Promoter Polymorphism G-6A, which Modulates Angiotensinogen Gene Expression, Is Associated with Non-Familial Sick Sinus Syndrome

Background: It is well known that familial sick sinus syndrome (SSS) is caused by functional alterations of ion channels and gap junction. Limited information is available on the mechanism of age-related non-familial SSS. Although evidence shows a close link between arrhythmia and the renin-angiotensin system (RAS), it remains to be determined whether the RAS is involved in the pathogenesis of non-familial SSS. Methods: In this study, 113 patients with documented non-familial SSS and 125 controls were screened for angiotensinogen (AGT) and gap junction protein-connexin 40 (Cx40) promoter polymorphisms by gene sequencing, followed by an association study. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The interaction between nuclear factors and the promoter polymorphism was characterized by an electrophoretic mobility shift assay (EMSA). Results: Association study showed the Cx40 -44/+71 polymorphisms are not associated with non-familial SSS; however, it indicated that four polymorphic sites at positions -6, -20, -152, and -217 in the AGT promoter are linked to non-familial SSS. Compared to controls, SSS patients had a lower frequency of the G-6A AA genotype (OR 2.88, 95% CI 1.58–5.22, P = 0.001) and a higher frequency of the G allele at -6 position (OR 2.65, 95% CI 1.54–4.57, P = 0.0003). EMSA and luciferase assays confirmed that nucleotide G at position -6 modulates the binding affinity with nuclear factors and yields a lower transcriptional activity than nucleotide A (P,0.01). Conclusion: G-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to nonfamilial SSS susceptibility

A Study of Success Rate of Miniscrew Implants as Temporary Anchorage Devices in Singapore

Objective. To find out the success rate of miniscrew implants in the National Dental Centre of Singapore (NDCS) and the impact of patient-related, location-related, and miniscrew implant-related factors. Materials and Methods. Two hundred and eighty-five orthodontic miniscrew implants were examined from NDCS patient records. Eleven variables were analysed to see if there is any association with success. Outcome was measured twice, immediately after surgery prior to orthodontic loading (T1) and 12 months after surgery (T2). The outcome at T2 was assessed 12 months after the miniscrew's insertion date or after its use as a temporary anchorage device has ceased. Results. Overall success rate was 94.7% at T1 and 83.3% at T2. Multivariate analysis revealed only the length of miniscrew implant to be significantly associated with success at both T1 ( = 0.002) and T2 ( = 0.030). Miniscrew implants with lengths of 10-12 mm had the highest success rate (98.0%) compared to other lengths, and this is statistically significant ( = 0.035). At T2, lengths of 10-12 mm had significantly ( = 0.013) higher success rates (93.5%) compared to 6-7 mm (76.7%) and 8 mm (82.1%) miniscrew implants. Conclusion. Multivariate statistical analyses of 11 variables demonstrate that length of miniscrew implant is significant in determining success

A Study of Success Rate of Miniscrew Implants as Temporary Anchorage Devices in Singapore

Objective. To find out the success rate of miniscrew implants in the National Dental Centre of Singapore (NDCS) and the impact of patient-related, location-related, and miniscrew implant-related factors. Materials and Methods. Two hundred and eighty-five orthodontic miniscrew implants were examined from NDCS patient records. Eleven variables were analysed to see if there is any association with success. Outcome was measured twice, immediately after surgery prior to orthodontic loading (T1) and 12 months after surgery (T2). The outcome at T2 was assessed 12 months after the miniscrew’s insertion date or after its use as a temporary anchorage device has ceased. Results. Overall success rate was 94.7% at T1 and 83.3% at T2. Multivariate analysis revealed only the length of miniscrew implant to be significantly associated with success at both T1 (P=0.002) and T2 (P=0.030). Miniscrew implants with lengths of 10–12 mm had the highest success rate (98.0%) compared to other lengths, and this is statistically significant (P=0.035). At T2, lengths of 10–12 mm had significantly (P=0.013) higher success rates (93.5%) compared to 6-7 mm (76.7%) and 8 mm (82.1%) miniscrew implants. Conclusion. Multivariate statistical analyses of 11 variables demonstrate that length of miniscrew implant is significant in determining success

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis

HuR cytoplasmic expression is associated with increased cyclin A expression and poor outcome with upper urinary tract urothelial carcinoma

BACKGROUND: HuR is an RNA-binding protein that post-transcriptionally modulates the expressions of various target genes implicated in carcinogenesis, such as CCNA2 encoding cyclin A. No prior study attempted to evaluate the significance of HuR expression in a large cohort with upper urinary tract urothelial carcinomas (UTUCs). METHODS: In total, 340 cases of primary localized UTUC without previous or concordant bladder carcinoma were selected. All of these patients received ureterectomy or radical nephroureterectomy with curative intents. Pathological slides were reviewed, and clinical findings were collected. Immunostaining for HuR and cyclin A was performed and evaluated by using H-score. The results of cytoplasmic HuR and nuclear cyclin A expressions were correlated with disease-specific survival (DSS), metastasis-free survival (MeFS), urinary bladder recurrence-free survival (UBRFS), and various clinicopathological factors. RESULTS: HuR cytoplasmic expression was significantly related to the pT status, lymph node metastasis, a higher histological grade, the pattern of invasion, vascular and perineurial invasion, and cyclin A expression (p = 0.005). Importantly, HuR cytoplasmic expression was strongly associated with a worse DSS (p < 0.0001), MeFS (p < 0.0001), and UBRFS (p = 0.0370) in the univariate analysis, and the first two results remained independently predictive of adverse outcomes (p = 0.038, relative risk [RR] = 1.996 for DSS; p = 0.027, RR = 1.880 for MeFS). Cyclin A nuclear expression was associated with a poor DSS (p = 0.0035) and MeFS (p = 0.0015) in the univariate analysis but was not prognosticatory in the multivariate analyses. High-risk patients (pT3 or pT4 with/without nodal metastasis) with high HuR cytoplasmic expression had better DSS if adjuvant chemotherapy was performed (p = 0.015). CONCLUSIONS: HuR cytoplasmic expression was correlated with adverse phenotypes and cyclin A overexpression and also independently predictive of worse DSS and MeFS, suggesting its roles in tumorigenesis or carcinogenesis and potentiality as a prognostic marker of UTUC. High HuR cytoplasmic expression might identify patients more likely to be beneficial for adjuvant chemotherapy

Relationship between Inflammation and Vasospastic Angina

Coronary artery spasm (CAS) is a dynamic coronary stenosis causing vasospastic angina (VSA). However, VSA is a potentially lethal medical condition with multiple presentations, including sudden cardiac death. Despite investigations to explore its pathogenesis, no single mechanism has been found to explain the entire process of VSA occurrence. The roles of elevated local and systemic inflammation have been increasingly recognized in VSA. Treatment strategies to decrease local and systemic inflammation deserve further investigation

Relationship between Inflammation and Vasospastic Angina

Coronary artery spasm (CAS) is a dynamic coronary stenosis causing vasospastic angina (VSA). However, VSA is a potentially lethal medical condition with multiple presentations, including sudden cardiac death. Despite investigations to explore its pathogenesis, no single mechanism has been found to explain the entire process of VSA occurrence. The roles of elevated local and systemic inflammation have been increasingly recognized in VSA. Treatment strategies to decrease local and systemic inflammation deserve further investigation