Comparative Study of BMP-2 Alone and Combined with VEGF Carried by Hydrogel for Maxillary Alveolar Bone Regeneration

The effect of vascular endothelial growth factor (VEGF) combined with bone morphogenetic protein-2 (BMP-2) for bone regeneration is still controversial as to whether or not VEGF has a synergistic or additive effect. This study attempted to evaluate the synergistic effect of VEGF and BMP-2 compared to BMP-2 alone for maxillary alveolar bone regeneration using collagen sponge/hydrogel complex sheets in a canine model. After mixing BMP-2 and VEGF with a hyaluronic acid-based hydrogel (HAH), the collagen sponge/hydrogel complex was transplanted into maxillary alveolar bone defects (n=14) after the extraction of canine upper first molars on both sides. Bone regeneration was evaluated in three groups (control group without growth factors, experimental groups I and II with BMP-2 alone and BMP-2 and VEGF, respectively) using micro-computed tomography and histological staining. The total amount of new bone formations and bone mineral density were significantly higher in the group with BMP-2 only and the group with BMP-2 combined with VEGF than it in the control group. The area with positive staining of von Willebrand factor bone defect was significantly greater in the group with BMP-2 only and with dual growth factors than the control. BMP-2 released from the HAH promoted new bone formation. However, the combination of BMP-2 and VEGF did not show a synergistic or additive effect on bone regeneration at canine maxillary alveolar bone defects.

Mitochondrial DNA 4977bp Deletion Mutation in Peripheral Blood Reflects Atrial Remodeling in Patients with Non-Valvular Atrial Fibrillation

PURPOSE: Recently, mitochondrial DNA 4977bp deletion (mtDNA4977-mut), a somatic mutation related to oxidative stress, has been shown to be associated with atrial fibrillation (AF). We hypothesized that patient age, as well as electroanatomical characteristics of fibrillating left atrial (LA), vary depending on the presence of mtDNA4977-mut in peripheral blood among patients with non-valvular AF. MATERIALS AND METHODS: Analyzing clinical and electroanatomical characteristics, we investigated the presence of the mtDNA4977-mut in peripheral blood of 212 patients (51.1+/-13.2 years old, 83.5% male) undergoing catheter ablation for non-valvular AF, as well as 212 age-matched control subjects. RESULTS: The overall frequency of peripheral blood mtDNA4977-mut in patients with AF and controls was not significantly different (24.5% vs. 19.3%, p=0.197). When the AF patient group was stratified according to age, mtDNA4977-mut was more common (47.4% vs. 20.0%, p=0.019) in AF patients older than 65 years than their age-matched controls. Among AF patients, those with mtDNA4977-mut were older (58.1+/-11.9 years old vs. 48.8+/-11.9 years old, p<0.001). AF patients positive for the mtDNA mutation had greater LA dimension (p=0.014), higher mitral inflow peak velocity (E)/diastolic mitral annular velocity (Em) ratio (p<0.001), as well as lower endocardial voltage (p=0.035), and slower conduction velocity (p=0.048) in the posterior LA than those without the mutation. In multivariate analysis, E/Em ratio was found to be significantly associated with the presence of mtDNA4977-mut in peripheral blood. CONCLUSION: mtDNA4977-mut, an age-related somatic mutation detected in the peripheral blood, is associated with advanced age and electro-anatomical remodeling of the atrium in non-valvular AF.

A Case of Long QT Syndrome Type 3 Aggravated by Beta-Blockers and Alleviated by Mexiletine: The Role of Epinephrine Provocation Test

Long QT syndrome (LQTs) is an uncommon genetic disease causing sudden cardiac death with Torsade de Pointes (TdP). The first line drug treatment has been known to be beta-blocker. We encountered a 15-year-old female student with LQTs who had prolonged QTc and multiple episodes of syncope or agonal respiration during sleep. Although her T wave morphology in surface electrocardiography resembled LQTs type 1, her clinical presentation was unusual. During the epinephrine test, TdP was aggravated during beta-blocker medication, but alleviated by sodium channel blocker (mexiletine). Therefore, she underwent implantable cardioverter defibrillator implantation.

Serological Predictors for the Recurrence of Atrial Fibrillation After Electrical Cardioversion

BACKGROUND AND OBJECTIVES: Although electrical cardioversion (CV) is effective in restoring sinus rhythm (SR) in patients with atrial fibrillation (AF), AF frequently recurs in spite of antiarrhythmic medications. We investigated the predictors of failed CV and AF recurrence after successful CV. SUBJECTS AND METHODS: In 81 patients (M:F=63:18, 59.1+/-10.5 years old) with AF who underwent CV, clinical findings and pre-CV serologic markers were evaluated. RESULTS: During 13.1+/-10.6 months of follow-up, 8.6% (7/81) showed failed CV, 27.16% (22/81) showed early recurrence atrial fibrillation (ERAF; 2 weeks), and 32.1% (26/81) remained in SR and had no recurrence (NR). Plasma levels of transforming growth factor beta (TGF)-beta were significantly higher in patients with failed CV than in those with successful CV (p=0.0260). Patients in whom AF recurred were older (60.4+/-9.0 years old vs. 55.3+/-12.5 years old, p=0.0220), and had lower plasma levels of stromal cell derived factor (SDF)-1alpha (p=0.0105). However, there were no significant differences in these parameters between ERAF patients and LRAF patients. CONCLUSION: Post-CV recurrence commonly occurs in patients aged >60 years and who have low plasma levels of SDF-1alpha. High plasma levels of TGF-beta predict failure of electrical CV.

Human Mesenchymal Stem Cell Transplantation Induces Sympathetic Nerve Sprouting and Reduces the Gap Junction With Potential Proarrhythmias in Dogs

BACKGROUND AND OBJECTIVES: Although human mesenchymal stem cell (hMSC) transplantation has been known to improve ventricular function, the potential proarrhythmic effects have not yet been studied. MATERIALS AND METHODS: We monitored the heart rhythm of 6 dogs for 4 weeks after transplantation of hMSC (1x10(7), epicardial injection) (hMSC group) and in 5 Sham dogs after the injection of the vehicle alone. Cardiac sympathetic nerve sprouting {nerve growth factor (NGF)-beta; tyrosine hydroxylase (TH)} and gap junction expression {connexin (Cx) 43} were evaluated in 10 dogs (5 hMSC and 5 Sham) that survived longer than 4 weeks. RESULTS: The hMSC group expressed higher levels of NGF-beta messenger ribonucleic acid (mRNA) (56.0+/-66.8 fold; p<0.01) with TH+ sympathetic nerves (0.51+/-0.40 vs. 0.15+/-0.13% area; p<0.03) than the Sham control. In contrast, the hMSC group expressed lower levels of Cx43 mRNA (0.59+/-0.29 fold, p<0.001) and Cx43+ (1.64+/-1.79 vs. 2.12+/-1.07% area, p<0.001) than the Sham control. The incidences of ventricular fibrillation were 33.3% and 0% in the hMSC group and Sham control, respectively. One of the dogs with ventricular fibrillation (VF) in the hMSC group died suddenly. CONCLUSION: hMSC transplantation may be proarrhythmic since NGF-beta expression increased with cardiac sympathetic hyperinnervation and the expression of Cx43 and the gap junction decreased.

Association of Interleukin-18 Polymorphisms with Adult Onset Still's Disease in Korea / 대한류마티스학회지

OBJECTIVE: It has been suggested that overproduction of interleukin -18 (IL-18) may contribute to the pathogenesis of adult onset Still's disease (AOSD). Recently, positive association between a polymorphism in the IL-18 gene and different diseases like diabetes, sarcoidosis and asthma has been reported. The aim of the present study was to investigate the potential association of two single-nucleotide polymorphisms (SNPs) at position -137 (G/C) and -607 (C/A) in the promoter region of the IL-18 gene with susceptibility and clinical feature of AOSD in the Korean population. METHODS: We examined two SNPs of IL-18 in 70 patients with AOSD and 204 healthy control individuals. The genotyping were performed using sequence specific PCR. Haplotypes were analyzed by the estimated haplotype program. The patients with AOSD were subdivided into groups according to disease course: monocyclic systemic, polycyclic systemic, and chronic articular type. RESULTS: As for the -607 genotypes, 13 of the 69 patients had CC genotype (18.8%), 36 the CA type (52.2%) and 20 the AA type (29.0%). AOSD patients had higher frequency of A allele at -607 when compared to controls (OR 1.48, 95% CI 1.00~2.18, p=0.048). AOSD patients had significantly higher frequency of AA genotypes at -607 when compared to controls (AA vs CA& CC, OR 1.90, 95% CI 1.01~3.58, p=0.044). As for the -137 genotypes, of the 68 patients, 57 had GG genotype (83.8%), 9 the GC type (13.2%) and 2 (2.9%) had the CC type. No differences were found in allele and genotype frequencies between two groups. The haplotype frequencies of the IL-18 polymorphism were not significantly different between patients with AOSD and controls. The frequency of -137 GG genotype was significantly increased in chronic articular type compared to healthy control and systemic type of AOSD. CONCLUSION: In IL-18 gene polymorphisms, the A allele and AA genotye at position -607 might be genetic risk factors for the development of AOSD in Korean population. Further investigation in larger groups is required to provide more conclusive evidence regarding the role of the IL-18 gene polymorphism in AOSD.

Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism in Korean Patients with Systemic Sclerosis

To determine whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with the development and clinical features of systemic sclerosis (SSc) in Korean, we studied seventy two Korean patients with SSc fulfilling the ACR preliminary classification criteria. The controls were 114 healthy, disease free Koreans. ACE I/D genotypes were determined by PCR method using oligonucleotides. Sixty eight patients (94.4%) were women and age at diagnosis was 43.5+/-12.6 yr old (mean+/-SD). Thirty nine patients (54.2%) had a diffuse type of SSc. There were no statistical differences in the frequencies of all ACE I/D genotypes and D allele between patients and controls, and neither between diffuse and limited types of SSc. ACE I/D gene polymorphism was not associated with the development of SSc in Korea. The investigation for the pathogenesis of SSc requires more studies about the role of other candidate genes such as endothelin, TGF-beta, nitric oxide, or angiotensin II receptor in addition to the ACE genes.

Angiotensin Converting Enzyme Insertion/Deletion Polymorphism in Korean Patients with Rheumatoid Vasculitis / 대한류마티스학회지

OBJECTIVE: Rheumatoid arthritis has various extra-articular manifestations including rheumatoid vasculitis. Angiotensin converting enzyme (ACE) gene shows insertion/deletion polymorphism and has II, ID, DD genotypes. ACE gene is related with vasoconstriction and endothelial dysfunction in cardiovascular disease. This study was undertaken to determine the association between ACE gene polymorphism and rheumatoid vasculitis. METHODS: Twenty-nine patients were collected as rheumatoid vasculitis group. DNA was isolated from blood samples collected from 114 Korean rheumatoid arthritis patients meeting American College of rheumatology 1987 revised criteria, and 114 healthy control group. Genotyping for the angiotensin converting enzyme gene insertion/deletion polymorphism was performed by polymerase chain reaction method. RESULTS: As vasculitis manifestation, 15 patients showed neuropathy, 13 showed scleritis, 3 showed skin rash. In rheumatoid vasculitis group, II, ID and DD polymorphism was seen in 8 (27.6%), 15 (51.7%), 6 (20.7%) patients respectively and 39 (34.2%), 57 (50.0%), and 18 (15.8%) in normal controls. There was no skewing of ACE I/D polymorphism in compared with normal group. In rheumatoid arthritis control group, II, ID and DD polymorphism was seen in 37 (32.5%), 64 (56.1%), and 13 (11.4%) patients. Among rheumatoid arthritis patient, there was no significant difference between patient with vasculitis and without vasculitis. CONCLUSION: Our results showed that genetic polymorphisms of angiotensin converting enzyme insertion/deletion gene has no association with the susceptibility to rheumatoid vasculitis.