Type 2 diabetes susceptibility genes on mouse chromosome 11 under high sucrose environment.

BACKGROUND: Both genetic and environmental factors contribute to type 2 diabetes development. We used consomic mice established from an animal type 2 diabetes model to identify susceptibility genes that contribute to type 2 diabetes development under specific environments. We previously established consomic strains (C3H-Chr 11NSY and C3H-Chr 14NSY) that possess diabetogenic Chr 11 or 14 of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes, in the genetic background of C3H mice. To search genes contribute to type 2 diabetes under specific environment, we first investigated whether sucrose administration deteriorates type 2 diabetes-related traits in the consomic strains. We dissected loci on Chr 11 by establishing congenic strains possessing different segments of NSY-derived Chr 11 under sucrose administration. RESULTS: In C3H-Chr 11NSY mice, sucrose administration for 10 weeks deteriorated hyperglycemia, insulin resistance, and impaired insulin secretion, which is comparable to NSY mice with sucrose. In C3H-Chr 14NSY mice, sucrose administration induced glucose intolerance, but not insulin resistance and impaired insulin secretion. To dissect the gene(s) existing on Chr 11 for sucrose-induced type 2 diabetes, we constructed four novel congenic strains (R1, R2, R3, and R4) with different segments of NSY-derived Chr 11 in C3H mice. R2 mice showed marked glucose intolerance and impaired insulin secretion comparable to C3H-Chr 11NSY mice. R3 and R4 mice also showed impaired insulin secretion. R4 mice showed significant decreases in white adipose tissue, which is in the opposite direction from parental C3H-Chr 11NSY and NSY mice. None of the four congenic strains showed insulin resistance. CONCLUSIONS: Genes on mouse Chr 11 could explain glucose intolerance, impaired insulin secretion, insulin resistance in NSY mice under sucrose administration. Congenic mapping with high sucrose environment localized susceptibility genes for type 2 diabetes associated with impaired insulin secretion in the middle segment (26.0-63.4 Mb) of Chr 11. Gene(s) that decrease white adipose tissue were mapped to the distal segment of Chr 11. The identification of diabetogenic gene on Chr 11 in the future study will facilitate precision medicine in type 2 diabetes by controlling specific environments in targeted subjects with susceptible genotypes.

Distinct Roles of Cytoskeletal Components in Immunological Synapse Formation and Directed Secretion.

A hallmark of CD4(+) T cell activation and immunological synapse (IS) formation is the migration of the microtubule organization center and associated organelles toward the APCs. In this study, we found that when murine CD4(+) T cells were treated with a microtubule-destabilizing agent (vinblastine) after the formation of IS, the microtubule organization center dispersed and all of the major cellular organelles moved away from the IS. Cytokines were no longer directed toward the synapse but were randomly secreted in quantities similar to those seen in synaptic secretion. However, if the actin cytoskeleton was disrupted at the same time with cytochalasin D, the organelles did not shift away from the IS. These findings suggest that there is a complex interplay between the microtubules and actin cytoskeleton, where microtubules are important for directing particular cytokines into the synapse, but they are not involved in the amount of cytokines that are produced for at least 1 h after IS formation. In addition, we found that they play a critical role in mobilizing organelles to reorient toward the synapse during T cell activation and in stabilizing organelles against the force that is generated through actin polymerization so that they move toward the APCs. These findings show that there is a complex interplay between these major cytoskeletal components during synapse formation and maintenance.

Genetic dissection of susceptibility genes for diabetes and related phenotypes on mouse chromosome 14 by means of congenic strains.

BACKGROUND: A susceptibility locus, Nidd2n, for type 2 diabetes has been mapped to mouse chromosome 14 (Chr 14) and confirmed using the consomic strain (C3H-Chr 14NSY) of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes. The aim of this study was to localize and characterize Nidd2n. RESULTS: We constructed two novel congenic strains homozygous for different segments of NSY-Chr 14 on the control C3H/HeNcrj (C3H) background: R1 (C3H.NSY-(D14Mit206-D14Mit5)) possesses the proximal and middle segment, and R2 (C3H.NSY-(D14Mit206-D14Mit186)) possesses the most proximal segment of NSY-Chr 14. Diabetes-related phenotypes were studied in comparison with those of consomic C3H-Chr 14NSY (R0) and parental NSY and C3H strains. Congenic R1 and R2 showed significantly higher post-challenge glucose than that in C3H mice. Fasting glucose, in contrast, was significantly lower in R1 and R2 than in C3H mice. Insulin sensitivity was significantly impaired in R1 and R2 compared to C3H mice. R2 showed significantly higher body weight and fat-pad weight than those in C3H and R1. Leptin level was significantly higher in R0, R1 and R2 than in C3H mice, with R2 showing the highest level, similar to that in NSY mice. Serum adiponectin level was significantly lower in R0, R1 and R2 than in C3H mice, while it was significantly higher in NSY than in C3H mice. CONCLUSIONS: These data indicate that Chr 14 harbors multiple genes for diabetes-related phenotypes. The original Nidd2n, which is located in the middle region of Chr 14, was divided into two segments; Nidd2.1n in proximal Chr 14 and Nidd2.2n in distal Chr 14. Nidd2.1n contributes to post-challenge hyperglycemia, insulin resistance and adiposity. Nidd2.2n contributes to fasting as well as post-challenge hyperglycemia and insulin resistance. Adp1n, which contributes to decreased adiposity and increased insulin sensitivity, rather than a diabetogenic gene, was mapped in the middle segment.

Analysis of the expression of candidate genes for type 1 diabetes susceptibility in T cells.

Type 1 diabetes is characterized by T-cell-mediated autoimmune destruction of pancreatic ß-cells. Currently, approximately 50 type 1 diabetes susceptibility genes or chromosomal regions have been identified. However, the functions of type 1 diabetes susceptibility genes in T cells are elusive. In this study, we evaluated the correlation between type 1 diabetes susceptibility genes and T-cell signaling. The expression levels of 22 candidate type 1 diabetes susceptibility genes in T cells from nonobese diabetic (NOD), control C57BL/6 (B6), and NOD-control F1 hybrid mice were analyzed in response to 2 key immunoregulatory cytokines: interleukin-2 (IL-2) and transforming growth factor ß (TGF-ß). Exogenous gene expression studies were also performed in EL4 and Jurkat E6.1 T-cell lines. Significant differences in the expression of Clec16a, Dlk1, Il2, Ptpn22, Rnls, and Zac1 (also known as Plagl1) were observed in T cells derived from the 3 strains of mice, and TGF-ß differentially influenced the expression of Ctla4, Foxp3, Il2, Ptpn22, Sh2b3, and Zac1. We found that TGF-ß induced Zac1 expression in both primary T cells and EL4 cells and that exogenous expression of Zac1 and ZAC1 in T-cell lines altered the expression of Il2 and DLK1, respectively. The results of our study indicate the possibility that additional genetic pathways underlying type 1 diabetes susceptibility, including those involving Clec16a, Dlk1, Rnls, Sh2b3, and Zac1 under IL-2 and TGF-ß signaling in T cells, may be shared between human and NOD mice.

High plasma human atrial natriuretic peptide and reduced transthoracic left atrial appendage wall-motion velocity are noninvasive surrogate markers for assessing thrombogenesis in patients with paroxysmal atrial fibrillation.

BACKGROUND: The clinical relevance of examining human atrial natriuretic peptide (HANP) or left atrial appendage (LAA) wall-motion velocity during sinus rhythm in paroxysmal atrial fibrillation (AF) patients has not been clearly elucidated. METHODS: The subjects were 38 patients with paroxysmal AF who underwent transesophageal and transthoracic echocardiography during sinus rhythm. The presence of spontaneous echocontrast (SEC) was examined with transesophageal echocardiography and LAA wall-motion velocity (LAAWV) was measured with transthoracic tissue Doppler echocardiography. Plasma HANP was measured within 3 hours after echocardiography. RESULTS: Human atrial natriuretic peptide ranged from 12 to 106 pg/mL with an average of 43 ± 24 pg/mL and had a significant correlation with LAAWV (r = -0.57) or LAA flow velocity (r = -0.41). HANP was significantly higher in patients with SEC than in patients without SEC (64 ± 29 vs. 34 ± 15 pg/mL, P = 0.008) and LAAWV was significantly lower in patients with SEC than in patients without SEC (13 ± 5 vs. 20 ± 5 cm/sec, P = 0.002). HANP >44 pg/mL had a sensitivity of 73% and specificity of 89% for diagnosing SEC. SEC was more frequently observed (73%) in patients with HANP >44 pg/mL and/or LAAWV <10 cm/sec as compared with patients (11%) with normal HANP and LAA wall-motion velocity (P < 0.0001). CONCLUSION: Higher plasma HANP and lower LAA wall-motion velocity may be noninvasive surrogate markers for assessing left atrial thrombogenesis during sinus rhythm in paroxysmal AF patients.

CD4+ T-cell synapses involve multiple distinct stages.

One very striking feature of T-cell recognition is the formation of an immunological synapse between a T cell and a cell that it is recognizing. Formation of this complex structure correlates with cytotoxicity in the case of killer (largely CD8(+)) T-cell activity, or robust cytokine release and proliferation in the case of the much longer lived synapses formed by helper (CD4(+)) T cells. Here we have used electron microscopy and 3D tomography to characterize the synapses of antigen-specific CD4(+) T cells recognizing B cells and dendritic cells at different time points. We show that there are at least four distinct stages in synapse formation, proceeding over several hours, including an initial stage involving invasive T-cell pseudopodia that penetrate deeply into the antigen-presenting cell, almost to the nuclear envelope. This must involve considerable force and may serve to widen the search for potential ligands on the surface of the cell being recognized. We also show that centrioles and the Golgi complex are always located immediately beneath the synapse and that centrioles are significantly shifted toward the late contact zone with either B lymphocytes or bone marrow-derived dendritic cells such as antigen-presenting cells, and that there are dynamic, stage-dependent changes in the organization of microtubules beneath the synapse. These data reinforce and extend previous data on cytotoxic T cells that one of the principal functions of the immunological synapse is to facilitate cytokine secretion into the synaptic cleft, as well as provide important insights into the overall dynamics of this phenomenon.

Analysis of hepatic gene expression profile in a spontaneous mouse model of type 2 diabetes under a high sucrose diet.

Both genetic factors and diabetogenic environmental factors, such as a high-sucrose diet (HSD), are involved in the development of type 2 diabetes. In this study, the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of type 2 diabetes and C3H mice used as controls, were fed a HSD, a high-fat diet (HFD) or a regular diet (RD) from weaning. In C3H mice, HFD significantly increased body weight gain, but maintained glucose tolerance. In contrast, in NSY mice, HSD resulted in increased body weight gain and liver steatosis and increased glucose intolerance to a greater extent than HFD. Furthermore, we performed DNA microarray analysis to detect differences in hepatic gene expression levels in both strains under HSD. We then performed RT-PCR analysis on selected genes to evaluate basal expression level under RD and changes under HSD conditions. HSD-fed NSY, but not C3H mice, exhibited increased hepatic expression levels of Pparg2, an isoform of Pparg as well as G0s2, a target of Pparg, which are known to be adipocyte-specific genes. Compared to RD-fed C3H mice, hepatic expression levels of Kat2b (transcriptional regulation), Hsd3b5 (steroid hormone metabolism) and Cyp7b1 (bile acid metabolism) were initially lower in RD-fed NSY mice, and were further decreased in HSD-fed NSY mice. Expression of Metallothionein (Mt1) and Metallothionein 2 (Mt2) was significantly lower in NSY mice compared to C3H mice, irrespective of dietary condition. These data suggest that elucidation of this heterogeneity in response to HSD might contribute to further understanding of the gene-environment interactions leading to diabetes in humans.

Efficacy of pulmonary vein isolation on left atrial function in paroxysmal and persistent atrial fibrillation and the dependency on its baseline function.

BACKGROUND: The effects of pulmonary vein (PV) isolation in atrial fibrillation (AF) on left atrial (LA) function or PV flow have not been well documented. METHODS: We examined the LA function and PV flow before and 3-6 months after PV isolation in 67 AF patients (34 paroxysmal [PAF] and 33 persistent [CAF]) using transesophageal echocardiography. RESULTS: AF recurred in 6/34 patients with PAF and in 6/33 patients with CAF 6 months after PV isolation. A larger LA dimension, a lower systolic PV flow velocity, and a lower ratio of systolic to diastolic PV flow velocity were related to a higher incidence of AF recurrence. The increment of left atrial appendage (LAA) flow velocity (55% vs. 22%) and systolic PV flow velocity (57% vs. 20%) after PV isolation tended to be greater in CAF than in PAF. The changes in LAA flow velocity had reverse correlations with the baseline values before PV isolation (PAF: r = -0.73, CAF: r = -0.58). The changes in mitral flow velocity during atrial contraction in PAF had reverse correlations with the baseline values before PV isolation (r = -0.84). The changes in systolic and diastolic PV flow velocity of PAF had reverse correlations with the baseline values before PV isolation (r = -0.56, r = -0.66). CONCLUSION: The baseline LA function may affect AF recurrence as well as the improvement of LA function, and the benefit of successful PV isolation might be greater in CAF than in PAF.

Primary cardiac lymphoma diagnosed by endomyocardial biopsy using transthoracic echocardiography in the substernal window.

We report a case of a 56-year-old man with a cardiac tumor, which grew and spread rapidly in the right heart. Using transthoracic echocardiography (TTE) in the substernal window, a transvenous biopsy of the tumor was performed safely. The tissue diagnosis revealed a diffuse large B cell lymphoma. After undergoing chemotherapy, the tumor was completely cured and the patient continues to be in good health. A biopsy using TTE in the substernal window may be a useful method to diagnose right-sided extensive tumors.

Usefulness of post-systolic index in facilitating stratification of risk in patients with intermediate- or low-risk non-ST-segment elevation acute coronary syndrome.

BACKGROUND: Although there is reportedly a usefulness of left ventricular global longitudinal strain (LV GLS) on 2D speckle-tracking echocardiography in excluding significant coronary artery disease (CAD) in suspected intermediate- or low-risk non-ST-segment elevation-acute coronary syndrome (NSTE-ACS), the efficacy of post-systolic index (PSI) in this context is yet unknown. Therefore, we explored the usefulness of PSI in facilitating stratification of risk in patients with intermediate- or low-risk NSTE-ACS. METHODS AND RESULTS: We assessed 50 consecutive patients suspected of intermediate- or low-risk NSTE-ACS, and finally analyzed 43 patients whose echocardiographic images were suitable for strain analysis. All patients underwent CAG. Among the 43 analyzed patients, 26 had CAD, and 21 underwent percutaneous coronary intervention (PCI). Patients with CAD had higher PSI (25% [20.8-40.3%] vs 15% [8.0-27.5%], P = 0.007). Receiver-operator characteristic curve analysis identified that a PSI of > 20% detected performance of PCI (sensitivity 80.7%, specificity 70.6%, area under curve [AUC] 0.72, 95% confidence interval [CI] 0.57-0.88). Moreover, the AUC obtained using the GRACE risk score was 0.57 (95% CI 0.39-0.75), and increased to 0.75 (95% CI 0.60-0.90) when PSI and LV GLS were added. Thus, the addition of PSI and LV GLS improved the classification of performance of PCI (net reclassification improvement [95%CI] 0.09 [0.0024-0.18], P = 0.04). CONCLUSIONS: Post-systolic index is a useful parameter that can facilitate stratification of risk in patients with intermediate- or low-risk NSTE-ACS. We recommend measuring PSI in routine clinical practice.

Novel loci for hyperglycemia identified by QTL mapping of longitudinal phenotypes and congenic analysis.

We previously reported that four hyperglycemia loci are located on three chromosomes in the Nagoya-Shibata-Yasuda (NSY) mouse model, commonly used to study type 2 diabetes. However, we did not search for hyperglycemia loci across all chromosomes. In this study, we performed quantitative trait loci (QTLs) mapping of longitudinal phenotypes from crosses between NSY (hyperglycemic) and C3H (normoglycemic) mice. We identified four new QTLs for hyperglycemia, namely Nidd5nsy, Nidd6nsy, Nidd1c3h, and Nidd2c3h, on Chromosome 1, 4, 10, and 13, respectively. These QTLs were associated with hyperglycemia in young mice and had attenuated effects in older mice. Nidd5nsy and Nidd6nsy were hyperglycemic with NSY alleles, and Nidd1c3h and Nidd2c3h were hyperglycemic with C3H alleles. We further bred Nidd5nsy congenic mice and demonstrated that Nidd5nsy has a strong effect on hyperglycemia when young, accompanied by insulin resistance and visceral fat accumulation. These results showed that the effects of individual QTLs strengthened or weakened with age, and that the sum of the effects of QTLs captured the age-related deterioration of glucose tolerance in individuals. Our results support the importance of longitudinal phenotypes in the genetic analysis of polygenic traits and have implications for the genetic basis and pathogenesis of type 2 diabetes in humans.

Feasibility of Simple Evaluation of Coronary Artery Calcium Using a Number of Chest Computed Tomography Slices: A Multicenter Study.

Objective: We aimed to evaluate the visual measurements of coronary artery calcium (CAC) on nonelectrocardiogram (ECG)-gated chest computed tomography (CT) using a simple scoring method that involves counting the number of CT slices containing CAC. Materials and Methods: We analyzed 163 participants who underwent both coronary and chest CT examinations at six centers within 3 months. Agatston scores were calculated on standard ECG-gated scans and classified as none (0), mild (1-99), moderate (100-400), or severe (>400). Next, chest CT images were reconstructed to standard 5.0 mm axial slices. Then, CAC on chest CT scans was measured using two methods: the Weston score (sum of the assigned score of each vessel, range: 0-12) and number of slices showing CAC (Ca-slice#). Results: When the Weston score and Ca-slice# were divided into four levels according to the optimal divisional levels corresponding to the Agatston score classes, good agreements with the 4-grade Agatston score were observed (kappa value=0.610 and 0.794, respectively). The sensitivity and specificity of Ca-slice# ≥9 to identify severe Agatston scores of >400 were 86% and 96%, respectively. Conclusion: The Ca-slice#, a simple scoring method using chest CT scans, was in good agreement with the ECG-gated Agatston score.

Significant Correlates of Nocturnal Hypertension in Patients With Hypertension Who Are Treated With Antihypertensive Drugs.

BACKGROUND: Nocturnal hypertension assessed by a home blood pressure monitoring (HBPM) device is associated with an increased risk of cardiovascular events. However, it is still difficult to assess nighttime blood pressure (BP) frequently. The purpose of this cross-sectional study was to identify significant correlates of nocturnal hypertension assessed by an HBPM device in patients with hypertension who are treated with antihypertensive drugs. METHODS: We measured nighttime BP, morning BP, and evening BP by an HBPM device for 7 consecutive days in 365 medicated patients with hypertension. RESULTS: Of the 365 subjects, 138 (37.8%) had nocturnal hypertension defined as a mean nighttime systolic BP of ≥ 120 mm Hg. Receiver operating characteristic curve analyses showed that the diagnostic accuracy of morning systolic BP for subjects with nocturnal hypertension was significantly superior to that of evening systolic BP (P = 0.04) and that of office systolic BP (P < 0.001). Multivariate analysis revealed that morning systolic BP of 125-<135 mm Hg (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.13-4.58; P = 0.02), morning systolic BP of ≥ 135 mm Hg (OR, 16.4; 95% CI, 8.20-32.7; P < 0.001), and a history of cerebrovascular disease (OR, 3.99; 95% CI, 1.75-9.13; P = 0.001) were significantly associated with a higher risk of nocturnal hypertension and that bedtime dosing of antihypertensive drugs was significantly associated with a lower risk of nocturnal hypertension (OR, 0.56; 95% CI, 0.32-0.97; P = 0.04). CONCLUSIONS: Morning systolic BP of ≥ 125 mm Hg, a history of cerebrovascular disease, and bedtime dosing were significant correlates of nocturnal hypertension in medicated patients with hypertension, and may help detect this risky BP condition. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN000019173).

Impact of platelet reactivity to adenosine diphosphate before implantation of drug-eluting stents on subsequent adverse cardiac events in patients with stable angina.

BACKGROUND: Diverse pharmacological effects of anti-platelet thienopyridines due to individual differences in metabolism have been reported. However, an association between on-treatment platelet reactivity and adverse ischemic events after drug-eluting stent (DES) implantation in Japanese patients has not been fully elucidated. METHODS AND RESULTS: A total of 450 consecutive patients on dual anti-platelet therapy (aspirin and ticlopidine) with stable angina who underwent DES implantation were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation was measured before DES implantation using the screen filtration pressure method. The ADP concentration necessary for 50% aggregation was designated as the platelet aggregation threshold index (PATI). A composite primary endpoint of cardiac death, myocardial infarction, target lesion revascularization (TLR), and stent thrombosis occurring within 1 year after stenting, was evaluated. A PATI value <4.8 µmol/L was defined as high on-treatment reactivity to ADP. The composite primary endpoint occurred in 55 patients (12.2%) in the 1-year-period after DES implantation, and the prevalence was 19.0% and 5.1% in groups with high and low on-treatment reactivity to ADP, respectively, showing a significantly higher prevalence in the high reactivity group (P<0.001). The main event was TLR (18.1% vs. 5.1%, P<0.001). CONCLUSIONS: These data suggested that high on-treatment platelet reactivity to ADP and subsequent occurrence of adverse ischemic events (particularly TLR) were correlated in patients with stable angina who underwent DES implantation.

A vegetation in a unique location without exposure to regurgitation or a shunt jet: A case report.

Bacteria can adhere to cardiac endothelium damaged by regurgitation or a shunt jet; however, healthy cardiac endothelium is supposedly resistant to bacterial adhesion. A 22-year-old man presented to our emergency department with fever. Physical examination revealed no obvious cardiac murmur, but there was evidence of splinter hemorrhages and Janeway lesions. Transthoracic echocardiography did not reveal vegetative lesions, but a 15 × 7-mm vegetation was identified on the surface of the left ventricular muscle just below the anterolateral commissure of the mitral valve without regurgitation or a shunt jet by means of transesophageal echocardiography. Surgery was performed on the seventh day, but the patient's postoperative course was unstable. Some complications occurred because the vegetation existed in a unique location. Although the patient continued to have an uncontrollable infection over the subsequent course, he was discharged on the 94th hospital day. We present a case of a vegetation in a unique location without exposure to regurgitation or a shunt jet. This case indicates that vegetative lesions may develop even in the absence of regurgitation and shunt jets. In case of infective endocarditis where a vegetation exists in a unique location, comprehensive testing or strategy are required to treat this condition. .

Six recurrences of myocarditis in 3 years: A case report.

A recent study revealed that recurrence of myocarditis occurs in a significant proportion of patients, but multiple recurrences of myocarditis have rarely been reported. The pathophysiology and best treatments for multiple recurrences of myocarditis remain unclear. A 60-year-old man presented to our emergency department with fever and chest pain. Physical examination, imaging, and laboratory findings were consistent with fulminant myocarditis. Paired titers confirmed adenovirus infection. The patient was treated with intra-aortic balloon pump and percutaneous cardiopulmonary support for 7 days and was discharged with near-normal electrocardiographic and echocardiographic findings on day 26. Over the subsequent 3 years, the patient experienced six episodes of recurrence of myocarditis with a progressive decrease in his ability to perform activities of daily living. At the time of his sixth recurrence, he died of ventricular fibrillation. Autopsy revealed mild enlargement of the left ventricle, extensive inflammatory cell infiltration, and mild interstitial fibrosis, suggesting left ventricle remodeling because of repetitive myocarditis. We have presented a case of multiple recurrences of myocarditis. This is the largest number of recurrences in a single patient reported to date. Further studies are needed to elucidate the underlying pathogenesis and best treatment of this condition. .

Clinical outcomes of sirolimus-eluting stenting after rotational atherectomy.

BACKGROUND: The efficacy of drug-eluting stents after rotational atherectomy (ROTA) has not been clarified. METHODS AND RESULTS: The 704 consecutive patients who underwent percutaneous coronary intervention (PCI) with a sirolimus-eluting stent (SES) (79 with and 625 without ROTA) were enrolled. The 2-year clinical outcome of these patients was compared with that of a group of 1,123 consecutive patients treated with bare-metal stents (BMS) (144 with and 979 without ROTA). At 2 years after index PCI, the use of SES after ROTA was associated with a lower crude incidence of major adverse cardiac events (MACE) than were BMS after ROTA (30.1% vs 43.1%, P=0.024). The difference was mainly derived from the reduction in target lesion revascularization (TLR) (25.0% vs 39.1%, P=0.022). After adjusting for confounders, ROTA-SES was associated with a reduction in MACE and TLR, with a similar hazard ratio to the non-ROTA group only with SES implantation. In a subgroup of dialysis patients, the incidence of TLR after ROTA with SES and BMS was similarly high. CONCLUSIONS: The use of SES after ROTA is an appropriate method for selected hard lesions, but has a limited effect in dialysis patients, even after lesion preparation with ROTA.

Verification That Mouse Chromosome 14 Is Responsible for Susceptibility to Streptozotocin in NSY Mice.

INTRODUCTION: Streptozotocin- (STZ-) induced diabetes is under polygenic control, and the genetic loci for STZ susceptibility are mapped to chromosome (Chr) 11 in Nagoya-Shibata-Yasuda (NSY) mice. In addition to Chr11, other genes on different chromosomes may contribute to STZ susceptibility in NSY mice. The aim of this study was to determine whether NSY-Chr14 contributes to STZ susceptibility and contains the STZ-susceptible region. MATERIALS AND METHODS: A consomic C3H-14NSY strain (R0: homozygous for NSY-derived whole Chr14 on the control C3H background), two congenic strains (R1: the region retained proximal and middle segments of NSY-Chr14 and R2: the region retained a proximal segment of NSY-Chr14), and parental NSY and C3H mice were intraperitoneally injected with a single injection of STZ at a dose of 175 mg/kg body weight at 12 weeks of age. Blood glucose levels and body weights were measured at days 0, 1, 2, 4, 5, 7, 8, and 14 after STZ injection. At day 14 after STZ injection, pancreata were dissected and fixed. RESULTS: After STZ injection, blood glucose levels were significantly higher in R0 mice than in C3H mice. However, blood glucose levels in R0 mice were not as severely affected as those in NSY mice. In R1 and R2 mice, blood glucose levels were similar to those in C3H mice and were significantly lower than those in R0 mice. Body weights were decreased in NSY and R0 mice; however, this change was not observed in R1, R2, and C3H mice. Although islet tissues in all strains exhibited degeneration and cellular infiltration, histological changes in NSY and R0 mice were more severe than those in R1, R2, and C3H mice. CONCLUSIONS: These data demonstrated that NSY-Chr14 was a STZ-susceptible chromosome and that STZ susceptibility was mapped to the distal segment of NSY-Chr14.