Zuo1, a ribosome-associated J protein, is involved in glucose repression in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, the J-protein Zuo1 and the nonconventional Hsp70 homologue Ssz1 stimulate the ATPase activity of the chaperone proteins Ssb1 and Ssb2 (Ssb1/2), which are associated with the ribosomes. The dephosphorylation of sucrose nonfermenting 1 (Snf1) on Thr210 is required for glucose repression. The Ssb1/2 and 14-3-3 proteins Bmh1 and Bmh2 appear to be responsible for the dephosphorylation of Snf1 on Thr210 and glucose repression. Here, we investigated the role of Zuo1 in glucose repression. The zuo1∆ strain as well as the ssb1∆ssb2∆ strain exhibited a glucose-specific growth defect during logarithmic growth on glucose. Many of the respiratory chain genes examined were statistically significantly upregulated, but less than 2-fold, in the zuo1∆ strain as well as in the ssb1∆ssb2∆ strain on glucose. In addition, excessive phosphorylation of Snf1 on Thr210 was observed in the zuo1∆ strain as well as in the ssb1∆ssb2∆ strain in the presence of glucose. The mRNA levels of SSB1/2 and BMH1 were statistically significantly reduced by approximately 0.5- to 0.8-fold relative to the wild-type level in the zuo1∆ strain on glucose. These results suggest that Zuo1 is responsible for glucose repression, possibly by increasing the mRNA levels of SSB1/2 and BMH1 during growth on glucose.

[Aortic valve-sparing operation for chronic dissecting aneurysm of the sinus of valsalva associated with redissection in a young woman who experienced out-of-hospital cardiac arrest].

A 38-year-old woman was admitted to our hospital because she experienced cardiopulmonary arrest at her wedding;her cardiac beats were resumed 20 min after cardiopulmonary resuscitation performed by her relatives and hotel staffs. Enhanced computed tomography revealed acute aortic redissection in chronic dissecting aneurysm in the right sinus of Valsalva, which was believed to have occurred in the 4th month of pregnancy 2 years before. Echocardiography showed moderate aortic regurgitation. We performed aortic valve-sparing operation and ascending aortic replacement with partial remodeling of the right sinus of Valsalva. She returned to work 2 months later without high-order dysfunction.

Anti-tachycardia pacing degenerated fast ventricular tachycardia into undetectable life-threatening tachyarrhythmia in a patient with non-ischemic dilated cardiomyopathy.

A 45-year-old man with dilated cardiomyopathy was admitted to our hospital due to congestive heart failure (CHF). Despite the optimal medical treatment, his condition had not improved because of severe left ventricular dysfunction. Because he experienced non-sustained ventricular tachycardia (VT), a biventricular implantable cardioverter-defibrillator (Bi-V ICD) was implanted for reduction of dyssynchrony and primary prevention of lethal tachyarrhythmia. After discharge, he developed CHF and was transported to our hospital by ambulance. In the ambulance, monomorphic sustained VT with 200 bpm suddenly occurred. The ICD detected it as fast VT and anti-tachycardia pacing (ATP) was delivered. After the ATP therapy, RR intervals of VT became irregular and prolonged. Ventricular fibrillation-like electrical activity was recorded by a far-field electrogram from the defibrillator, but the tachycardia cycle length exceeded 400 ms which is under the tachycardia detection rate. The device failed to deliver a shock and the patient had to be rescued with an external shock. This is a rare case of fast VT that degenerated into undetectable life-threatening tachyarrhythmia by ATP.

Relationship between circulating levels of monocyte chemoattractant protein-1 and systolic dysfunction in patients with hypertrophic cardiomyopathy.

BACKGROUND: Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism of the transition from hypertrophy to dysfunction has not been elucidated. It has been reported that circulating levels of monocyte chemoattractant protein-1 (MCP-1), which is a major factor promoting the accumulation of macrophages, are increased in patients with congestive heart failure. We measured circulating levels of MCP-1 in patients with HCM and examined whether MCP-1 was expressed in the myocardium of HCM patients. We also examined whether circulating levels of MCP-1 were correlated with left ventricular dysfunction. METHODS: Circulating levels of MCP-1 were measured by an enzyme immunoassay in 26 patients with HCM (60+/-2 years old) and 20 control subjects (57+/-2 years old). Cardiac function was evaluated by two-dimensional echocardiography and cardiac catheterization. RESULTS: HCM patients had significantly elevated levels of MCP-1 (HCM: 309+/-30 vs. control: 178+/-8 pg/ml, P<.001). MCP-1 levels in patients with systolic dysfunction were significantly higher than those in patients without systolic dysfunction (P<.05) and were also significantly higher than those in patients with outflow obstruction (P<.05). Immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from HCM patients with systolic dysfunction. Furthermore, MCP-1 levels were inversely correlated with fractional shortening (r=-.401, P<.05) and correlated with left ventricular end-diastolic pressure (r=-.579, P<.01). CONCLUSION: These results show that MCP-1 is associated with, and might be involved in the pathogenesis of, left ventricular systolic dysfunction in patients with HCM.

Prognostic significance of right bundle branch block in patients with acute inferior myocardial infarction.

There is little information available concerning the influence of right bundle branch block (RBBB) on the prognosis of patients with inferior myocardial infarction (MI). In this study we evaluated the influence of RBBB on the short-term prognosis of patients with inferior MI. Our study subjects were 1,265 hospitalized patients with Q wave MI. Patients were divided into 4 groups based on the presence or absence of RBBB and on the location of the infarction. RBBB was classified into 4 categories according to the timing of its appearance and its duration as new permanent, transient, old and age indeterminate. In-hospital death and pulmonary congestion were observed more frequently in patients with RBBB than in those without RBBB. Moreover, in inferior MI as in anterior MI, in-hospital death and pulmonary congestion occurred more frequently in new permanent RBBB patients than in patients with other types of RBBB. Multivariate regression analysis reveals that new permanent RBBB was a strong independent predictor for an adverse short-term prognosis in patients with inferior MI, as well as in patients with anterior MI. New permanent RBBB during inferior MI is a strong independent predictor for increased in-hospital mortality, regardless of the infarction location.

Deficiency in chromosome congression by the inhibition of Plk1 polo box domain-dependent recognition.

Polo-like kinase 1 (Plk1) is one of the key regulators of mitotic cell division. In addition to an N-terminal protein kinase catalytic domain, Plk1 possesses a phosphopeptide binding domain named polo box domain (PBD) at its C terminus. PBD is postulated to be essential for Plk1 localization and substrate targeting. Here, we developed a high-throughput screening system to identify inhibitors of PBD-dependent binding and screened a chemical library. We isolated a benzotropolone-containing natural compound derived from nutgalls (purpurogallin (PPG)) that inhibited PBD-dependent binding in vitro and in vivo. PPG not only delayed the onset of mitosis but also prolonged the progression of mitosis in HeLa cells. Although apparently normal bipolar spindles were formed even in the presence of PPG, the perturbation of chromosome alignment at metaphase plates activated the spindle assembly checkpoint pathway. These results demonstrate the predominant role of PBD-dependent binding on smooth chromosome congression at metaphase.

Atrial fibrillation in patients with Brugada syndrome relationships of gene mutation, electrophysiology, and clinical backgrounds.

OBJECTIVES: The goal of our work was to examine the relationships of atrial fibrillation (AF) with genetic, clinical, and electrophysiological backgrounds in Brugada syndrome (BrS). BACKGROUND: Atrial fibrillation is often observed in patients with BrS and indicates that electrical abnormality might exist in the atrium as well as in the ventricle. SCN5A, a gene encoding the cardiac sodium channel, has been reported to be causally related to BrS. However, little is known about the relationships of atrial arrhythmias with genetic, clinical, and electrophysiological backgrounds of BrS. METHODS: Seventy-three BrS patients (49 +/- 12 years of age, men/women = 72/1) were studied. The existence of SCN5A mutation and clinical variables (syncopal episode, documented ventricular fibrillation [VF], and family history of sudden death) were compared with spontaneous AF episodes. Genetic and clinical variables were also compared with electrophysiologic (EP) parameters: atrial refractory period, interatrial conduction time (CT), repetitive atrial firing, and AF induction by atrial extra-stimulus testing. RESULTS: Spontaneous AF occurred in 10 (13.7%) of the BrS patients and SCN5A mutation was detected in 15 patients. Spontaneous AF was associated with higher incidence of syncopal episodes (60.0% vs. 22.2%, p < 0.03) and documented VF (40.0% vs. 14.3%, p < 0.05). SCN5A mutation was associated with prolonged CT (p < 0.03) and AF induction (p < 0.05) in EP study, but not related to the spontaneous AF episode and other clinical variables. In patients with documented VF, higher incidence of spontaneous AF (30.8% vs. 10.0%, p < 0.05), AF induction (53.8% vs. 20.0%, p < 0.03), and prolonged CT was observed. CONCLUSIONS: Spontaneous AF and VF are closely linked clinically and electrophysiologically in BrS patients. Patients with spontaneous AF have more severe clinical backgrounds in BrS. SCN5A mutation is associated with electrical abnormality but not disease severity.

The predictors of central and obstructive sleep apnoea in haemodialysis patients.

BACKGROUND: Sleep apnoea (SA) is often observed in haemodialysis patients, but there have been few studies on types of SA and their predictors. We therefore investigated the prevalence and types of SA and the associations between types of SA and clinical factors in haemodialysis patients. METHODS: We initially examined nocturnal oxygen desaturation index (ODI) (desaturation of >4%/events per hour) in 119 haemodialysis patients (68 males, mean age of 61.4 years). Patients with ODI of more than five were diagnosed as having SA. Then, 30 patients underwent polysomnography and we measured Apnoea-hypopnoea index (AHI), which was calculated as the number of apnoeas plus hypopnoeas per hour of sleep. Clinical characteristics were examined in all patients. RESULTS: Forty-one (34.5%) of the 119 patients had SA. Twenty-seven (22.7%) of the 119 patients had SA with subjective symptoms such as daytime somnolence and snoring. There was a significant difference between body mass index (BMI) in patients with SA and that in patients without SA (22.5 vs 19.8 kg/m2, P<0.001). There were significantly higher prevalences of hypertension (85.4 vs 66.7%, P<0.05) and diabetes mellitus (36.6 vs 10.3%, P<0.01) in patients with SA than those in patients without SA. Multivariable analysis showed that BMI was independently associated with the occurrence of SA (OR 1.20, 95% CI 1.05-1.38). Mean AHI of 30 patients who underwent polysomnography was 53.2+/-28.9 [central apnoea, 4.1+/-5.6 (8%); obstructive apnoea, 21.7+/-21.5 (42%); mixed apnoea, 4.9+/-8.0 (9%); hypopnoea, 21.4+/-15.5 (41%)]. The number of obstructive apnoea events per hour was significantly correlated with BUN (r=0.490, P<0.01), Cr (r=0.418, P<0.05) and BMI (r=0.489, P<0.01) and was inversely correlated with serum bicarbonate (r=-0.646, P<0.01) and brain natriuretic peptide (BNP) (r=-0.481, P<0.01). The number of central apnoea events per hour was correlated inversely with PaO2 (r=-0.393, P<0.05) and PaCO2 (r=-0.388, P<0.05) and tended to be correlated with cardiothoracic ratio (CTR) (r=0.347, P=0.060). CONCLUSIONS: There is a high prevalence of SA in haemodialysis patients. The dominant type of SA in haemodialysis patients is obstructive sleep apnoea (OSA). Uraemia (BUN, Cr), metabolic acidosis (serum bicarbonate) and BMI are good predictors of OSA. PaO2, PaCO2 and CTR are good predictors of central sleep apnoea (CSA). Good management of these factors might improve SA in haemodialysis patients.

Aortic stiffness is an independent determinant of B-type natriuretic peptide in patients with coronary artery disease.

Previous studies demonstrated that the B-type natriuretic peptide (BNP) level is high in some patients with coronary artery disease (CAD) despite a preserved left ventricular function, although the mechanism underlying this increase in patients with CAD has not been fully elucidated. Because aortic stiffness is greater in patients with CAD and increases with CAD severity, there is a possibility that an increased aortic stiffness in turn increases the elevation of the BNP level in patients with CAD. In this study, we measured BNP level and brachial-ankle pulse wave velocity (baPWV) in 134 patients with CAD, and evaluated the relationship between BNP and baPWV. The patients were classified on the basis of the quartiles of BNP level to identify the characteristics of patients with a high BNP level. baPWV was significantly greater in patients classified into the highest quartile of BNP level than in those classified into the other quartiles. Multivariate analysis demonstrated that baPWV and left ventricular ejection fraction independently correlated with BNP level. Logistic regression analysis demonstrated that the odds ratio for the highest quartile of BNP level increased with baPWV quartile. This association remained significant after adjustment for systolic and diastolic function. In conclusion, increased aortic stiffness possibly underlies the increase in the BNP level in patients with CAD.

MRI of the popliteomeniscal fasciculi.

OBJECTIVE: The purpose of this study was to further our understanding of the normal appearance of the popliteomeniscal fasciculi (PMF) on MRI after the determination of finely tuned imaging parameters. For this purpose we performed the study in two stages. Stage I was to determine suitable parameters for depicting the popliteomeniscal fasciculi. Stage II was to classify the "normal" image. CONCLUSION: The findings presented in this article will contribute to the understanding of the normal appearance of the popliteomeniscal fasciculi on MRI, and of the degree of variation of this structure among the population.

Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways.

At the onset of M phase, the activity of somatic Wee1 (Wee1A), the inhibitory kinase for cyclin-dependent kinase (CDK), is down-regulated primarily through proteasome-dependent degradation after ubiquitination by the E3 ubiquitin ligase SCF(beta-TrCP). The F-box protein beta-TrCP (beta-transducin repeat-containing protein), the substrate recognition component of the ubiquitin ligase, binds to its substrates through a conserved binding motif (phosphodegron) containing two phosphoserines, DpSGXXpS. Although Wee1A lacks this motif, phosphorylation of serines 53 and 123 (S53 and S123) of Wee1A by polo-like kinase 1 (Plk1) and CDK, respectively, are required for binding to beta-TrCP. The sequence surrounding phosphorylated S53 (DpSAFQE) is similar to the conserved beta-TrCP-binding motif; however, the role of S123 phosphorylation (EEGFGSSpSPVK) in beta-TrCP binding was not elucidated. In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2), to create two phosphodegrons on Wee1A. In the case of Plk1, S123 phosphorylation created a polo box domain-binding motif (SpSP) on Wee1A to accelerate phosphorylation of S53 by Plk1. CK2 could phosphorylate S121, but only if S123 was phosphorylated first, thereby generating the second beta-TrCP-binding site (EEGFGpS121). Using a specific inhibitor of CK2, we showed that the phosphorylation-dependent degradation of Wee1A is important for the proper onset of mitosis.

Aortic stiffness is an independent predictor of left ventricular function in patients with coronary heart disease.

Although aortic stiffness plays an important role in patients with coronary artery disease (CAD), the influence of aortic stiffness on left ventricular systolic function has not yet been fully evaluated. In the present study, we measured brachial-ankle pulse wave velocity (baPWV), which is a new index of aortic stiffness, in patients with CAD (CAD group, n = 170, 67 +/- 9 years old) and without CAD (non-CAD group, n = 81, 63 +/- 8 years old), and evaluated the relationship between baPWV and left ventricular systolic function in patients with CAD. baPWV in the CAD group was significantly higher than that in the non-CAD group (1,794 +/- 350 vs. 1,469 +/- 292 cm/s, p < 0.05), although both systolic and diastolic blood pressure were comparable between the two groups. In the CAD group, the baPWV was higher in patients with three-vessel disease than that in patients with one-vessel disease (1,885 +/- 542 vs. 1,720 +/- 373 cm/s, p < 0.05). In the CAD group, multivariate analysis demonstrated that baPWV and pulse pressure independently correlated with left ventricular ejection fraction (LVEF). In conclusion, in patients with CAD, baPWV, which is a simple marker of aortic stiffness, increases with CAD severity and correlates with left ventricular systolic function independent of CAD severity.