molecules are different between cardiac and lung sarcoidosis, whereas thoses for conferring a resistant trait may be similar to each other. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris is associated with the HLA-Cw6 and Cw7 antigens. We have previously narrowed down the critical region most likely to contain the psoriasis vulgaris gene to 111 kb spanning 89 kb to 200 kb telomeric of the HLA-C locus by microsatellite mapping. This segment includes three known genes (POU5F1, SC1 and S) and four new expressed genes. Among them, SC1 (TCF19) is the cell growth regulated gene possibly with transactivator activity. Since psoriasis vulgaris is a common skin disorder characterized by hyperproliferation of epidermal cells, it is tempting to speculate that the SCI gene is one of the strong candidate genes responsible for the development of psoriasis vulgaris. Here, we investigated genetic polymorphisms in the SC1 gene by direct DNA sequencing and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) techniques. Three single nucleotide polymorphisms in exon 2, two of which are accompanied by amino-acid substitutions, were identified. Further, one 4-bp deletion polymorphism was detected around the acceptor site of the lariat-shaped structure necessary for RNA splicing in intron 2. No significant difference in the dimorphic or haplotypic distribution at these four polymorphic sites was observed between the patients with psoriasis vulgaris and healthy controls. This suggests that the susceptible gene for psoriasis vulgaris is not the SC1 gene itself, although a unique homozygous haplotype was identified in the patients. [ABSTRACT FROM AUTHOR]

Intergeneric F[SUB1] hybrids between Raphanus sativus (2n = 18, RR) and Moricandia arvensis (2n = 28, MaMa) have been produced through ovary culture followed by embryo culture, when M. arvensis was used as a pistillate parent. Six BC[SUB1] plants were also obtained through ovary culture followed by embryo culture in the backcross of an amphidiploid F[SUB1] hybrid with R. sativus cv. 'Pink ball'. Two BC[SUB1] plants were sesquidiploids (2n 32, MaRR), and the other BC[SUB1] plants were hyperploid with 2n = 55, having MaMaRRR genomes. BC[SUB2] seeds were obtained by conventional pollination in the successive backcross of two sesquidiploid BC[SUB1] plants with R. sativus cv. 'Pink ball'. Their seed set percentages were 12.7% and 17.0%, respectively. These novel hybrid plants and derived progenies may be valuable materials for the genetic investigation and breeding of Brassiceae, including R. sativus. [ABSTRACT FROM AUTHOR]

In most interspecific hybridization among diploid Brassica species (n = 8, 9, 10), few or no hybrids are obtained, and the three crosses of tetraploid (n = 17, 18, 19) by diploid species are usually only partially successful, especially in one of the reciprocal crosses. Such a cross-incompatibility complex is explained in this paper by a polar-nuclei activation (PNA) hypothesis which proposes two reversible functions, a normal reproduction and a sexual barrier, of double fertilization in higher plants. The first, i.e. the relative activating value (AV) of diploid species, was estimated as 1.0-3.5, whereas that of tetraploid species was 2.7-5.2. In addition, crosses with a polar nuclei activation index (AI) of about 15-87 % were compatible but those beyond the two limits were incompatible, 50 % of those showing normal seed development after self-pollination. [ABSTRACT FROM AUTHOR]

We investigated whether thrombocytopenia in patients with chronic hepatitis C is due to anti-platelet autoantibodies. Platelet-associated IgG (PAIgG) and platelet-associated IgM (PAIgM) were measured by direct immunofluorescent flow cytometric analysis. Elevation of PAIgM level was detected in 70% of chronic hepatitis C patients, while only a mild elevation of PAIgG level was detected in 32% of the cases. The elevation of PAIgM values in these patients was comparable to that in patients with chronic immune thrombocytopenic purpura (ITP). However, elevated PAIgM was also found in both patients with and without thrombocytopenia, and no correlation was found between PAIgM and platelet count. Eluted PAIgM did not react with normal platelets in all cases with a positive PAIgM value, indicating that eluted PAIgM contained no detectable anti-platelet antibodies. During alpha-interferon therapy, the level of PAIgM increased in association with the decrease in platelet counts in 75% of the cases; however, eluted PAIgM at any day point never reacted with platelets from normal donors. PAIgM was elevated in patients with chronic hepatitis C, but contained no detectable anti-platelet autoantibodies. Thrombocytopenia in these patients is not due to anti-platelet autoantibodies. [ABSTRACT FROM AUTHOR]

The mechanism by which high doses of estrogen influences lipid metabolism was studied with a microtubular blocking agent. Castrated male rats received oral injection daily for 14 days of 3 mg hexestrol in olive oil, or oil alone as controls. About half of the animals in each group were injected intraperitoneally with 4 mg/100 g body weight colchicine 3 hr before they were killed. Hexestrol treatment caused an accumulation of esterified cholesterol in the liver while it decreased those in serum. Triglyceride concentrations slightly decreased in the liver but were unaffected in serum. On polyacrylamide-gel disc electrophoresis, the peaks of high density lipoproteins (HDL) and low density lipoproteins (LDL) were decreased remarkably. Electron microsopic examination of hepatocytes revealed electron-lucent lipid droplets in the cytoplasm. After a colchicine treatment of the control animals, concentrations of esterified cholesterol and triglycerides markedly increased in the liver, while those in serum decreased. Electron microscopic examination of hepatocytes revealed numerous secretory vesicles filled with nascent VLDL. In hexestrol-treated animals, the colchicine treatment was associated with marked decreases in serumesterified cholesterol and triglyceride as seen in the controls. However, there were no further increases of esterified cholesterol in the liver, and the increase of triglycerides was slight. Electron microscopic examination showed less secretory droplets than in the controls. These data suggest that very low density lipoproteins (VLDL) synthesis in the liver of hexestrol treated rats was inhibited. An accumulation of esterified cholesterol with a marked decrease in serum could not be accounted for by the inhibition of lipoproteins secretion, but rather by their enhanced entry into the liver. [ABSTRACT FROM AUTHOR]

Administration of 4,4′-diethylamino-ethoxyhexestrol increased total phospholipids and free cholesterol in rat liver. An elevation of a peculiar glycerophospholipid, lysobisphosphatidic acid, was marked both in liver and spleen. An increase in phosphatidylinositol was also noticed in spleen. However these changes in rats were not so marked as in human cases. There was an accumulation of a substance in rat tissue which was identified as a derivative of the drug, while the intact drug accumulated in large amount in human cases. Differences in the effect of 4,4′-diethylaminoethoxyhexestrol on lipid metabolism between human and rat seem to be related to the difference in drug digesting ability between these two animal species. [ABSTRACT FROM AUTHOR]

Intergeneric crosses were made between Brassica oleracea and Moricandia arvensis utilizing embryo rescue. Six F1 hybrid plants were generated in the cross-combination of B. oleracea × M. arvensis from 64 pods by the placenta-embryo culture technique, whereas three plants were produced in the reciprocal cross from 40 pods by the ovary culture technique. The hybrid plants were ascertained to be amphihaploid with 2n = 23 chromosomes in mitosis and a meiotic chromosome association of (0–3)II + (17–23)I at metaphase I (M I). In the backcross with B. oleracea, some of these hybrids developed sesquidiploid BC1 plants with 2n = 32 chromosomes that predominantly exhibited a meiotic configuration of (9II + 14I) in pollen mother cells. The following backcross of BC2 plants to B. oleracea generated 48 BC3 progeny with somatic chromosomes from 2n = 19 to 2n = 41. The 2n = 19 plants showed a chromosomal association type of (9II + 1I) and a chromosomal distribution type of (91/2 + 91/2) or (9 + 10) at M I and M II, respectively. These facts might suggest that they were monosomic addition lines (MALs) of B. oleracea carrying a single chromosome of M. arvensis that could offer potential for future genetic and breeding research, together with other novel hybrid progeny developed in this intergeneric hybridization. [ABSTRACT FROM AUTHOR]

Abstract Six haploid plants of radish were obtained via alien monosomic addition lines (2n = 19). One plant was derived from anther culture of an Raphanus sativus-Brassica oleracea addition line, one plant from the selected smaller seed of an R. sativus-Sinapis arvensis addition line and four plants from an R. sativus-B. rapa addition line. During metaphase I of pollen mother cells, two plants exhibited the chromosome pairing of (0–3)II+(3–9)I, three showed (0–1)III + (0–3)II + (3–9)I and the remaining plant (0–2)II + (5–9)I. Trivalents seemed to be formed by the pairing between two larger chromosomes and the smaller one with somewhat loose pairing. All haploid plants were inferior to the radish cv. ‘Shogoin’ (2n = 18) with respect to vegetative growth. Their flowers were smaller, with sterile pollen grains, but a few normal flowers with fertile pollen sporadically developed and then produced a few seeds. It is suggested that the radish genome (R, n = 9) might comprise three pairs of homoeologous chromosomes, with the remaining three chromosomes carrying the homologous region(s) that results in a trivalent formation. [ABSTRACT FROM AUTHOR]

Eight plants of the putative double monosomic addition line (DMAL, 2n =20) were developed by crossing a monosomic chromosome addition line of radish [f(A)-type monosomic addition line (MAL) (2n =19)] carrying the f chromosome of Brassica rapa (2n =20, AA) with another [e(C)-type MAL (2n =19)] having the echromosome of Brassica oleracea (2n =18, CC). The homoeological relationships between the two alien chromosomes were investigated by morphological, cytogenetic and random amplified polymorphic DNA (RAPD) analysis. Seventeen morphological traits that were not present in the radish cv. `Shogoin' were observed in both MALs and these traits were substantially exhibited in DMAL plants. At the first metaphase of pollen mother cells (PMCs), the two parental MALs showed a chromosome configuration of 9II + 1I, demonstrating impossibility of recombination between the R and the added chromosomes. The DMALs formed 10II in approximately 73% of PMCs, with one bivalent showing loose pairing between two chromosomes differing in size. In an attempt to identify the two MALs by RAPD-specific markers using 26 selected random primers, 13 and 20 bands were specific for the f(A)-type and the e(C)-type MALs, respectively; 12 bands were common to both MALs (26.7%). In conclusion, the f chromosome of B. rapa is homoeologous to the e chromosome of B. oleracea . The genetic domain (genes) for 17 morphological traits are linked to each homoeologous chromosome bearing 27% of the corresponding RAPD markers. [ABSTRACT FROM AUTHOR]

For the development of a new cytoplasmic male sterility (CMS) system in Brassica rapa (2n = 20, AA), intergeneric hybridization was performed in Eruca sativa (2n = 22, EE) × B. rapa. The original amphihaploid F[sub 1] plant (2n = 21, EA) generated via embryo rescue produced a sesquidiploid F[sub 2] plant (2n = 31, EAA), from which the alloplasmic F[sub 3] plants were generated. In F[sub 3], some progenies with malformed anthers were maintained as male-sterile lines up to the F[sub 6] generation. In the F[sub 7] and F[sub 8] generations, the alloplasmic male-sterile plants were bred by backcrossing to several B. rapa genotypes and were then classified into the three distinctive types: petaloid, antherless and brown anther, in addition to three intermediate types between them. By southern blot analysis, each plant of the petaloid and antherless types was shown to carry the cytoplasm genome of E. sativa. These male-sterile plants produced as many viable seeds as the corresponding male-fertile plants, although their nectary gland development was minimal. Consequently, CMS lines of the petaloid and antherless types with enhanced seed fertility and nectary gland development could provide promising plant materials for F[sub 1] seed production in B. rapa. [ABSTRACT FROM AUTHOR]

Clinical studies in recent years have demonstrated that the extent of obesity does not necessarily determine the development of obesity-related diseases such as type2 diabetes, hyperlipidemia, hypertension, but fat distribution is a much more important determinant In 1983, we reported a method for fat analysis using CT scan which enabled us to analyze in intraabdominal adipose tissue, namely visceral fat as well as subcutaneous fat. Then we demonstrated that visceral fat accumulation correlated to the disturbance of lipid and glucose metabolism, insulin resistance, hypertension and cardiovascular disease in obese subjects and even in non-obese subjects. From these clinical studies, we proposed the concept of ‘visceral fat syndrome’ in which multiple risk factors cluster through visceral fat accumulation. Besides, this syndrome is designated to be a very atherogenic state. Visceral fat syndrome is corresponding to the concept of metabolic syndrome recently noted. In order to clarify the molecular mechanism why visceral fat accumulation correlates to plural common diseases and also directly to atherosclerosis, we started a project for the analysis of adipose tissue using random sequence of expressed genes in adipose tissues. We found unexpectedly that adipose tissue, especially visceral fat, expressed strongly the genes encoding secretory proteins most of which are important bioactive substances (named as adipocytokines). In addition to known adipocytokines, several novel adipose-specific genes were identified. Among them, a collagen-like protein encoded by an adipose most abundant gene (apM-1) is the most important novel adipocytokine which is named adiponectin. Adiponectin has anti-diabetic, anti-atherogenic, anti-oncogenic and anti-inflammatory properties and its plasma levels decreases with visceral fat accumulation, suggesting that this molecules may play a central role in the visceral fat syndrome or metabolic syndrome. In this lecture, I would like to present the importance of adiponectin together with other adipocytokines in lifestyle-related diseases relevant to visceral fat accumulation. [ABSTRACT FROM AUTHOR]

The specific monosomic addition line of radish, Raphanus sativus, carrying the e chromosome of Brassica oleracea (2n = 19, e-type MAL) with the genetic background of the late-bolting cv. ‘Tokinashi’ was produced by successive backcrossing of the original e-type MAL of radish that showed early bolting in the genetic background of the cv. ‘Shogoin’. The early-bolting trait specific to the e-type MAL was constantly expressed in the backcrossed progenies (BC2, BC3 and BC4), whereas the reverted radish-like plants (2n = 18) were gradually converted to bolting as late as ‘Tokinashi’. The added e-chromosome expressed an epistatic effect against the genome of Japanese radish. Its early-bolting trait was dominant to the late-bolting trait of ‘Tokinashi’ which may be under the control of a few genes. Moreover, e-type specific RAPD markers detected in eight primers were invariably transmitted in the backcrossed progenies by ‘Tokinashi’. From the analysis of the similarities to the e-type MAL and e-type specific RAPD markers, it is suggested that the added e chromosome of kale (B. oleracea) was transmitted from generation to generation without any recombination with the radish chromosome. The gene(s) for the early-bolting trait detected in this study may be useful for breeding work in radish, especially in the tropical areas. [ABSTRACT FROM AUTHOR]

Background: Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes., Methods and Results: In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P =0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P <0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes., Conclusions: Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.

Background: A delayed and recurrent complete atrioventricular block (CAVB) is a life-threatening complication of transcatheter aortic valve replacement (TAVR). Post-TAVR evaluation may be important in predicting delayed and recurrent CAVB requiring permanent pacemaker implantation (PPI). The impact of new-onset right bundle-branch block (RBBB) after TAVR on PPI remains unknown., Methods and Results: In total, 407 patients with aortic stenosis who underwent TAVR were included in this analysis. Intraprocedural CAVB was defined as CAVB that occurred during TAVR. A 12-lead ECG was evaluated at baseline, immediately after TAVR, on postoperative days 1 and 5, and according to the need to identify new-onset bundle-branch block (BBB) and CAVB after TAVR. Forty patients (9.8%) required PPI, 17 patients (4.2%) had persistent intraprocedural CAVB, and 23 (5.7%) had delayed or recurrent CAVB after TAVR. The rates of no new-onset BBB, new-onset left BBB, and new-onset RBBB were 65.1%, 26.8%, and 4.7%, respectively. Compared with patients without new-onset BBB and those with new-onset left BBB, the rate of PPI was higher in patients with new-onset RBBB (3.4% versus 5.6% versus 44.4%, P <0.0001). On post-TAVR evaluation in patients without persistent intraprocedural CAVB, the multivariate logistic regression analysis showed that new-onset RBBB was a statistically significant predictor of PPI compared with no new-onset BBB (odds ratio [OR], 18.0 [95% CI, 5.94-54.4]) in addition to the use of a self-expanding valve (OR, 2.97 [95% CI, 1.09-8.10])., Conclusions: Patients with new-onset RBBB after TAVR are at high risk for PPI.

Background Contradictions between management modalities of type A acute aortic dissection (TAAAD) and ST-elevation-myocardial infarction (STEMI) may result in clinical catastrophe. Therefore, we aimed to explore which 2-dimensional echocardiography (2DE) findings are optimal for differentiating TAAAD from STEMI. Methods and Results This study included 340 patients with STEMI and 340 patients with TAAAD who underwent 2DE in the emergency department between 2012 and 2021. The proximal ascending aorta (PAA) diameter and other echocardiographic parameters were analyzed. PAA diameters were measured at 4 levels in the parasternal view: Valsalva, the sinotubular junction (STJ), the PAA at 1 cm above the STJ, and the PAA at 2 cm above the STJ. Receiver-operating characteristic curve analysis showed that Valsalva, STJ, PAA at 1 cm above the STJ, and PAA at 2 cm above the STJ were significant predictors of TAAAD (areas under the curve: 0.777, 0.924, 0.965, and 0.975, respectively; P <0.001) with the respective cutoff values of 39.4, 38.5, 39.8, and 41.2 mm. Multivariable analysis suggested that all 2DE parameters were significant predictors of TAAAD. Among the 2DE parameters examined, the incorporation of PAA at 2 cm above the STJ to clinical indicators exhibited the most significant diagnostic capability (C-statistics, 0.97; net reclassification improvement, 1.81; integrated discrimination improvement, 0.61). When only TAAAD with coronary malperfusion and STEMI were analyzed, the diagnostic utility of PAA at 1 cm above the STJ was evident (C-statistics, 0.99; net reclassification improvement, 1.79; integrated discrimination improvement, 0.67), with PAA at 2 cm above the STJ ranking second in diagnostic significance (C-statistics, 0.99; net reclassification improvement, 1.12; integrated discrimination improvement, 0.66). Conclusions PAA measurements were the most beneficial for diagnosing TAAAD in all 2DE findings and TAAAD from STEMI.

Aim: To characterize the long-term changes in body composition associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors., Materials and Methods: In this multicentre, single-arm, open-label study, 107 patients with type 2 diabetes were treated with canagliflozin 100 mg, as add-on therapy, for 12 months. Body composition was measured with a body composition analyser (T-SCAN PLUS) using the impedance method to prospectively analyse changes in body components, including percentage of body fat, body fat mass, total body water, muscle mass and mineral mass. Estimated plasma volume (PV) was calculated using the Kaplan formula., Results: Body weight showed a significant decrease from 1 month to 12 months of treatment with canagliflozin, with a higher rate of decrease in body fat in body composition. A significant decrease in mineral mass was also observed, but its rate was low. Following treatment with canagliflozin, changes in total body water did not affect intracellular water, and a significant decrease in extracellular water, including plasma components, was observed early and was sustained up to 12 months. Protein mass, a component of muscle mass, was not affected, with only a slight decrease in water volume observed., Conclusions: Canagliflozin decreased extracellular fluid and PV in addition to decreasing fat in the body via calorie loss resulting from urinary glucose excretion. This study suggested that SGLT2 inhibitors might reduce body weight by regulating fat mass or water distribution in the body and might have cardiac and renal protective effects by resetting the homeostasis of fluid balance., (© 2021 John Wiley & Sons Ltd.)

Background Among patients with atrial fibrillation and stable coronary artery disease, those with histories of atherothrombotic disease are at high-risk for future ischemic events. This study investigated the efficacy and safety of rivaroxaban monotherapy in patients with atrial fibrillation, coronary artery disease, and histories of atherothrombotic disease. Methods and Results This was a post hoc subanalysis of the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial. Patients with non-valvular atrial fibrillation and coronary artery disease were recruited and randomized to receive the rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. For the purpose of this sub-study, participants were divided into 2 subgroups, including the atherothrombosis group (those with histories of myocardial infarction, stroke, and/or peripheral artery disease; n=1052, 47.5%) and non-atherothrombosis group (n=1163, 52.5%). The efficacy end point included cardiovascular events or all-cause death, while the safety end point was major bleeding. Net adverse events consisted of all-cause death, myocardial infarction, stroke, or major bleeding. In the atherothrombosis group, rivaroxaban monotherapy was significantly associated with a lower risk of net adverse events when compared with combination therapy (hazard ratio [HR], 0.50; 95% CI, 0.34-0.74; P <0.001), with a decrease in both efficacy (HR, 0.68; 95% CI, 0.47-0.99; P =0.044) and safety (HR, 0.37; 95% CI, 0.19-0.71; P =0.003) end points. By contrast, there were no differences between treatment outcomes for the non-atherothrombosis group. Conclusions Rivaroxaban monotherapy significantly reduced net adverse events as compared with combination therapy for patients with atrial fibrillation, coronary artery disease, and prior atherothrombotic disease. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000016612. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02642419.

Background Myocardial bridge (MB), common anatomic variant, is generally considered benign, while previous studies have shown associations between MB and various cardiovascular pathologies. This study aimed to investigate for the first time possible impact of MB on long-term outcomes in patients with implantable cardioverter defibrillator, focusing on life-threatening ventricular arrhythmia (LTVA). Methods and Results This retrospective analysis included 140 patients with implantable cardioverter defibrillator implantation for primary (n=23) or secondary (n=117) prevention of sudden cardiac death. Angiographically apparent MB was identified on coronary angiography as systolic milking appearance with significant arterial compression. The primary end point was the first episode(s) of LTVA defined as appropriate implantable cardioverter defibrillator treatments (antitachyarrhythmia pacing and/or shock) or sudden cardiac death, assessed for a median of 4.5 (2.2-7.1) years. During the follow-up period, LTVA occurred in 37.9% of patients. Angiographically apparent MB was present in 22.1% of patients; this group showed younger age, lower rates of coronary risk factors and ischemic cardiomyopathy, higher prevalence of vasospastic angina and greater left ventricular ejection fraction compared with those without. Despite its lower risk profiles above, Kaplan-Meier analysis revealed significantly lower event-free rates in patients with versus without angiographically apparent MB. In multivariate analysis, presence of angiographically apparent MB was independently associated with LTVA (hazard ratio, 4.24; 95% CI, 2.39-7.55; P <0.0001). Conclusions Angiographically apparent MB was the independent determinant of LTVA in patients with implantable cardioverter defibrillator. Although further studies will need to confirm our findings, assessment of MB appears to enhance identification of high-risk patients who may benefit from closer follow-up and targeted therapies.

Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is characterized by alterations of SATB2. Its clinical features include intellectual disability and craniofacial abnormalities, such as cleft palate, dysmorphic features, and dental abnormalities. Here, we describe three previously undiagnosed, unrelated patients with SAS who exhibited dental abnormalities, including multiple odontomas. Although isolated odontomas are common, multiple odontomas are rare. Individuals in families 1 and 3 underwent whole-exome sequencing. Patient 2 and parents underwent targeted amplicon sequencing. On the basis of the hg19/GRCh37 reference and the RefSeq mRNA NM&#95;001172517, respective heterozygous mutations were found and validated in Patients 1, 2, and 3: a splice-site mutation (chr2:g.200137396C > T, c.1741-1G > A), a nonsense mutation (chr2:g.200213750G > A, c.847C > T, p.R283*), and a frame-shift mutations (chr2:g.200188589&#95;200188590del, c.1478&#95;1479del, p.Q493Rfs*19). All mutations occurred de novo. The mutations in Patients 1 and 3 were novel; the mutation in Patient 2 has been described previously. Tooth mesenchymal cells derived from Patient 2 showed diminished SATB2 expression. Multiple odontomas were evident in the patients in this report; however, this has not been recognized previously as a SAS-associated phenotype. We propose that multiple odontomas be considered as an occasional manifestation of SAS., (© 2018 Wiley Periodicals, Inc.)

In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium-glucose co-transporter-2 inhibitor-naïve and incretin-related agent-naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of β-cell function and decreases in proinsulin-to-insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on β-cell function., (© 2018 John Wiley & Sons Ltd.)

Background: The biphasic inflammation after ST-segment elevation myocardial infarction (STEMI) plays an important role in myocardial healing and progression of systemic atherosclerosis. The purpose of this study is to investigate the impact of fever during the first and second phases of post-STEMI inflammation on long-term cardiac outcomes., Methods and Results: A total of 550 patients with STEMI were enrolled in this study. Axillary body temperature (BT) was measured and maximum BTs were determined for the first (within 3 days: max-BT 1-3d ) and second (from 4 to 10 days after admission: max-BT 4-10d ) phases, respectively. Patients were followed for cardiac events (cardiovascular death, acute coronary syndrome, and rehospitalization for heart failure) for a median 5.3 years. During the follow-up period, 80 patients experienced cardiac events. A high max-BT 4-10d was strongly associated with long-term cardiac events (hazard ratio, 95% CI) for a 1°C increase in the max-BT 4-10d : 2.834 (2.017-3.828), P <0.0001, whereas the max-BT 1-3d was not associated with cardiac events (1.136 [0.731-1.742], P =0.57). Even after adjustment for coronary risk factors, estimated glomerular filtration rate, infarct size, pericardial effusion, and medications on discharge, fever during the second phase (max-BT 4-10d ≥37.1°C) was significantly associated with future cardiac events (hazard ratio [95% CI] 2.900 [1.710-5.143], P <0.0001)., Conclusions: Fever during the second phase but not the first phase of post-STEMI inflammation was a strong associated factor with worse long-term cardiac outcomes in patients after STEMI, suggesting the need to consider the optimal timing for anti-inflammatory strategies after STEMI., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The study compared downstream coronary and conduit disease progression in the left anterior descending coronary artery treated with coronary artery bypass grafting using the left internal mammary artery (LIMA) versus percutaneous coronary intervention with bare metal stent (BMS) or drug eluting stent (DES)., Methods and Results: A total of 12 301 consecutive patients underwent isolated primary coronary revascularization, of which 2386 met our inclusion criteria (Percutaneous coronary intervention, n=1450; coronary artery bypass grafting, n=936). Propensity score analysis matched 628 patients, of which 468 were treated to the left anterior descending with coronary artery bypass grafting with LIMA (n=314), percutaneous coronary intervention with BMS (n=94), and DES (n=60). Coronary angiograms were analyzed by quantitative coronary angiography (QCA; n=433). Cumulative downstream coronary and conduit disease progression were estimated by Kaplan-Meier method and effect of treatment type by Cox proportional hazard models. Patients treated with LIMA had significantly lower risk of downstream coronary disease progression at follow-up angiogram compared with BMS and DES (hazard ratio [HR] [95% CI], 0.34; [0.20-0.59]; P=0.0002; and HR [95% CI], 0.39; [0.20-0.79]; P=0.01, respectively). LIMA was associated with a lower risk of conduit disease progression compared to BMS and DES (HR [95% CI], 0.18; [0.12-0.28]; P<0.001; and HR [95% CI], 0.27; [0.16-0.46]; P<0.001, respectively). BMS was associated with higher HR for downstream coronary and conduit disease progression compared with DES, but the difference did not reach statistical significance (HR [95% CI], 1.13; [0.57-2.36]; P=0.73; and HR [95% CI], 1.46; [0.88-2.50]; P=0.14, respectively)., Conclusions: LIMA grafting to left anterior descending is associated with significantly lower risk of downstream coronary and conduit disease progression compared to percutaneous coronary intervention with BMS and DES., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: The mechanisms of atrial fibrillation (AF) are highly divergent. The prevalence of AF increases significantly with age, and underling mechanisms might vary with age. Endothelial dysfunction may be associated with AF and atrial arrhythmia recurrence after catheter ablation. We tested the hypothesis that the impact of endothelial dysfunction on arrhythmia recurrence following catheter ablation is age dependent., Methods and Results: This study enrolled 92 participants with AF undergoing catheter ablation. Endothelial function was assessed by peripheral arterial tonometry before ablation, and the natural logarithmic transformation of reactive hyperemia index was calculated. Endothelial dysfunction was defined as a natural logarithmic transformation of reactive hyperemia index <0.618 (median). Participants were followed for atrial tachycardia, flutter, and fibrillation recurrence for a median of 14 months. The mean age was 57±10 years. There was significant interaction between age and endothelial dysfunction in association with recurrence of AF (P=0.029) and any atrial arrhythmia (P=0.015), and the risk associated with endothelial dysfunction for arrhythmia recurrence was higher in younger versus older participants. Participants were divided into 2 age groups at a threshold of 60 years. Among participants aged ≤60 years, multivariate Cox proportional hazards analysis revealed the independent association between endothelial dysfunction and increased risk of arrhythmia recurrence (hazard ratio for AF 4.18 [95% CI 1.33-15.82], P=0.014, and for any atrial arrhythmia 3.62 [95% CI 1.29-11.81], P=0.014). Kaplan-Meier analysis showed that participants with endothelial dysfunction had significantly higher rates of recurrence of AF (P=0.01) and any atrial arrhythmia (P=0.002)., Conclusions: The risk associated with endothelial dysfunction for arrhythmia recurrence following catheter ablation was age dependent and was higher in younger participants., (© 2016 The Authors and Mayo Foundation for Medical Education and Research. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Endothelial dysfunction plays a pivotal role in cardiovascular disease progression, and is associated with adverse events. The purpose of this systematic review and meta-analysis was to investigate the prognostic magnitude of noninvasive peripheral endothelial function tests, brachial artery flow-mediated dilation (FMD), and reactive hyperemia--peripheral arterial tonometry (RH-PAT) for future cardiovascular events., Methods and Results: Databases of MEDLINE, EMBASE, and the Cochrane Library were systematically searched. Clinical studies reporting the predictive value of FMD or RH-PAT for cardiovascular events were identified. Two authors selected studies and extracted data independently. Pooled effects were calculated as risk ratio (RR) for continuous value of FMD and natural logarithm of RH-PAT index (Ln&#95;RHI) using random-effects models. Thirty-five FMD studies of 17 280 participants and 6 RH-PAT studies of 1602 participants were included in the meta-analysis. Both endothelial function tests significantly predicted cardiovascular events (adjusted relative risk [95% CI]: 1% increase in FMD 0.88 [0.84-0.91], P<0.001, 0.1 increase in Ln&#95;RHI 0.79 [0.71-0.87], P<0.001). There was significant heterogeneity in the magnitude of the association across studies. The magnitude of the prognostic value in cardiovascular disease subjects was comparable between these 2 methods; a 1 SD worsening in endothelial function was associated with doubled cardiovascular risk., Conclusions: Noninvasive peripheral endothelial function tests, FMD and RH-PAT, significantly predicted cardiovascular events, with similar prognostic magnitude. Further research is required to determine whether the prognostic values of these 2 methods are independent of each other and whether an endothelial function-guided strategy can provide benefit in improving cardiovascular outcomes., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Cardiac allograft vasculopathy is the leading cause of graft failure and death in heart transplant (HTx) recipients; however, the association between the etiology of heart failure (ischemic cardiomyopathy [ICM] or non-ICM) that led to HTx and progression of cardiac allograft vasculopathy, and adverse events after HTx has not been explored., Methods and Results: We retrospectively included 165 HTx patients, who were followed-up with at least 2 virtual histology-intravascular ultrasound examinations after HTx, and grouped them as ICM (n=46) or non-ICM (n=119). Coronary artery plaque volume was analyzed using virtual histology-intravascular ultrasound, and cardiovascular event data-a composite of myocardial infarction, hospitalization for heart failure and arrhythmia, revascularization, retransplantation, and death including cardiovascular death-were collected from the medical records of all study subjects. ICM patients had significantly higher plaque volume at both first (P=0.040) and follow-up (P=0.015) intravascular ultrasound examinations. After multivariate adjustment for traditional coronary risk factors, ICM was significantly associated with plaque progression (odds ratio 3.10; CI 1.17 to 9.36; P=0.023). Ten-year cardiovascular event-free survival was 50% in ICM patients compared with 84% in non-ICM patients (log-rank test P=0.003). In multivariate Cox proportional hazard analysis, ICM was significantly associated with a higher event rate after HTx (hazard ratio 2.02; 95% CI 1.01 to 4.00; P=0.048)., Conclusion: Our study demonstrates that ischemic etiology of cardiomyopathy prior to HTx may be independently associated with plaque progression and higher event rate after HTx., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Pentraxin 3 (PTX3) is a novel inflammatory marker produced by various cell types including those of the vasculature and the heart. The relationship between inflammatory markers and prognosis of patients with heart failure with normal ejection fraction (HFNEF) remains unknown. We investigated whether plasma PTX3 levels can predict future cardiovascular events in patients with HFNEF., Methods and Results: Plasma PTX3, high-sensitivity C-reactive protein, and B-type natriuretic peptide levels were measured prospectively in 360 stable patients with HFNEF. The subsequent incidence of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction (MI), unstable angina pectoris, nonfatal ischemic stroke, hospitalization for heart failure decompensation, and coronary revascularization, was determined. During a mean 30-month follow-up, 106 patients experienced cardiovascular events. These events were more frequent in patients with high plasma PTX3 levels (>3.0 ng/mL) than low levels (≤3.0 ng/mL). Multivariable Cox hazard analysis showed that PTX3 (hazard ratio: 1.16; 95% CI: 1.05 to 1.27; P<0.01) and B-type natriuretic peptide (hazard ratio: 1.08; 95% CI: 1.03 to 1.14; P<0.001), but not high-sensitivity C-reactive protein levels, were significant predictors of future cardiovascular events. Multivariable Cox analysis with the forced inclusion model, including 5 previously identified prognostic factors, found that PTX3 was a significant predictor of cardiovascular events (hazard ratio: 1.16; 95% CI: 1.06 to 1.27; P<0.01). The C-statistics for cardiovascular events substantially increased from 0.617 to 0.683 when PTX3 was added to the 5 previously identified prognostic factors., Conclusions: High plasma PTX3 levels, but not other inflammatory markers, are correlated with future cardiovascular events in patients with HFNEF. PTX3 may be a useful biomarker for assessment of risk stratification in HFNEF., Clinical Trial Registration Url: http://www.umin.ac.jp; Unique identifier: UMIN000002170., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: The prevalence, clinical features, and long-term outcome of patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) associated with coronary spasm are not fully investigated., Methods and Results: This observational multicenter study enrolled 1601 consecutive patients with suspected NSTE-ACS who underwent cardiac catheterization between January 2001 and December 2010. A culprit lesion was found in 1152 (72%) patients. In patients without a culprit lesion, the acetylcholine provocation test was performed in 221 patients and was positive in 175 patients. In the other patients, coronary spasm was verified in 145 patients during spontaneous attack. Spasm-induced NSTE-ACS was diagnosed in 320 (20%) patients. Multivariable analysis identified age <70 years (odds ratio [OR] 2.19, 95% CI 1.58 to 3.04), estimated glomerular filtration rate >60 mL/min per 1.73 m(2) (OR 1.72, 95% CI 1.16 to 2.56), and lack of hypertension (OR 2.55, 95% CI 1.90 to 3.41), dyslipidemia (OR 2.76, 95% CI 2.05 to 3.73), diabetes mellitus (OR 2.49, 95% CI 1.78 to 3.48), previous myocardial infarction (OR 5.37, 95% CI 2.89 to 10.0), and elevated cardiac biomarkers (OR 2.84, 95% CI 2.11 to 3.83) as significant correlates of spasm-induced NSTE-ACS (P<0.01 for all variables). Transient ST-segment elevation during spontaneous attack (variant angina) was observed in 119 patients with spasm-induced NSTE-ACS. Variant angina was more common in nondyslipidemic men among patients with spasm-induced NSTE-ACS., Conclusions: The study showed frequent involvement of coronary spasm in the pathogenesis of NSTE-ACS. Variant angina was observed in one third of patients with spasm-induced NSTE-ACS. Coronary spasm should be considered even in patients with less coronary risk factors and nonobstructive coronary arteries.

Background: Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high-risk patients., Methods and Results: We undertook a two-center prospective study in 528 stable patients at high-risk for cardiovascular events from the years 2006-2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow-up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure-induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person-years of follow-up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B-type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C-statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031)., Conclusions: Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high-risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc., Clinical Trial Registration Url: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.

Background: Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers., Methods and Results: Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor-borderline ischemic electrocardiogram findings at rest, limited-baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate-induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months., Conclusions: Microvascular CAS causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided., Clinical Trial Registration: URL: www.umin.ac.jp/ctr. Unique identifier: UMIN000003839.

Very late antigen (VLA)-4 integrin has been suggested to play an important role in haemopoiesis. However, little is known concerning the roles of the fibronectin (FN)/VLA-4 interaction in the proliferation of human B cells. In this study we investigated the effect of immobilized FN on the proliferation of various B-cell lines, including a newly-established B-cell line, OPM-3, and human tonsillar B cells, that primarily express VLA-4 but not VLA-5. Immobilized FN significantly promoted the proliferation of OPM-3 cells and normal B cells via VLA-4. The cross-linking of beta1 integrins of OPM-3 cells resulted in the phosphorylation of the focal adhesion kinase (FAK) associated 90 kD protein, an increase in FAK-associated kinase activity, and the phosphorylation of Raf-1. Furthermore, the MEK1 inhibitor, PD98059, inhibited the FN-promoted proliferation of OPM-3 cells. These results demonstrate that the FN/VLA-4 interaction transmits the growth signal(s) which may be mediated by Ras pathway in OPM-3 cells, and suggest that OPM-3 cells may be of great value in studying the roles of the FN/VLA-4 interaction in human B-cell growth.

Background: We have previously shown that eradication of Helicobacter pylori increases acid secretion in H. pylori-associated enlarged fold gastritis., Aim: To investigate whether locally produced interleukin-1 beta is possibly involved in the inhibition of acid secretion in H. pylori gastritis., Methods: IL-1 beta release from the gastric body mucosa was determined by short-term culture of biopsy specimens in 13 patients with enlarged fold gastritis (all H. pylori-positive), five H. pylori-positive and 10 H. pylori-negative patients without enlarged folds. The acid-inhibitory effect of locally produced IL-1 beta was examined by [14C]-aminopyrine uptake assay using isolated rabbit gastric glands., Results: IL-1 beta release was significantly greater in patients with enlarged fold gastritis, significantly correlated with both basal and tetragastrin-stimulated acid outputs in the H. pylori-positive patients (r = -0.591 and r = -0.641, respectively; P < 0.01), and significantly decreased with concomitant increases in acid secretions after eradication of H. pylori. [14C]-aminopyrine uptake was inhibited by IL-1 beta in a dose-dependent manner., Conclusions: Increased production of IL-1 beta caused by H. pylori infection is possibly involved in the inhibition of acid secretion in enlarged fold gastritis.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to be a potent smooth muscle cell (SMC) mitogen and chemoattractant, and might be a candidate factor for the progression of atherosclerosis. We have investigated the effects of high glucose and hyperosmolarity on HB-EGF production in cultured human aortic endothelial cells. Following the culture of the cells for 2 days with high concentrations of glucose or in the hyperosmolar conditions, we measured the content of HB-EGF and the rate of production in the cells using a semi-quantitative immunofluorescent technique and a metabolic radiolabelling method. With high glucose (16.6 mmol) and hyperosmolar conditions (glucose 5.5 mmol + mannitol 11.1 mmol or glucose 5.5 mmol + raffinose 11.1 mmol), the content of HB-EGF was significantly increased and the metabolic rate was also significantly increased (more than a twofold increase, compared to that of 5.5 mmol glucose). In conclusion, conditions of high glucose or hyperosmolarity increase HB-EGF production in human aortic endothelial cells. These results suggest that diabetic macroangiopathy might be attributed at least in part to HB-EGF-related vascular changes which may be induced by glucose.

The circulating thrombopoietin (TPO) level in 43 patients with chronic immune thrombocytopenic purpura (ITP) was examined by an ELISA system. The TPO level (mean +/- SD) in ITP patients was mildly elevated (1.86 +/- 1.17 fmol/ml) compared to that in normal subjects (0.76 +/- 0.21), and was within the normal range in 30% of ITP patients. In contrast, the TPO level in patients with aplastic anaemia was very high, 12.35 +/- 6.42 fmol/ml. There was no correlation between TPO level and platelet count in ITP patients. Splenectomy was performed in two ITP patients, after which platelet counts increased to normal levels and TPO levels showed a transient increase. These data suggest that reactive TPO production against thrombocytopenia in ITP is small when compared to that in aplastic anaemia. Relative endogenous TPO deficiency may play some role in the pathophysiology of thrombocytopenia in ITP patients.

Objective: Autoimmunity-prone (New Zealand white x BXSB)F1 ([NZW x BXSB]F1) mice have been shown to be useful as a model of antiphospholipid syndrome with myocardial infarction. The aim of this study was to examine the cross-reactivity of anticardiolipin antibody (aCL) derived from (NZW x BXSB)F1 mice with oxidized low-density lipoprotein (ox-LDL), which is closely associated with atherosclerosis., Methods: Six monoclonal antibodies (MAb) against CL were established from (NZW x BXSB)F1 mice, and reactivity of aCL with ox-LDL was examined by micro-enzyme-linked immunosorbent assay., Results: Higher titers of anti-ox-LDL autoantibodies were found in adult (NZW x BXSB)F1 mice compared with other autoimmunity-prone mouse strains (P < 0.01) or a control strain (P < 0.005). There was a significant positive correlation between titers of aCL and those of anti-ox-LDL in (NZW x BXSB)F1 mice (r = 0.79, P < 0.001). Of the 6 MAb against CL, 2 clones that showed beta 2-glycoprotein 1-dependent reactivity also cross-reacted with ox-LDL. Binding of monoclonal aCL to solid-phase cardiolipin was inhibited by ox-LDL, but not by native LDL., Conclusion: We confirmed that aCL derived from (NZW x BXSB)F1 mice can cross-react with ox-LDL. This result suggests that aCL, which is closely associated with lupus-associated thrombosis, may also play an important role in atherosclerotic complications in patients with systemic lupus erythematosus.

We studied a female patient with cyclic fluctuation in platelet count following splenectomy for autoimmune thrombocytopenia. The cyclical fluctuation appeared to be in phase with her menstrual cycle and her platelet count was low during menses. Bone marrow examinations performed at the peak as well as the bottom of the platelet count showed normal or increased numbers of megakaryocytes. The patient's platelet count increased rapidly after intravenous gamma-globulin (IVIgG) therapy, suggesting that a failure of platelet production is unlikely to account for the cycle. Platelet-associated IgM (PAIgM) was markedly elevated, whereas PAIgG was normal at any stage of the cycle. MACE assay demonstrated that PAIgM contained IgM anti-glycoprotein (GP) IIb-IIIa autoantibodies. Comparison between MACE assay using untreated and EDTA-treated platelets at 37 degrees C demonstrated that the platelet-associated IgM autoantibodies mainly recognized divalent cation-dependent conformation(s) of GPIIb-IIIa. No antibodies were, however, detected in her serum. The levels of IgM anti-GPIIb-IIIa showed an inverse relationship with the platelet count. In spite of the marked increase in platelet count after IVIgG, however, the levels of IgM anti-GPIIb-IIIa remained elevated. These findings suggest that platelet-associated IgM anti-GPIIb-IIIa autoantibodies are of pathogenic significance in this patient.