Systematic review and meta-analysis of pulmonary hypertension specific therapy for exercise capacity in chronic obstructive pulmonary disease.

Some patients with chronic obstructive pulmonary disease (COPD) have pulmonary hypertension (PH) that adversely affects survival. We performed a systematic review and meta-analysis to assess whether PH-specific therapies have an effect for stable COPD. Data sources were Medline, EMBASE, Cochrane Central Register of Controlled Trials, Korea med and references from relevant publications. Randomized prospective trials that compared PH specific therapy in COPD for more than 6 weeks with placebo were included. The outcomes were the exercise capacity and adverse events. Four randomized controlled trials involving 109 subjects were included in the analysis. Two trials involved bosentan, one sildenafil and one beraprost. The studies varied in duration of treatment from 3 to 18 months. In a pooled analysis of four trials, exercise-capacity was not significantly improved with PH-specific treatment for COPD (risk ratio, -5.1; 95% CI, -13.0 to 2.8). COPD with overt PH significantly improved the exercise capacity (mean difference, 111.6; 95% CI, 63.3 to 159.9) but COPD with PH unknown did not (mean difference, 26.6; 95% CI, -24.3 to 77.5). There was no significant difference in hypoxemia (mean difference, 2.6; 95% CI, -3.7 to 8.8). PH specific treatments have a significant effect in improving exercise capacity in COPD with overt PH.

Plasma carbonic anhydrase II protein is elevated in Alzheimer's disease.

Carbonic anhydrase (CA) plays a critical role in pH regulation, long-term synaptic transformation, and is associated with mental retardation, Alzheimer's disease (AD), and Down syndrome. There is accumulating evidence that CAII is increased in AD brain. The present study focused on the determination of CAII protein level in blood plasma samples using immunoblot and ELISA methods. We compared plasma from 91 AD patients (average age 74.8 y), 83 persons with amnestic mild cognitive impairment (MCI) (average age 73.7 y), and 113 cognitively normal controls (average age 70.8 y). The plasma level of CAII was significantly increased in AD patients, as compared to control groups. CAII levels were higher in males than females. There was an age-dependent increase of CAII. These results provide further evidence that changes in CAII level may play a role in the pathogenesis of AD.

A novel micelle-encapsulated platinum(II) anticancer agent.

A hydrophobic and water-insoluble platinum(II) compound, cis-(cha)(2)Pt(NO(3))(2) was encapsulated by macromolecular micelles self-assembled from an amphiphilic cyclotriphosphazene [NP(MPEG750)(GlyPheLeu)(2)Et](3) (CP750). The micelle-encapsulated platinum(II) compound exhibited outstanding pharmacokinetics in rats by showing long blood circulation and much larger systemic exposure (AUC=43.5 µgh/ml) compared with the free carboplatin (AUC=4.32 µgh/ml). Biodistribution study of the micellar platinum(II) compound using male Sprague-Dawley rats has shown excellent tumor to tissue ratios of 4.03 at 2h post injection and 4.67 at 24h post injection. Furthermore, the micellar platinum(II) compound exhibited more than 6 times higher cellular uptake in human cervical (HeLa) and lung (A549) tumor cells compared with the free platinum compound. Also it is surprising that the micellar platinum(II) compound displayed specifically high cytotoxicity against the stomach tumor cells (SNU638), which are one of the least responsive to chemotherapeutic agents currently in clinical use. The acute toxicity study has shown that the LD(50) values of free and the micellar cis-(cha)(2)Pt(NO(3))(2) are approximately 70 mg/kg and 90 mg/kg, respectively. Thus the platinum compound encapsulated by cyclotriphosphazene micelles is a promising candidate for preclinical studies.

Obesity and depressive symptoms in elderly Koreans: evidence for the "Jolly Fat" hypothesis from the Ansan Geriatric (AGE) Study.

The current study is to examine the association between obesity and depressive symptoms and to test the validity of "Jolly Fat" hypothesis in elderly Koreans. A total of 1229 elderly (60-85 years old) Koreans selected from the Ansan Geriatric Study participated in this study. Body mass index (BMI) was calculated from the measured weights and heights of subjects. Overweight and obese were defined as BMI > or =23 and > or =25, respectively. Depressive symptoms were measured using the 30-item Korean version of the Geriatric Depression Scale (K-GDS), with a cutoff point of 18. The prevalence of depressive symptoms in elderly Korean women was higher than in men (20.9% vs. 9.2%, p<0.001). Among elderly women, higher mean values of obesity indexes, such as weight, BMI, waist circumference, waist-hip ratio, and body fat mass, were found in normal subjects than in those with depressive symptoms. No such differences were found in elderly men. Obese elderly women were less likely to suffer from depressive symptoms compared to those with apparently normal weight (odds ratio (OR)=0.63, 95% CI: 0.41-0.96). This inverse association was evident after adjustment for confounders, such as age, education, personal expenses, smoking, alcohol consumption, regular exercise, self-perceived health, presence of chronic disease, and cognitive function. Our data are consistent with the "Jolly Fat" hypothesis being valid only in women, but not in men, among elderly Koreans. A causal relationship between obesity and depressive symptoms should be evaluated in future studies in elderly Korean women.

Serum Homocysteine and Folate Levels are Associated With Late-life Dementia in a Korean Population.

OBJECTIVES: We aimed to determine whether serum levels of homocysteine (Hcy) and its biological determinants, folate and vitamin B12, are related to cognitive decline in elderly people. METHODS: The concentrations of total Hcy, folate, and vitamin B12 were measured in serum samples from 424 cognitively normal controls, 382 mild cognitive impairment patients, and 56 dementia patients from Ansan Geriatric cohort. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery was used to evaluate cognitive functions. RESULTS: The dementia patients had higher serum Hcy (dementia, 17.6 ± 6.9 µmol/L; control, 12.9 ± 5.0 µmol/L; p < 0.001) and lower serum folate (dementia, 7.9 ± 4.8 ng/mL; control, 10.0 ± 7.1 ng/mL; p = 0.034) levels compared with controls. There was an inverse relationship between Hcy levels and serum folate or vitamin B12 concentrations. The cognitive status as measured by the (CERAD) score was inversely related to Hcy levels. The adjusted odds ratio of dementia was 5.18 (95% confidence interval: 1.91-14.10; p = 0.001) for moderate (30 ≥ Hcy > 15) hyperhomocysteinemia compared with normal Hcy levels (≤15 µmol/L). In addition, there was weak association between low serum folate (<3.0 ng/mL) and the risk for dementia (crude odds ratio = 3.68; 95% confidence interval: 1.07-12.69; p = 0.039). CONCLUSION: Elevated serum Hcy and decreased serum folate concentrations are associated with the risk of dementia in Korean elders.

Tripodal amphiphiles tunable for self-assembly to polymersomes.

Cyclotriphosphazenes grafted with equimolar amounts of a hydrophilic polyethylene glycol and a hydrophobic oligopeptide in cis-nongeminal way form a new class of tripodal amphiphiles allowing both intra- and intermolecular hydrophobic interactions that differ from linear block copolymer amphiphiles. It has been found in this study that the tripodal amphiphiles can be tuned for self-assembly from micelles to bilayered polymersomes by controlling the hydrophobicity of the oligopeptide grafted. For instance, the tripodal amphiphiles with an intermediate hydrophobicity (01) remain as stable micelles in aqueous solution. These biodegradable polymersomes exhibit outstanding physicochemical properties required for practical drug delivery and other biomedical applications. In particular, the cyclic phosphazene trimer platinated with a hydrophobic cis-bis(cyclohexylamine)Pt-moiety forms very stable polymersomes with excellent tumor selectivity by EPR effect and seems to be a promising candidate for preclinical studies.

Ubc9 gene polymorphisms and late-onset Alzheimer's disease in the Korean population: a genetic association study.

Ubiquitin-conjugating enzyme E2I (Ubc9) ligates small ubiquitin-related modifier (SUMO) to target proteins, resulting in changes of their localization, activity, or stability. Sumoylation of amyloid precursor protein (APP) was reported to be associated with decreased levels of beta amyloid (Abeta) aggregates, suggesting that sumoylation may play a role in the pathogenesis of Alzheimer's disease (AD). We investigated the association between genetic variations of Ubc9 gene (UBE2I) and late-onset Alzheimer's disease (AD). Five single nucleotide polymorphisms (SNPs) in UBE2I were genotyped in the DNA samples of 312 AD patients, 347 subjects with mild cognitive impairment (MCI), and 489 cognitively healthy controls. The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p=0.046, 95% CI: 1.01-2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p=0.04, OR=1.43. 95% CI; 1.01-2.01). Stratification by the ApoE-epsilon4 allele gave no significant difference between the groups. When the samples were stratified by gender, the genotypes of two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. Our investigation suggests that UBE2I polymorphisms might be associated with a risk of AD and MCI.

In vitro effects of a fraction separated from Polygonum cuspidatum root on the viability, in suspension and biofilms, and biofilm formation of mutans streptococci.

Polygonum cuspidatum (Polygonaceae) has traditionally been used in folk medicine to control oral diseases. Nevertheless, there are no reports related to its possible effect on the diseases, particularly on biofilm-related diseases such as dental caries. In this study, we evaluated in vitro effects of a fraction separated from Polygonum cuspidatum root on the viability, in both suspension and biofilms, and the biofilm formation of mutans streptococci. The separated fraction (F1) showed bacteriostatic and bactericidal activity against mutans streptococci in suspension, with minimum inhibitory concentration (MIC) range of 31.3-250 microg/ml and minimum bactericidal concentration (MBC) range of 0.5-1 mg/ml. At a concentration of 1.5 mg/ml, F1 killed approximately 2 log(10)CFU/ml of Streptococcus mutans and Streptococcus sobrinus after 2h of exposure. In biofilms, F1 also inhibited the viability of Streptococcus mutans and Streptococcus sobrinus, dependent on the biofilm age, the concentration of F1, and the treatment time. Four hours of exposure to 1.5 mg/ml F1 reduced the viable counts of Streptococcus mutans and Streptococcus sobrinus by greater than 2 log(10)CFU/disc. Furthermore, at sub-MIC levels, F1 inhibited biofilm formation by Streptococcus mutans and Streptococcus sobrinus in a dose-dependent fashion. Based on the preliminary phytochemical analysis, the activity of F1 may be related to the presence of anthraquinones, cardiac glycosides, terpenoids, and phenolics. These results indicate that F1 is probably useful in the control of oral biofilms and subsequent dental caries development.

In vitro inhibitory effects of Polygonum cuspidatum on bacterial viability and virulence factors of Streptococcus mutans and Streptococcus sobrinus.

OBJECTIVES: Polygonum cuspidatum has been used in Korean folk medicine to improve oral hygiene. This study was performed to evaluate the effects of methanol extract from root of P. cuspidatum (MEP) on bacterial viability and the virulence factors of Streptococcus mutans and Streptococcus sobrinus. METHODS: To test the effects of MEP on bacterial viability, we determined the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against 20 bacterial strains, including S. mutans and S. sobrinus, using a micro-dilution assay. In case of S. mutans and S. sobrinus, the assays for time-kill and bacterial growth rate at sub-MIC concentrations were also performed. To determine effects of the extract on the virulence factors of S. mutans and S. sobrinus, the assays for sucrose-dependent adherence, water-insoluble glucan formation, glycolytic acid production, and acid tolerance were performed at sub-MIC levels. Phytochemical analysis for constituents of MEP was carried out. RESULTS: MEP showed a broad antibacterial range (MIC 0.5-4 mg/ml). The MBC was two to four times higher than the MIC. The time-kill curves showed S. mutans and S. sobrinus were significantly killed after 1h of incubation. At sub-MIC levels, doubling times of S. mutans and S. sobrinus dose-dependently increased up to 211% and 123%, respectively. At sub-MIC levels, MEP also showed inhibitory effects on the virulence factors of S. mutans and S. sobrinus in a dose-dependent fashion. Phytochemical analysis revealed the presence of alkaloids, sterol/terpenes, tannins, flavonoids, and carbohydrates. CONCLUSION: These data indicate that MEP has inhibitory effects on bacterial viability at higher concentrations (> or =MIC) and the virulence factors of S. mutans and S. sobrinus at sub-MIC concentrations, suggesting that it might be useful for the control of dental plaque formation and subsequent dental caries formation.

In vitro anti-cariogenic activity of dichloromethane fraction from Rheum undulatum L. root.

This study aimed to evaluate in vitro effects of Rheum undulatum L. root on the development of dental caries, especially its effects on viability, dental plaque formation, and glycolytic acid production of Streptococcus mutans and Streptococcus sobrinus. Methanol extract of Rheum undulatum L. root and its fractions were prepared and tested. Among the test extract and fractions, dichloromethane fraction (DF) showed the most active antibacterial activity (inhibition zone: 13-17 mm) against S. mutans and S. sobrinus in a disc diffusion method. Minimal inhibitory concentrations (MICs) of DF against these bacteria ranged from 0.25 to 0.5 mg/mL. Furthermore, DF significantly inhibited the caries-inducing factors of these bacteria. At sub-MIC levels, DF inhibited in vitro dental plaque formation by S. mutans and S. sobrinus (IC50= 0.079 and 0.142 mg/mL, respectively), which was caused, in part, by the inhibitory effect on the activity of glucosyltransferases. A significant reduction of glycolytic acid production was found at the concentration as low as 0.032 mg/mL for S. mutans and 0.063 mg/mL for S. sobrinus. The possible bioactive compounds that are inducing in vitro anti-cariogenic activity of DF are unknown. Based on the preliminary phytochemical analysis, the activity of DF may be related to the presence of anthraquinones, cardiac glycosides, coumarines, sterols/terpenes, and phenolics. These results indicate that DF is probably useful for the control of dental plaque formation and subsequent dental caries development.

The polymorphisms of Tim-1 promoter region are associated with rheumatoid arthritis in a Korean population.

It has been determined that the family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is expressed on T cells. A member of the TIM family, TIM-1, is considered to be a membrane protein associated with the development of Th2-biased immune responses and selectively expressed on Th2 cells. We previously showed that the exon 4 variations of Tim-1 are associated with susceptibility to allergic diseases, as well as autoimmune diseases such as rheumatoid arthritis (RA). In this study, we assessed the association between genotype and allele frequencies of the Tim-1 gene promoter region, in both RA patients and the controls without RA, using polymerase chain reaction-restriction fragment length polymorphism and single-base extension methods. We further investigated the relationships among the genotypes of each polymorphism and C-reactive protein or rheumatoid factor levels in RA patients. The genotype and allele frequencies of the -1637A>G polymorphism in RA patients are significantly different from those in the non-RA controls (P=0.0004 and P=0.001, respectively). Our results strongly suggest that polymorphism in the Tim-1 promoter region might be associated with susceptibility to RA.

Molecular variations in Th1-specific cell surface gene Tim-3.

The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of Tim family, Tim-3 (T cell immunoglobulin mucin 3) is selectively expressed on the surface of differentiated Th1 cells. Tim-3 might have an important role in the induction of autoimmune diseases by regulating macrophage activation and interacts with Tim-3 ligand to regulate Th1 responses. To determine the variation sites in the coding and promoter region of human Tim-3 gene, we performed variation scanning by direct sequencing using the genomic DNA isolated from the patients with asthma or allergic rhinitis and healthy controls without asthma and allergic rhinitis. We identified four single nucleotide polymorphisms (SNPs) including one novel SNPs (-1541C>T) and two variation sites (-1292_-1289delTAAA and -1282_-1278dupTAAAA) in the coding and promoter region of human Tim-3 gene in both the patients and healthy groups.

Analysis of the polymorphisms in eotaxin gene family and their association with asthma, IgE, and eosinophil.

The eotaxin gene family (eotaxin, eotaxin-2, and eotaxin-3) has been implicated in the recruitment of eosinophils, basophiles, and Th2 lymphocytes that is a central aspect of allergic diseases such as asthma. To determine whether the single nucleotide polymorphisms (SNPs) of eotaxin gene family are associated with susceptibility to asthma, we scanned 225 asthma patients and 294 non-asthmatic controls using the direct sequencing method. We further investigated the relationships among each SNP, eosinophils, and serum total IgE levels in asthma patients. Eleven SNPs were identified in the eotaxin gene family. We found that EoB179T > C (P = 0.0001), EoB275C > T (P = 0.018) of the eotaxin-2 and EoA2497T > G (P = 0.003) of the eotaxin-3 were significantly associated with the susceptibility of asthma. Furthermore, our data demonstrated for the first time that EoA2497T > G (P = 0.005) is related to serum total IgE level while EoA77C > T (P = 0.035) and EoA2497T > G (P = 0.033) are related to the peripheral blood eosinophil counts in asthma. Our results suggest that the polymorphisms of the eotaxin gene family are associated with the susceptibility of asthma and Eotaxin-3 might play the critical role for the recruitment of eosinophils and the maintenance of IgE levels.

The exon 4 variations of Tim-1 gene are associated with rheumatoid arthritis in a Korean population.

The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of Tim family, TIM-1, is considered as a membrane protein that is associated with the development of Th2 biased immune responses and selectively expressed on Th2 cells. In the present study, we analyzed the association of genotype and allele frequencies between rheumatoid arthritis (RA) patients and the controls without RA using large samples size at 5383_5397del and 5509_5511delCAA variations of Tim-1 gene. We further investigated the relationships among these variations to C-reactive protein (CRP) and rheumatoid factor (RF) levels in RA patients. Although these factors were not associated with exon 4 variations in RA patients, the genotype and allele frequencies of 5383_5397del variation site (P = 0.015 and 0.014, respectively) as well as 5509_5511delCAA variation site (P = 0.0002 and 0.0001, respectively) in RA patients were significantly different from those in the non-RA controls. Our results strongly suggest that the variations of Tim-1 exon 4 might be associated with the susceptibility to RA.

Molecular variations in the promoter and coding regions of human Tim-1 gene and their association in Koreans with asthma.

The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of Tim family, TIM-1, was considered as a membrane protein that is associated with the development of helper T cell (Th2) biased immune responses, and may be selectively expressed on Th2 cells. In the present study we performed single nucleotide polymorphism (SNP) scanning of the coding and promoter regions of human Tim-1 gene. We identified a total of ten SNPs including five novel SNPs (-1166C>G, -416G>C, -232A>G, 5365C>T, and 5529A>G) in the coding and promoter regions, one novel variation site (-2278_-2276dupATT) in the promoter region and three variations (5383_5397del, 5387_5389insAAC, and 5509_5511delCAA) in exon 4 of human Tim-1 gene. Our results suggest that the exon 4 variation site in human Tim-1 gene is associated with the susceptibility of allergic disease.

The association of the exon 4 variations of Tim-1 gene with allergic diseases in a Korean population.

The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of Tim family, TIM-1, is considered as a membrane protein that is associated with the development of Th2 biased immune responses and may be selectively expressed on Th2 cells. In the present study, we analyzed the association of allele and genotype frequencies between asthma or atopy patients and the controls without asthma and atopy using large sample size at 5383_5397del and 5509_5511delCAA variations of Tim-1 gene. Although the allele frequency of 5509_5511delCAA variation in asthma was not significantly different (P=0.085), the genotype of 5509_5511delCAA variation in asthma was significantly associated with the susceptibility to asthma (P=0.037). The genotype and allele frequencies of 5383_5397del variation in atopic dermatitis were significantly different from those in the non-asthmatic and non-atopic controls (P=0.005 and P=0.002, respectively). Our results strongly suggest that the 5383_5397del variation site of Tim-1 exon 4 might be associated with atopic dermatitis susceptibility.