Enhanced x-ray emission coinciding with giant radio pulses from the Crab Pulsar.

Giant radio pulses (GRPs) are sporadic bursts emitted by some pulsars that last a few microseconds and are hundreds to thousands of times brighter than regular pulses from these sources. The only GRP-associated emission outside of radio wavelengths is from the Crab Pulsar, where optical emission is enhanced by a few percentage points during GRPs. We observed the Crab Pulsar simultaneously at x-ray and radio wavelengths, finding enhancement of the x-ray emission by 3.8 ± 0.7% (a 5.4σ detection) coinciding with GRPs. This implies that the total emitted energy from GRPs is tens to hundreds of times higher than previously known. We discuss the implications for the pulsar emission mechanism and extragalactic fast radio bursts.

A multidirectional approach to risk assessment in patients with three-vessel coronary artery disease undergoing percutaneous intervention.

BACKGROUND: The SYNTAX score (SS) and Clinical SYNTAX score (CSS) have demonstrated utility as risk-stratifying tools following percutaneous coronary intervention (PCI). However, useful determinants for predicting hard clinical events (HCE: death, nonfatal myocardial infarction, and stroke) in the setting of routinely-performed-angiographic follow-up have yet to be elucidated. METHODS AND RESULTS: We retrospectively examined the clinical outcomes of 252 three-vessel disease (TVD) patients following PCI. The incidence of HCE at 3 years significantly differed according to CSS (High, 20.2%; Intermediate, 1.2%; and Low, 6.0%; log-rank p<0.001), but not according to SS (High, 14.0%; Intermediate, 5.8%; and Low, 7.3%; log-rank p=0.13). The incidence of repetitive revascularization at 3 years did not differ significantly both among SS (High, 45.2%; Intermediate, 36.5%; and Low, 38.2%; log-rank p=0.22) and CSS (High, 36.9%; Intermediate, 41.7%; and Low, 41.7%; log-rank p=0.88,). CONCLUSION: Prediction of HCE in patients with TVD following PCI was more accurate with CSS than with SS.

Vaporizing thrombus with excimer laser before coronary stenting improves myocardial reperfusion in acute coronary syndrome.

BACKGROUND: Mechanical reperfusion has proven to be an unquestionably superior treatment strategy over that of thrombolytic therapy in patients with acute coronary syndrome (ACS). Excimer laser coronary angioplasty (ELCA) is a unique revascularization device that has a lytic effect on thrombus, in addition to its debulking effect on the atherosclerotic plaque beneath the thrombus. METHODS AND RESULTS: This single-center retrospective analysis consisted of consecutive ACS patients treated with ELCA (n=50) and age- and sex-matched ACS patients treated with manual aspiration (n=48) without use of a distal protection device. Success rate was judged by lesion crossability, procedure complications, and significant reduction of stenosis. Tissue-level perfusion was assessed on antegrade Thrombolysis In Myocardial Infarction (TIMI) flow grade, myocardial blush grade (MBG), and ST-segment elevation resolution (STR). Short-term outcome was evaluated according to occurrence of in-hospital major adverse cardiac events (MACE; myocardial infarction, target lesion revascularization, coronary artery bypass graft, and death). Lesion crossability was higher in the ELCA group than in the aspiration group (96.2% vs. 82.6%, P=0.04). Attainment of TIMI 3 flow (86.0% vs. 68.8%, P=0.04) and MBG 3 (76.0% vs. 54.2%, P=0.02) was also higher in the ELCA group than in the aspiration group. Complete STR was similar between the 2 groups. In-hospital MACE were significantly more frequent in the aspiration group. CONCLUSIONS: ELCA is feasible, safe, and effective for the treatment of patients with ACS and appears to be useful as an adjunctive lesion preparation device.

Comparison of real-world clinical outcomes between Cypher- and Taxus-eluting stents: the GARA-GARA study.

To evaluate real-world outcomes of PCI in unselected individuals using sirolimus-eluting (SESs) or paclitaxel-eluting stents (PESs) in a single-center randomized trial. Eight hundred consecutive patients (919 lesions) with coronary artery disease were randomized to receive SES or PES implantation. In-hospital, mid-term, and 1-year clinical and angiographical outcomes in both groups were compared. MACEs were defined as cardiac death, myocardial infarction, CABG and target vessel revascularization (TLR). Follow-up angiography was performed in 80.7% of patients. The baseline clinical characteristics were similar in both groups. Pre- and postprocedural reference vessel diameter, minimum length diameter, and diameter stenosis (%DS) were similar in both groups, as was incidence of in-hospital and mid-term MACEs. SESs significantly reduced the risk of TLR, compared with PESs (SES = 5.5%, PES = 10.5%). The superiority of SESs for TLR was also demonstrated with regard to small vessel lesions (stent diameter <2.5 mm) (SES = 6.0%, PES = 15.9%), whereas larger vessel (stent diameter >2.5 mm) lesions did not differ between groups (SES = 5.3%, PES = 8.4%). The safety and efficacy of both DESs were nearly equivalent. SESs, however, were superior to PESs in reducing mid-term TLR, particularly in the small vessel lesion subsets.

Trinucleotide repeats of programmed cell death-1 gene are associated with susceptibility to type 1 diabetes mellitus.

Multiple genes are involved in conferring susceptibility to autoimmune type 1 diabetes mellitus. The immunoreceptor programmed cell death-1 (PDCD-1), an inhibitory costimulatory molecule regulating peripheral tolerance, is reported to play an important role in the development of type 1 diabetes mellitus, making the human PDCD-1 gene, PDCD1, a candidate for disease susceptibility. The aim of this study was to clarify the contribution of PDCD1 to genetic susceptibility to type 1 diabetes mellitus in humans. To screen for sequence variants, we sequenced all 5 exons and exon-intron junctions of PDCD1 in Japanese subjects, 16 with type 1 diabetes mellitus and 16 without the disease. Some of the sequence variations identified were genotyped in larger samples (n = 275) with and without type 1 diabetes mellitus by polymerase chain reaction restriction fragment length polymorphism method or a fluorescence-based method. The distributions of polymorphisms were compared between patients with type 1 diabetes mellitus and healthy controls by contingency table analysis and Pearson chi(2) test. In this study, we found 16 sequence variants, including a TGC repeating variant in the 3' untranslated region. We found this variant to be associated with the development of type 1 diabetes mellitus. These data suggest the contribution of PDCD1 and its gene product to the development of type 1 diabetes mellitus.

Present state of diabetes management in the elderly, Japan.

A recent dramatic increase in elderly patients with diabetes mellitus has made the proper management of the disease in this population more important. Here, we discuss the present status of diabetes management in the elderly in Japan. As a characteristic feature of elderly persons, body weight reduction is difficult, because of the profound adaptive reduction in resting energy expenditure under calorie restriction in the elderly. However, hyperglycemia increases the risk for diabetic complications, except proliferative retinopathy, similarly in elderly and non-elderly. Of note, there is marked clinical heterogeneity in this generation in the following aspects: duration, complication status (past aspect), insulin secretion, insulin sensitivity, familial support and physical exercise/activity (present aspect), as well as the expected lifespan (future aspect). This heterogeneity among the elderly should render diabetes treatment diverse, and in fact, one of the largest surveys in Japan demonstrated significant diversity in diabetes management in the elderly. In Japan, thus, the present management of diabetes in the elderly is considerably diverse, reflecting the clinical heterogeneity among elderly patients with diabetes. Further clinical evidence is awaited for the establishment of proper and safe management of diabetes in the elderly.

Molecular scanning of interleukin-21 gene and genetic susceptibility to type 1 diabetes.

A recent study in the nonobese diabetic (NOD) mouse demonstrated the involvement of interleukin (IL)-21 in the pathogenesis of type 1 diabetes. A strong susceptibility locus, Idd3, has also been mapped to the interval containing the murine gene for IL-21 (Il21), making Il21 and the human orthologue IL21 a functional and positional candidate gene for type 1 diabetes. To investigate the contribution of the human genes for IL-21 and its receptor (IL-21R) to susceptibility to type 1 diabetes, we re-sequenced IL21 to identify novel sequence variants, searched for informative variants of IL21R, and studied the association of these variants with the disease. Two polymorphisms, a single nucleotide polymorphism (SNP) and a mononucleotide repeat polymorphism, were identified for IL21, and an allele of the mononucleotide repeat polymorphism was positively associated with the disease. Two novel microsatellite polymorphisms of IL21R were identified, one of which was associated with the disease. Scoring of individuals according to the status of these alleles showed a significant trend for high scores for susceptibility in diabetes patients, suggesting the contribution of IL21 and IL21R to disease susceptibility in an additive manner. These data suggest a contribution of IL21 and IL21R to genetic susceptibility to type 1 diabetes and possible involvement of IL-21 and its receptor system in the disease pathogenesis.

Role of sigmaH paralogs in intracellular melanin formation and spore development in Streptomyces griseus.

Streptomyces griseus possesses multiple stress-response sigma factors including sigma(H). Previously, we have suggested that sigma(H) and related sigma factors are involved in the developmental control of S. griseus. Herein, we studied the role of two sigma(H) paralogs--sigma(F) and sigma(N)--which are encoded in tandem coding sequences of sigF-sigN in S. griseus [sigma(N) has been described as sigma(L) previously (Gene 320:127, 2003)]. A sigF mutant produced decreased levels of intracellular melanin and formed irregular spores. A triple mutant for sigHNF exhibited defective melanin production. While sigN was transcribed by three tandem promoters during the early to late growth phases, sigF was transcribed in the late developmental phase by a single promoter. The activity of the promoter preceding the rpp operon (Prpp), which is responsible for the intracellular melanin biosynthesis, was decreased in the sigF mutant and abolished in the sigHNF, adpA and A-factor biosynthesis mutants. The in vitro transcription assay demonstrated that Esigma(F) transcribed the rpp promoter. Both Esigma(F) and Esigma(N) transcribed a sigma(H)-dependent promoter that preceded the sigH operon, and their activities were repressed by the addition of RshA, an anti-sigma(H) protein. Overall, the results suggest that the three sigma factors have similar functions and that they are required for spore development and pigmentation. The transcription of the rpp operon is regulated both by the stress-response sigma factors and the A-factor regulatory cascade.

Association of small ubiquitin-like modifier 4 (SUMO4) variant, located in IDDM5 locus, with type 2 diabetes in the Japanese population.

CONTEXT: Despite distinct differences in the pathogenesis, epidemiological data have indicated familial clustering of type 1 and type 2 diabetes, suggesting a common genetic basis between these two types of diabetes. Few shared susceptibility genes, however, have been reported to date. OBJECTIVE: Small ubiquitin-like modifier 4 (SUMO4) has been identified as a candidate gene for the IDDM5 locus and suggested to have possible involvement in immune responses, such as autoimmunity and inflammation. Recent reports demonstrated that a polymorphism with an amino acid substitution (Met55Val) in SUMO4 was associated with type 1 diabetes in Asian populations, although no association was reproduced in subjects of Caucasian descent. The present study aimed to clarify the contribution of SUMO4 to type 2 diabetes susceptibility in the Japanese population. SUBJECTS: The 753 subjects included 355 cases and 398 control subjects. METHODS: The SUMO4 Met55Val (rs237025) and 001Msp (rs577001) polymorphisms were genotyped. RESULTS: Strong linkage disequilibrium (D': 1.0 in each pair of single-nucleotide polymorphisms) across the MAP3K7IP2/SUMO4 region was shown in the Japanese population. The frequency of genotypes with the G allele of the SUMO4 Met55Val polymorphism was significantly higher in patients with type 2 diabetes [odds ratio, 1.46; 95% confidence interval (CI), 1.08-1.93; P = 0.01, chi(2) test]. The association was concentrated in patients without insulin therapy (odds ratio, 1.56; 95% CI, 1.13-2.15; P = 0.0072), but not in those with insulin (odds ratio, 1.24; 95% CI, 0.81-1.89; not significant). CONCLUSIONS: These data, together with previous reports, suggest the contribution of the SUMO4 Met55Val polymorphism to both type 1 and type 2 diabetes susceptibility in the Japanese population.

Association of SUMO4, as a candidate gene for IDDM5, with susceptibility to type 1 diabetes in Asian populations.

Recent study demonstrated that M55V variant in SUMO4 at IDDM5 was associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association. To clarify the population-wide effect on the association of SUMO4 with type 1 diabetes, we have performed meta-analysis including our own data in Asian populations, which confirmed a highly significant association in Asian populations (summary odds ratio [OR]: 1.29, P = 7.0 x 10(-6)), but indicated significant heterogeneity in the genetic effect of the SUMO4 gene on type 1 diabetes among diverse ethnic groups. These observations indicated the association of SUMO4 with type 1 diabetes in Asian populations.

The gene for human IL-21 and genetic susceptibility to type 1 diabetes in the Japanese.

Type 1 diabetes is under polygenic control both in humans and the NOD mouse. Recently a possible role of IL-21 in the pathogenesis of type 1 diabetes was demonstrated in the NOD mouse. Furthermore, the murine IL-21 gene is mapped to the Idd3 interval, making the human IL-21 gene (IL21) a functional as well as positional candidate for susceptibility. We therefore screened sequence variants of IL21 and studied the association with type 1 diabetes. Preliminary data showed no association of IL21 polymorphisms with the disease, suggesting that IL21 plays little role in susceptibility to type 1 diabetes in Japanese.

A second component of HLA-linked susceptibility to type 1 diabetes maps to class I region.

Type 1 diabetes is a polygenic disease with a major susceptibility locus, IDDM1, located in the human leukocyte antigen (HLA) region. Although class II loci, DR and DQ genes in particular, are major components of IDDM1, accumulating lines of evidence indicated that IDDM1 consists of multiple components and that non-class II genes in addition to class II genes contribute to susceptibility to and/or age-at-onset of type 1 diabetes. To identify a second component of IDDM1, we investigated the association of a panel of polymorphisms in 2.2 Mb region of the HLA encompassing from class II to class I regions with type 1 diabetes. Polymorphisms types were: DRB1 and DQB1 in class II; two microsatellite markers, BAT2-GT and TNFa in class III; and, five microsatellite markers, STR-MICA, MIB, C1-3-1, C2-4-4, and C3-2-10 in class I region. A total of >200 Japanese patients and healthy control subjects were studied. Class II DRB1*0405 and DQB1*0401 were significantly associated with susceptibility to, but not with age-at-onset of, type 1 diabetes. C1-3-1, located near C locus, was significantly associated with not only susceptibility to, but also age-at-onset of type 1 diabetes. These data suggest that a second component of IDDM1 maps to the HLA class I region, contributing to susceptibility to as well as age-at-onset of type 1 diabetes.

Molecular scanning of the gene for programmed cell death-1 (PDCD-1) as a candidate for type 1 diabetes susceptibility.

Multiple genes are involved in the susceptibility to autoimmune type 1 diabetes. The immunoreceptor programmed cell death-1 (PDCD-1), an inhibitory costimulatory molecule regulating peripheral tolerance, was reported to play a role in the development of type 1 diabetes, making the human PDCD-1 gene, PDCD1, as a candidate for disease susceptibility. In this article, we sequenced all 5 exons and exon-intron junctions of PDCD1 in Japanese subjects, and found 10 sequence variants. Preliminary data suggested no association of these polymorphisms with type 1 diabetes. These sequence variants are valuable for further studies to clarify contribution of PDCD1 to susceptibility to type 1 diabetes.

Genetic heterogeneity in association of the SUMO4 M55V variant with susceptibility to type 1 diabetes.

Association studies are a potentially powerful approach to identifying susceptibility variants for common multifactorial diseases such as type 1 diabetes, but the results are not always consistently reproducible. The IDDM5 locus has recently been narrowed to an approximately 200-kb interval on chromosome 6q25 by two independent groups. These studies demonstrated that alleles at markers in the mitogen-activating protein kinase 7 interacting protein 2 (MAP3K7IP2)/SUMO4 region were associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association of the SUMO4 gene with type 1 diabetes. To clarify the contribution of the M55V polymorphism of the SUMO4 gene to type 1 diabetes susceptibility, 541 type 1 diabetic patients and 768 control subjects were studied in Asian populations. The M55V polymorphism was significantly associated with type 1 diabetes in Asian populations (summary odds ratio [OR] 1.46, P = 0.00083, Mantel-Haenszel test). Meta-analysis of published studies and the present data confirmed a highly significant association in Asian populations (summary OR 1.29, P = 7.0 x 10(-6)) but indicated heterogeneity in the genetic effect of the SUMO4/MAP3K7IP2 locus on type 1 diabetes among diverse ethnic groups. These data indicate that the MAP3K7IP2/SUMO4 locus in the IDDM5 interval is associated with type 1 diabetes in Asian populations.

Detection of TIMI-3 flow before mechanical reperfusion with ultrasonic tissue characterization in patients with anterior wall acute myocardial infarction.

BACKGROUND: Spontaneous coronary reperfusion with TIMI-3 flow is associated with favorable clinical outcomes in patients with acute myocardial infarction (AMI). We investigated the ability of analyzing cardiac cycle-dependent variation of myocardial integrated backscatter (IBS) for predicting spontaneous reperfusion in anterior AMI. METHODS AND RESULTS: We recorded IBS images on admission in 104 patients with first anterior wall AMI and subsequently performed coronary angiography and coronary intervention. We measured the cyclic variation of IBS within the infarct zone and expressed its magnitude as phase-corrected magnitude (PCM) by giving positive and negative values when it showed synchronous and asynchronous contraction, respectively. Twenty-three patients showing TIMI-3 flow at the initial coronary angiography had smaller peak creatine kinase value than 57 patients with initial TIMI-0/1 flow (864+/-961 versus 2358+/-1757 IU/L; P=0.0002) and better percent wall thickening within risk area (36.1+/-15.1%) than those with TIMI-2 (16.7+/-12.8%, P<0.0001) or TIMI-0/1 (5.1+/-11.6, P<0.0001). The patients with initial TIMI-3 had higher PCM (2.7+/-1.3 dB) than those with TIMI-2 (-0.3+/-2.2 dB, P<0.0001) or those with TIMI-0/1 (-1.1+/-2.4 dB, P<0.0001). Using PCM=1.0 dB as the cutoff point, PCM detected TIMI-3 flow with 95.7% sensitivity and 90.1% specificity. Multivariable logistic regression analysis revealed that only PCM is an independent predictor for spontaneous reperfusion among the hemodynamic, echocardiographic, and electrocardiographic variables. CONCLUSIONS: Analysis of myocardial IBS could detect spontaneous reperfusion noninvasively in the emergent stage of anterior AMI.

Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction.

OBJECTIVES: We investigated the association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction (AMI). BACKGROUND: Hyperglycemia is associated with increased risks of heart failure, cardiogenic shock, and death after AMI, but its underlying mechanism remains unknown. METHODS: A total of 146 consecutive patients with a first AMI were studied by intracoronary myocardial contrast echocardiography (MCE) after successful reperfusion within 24 h after symptom onset. Two-dimensional echocardiography was recorded on day 1 and three months later to determine the change in the wall motion score (DeltaWMS; sum of 16 segmental scores; dyskinesia = 4 to normokinesia = 0). RESULTS: The no-reflow phenomenon was found on MCE in 49 (33.6%) of 146 patients; their glucose level on hospital admission was significantly higher than that of patients who did not exhibit this phenomenon (209 +/- 79 vs. 159 +/- 56 mg/dl; p < 0.0001). There was no difference in glycosylated hemoglobin or in the incidence of diabetes mellitus between the two subsets. The no-reflow phenomenon was more often observed in the 75 patients with hyperglycemia (>/=160 mg/dl) than in those without hyperglycemia (52.0% vs. 14.1%; p < 0.0001). Patients with hyperglycemia had a higher peak creatine kinase level (2,497 +/- 1,603 vs. 1,804 +/- 1,300 IU/l; p = 0.005) and a lower DeltaWMS (3.7 +/- 4.8 vs. 5.7 +/- 4.3; p = 0.01) than did those without hyperglycemia. The blood glucose level was an independent prognostic factor for no reflow, along with age, gender, absence of pre-infarction angina, complete occlusion of the culprit lesion, and anterior AMI. CONCLUSIONS: Hyperglycemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and worse functional recovery.