The impact of hearing aids on cognitive function and quality of life in patients with hearing impairment: A cross-sectional study.

OBJECTIVE: Age-related cognitive decline involves a complex set of factors. Among these factors, hearing loss is considered to have a significant impact, but the effect of hearing aid use remains unresolved. The purpose of this study was to evaluate the effects of hearing aid use by simultaneously assessing various factors not only cognitive function but also frailty, anxiety, depression, and quality of life (QOL) in patients with hearing loss. METHODS: The cross-sectional study at the Hearing Aid (HA) Center was conducted between 2020 and 2021. Initially, associations with cognitive function, QOL, frailty, and mental state among patients with hearing loss were examined, irrespective of whether they wore a hearing aid or not. Next, these patients were divided into HA users (using HA for more than 1 year) and non-users (no prior use of HA) with 42 patients in each group. The average age and 6-frequency pure tone audiometry (PTA) was 74.5 ± 6.5 years and 50.6 ± 12.1 dB, respectively. All participants filled out the questionnaire about their life style, medical condition. Mini-Mental State Examination (MMSE) for cognitive function, Hospital Anxiety and Depression Scale for mental state, Short Form 36 version 2 (SF-36v2) for QOL, and Kihon Checklist for frailty were compared between HA users and non-users and correlated with the auditory data (PTA and speech discrimination). RESULTS: Among 84 patients, 40 had an MMSE score ≦26. All eight scores and three components of SF-36v2 were lower than those of the control group. The patients with hypertension were significantly more in HA user than in non-HA user, whereas there was no difference in diabetes, heart attack, stroke and education. Although HA users were older and showed hypertension more their PTA was worse than that of non-users, MMSE scores were not different between the groups. MMSE scores correlated with both PTA and speech discrimination in non-users but not in HA users. However, a multivariate analysis of the effect of HA use on MMSE scores adjusting for age, hypertension, and hearing loss, could not be revealed. The vitality and mental component summary of the SF-36v2 was better in HA users than in non-users. CONCLUSION: Elderly patients with hearing loss were cognitively impaired and had low QOL. HA users showed better QOL score than non-HA user, especially about the mental condition. The absence of a correlation between MMSE scores and hearing loss in HA users suggests the potential use of HA in preventing cognitive decline.

Neonatal administration of synthetic estrogen, diethylstilbestrol to mice up-regulates inflammatory Cxclchemokines located in the 5qE1 region in the vaginal epithelium.

A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process remains unclear. By Cap Analysis of Gene Expression method, we found that neonatal DES exposure up-regulated inflammatory Cxcl chemokines 2, 3, 5, and 7 located in the 5qE1 region in the vaginal epithelium of mice 70 days after birth. When we examined the gene expressions of these genes much earlier stages, we found that neonatal DES exposure increased these Cxcl chemokine genes expression even after 17 days after birth. It implies the DES-mediated persistent activation of inflammatory genes. Intriguingly, we also detected DES-induced non-coding RNAs from a region approximately 100 kb far from the Cxcl5 gene. The non-coding RNA up-regulation by DES exposure was confirmed on the 17-day vagina and continued throughout life, which may responsible for the activation of Cxcl chemokines located in the same region, 5qE1. This study shows that neonatal administration of DES to mice causes long-lasting up-regulation of inflammatory Cxcl chemokines in the vaginal epithelium. DES-mediated inflammation may be associated with the carcinogenic process.

Identification of interatrial epicardial connections between the right-sided pulmonary veins and right atrium using coherent map.

A 43-year-old man underwent circumferential pulmonary vein isolation (PVI) for persistent atrial fibrillation. Although first-pass circumferential PV antrum ablation was performed, complete PVI was not obtained. A gap map showed the site of earliest activation was the right-sided PV carina, which was the same site of breakthrough on the left atrium map before ablation. Using a coherent map enabled us easily and clearly to evaluate the breakthrough sites. To identify whether the conduction from the right PV carina connected to adjacent structures, an activation map was obtained during pacing from the right PV carina. This revealed that the site of earliest activation was the posterior right atrium (RA) and implied a direct connection between the right-sided PVs and RA. The first radiofrequency (RF) application in the posterior RA resulted in only temporary isolation of the right-sided PVs with bi-directional block. Therefore, we performed a second set of RF applications to the right PV carina. PVI was obtained immediately after initiating the second set of applications and no further reconnection was observed. Learning objective: Pulmonary vein isolation (PVI) is widely accepted as an atrial fibrillation ablation procedure. Previous anatomical studies have revealed the presence of epicardial muscular bundles/fibers connecting the right-sided PVs and right atrium. In some patients, the presence of epicardial connections (ECs) precludes successful first-pass PVI. Identification and elimination of these connections is imperative to achieve complete PVI. The coherent map was useful for evaluating ECs.

Sense-overlapping lncRNA as a decoy of translational repressor protein for dimorphic gene expression.

Long noncoding RNAs (lncRNAs) are vastly transcribed and extensively studied but lncRNAs overlapping with the sense orientation of mRNA have been poorly studied. We analyzed the lncRNA DAPALR overlapping with the 5´ UTR of the Doublesex1 (Dsx1), the male determining gene in Daphnia magna. By affinity purification, we identified an RNA binding protein, Shep as a DAPALR binding protein. Shep also binds to Dsx1 5´ UTR by recognizing the overlapping sequence and suppresses translation of the mRNA. In vitro and in vivo analyses indicated that DAPALR increased Dsx1 translation efficiency by sequestration of Shep. This regulation was impaired when the Shep binding site in DAPALR was deleted. These results suggest that Shep suppresses the unintentional translation of Dsx1 by setting a threshold; and when the sense lncRNA DAPALR is expressed, DAPALR cancels the suppression caused by Shep. This mechanism may be important to show dimorphic gene expressions such as sex determination and it may account for the binary expression in various developmental processes.

Fibrosis-4 index reflects right ventricular function and prognosis in heart failure with preserved ejection fraction.

AIMS: Fibrosis-4 index (FIB-4 index), calculated by age, aspartate aminotransferase, alanine aminotransferase, and platelet count, is a simple marker to evaluate liver fibrosis and is associated with right-sided heart failure. However, the clinical relevance of FIB-4 in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. We investigated the prognostic implication of the FIB-4 index regarding right ventricular dysfunction in patients with HFpEF. METHODS AND RESULTS: This prospective study included 116 consecutive HFpEF patients (mean age 79 years, 43% male) hospitalized with acute decompensated heart failure. We evaluated the association of the FIB-4 index with right ventricular function determined by tricuspid annular plane systolic excursion (TAPSE) and tricuspid lateral annular systolic velocity (S') before discharge. Cox regression analysis was performed to evaluate the association between the FIB-4 index and major adverse cardiovascular events (MACE) defined as the composite of cardiovascular death, readmission for heart failure, nonfatal myocardial infarction, and nonfatal stroke. FIB-4 index before discharge was significantly lower than that at admission (2.62 [1.92-3.46] and 3.03 [2.05-4.67], median [interquartile range], P < 0.001). Left ventricular ejection fraction, TAPSE, and S' before discharge were 62.7 (55.9-68.6) %, 17.5 ± 4.6 mm (mean ± standard deviation), and 10.0 (8.0-12.0) cm/s, respectively. In multiple linear regression analysis, the FIB-4 index before discharge was inversely correlated with TAPSE (ß minus;0.244, P = 0.014) and S' (ß -0.266, P = 0.009). During a median follow-up of 736 days, 37 MACE occurred. Multivariate Cox regression analysis revealed that a high FIB-4 index before discharge (per 1 point) was a significant predictor of MACE (hazard ratio 1.270, 95% confidence interval 1.052-1.532) after adjustment for male, serum creatinine, and haemoglobin. Receiver operating characteristic analysis indicated that the optimal cut-off value of FIB-4 index before discharge to predict MACE was 3.11. Kaplan-Meier survival analysis showed that patients with a FIB-4 index before discharge ≥3.11 had a significantly poorer prognosis than patients with FIB-4 index before discharge <3.11 (P = 0.029). Patients with an FIB-4 index ≥3.11 had a 2.202-fold (95% confidence interval 1.110-4.368) increased risk of MACE compared with those with an FIB-4 index <3.11 after adjustment for male, serum creatinine, and haemoglobin. CONCLUSIONS: An increase in the FIB-4 index was associated with right ventricular dysfunction and a higher risk of future MACE in patients with HFpEF.

Favorable effect of catheter ablation on nocturnal hypertension in patients with paroxysmal atrial fibrillation.

OBJECTIVES: The current study was performed to determine whether pulmonary vein isolation (PVI) improves nocturnal hypertension in patients with paroxysmal atrial fibrillation (PAF). BACKGROUND: Abnormal night-time blood pressure (BP) fluctuation is a risk factor for atrial fibrillation. Imbalance of autonomic nervous function is a risk factor common to both of these abnormalities. PVI can reportedly modify the autonomic nervous function balance in patients with atrial fibrillation. METHODS: The study population comprised 50 consecutive patients (mean age, 69.8 ±â€Š7.5 years; 35.0% male) with PAF scheduled for PVI. Both 24-h ambulatory BP monitoring and heart rate variability analysis were performed before and at 3 months after PVI. RESULTS: Patients were classified into two groups according to the presence of nocturnal BP dipping before PVI: the normal dipping group (n = 27) and the nondipping group (n = 23). The low-frequency spectrum power and the ratio of low-frequency spectrum power to high-frequency spectrum power (low-frequency spectrum/high-frequency spectrum) were higher in the nondipping than the normal dipping group (low-frequency spectrum: 219.9 ±â€Š210.2 vs. 92.7 ±â€Š50.5 ms, respectively, P = 0.03; low-frequency spectrum/high-frequency spectrum: 1.8 ±â€Š1.9 vs. 0.9 ±â€Š0.8, respectively, P = 0.05). In the nondipping group, the elevated night-time BP disappeared in eight (35%) patients at 3 months after PVI, which was associated with an increase in high-frequency spectrum power. These patients did not develop atrial fibrillation recurrence during follow-up (mean, 568 ±â€Š218 days). CONCLUSION: Among patients with PAF, the nondipping group showed greater sympathetic activity (higher low-frequency spectrum power and low-frequency spectrum/high-frequency spectrum) than the dipping group. Restoration of BP dipping after PVI is associated with increased parasympathetic activity (higher high-frequency spectrum power) and reduced recurrence of arrhythmic events.

A 5' UTR-Overlapping LncRNA Activates the Male-Determining Gene doublesex1 in the Crustacean Daphnia magna.

Long noncoding RNAs (lncRNAs) are pervasively transcribed in the eukaryotic genome [1] and are important for the control of master regulatory genes that are involved in cell differentiation and development [2, 3]. Here, we show that a 5' UTR-overlapping lncRNA regulates the male-specific expression of the DM-domain gene doublesex1 (dsx1) in the crustacean Daphnia magna, which produces males in response to environmental stimuli. This lncRNA, named doublesex1 alpha promoter-associated long RNA (DAPALR), is transcribed upstream the transcription start site (TSS) in a sense orientation and subjected to 5' end capping and 3' end processing at a stem-loop structure before the dsx1 coding exon. Similar to dsx1, its expression is only activated in males by the juvenile hormone (JH) and basic-leucine zipper (bZIP) transcription factor Vrille (Vri) and is maintained during embryogenesis. Knockdown of DAPALR in males silenced dsx1 and led to feminization, including egg production, whereas ectopic expression of DAPALR in dsx1-silenced females resulted in the de-repression of dsx1. We further demonstrate that the DAPALR transcript overlaps the dsx1 5'-UTR, and this overlapping region is required for dsx1 activation. Our results suggest that DAPALR can transactivate and possibly maintain dsx1 expression. This might be important for converting transient environmental signals into stable male development, controlled by the continuous expression of dsx1.

A murine model of atopic dermatitis can be generated by painting the dorsal skin with hapten twice 14 days apart.

Drug development involves pharmacometric experiments in animals. Such experiments should limit animal pain and stress. Conventional murine models of atopic dermatitis (AD) used in drug development are generated by weekly painting of hapten on dorsal skin for 5 weeks. The present study aimed to develop a protocol that involves less animal distress. The experiments focused on serum total IgE levels, which are a marker of AD. The conventional protocol induced ever rising IgE levels. Experiments with extended intervals between sensitizations showed that IgE peaked ~5 days after the second sensitization, after which it returned to the control level within 12-19 days. An additional third sensitization on day 28 further increased the serum IgE level. In the 4-5 days after the second sensitization, the dorsal skin exhibited typical AD-like lesions with edema, scabs, epithelial-cell hypertrophy, marked mast-cell and lymphocyte infiltration of dermis, and increased IL-4, IL-6, IL-10, IL-1ß, IL-17A, IFN-γ and TNF-α expression. Thus, two 2,4-dinitrofluorobenzene sensitizations yield a murine AD model in less than 20 days. This study shows that animal model protocols used in drug development can be fine-tuned so that they remain effective yet cause animals less stress and pain.

Influence of arterial stiffness on cardiovascular outcome in patients without high blood pressure.

OBJECTIVE: Although blood pressure (BP) is a major determinant of arterial stiffness, whether high pulse wave velocity (PWV) adversely influences cardiac parameters and cardiovascular (CV) outcome in patients without high BP remains unclear. METHODS: Outpatients without high BP (n=320), defined as systolic BP ≥140 mm Hg, were enrolled in this retrospective study. At baseline, all patients underwent echocardiography and multidetector CT to determine the coronary artery calcification (CAC) score. Arterial stiffness was assessed based on brachial-ankle PWV (baPWV), from which patients were classified into two groups: those with high (≥18 m/s, n=89) and low baPWV (<18 m/s, n=231). Cardiac parameters and CV event incidence during the follow-up period were compared between these groups. RESULTS: In multivariable linear regression analysis, baPWV was significantly associated with CAC score and serum N-terminal pro-brain natriuretic peptide hormone level, after adjustment for confounding factors. In multivariable logistic regression analysis, baPWV ≥18 m/s was significantly associated with CAC score ≥400 (OR 2.466, 95% CI 1.012 to 6.009, p=0.0471). Kaplan-Meier analysis showed that the high-baPWV group experienced more CV events during the 575 days of follow-up (20% vs 6%, p=0.0003). CONCLUSIONS: High baPWV was associated with greater CAC and a high risk of a future CV event, especially coronary artery disease, even in patients without high BP.

Association between COMT Val158Met polymorphism and competition results of competitive swimmers.

Recent studies have shown the contribution of genetic determinants to athletes' physical ability. However, despite the fact that cognitive abilities like self-control and stress-tolerance influence athletes' competitive performance, few studies to date have investigated the association between genetic polymorphism, which is linked to cognitive ability and athletic performance. The present study investigated the link between single-nucleotide polymorphisms (SNPs), which are known to exert influences on dopaminergic neural function and competitive performance of swimmers. The results have revealed superior competitive performance in competitive swimmers with Met allele of catechol-O-methyltransferase Val158Met polymorphism than those with Val/Val genotype. The investigated SNPs of DRD2 and DRD3 were not associated with swimmer's competitive performance. This finding indicates that genetic polymorphism linked to cognitive ability influences the athletes' performance.

Impact of premature activation of the right ventricle with programmed stimulation in Brugada syndrome.

BACKGROUND: In Brugada syndrome (BrS), it has been reported that delayed activation in the RV is related to the development of type-1 ECG, which is more critical than type-2. On the other hand, the coexistence of complete right bundle-branch block (CRBBB), which also causes delayed activation in the RV, sometimes makes typical BrS ECG misleading. We hypothesized that premature stimulation of the RV can unmask the influence of delayed activation in the RV and convert the morphology of ECG in BrS patients. METHODS AND RESULTS: In 35 BrS patients with type-1 ECG including 8 patients with concomitant CRBBB and 6 control subjects with CRBBB, progressively premature single stimulations were delivered from the RV apex on electrophysiological study. Then we evaluated QRS morphology of fusion beats created by single premature stimulation in each patient. In 29 (83%) of 35 of the BrS patients, conversion from type-1 to type-2 ECG was observed during the process of single premature stimulation. Additionally, in all 8 BrS patients with concomitant CRBBB, type-1 or type-2 BrS ECG was revealed by premature stimulation with relief of CRBBB. These findings were not observed in any of the control subjects with CRBBB. CONCLUSION: Single premature stimulation of the RV converts ECG from type-1 to type-2 in most BrS cases and unmasks type-1 ECG in all BrS cases with CRBBB. Our results could suggest that type-1 ECG is associated with delayed activation of the RV compared with type-2 ECG.

Local Left Ventricular Epicardial J Waves and Late Potentials in Brugada Syndrome Patients with Inferolateral Early Repolarization Pattern.

Background: Brugada syndrome (BrS) is characterized by J-point or ST-segment elevation on electrocardiograms (ECGs) and increased risk of ventricular fibrillation (VF). In BrS, epicardial depolarization abnormality with delayed potential on the right ventricular outflow tract is reportedly the predominant mechanism underlying VF. Yet VF occurrence is also associated with early repolarization (ER) pattern in the inferolateral ECG leads, which may represent the inferior and/or left lateral ventricular myocardium. The aim of this study was to examine epicardial electrograms recorded directly at the left ventricle (LV) in BrS patients after VF episodes. Methods: In 12 BrS patients who had experienced VF episodes and 17 control subjects, a multipolar catheter was introduced into the left lateral coronary vein for unipolar and bipolar electrogram recordings at the LV epicardium. Both inferior and lateral ER patterns on ECG were observed in three BrS patients and six control subjects. Results: In the epicardium, prominent J waves were detected using unipolar recording, and potentials after the QRS complex were detected using bipolar recording in three of the 12 BrS patients. These three patients also showed both inferior and lateral ER patterns on ECG. Neither prominent J waves nor potentials after the QRS complex were recorded at the endocardium of the LV in any of these three patients; nor were they seen at the epicardium in any of the control subjects. These features were accentuated on pilsicainide administration (n = 2) but diminished on constant atrial pacing (n = 3) and isoproterenol administration (n = 1). The J waves observed through unipolar recording coincided with the potentials after QRS complex observed through bipolar recording and with the inferolateral ER patterns on ECG. Conclusions: We recorded prominent J waves in unipolar electrogram and potentials after QRS complex in bipolar electrogram at the LV epicardium in BrS patients with global ER pattern. The prominent J waves coincided with the potentials after QRS complex and the inferolateral ER pattern on ECG. The characteristics of the inferolateral ER pattern on ECG in these patients primarily represent depolarization feature.

A case of life-threatening supraventricular tachycardia storm associated with theophylline toxicity.

A 76-year-old man taking theophylline was admitted to our hospital with congestive heart failure and supraventricular tachycardia (SVT). After admission, he developed cardiogenic shock as a result of SVT storm, which was refractory to medical treatment including adenosine and electrical cardioversion. The serum theophylline concentration at admission was identified as toxic. Therefore, theophylline toxicity was considered as a major cause of the SVT storm. Hemodynamic stability was achieved by using mechanical circulatory support. Additionally, continuous hemodiafiltration was performed to remove theophylline, and it was effective for suppression of SVT. The patient was successfully weaned off mechanical circulatory support. After the patient's general status had improved, an electrophysiological study was performed, and it showed orthodromic atrioventricular reentrant tachycardia with a right free wall accessory pathway. Radiofrequency catheter ablation was successfully performed. .

Diagnostic performance of 320-slice computed tomography coronary angiography for symptomatic patients in clinical practice.

OBJECTIVE: Multi-slice computed tomography (MSCT) coronary angiography has been reported as an effective alternative to invasive conventional coronary angiography (CCA) for the diagnosis of coronary artery disease (CAD). However, in previous reports, the diagnostic accuracy of MSCT has not been significant enough to be of benefit in symptomatic patients. The aim of this study was to identify the usefulness of 320-slice computed tomography coronary angiography (320-CTA) for symptomatic patients in terms of the diagnostic accuracy of 320-CTA and the prevalence of vasospastic angina pectoris (VSAP) within the study cohort. METHODS: We retrospectively analyzed 513 consecutive symptomatic patients with suspected CAD who had undergone 320-CTA and CCA. We determined the diagnostic accuracy of 320-CTA using CCA as the reference standard. Ergonovine provocation tests were performed on patients without significant coronary artery stenosis on CCA. RESULTS: Of the total cohort of 513 symptomatic patients, 39% had obstructive CAD. The patient based analysis of the accuracy of 320-CTA showed a sensitivity of 91.0%, a specificity of 71.0%, a positive predictive value of 66.5%, and a negative predictive value of 92.5%. Of the 314 symptomatic patients who did not have significant coronary artery stenosis on CCA, 58 (18%) were diagnosed with VSAP using ergonovine provocation tests. DISCUSSION: The negative and positive predictive values indicate that 320-CTA cannot replace CCA for symptomatic patients. Indeed, a combination of CCA and ergonovine provocation tests should be taken into consideration for symptomatic patients.

A novel dual lock method for down-regulation of genes, in which a target mRNA is captured at 2 independent positions by linked locked nucleic acid antisense oligonucleotides.

Nuclear factor κB (NFκB), which is composed of the RelA and p50 subunits, binds to NFκB response elements (NREs) and stimulates the transcription of inflammation-related genes. Here, locked nucleic acid (LNA) antisense oligonucleotides (ASOs) complementary to the termini of the 3'- and 5'-untranslated regions (UTRs) of the RelA mRNA were generated; these molecules were named 3'-LNA and 5'-LNA, respectively. To evaluate their effects on NFκB activity, HeLa cells were co-transfected with the LNA ASOs and a luciferase reporter gene carrying an NRE. Transfection of the cells with 3'-LNA reduced NFκB activity by 30-40%, without affecting RelA mRNA accumulation. Concomitant transfection of HeLa cells with 5'-LNA and 3'-LNA resulted in a 70% reduction in NFκB activity. Furthermore, partial poly(A) tail shortening occurred in LNA ASO-transfected cells. We also employed triethylene glycol as a spacer to link 5'-LNA and 3'-LNA. Reporter gene assays showed that the spacer-linked LNA ASO reduced NFκB activity similarly to a combination of 5'-LNA and 3'-LNA. In addition, an in vitro translation assay revealed that spacer-linked LNA ASOs inhibited the translation of a target mRNA in a specific manner. In summary, this study describes a novel antisense method capturing the target mRNA at independent positions.

Clinical characteristics of responders to treatment with tolvaptan in patients with acute decompensated heart failure: Importance of preserved kidney size.

BACKGROUND: Recent clinical trials have demonstrated the efficacy of short-term treatment with tolvaptan, an oral vasopressin V2 receptor antagonist, in patients with heart failure. However, the response to tolvaptan varies among patients. The aim of this study was to determine factors associated with response to tolvaptan in patients with acute decompensated heart failure (ADHF). METHODS: The Tolvaptan Registry, a prospective, observational, multicenter cohort study performed in Japan, aims to determine factors affecting the responsiveness of tolvaptan in patients with ADHF. We enrolled ADHF patients treated with tolvaptan and they were divided into two groups: responders and non-responders. Responders were defined as subjects who met all of the following three conditions: (1) increasing urine volume during a 24-hour period after the start of tolvaptan treatment; (2) improvement in New York Heart Association functional class; and (3) decrease in cardiothoracic ratio assessed by chest X-ray on day 3 of tolvaptan administration. RESULTS: Among the 114 patients, treatment with tolvaptan improved three conditions of heart failure in more than half of all the cohorts (71 patients, 62%). As for baseline characteristics, estimated glomerular filtration rate, urine osmolality, and kidney size were significantly greater in responders than in non-responders. Multivariate logistic analysis revealed that kidney size was independently associated with responders (odds ratio: 1.083, p=0.001, 95% confidence interval 1.031-1.137). CONCLUSIONS: The main clinical characteristic of responders to treatment with tolvaptan is that kidney size is preserved.

Incidence and Clinical Significance of Brugada Syndrome Masked by Complete Right Bundle-Branch Block.

BACKGROUND: Brugada syndrome (BrS)-type electrocardiogram (ECG) is concealed by complete right bundle-branch block (CRBBB) in some cases of BrS. Clinical significance of BrS masked by CRBBB is not well known. METHODS AND RESULTS: We reviewed an ECG database of 326 BrS patients who had type 1 ECG with or without pilsicainide. "BrS masked by CRBBB" was defined on ECG as <2-mm elevation of the J point at the time of CRBBB in the right precordial leads, and BrS-type J-point elevation ≥2 mm at the time of normalized QRS complex on relieved CRBBB. We identified 25 BrS patients (7.7%) with persistent (n=12) or intermittent CRBBB (n=13). Relief of CRBBB by pacing was performed in patients with persistent CRBBB. The prevalence of BrS masked by CRBBB was 3.1% (10/326 patients). Three patients had type 1 ECG, and 7 patients had type 2 or 3 ECG on relief of CRBBB. Two of these 10 patients had lethal arrhythmic events during the follow-up period (mean, 86.4±57.2 months). There was no prognostic difference between BrS masked by CRBBB and other BrS. CONCLUSIONS: In a small BrS population, CRBBB can completely mask typical BrS-type ECG. BrS masked by CRBBB is associated with the same risk of fatal ventricular tachyarrhythmia as other BrS.

Sialidase NEU3 contributes neoplastic potential on colon cancer cells as a key modulator of gangliosides by regulating Wnt signaling.

The plasma membrane-associated sialidase NEU3 is a key enzyme for ganglioside degradation. We previously demonstrated remarkable up-regulation of NEU3 in various human cancers, with augmented malignant properties. Here, we provide evidence of a close link between NEU3 expression and Wnt/ß-catenin signaling in colon cancer cells by analyzing tumorigenic potential and cancer stem-like characteristics. NEU3 silencing in HT-29 and HCT116 colon cancer cells resulted in significant decrease in clonogenicity on soft agar and in vivo tumor growth, along with down-regulation of stemness and Wnt-related genes. Analyses further revealed that NEU3 enhanced phosphorylation of the Wnt receptor LRP6 and consequently ß-catenin activation by accelerating complex formation with LRP6 and recruitment of GSK3ß and Axin, whereas its silencing exerted the opposite effects. NEU3 activity-null mutants failed to demonstrate the activation, indicating the requirement of ganglioside modulation by the sialidase for the effects. Under sphere-forming conditions, when stemness genes are up-regulated, endogenous NEU3 expression was found to be significantly increased, whereas NEU3 silencing suppressed sphere-formation and in vivo tumor incidence in NOD-SCID mice. Increased ability of clonogenicity on soft agar and sphere formation by Wnt stimulation was abrogated by NEU3 silencing. Furthermore, NEU3 was found to regulate phosphorylation of ERK and Akt via EGF receptor and Ras cascades, thought to be additionally required for tumor progression. The results indicate an essential contribution of NEU3 to tumorigenic potential through maintenance of stem-like characteristics of colon cancer cells by regulating Wnt signaling at the receptor level, in addition to tumor progression via Ras/MAPK signaling.

Increased sialidase activity in serum of cancer patients: Identification of sialidase and inhibitor activities in human serum.

Aberrant sialylation in glycoproteins and glycolipids is a characteristic feature of malignancy. Human sialidases, which catalyze the removal of sialic acid residues from glycoconjugates, have been implicated in cancer progression. They have been detected in a wide variety of human cells and tissues, but few studies have focused on their existence in human serum. Among the four types identified to date, we previously demonstrated that plasma membrane-associated ganglioside sialidase (NEU3) is markedly upregulated in various human cancers, including examples in the colon and prostate. Here, using a sensitive assay method, we found a significant increase of sialidase activity in the serum of patients with prostate cancer compared with that in healthy subjects having low activity, if any. Activity was apparent with gangliosides as substrates, but only to a very limited extent with 4-methylumbelliferyl sialic acid, a good synthetic substrate for sialidases other than human NEU3. The serum sialidase was also almost entirely immunoprecipitated with anti-NEU3 antibody, but not with antibodies for other sialidases. Interestingly, sera additionally contained inhibitory activity against the sialidase and also against recombinant human NEU3. The sialidase and inhibitor activities could be separated by exosome isolation and by hydrophobic column chromatography. The serum sialidase was assessed by a sandwich ELISA method using two anti-NEU3 antibodies. The results provide strong evidence that the serum sialidase is, in fact, NEU3, and this subtype may, therefore, be a potential utility for novel diagnosis of human cancers.

A clinical study of malignant tumors of Stensen's duct.

CONCLUSION: Malignant tumors of Stensen's duct are often squamous cell carcinomas. Surgery is the treatment of choice, and maintaining an adequate safety margin and performing parotidectomy may help to reduce postoperative recurrence. OBJECTIVES: Since malignant tumors of Stensen's duct are extremely rare, the number of cases is limited in single-facility studies, making it difficult to perform a sufficient number of clinical examinations. Therefore, we reviewed 26 cases with Stensen's duct malignancies to examine their clinical features. METHODS: We conducted a retrospective study of 26 cases with Stensen's duct malignancies, including 1 patient whom we treated and 25 cases previously reported in the English literature, and analyzed their clinical parameters, including age, sex, affected side, chief complaint, tumor size, histopathology, treatment method, and treatment outcome. RESULTS: Most cases were diagnosed in patients between 40 and 69 years of age. The chief complaint was swelling in the cheek in 24 patients, in 14 of whom the swelling was painful. The most common tumor diameter range was 10-19 mm. Squamous cell carcinoma was the most frequent histopathology. The recurrence rate in surgical patients who did not undergo parotidectomy was 60%, whereas in patients who underwent parotidectomy, the recurrence rate was only 7%.