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1.  Epigenetic Changes of Serotonin Transporter in the Patients with Alcohol Dependence: Methylation of an Serotonin Transporter Promoter CpG Island 
Psychiatry Investigation  2010;8(2):130-133.
Objective
Psychiatric disorders such as depression, anxiety and alcohol dependence are associated with serotonin metabolism. We assessed the methylation level of the serotonin transporter (5-HTT) promoter region in control and alcohol dependent patients.
Methods
Twenty seven male patients who met the Diagnostic and Statistical Manual of Mental Disorder IV (DSM-IV) criteria for alcohol dependence were compared with fifteen controls. Polymerase chain reaction (PCR) assays of bisulfate-modified DNA were designed to amplify a part of the CpG island in the 5HTT gene. Pyrosequencing was performed and the methylation level at seven CpG island sites was measured.
Results
We found no differences in the methylation patterns of the serotonin transporter linked promoter region (5-HTTLPR) between alcohol-dependent and control subjects.
Conclusion
Our negative finding may be because 5-HTT epigenetic variation may not affect the expression for 5-HTT or there may be other methylation site critical for its expression. To find out more conclusive result, repeating the study in more methylation sites with a larger number of samples in a well-controlled setting is needed.
doi:10.4306/pi.2011.8.2.130
PMCID: PMC3149107  PMID: 21852989
Serotonin transporter region (5-HTTLPR); Methylation; Alcohol dependence
2.  PI(3,4,5)P3 and PI(4,5)P2 Lipids Target Proteins with Polybasic Clusters to the Plasma Membrane 
Science (New York, N.Y.)  2006;314(5804):1458-1461.
Many signaling, cytoskeletal, and transport proteins have to be localized to the plasma membrane (PM) in order to carry out their function. We surveyed PM-targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein–conjugated Ras, Rab, Arf, and Rho proteins. Out of 48 proteins that were PM-localized, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipids, we developed a chemical phosphatase activation method to deplete PM PI(4,5)P2. Unexpectedly, proteins with polybasic clusters dissociated from the PM only when both PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] were depleted, arguing that both lipid second messengers jointly regulate PM targeting.
doi:10.1126/science.1134389
PMCID: PMC3579512  PMID: 17095657
3.  Mitochondrial DNA deletions and differential mitochondrial DNA content in Rhesus monkeys: implications for aging 
Biochimica et biophysica acta  2011;1822(2):111-119.
The purpose of this study was to determine the relationship between mitochondrial DNA (mtDNA) deletions, mtDNA content and aging in rhesus monkeys. Using 2 sets of specific primers, we amplified an 8 kb mtDNA fragment covering a common 5.7 kb deletion and the entire 16.5 kb mitochondrial genome in the brain and buffy-coats of young and aged monkeys. We studied a total of 66 DNA samples: 39 were prepared from a buffy-coat and 27 were prepared from occipital cortex tissues. The mtDNA data were assessed using a permutation test to identify differences in mtDNA, in the different monkey groups. Using real-time RT-PCR strategy, we also assessed both mtDNA and nuclear DNA levels for young, aged and male and female monkeys. We found a 5.7 kb mtDNA deletion in 81.8% (54 of 66) of the total tested samples. In the young group of buffy-coat DNA, we found 5.7 kb deletions in 7 of 17 (41%), and in the aged group, we found 5.7 kb deletions in 12 of 22 (54%), suggesting that the prevalence of mtDNA deletions is related to age. We found decreased mRNA levels of mtDNA in aged monkeys relative to young monkeys. The increases in mtDNA deletions and mtDNA levels in aged rhesus monkeys suggest that damaged DNA accumulates as rhesus monkeys age and these altered mtDNA changes may have physiological relevance to compensate decreased mitochondrial function.
doi:10.1016/j.bbadis.2011.10.014
PMCID: PMC3249524  PMID: 22056405
4.  Xaml1/Runx1 is required for the specification of Rohon-Beard sensory neurons in Xenopus 
Developmental Biology  2011;362(1):65-75.
Lower vertebrates develop a unique set of primary sensory neurons located in the dorsal spinal cord. These cells, known as Rohon-Beard (RB) sensory neurons, innervate the skin and mediate the response to touch during larval stages. Here we report the expression and function of the transcription factor Xaml1/Runx1 during RB sensory neurons formation. In Xenopus embryos Runx1 is specifically expressed in RB progenitors at the end of gastrulation. Runx1 expression is positively regulated by Fgf and canonical Wnt signaling and negatively regulated by Notch signaling, the same set of factors that control the development of other neural plate border cell types, i.e. the neural crest and cranial placodes. Embryos lacking Runx1 function fail to differentiate RB sensory neurons and lose the mechanosensory response to touch. At early stages Runx1 knockdown results in a RB progenitor-specific loss of expression of Pak3, a p21-activated kinase that promotes cell cycle withdrawal, and of N-tub, a neuronal-specific tubulin. Interestingly, the pro-neural gene Ngnr1, an upstream regulator of Pak3 and N-tub, is either unaffected or expanded in these embryos, suggesting the existence of two distinct regulatory pathways controlling sensory neuron formation in Xenopus. Consistent with this possibility Ngnr1 is not sufficient to activate Runx1 expression in the ectoderm. We propose that Runx1 function is critically required for the generation of RB sensory neurons, an activity reminiscent of that of Runx1 in the development of the mammalian dorsal root ganglion nociceptive sensory neurons.
doi:10.1016/j.ydbio.2011.11.016
PMCID: PMC3257842  PMID: 22173066
Rohon-Beard; Sensory neurons; Runx1; Ngnr1; N-Tub; Pak3; Xenopus
5.  Reliability on Intra-Laboratory and Inter-Laboratory Data of Hair Mineral Analysis Comparing with Blood Analysis 
Annals of Dermatology  2013;25(1):67-72.
Background
Nowadays, although its clinical value remains controversial institutions utilize hair mineral analysis. Arguments about the reliability of hair mineral analysis persist, and there have been evaluations of commercial laboratories performing hair mineral analysis.
Objective
The objective of this study was to assess the reliability of intra-laboratory and inter-laboratory data at three commercial laboratories conducting hair mineral analysis, compared to serum mineral analysis.
Methods
Two divided hair samples taken from near the scalp were submitted for analysis at the same time, to all laboratories, from one healthy volunteer. Each laboratory sent a report consisting of quantitative results and their interpretation of health implications. Differences among intra-laboratory and interlaboratory data were analyzed using SPSS version 12.0 (SPSS Inc., USA).
Results
All the laboratories used identical methods for quantitative analysis, and they generated consistent numerical results according to Friedman analysis of variance. However, the normal reference ranges of each laboratory varied. As such, each laboratory interpreted the patient's health differently. On intra-laboratory data, Wilcoxon analysis suggested they generated relatively coherent data, but laboratory B could not in one element, so its reliability was doubtful. In comparison with the blood test, laboratory C generated identical results, but not laboratory A and B.
Conclusion
Hair mineral analysis has its limitations, considering the reliability of inter and intra laboratory analysis comparing with blood analysis. As such, clinicians should be cautious when applying hair mineral analysis as an ancillary tool. Each laboratory included in this study requires continuous refinement from now on for inducing standardized normal reference levels.
doi:10.5021/ad.2013.25.1.67
PMCID: PMC3582931  PMID: 23467102
Blood minerals; Hair minerals; Minerals; Scalp hair
6.  Extramammary Paget's Disease of External Genitalia with Bowenoid Features 
Annals of Dermatology  2013;25(1):88-91.
Extramammary Paget's disease (EMPD) is an uncommon intraepithelial adenocarcinoma, primarily affecting the apocrine-bearing skin. Bowen disease is an intraepithelial squamous cell carcinoma having the potential to become invasive carcinoma. The histopathological concomitant features between EMPD and Bowen disease have been described. One theory is that primary EMPD arises multicentrically, within the epidermis from the pluripotent stem cells. Herein, we describe a case of EMPD that had bowenoid features, and review the previous cases associated with the origin of EMPD.
doi:10.5021/ad.2013.25.1.88
PMCID: PMC3582935  PMID: 23467383
Bowen's disease; Extramammary Paget's disease; Male genitalia
7.  Association Analysis Between FILIP1 Polymorphisms and Aspirin Hypersensitivity in Korean Asthmatics 
Purpose
Aspirin exacerbated respiratory disease (AERD) results in a severe asthma attack after aspirin ingestion in asthmatics. The filamin A interacting protein 1 (FILIP1) may play a crucial role in AERD pathogenesis by mediating T cell activation and membrane rearrangement. We investigated the association of FILIP1 variations with AERD and the fall rate of forced expiratory volume in one second (FEV1).
Methods
A total of 34 common FILIP1 single nucleotide polymorphisms (SNPs) were genotyped in 592 Korean asthmatic subjects that included 163 AERD patients and 429 aspirin-tolerant asthma (ATA) controls.
Results
This study found that 5 SNPs (P=0.006-0.01) and 2 haplotypes (P=0.01-0.03) of FILIP1 showed nominal signals; however, corrections for the multiple testing revealed no significant associations with the development of AERD (Pcorr>0.05). In addition, association analysis of the genetic variants with the fall rate of FEV1, an important diagnostic marker of AERD, revealed no significant evidence (Pcorr>0.05).
Conclusions
Although further replications and functional evaluations are needed, our preliminary findings suggest that genetic variants of FILIP1 might be not associated with the onset of AERD.
doi:10.4168/aair.2013.5.1.34
PMCID: PMC3529227  PMID: 23277876
Filamin A interacting protein 1; single nucleotide polymorphism; haplotype; asthma; aspirin exacerbated respiratory disease
8.  Diffusion-Weighted Magnetic Resonance Imaging for the Evaluation of Prostate Cancer: Optimal B Value at 3T 
Korean Journal of Radiology  2012;14(1):61-69.
Objective
To retrospectively determine the optimal b value of diffusion-weighted imaging (DWI) for predicting the presence of localized prostate cancer, and to evaluate the utility of DWI under different b values in differentiating between cancers and benign prostatic tissues.
Materials and Methods
Eighty patients with suspected prostate cancer underwent MRI including DWI at 3T, followed by radical prostatectomy. DWI was examined under different b values. Apparent diffusion coefficient (ADC) maps were generated by using b = 0, and other b values of 300, 700, 1000 or 2000 s/mm2. For predicting the presence of cancers, four different ADC maps were analyzed independently by two blinded readers. ADCs were measured in benign and malignant tissues.
Results
For predicting the presence of 110 prostate cancers, the sensitivity and area under the curve (AUC) for an experienced reader was significantly greater at b = 1000 (85% and 0.91) than b = 300, 700 or 2000 s/mm2 (p < 0.01). For a less-experienced reader, the AUC was significantly greater at b = 700, 1000 or 2000 than b = 300 s/mm2 (p < 0.01). Mean ADCs of the cancers in sequence from b = 300 to 2000 s/mm2 were 1.33, 1.03, 0.88 and 0.68 × 10-3 mm2/s, which were significantly lower than those of benign tissues (p < 0.001).
Conclusion
The optimal b value for 3T DWI for predicting the presence of prostate cancer may be 1000 s/mm2.
doi:10.3348/kjr.2013.14.1.61
PMCID: PMC3542304  PMID: 23323032
Diffusion-weighted MR imaging; Prostate neoplasm; Apparent diffusion coefficient; Diagnosis
9.  Extensive Intramuscular Venous Malformation in the Lower Extremity 
Annals of Rehabilitation Medicine  2012;36(6):893-896.
Typical venous malformations are easily diagnosed by skin color changes, focal edema or pain. Venous malformation in the skeletal muscles, however, has the potential to be missed because their involved sites are invisible and the disease is rare. In addition, the symptoms of intramuscular venous malformation overlaps with myofascial pain syndrome or muscle strain. Most venous malformation cases have reported a focal lesion involved in one or adjacent muscles. In contrast, we have experienced a case of intramuscular venous malformation that involved a large number of muscles in a lower extremity extensively.
doi:10.5535/arm.2012.36.6.893
PMCID: PMC3546197  PMID: 23342327
Intramuscular; Lower extremity; Venous malformation
10.  Loss of naïve T-cells and repertoire constriction predict poor response to vaccination in old primates1 
Aging is usually accompanied by diminished immune protection upon infection or vaccination. While aging results in well-characterized changes in the T-cell compartment of long-lived, outbred, and pathogen-exposed organisms, their relevance for primary antigen responses remain unclear. Therefore, it remains unclear whether and to what extent the loss of naïve T-cells, their partial replacement by oligoclonal memory populations, and the consequent constriction of T-cell receptor (TCR) repertoire, limit the antigen responses in aging primates.
doi:10.4049/jimmunol.0904193
PMCID: PMC3504654  PMID: 20483749
11.  Immunization with a Hemagglutinin-Derived Synthetic Peptide Formulated with a CpG-DNA-Liposome Complex Induced Protection against Lethal Influenza Virus Infection in Mice 
PLoS ONE  2012;7(11):e48750.
Whole-virus vaccines, including inactivated or live-attenuated influenza vaccines, have been conventionally developed and supported as a prophylaxis. These currently available virus-based influenza vaccines are widely used in the clinic, but the vaccine production takes a long time and a huge number of embryonated chicken eggs. To overcome the imperfection of egg-based influenza vaccines, epitope-based peptide vaccines have been studied as an alternative approach. Here, we formulated an efficacious peptide vaccine without carriers using phosphodiester CpG-DNA and a special liposome complex. Potential epitope peptides predicted from the hemagglutinin (HA) protein of the H5N1 A/Viet Nam/1203/2004 strain (NCBI database, AAW80717) were used to immunize mice along with phosphodiester CpG-DNA co-encapsulated in a phosphatidyl-β-oleoyl-γ-palmitoyl ethanolamine (DOPE):cholesterol hemisuccinate (CHEMS) complex (Lipoplex(O)) without carriers. We identified a B cell epitope peptide (hH5N1 HA233 epitope, 14 amino acids) that can potently induce epitope-specific antibodies. Furthermore, immunization with a complex of the B cell epitope and Lipoplex(O) completely protects mice challenged with a lethal dose of recombinant H5N1 virus. These results suggest that our improved peptide vaccine technology can be promptly applied to vaccine development against pandemic influenza. Furthermore our results suggest that potent epitopes, which cannot be easily found using proteins or a virus as an antigen, can be screened when we use a complex of peptide epitopes and Lipoplex(O).
doi:10.1371/journal.pone.0048750
PMCID: PMC3492448  PMID: 23144954
12.  Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection 
Memory CD4+ T cell homeostasis and AIDS progression are independent of naive CD4+ T cells in SIV infection of nonhuman primates.
The development of AIDS in chronic HIV/simian immunodeficiency virus (SIV) infection has been closely linked to progressive failure of CD4+ memory T cell (TM) homeostasis. CD4+ naive T cells (TN) also decline in these infections, but their contribution to disease progression is less clear. We assessed the role of CD4+ TN in SIV pathogenesis using rhesus macaques (RMs) selectively and permanently depleted of CD4+ TN before SIV infection. CD4+ TN-depleted and CD4+ TN-repleted RMs were created by subjecting juvenile RMs to thymectomy versus sham surgery, respectively, followed by total CD4+ T cell depletion and recovery from this depletion. Although thymectomized and sham-treated RMs manifested comparable CD4+ TM recovery, only sham-treated RMs reconstituted CD4+ TN. CD4+ TN-depleted RMs responded to SIVmac239 infection with markedly attenuated SIV-specific CD4+ T cell responses, delayed SIVenv-specific Ab responses, and reduced SIV-specific CD8+ T cell responses. However, CD4+ TN-depleted and -repleted groups showed similar levels of SIV replication. Moreover, CD4+ TN deficiency had no significant effect on CD4+ TM homeostasis (either on or off anti-retroviral therapy) or disease progression. These data demonstrate that the CD4+ TN compartment is dispensable for CD4+ TM homeostasis in progressive SIV infection, and they confirm that CD4+ TM comprise a homeostatically independent compartment that is intrinsically capable of self-renewal.
doi:10.1084/jem.20112071
PMCID: PMC3328373  PMID: 22451717
13.  Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques 
Age  2010;33(3):275-289.
Aging is associated with a general dysregulation in immune function, commonly referred to as “immune senescence”. Several studies have shown that female sex steroids can modulate the immune response. However, the impact of menopause-associated loss of estrogen and progestins on immune senescence remains poorly understood. To help answer this question, we examined the effect of ovariectomy on T-cell homeostasis and function in adult and aged female rhesus macaques. Our data show that in adult female rhesus macaques, ovariectomy increased the frequency of naïve CD4 T cells. In contrast, ovariectomized (ovx) aged female rhesus macaques had increased frequency of terminally differentiated CD4 effector memory T cells and inflammatory cytokine-secreting memory T cells. Moreover, ovariectomy reduced the immune response (T-cell cytokine and IgG production) following vaccination with modified vaccinia ankara in both adult and aged female rhesus macaques compared to ovary-intact age-matched controls. Interestingly, hormone therapy (estradiol alone or in conjunction with progesterone) partially improved the T-cell response to vaccination in aged ovariectomized female rhesus macaques. These data suggest that the loss of ovarian steroids, notably estradiol and progesterone, may contribute to reduced immune function in post-menopausal women and that hormone therapy may improve immune response to vaccination in this growing segment of the population.
doi:10.1007/s11357-010-9178-0
PMCID: PMC3168610  PMID: 20814751
Aging; Immune senescence; Ovariectomy; T cells; Vaccine; Estrogen; Progestin
14.  Radiobiological model-based bio-anatomical quality assurance in intensity-modulated radiation therapy for prostate cancer 
Journal of Radiation Research  2012;53(6):978-988.
A bio-anatomical quality assurance (QA) method employing tumor control probability (TCP) and normal tissue complication probability (NTCP) is described that can integrate radiobiological effects into intensity-modulated radiation therapy (IMRT). We evaluated the variations in the radiobiological effects caused by random errors (r-errors) and systematic errors (s-errors) by evaluating TCP and NTCP in two groups: patients with an intact prostate (Gintact) and those who have undergone prostatectomy (Gtectomy). The r-errors were generated using an isocenter shift of ±1 mm to simulate a misaligned patient set-up. The s-errors were generated using individual leaves that were displaced inwardly and outwardly by 1 mm on multileaf collimator field files. Subvolume-based TCP and NTCP were visualized on computed tomography (CT) images to determine the radiobiological effects on the principal structures. The bio-anatomical QA using the TCP and NTCP maps differentiated the critical radiobiological effects on specific volumes, particularly at the anterior rectal walls and planning target volumes. The s-errors showed a TCP variation of –40–25% in Gtectomy and –30–10% in Gintact, while the r-errors were less than 1.5% in both groups. The r-errors for the rectum and bladder showed higher NTCP variations at ±20% and ±10%, respectively, and the s-errors were greater than ±65% for both. This bio-anatomical method, as a patient-specific IMRT QA, can provide distinct indications of clinically significant radiobiological effects beyond the minimization of probable physical dose errors in phantoms.
doi:10.1093/jrr/rrs049
PMCID: PMC3483850  PMID: 22915778
Bio-anatomical quality assurance; tumor control probability; normal tissue complication probability; intensity-modulated radiation therapy; prostate cancer
15.  Risk Factors for Occurrence and 30-Day Mortality for Carbapenem-Resistant Acinetobacter baumannii Bacteremia in an Intensive Care Unit 
Journal of Korean Medical Science  2012;27(8):939-947.
To assess the risk factors for carbapenem-resistant Acinetobacter baumannii (CRAB) bacteremia and for 30-day mortality in patients with CRAB bacteremia in the intensive care unit (ICU), we conducted a retrospective study in the ICU at Severance Hospital in Korea from January 2008 to December 2009. Patients who acquired CRAB bacteremia in the ICU were enrolled as the case group and patients whose specimens of blood culture, sputum/endotracheal aspirate and urine revealed no AB were enrolled as controls. The case group comprised 106 patients and 205 patients were included as controls. Risk factors independently associated with CRAB bacteremia included prior chemotherapy or radiotherapy treatment (Odds ratio [OR], 3.6; P = 0.003), recent central venous catheter insertion (OR, 5.7; P < 0.001) or abdominal drainage insertion (OR, 21.9; P = 0.004), the number of antibiotics treated with (OR, 1.3; P = 0.016), and respiratory failure in the ICU (OR, 2.5; P = 0.035). The 30-day mortality was 79.8%. Renal failure during ICU stay was independently associated with 30-day mortality (OR, 3.7; P = 0.047). It is important to minimize invasive procedures, and to restrict excessive use of antibiotics, especially in immunocompromised patients, in order to prevent the development of CRAB bacteremia. Greater concern for CRAB bacteremia patients is needed when renal failure develops during ICU stay.
doi:10.3346/jkms.2012.27.8.939
PMCID: PMC3410244  PMID: 22876063
Drug Resistance, Multiple; Acinetobacter baumannii; Risk Factors; Mortality; Bacteremia; Intensive Care Units
16.  Utilization of evidence-based treatment in elderly patients with chronic heart failure: using Korean Health Insurance claims database 
Background
Chronic heart failure accounts for a great deal of the morbidity and mortality in the aging population. Evidence-based treatments include angiotensin-2 receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers, and aldosterone antagonists. Underutilization of these treatments in heart failure patients were frequently reported, which could lead to increase morbidity and mortality. The aim of this study was to evaluate the utilization of evidence-based treatments and their related factors for elderly patients with chronic heart failure.
Methods
This is retrospective observational study using the Korean National Health Insurance claims database. We identified prescription of evidence based treatment to elderly patients who had been hospitalized for chronic heart failure between January 1, 2005, and June 30, 2006.
Results
Among the 28,922 elderly patients with chronic heart failure, beta-blockers were prescribed to 31.5%, and ACE-I or ARBs were prescribed to 54.7% of the total population. Multivariable logistic regression analyses revealed that the prescription from outpatient clinic (prevalent ratio, 4.02, 95% CI 3.31–4.72), specialty of the healthcare providers (prevalent ratio, 1.26, 95% CI, 1.12–1.54), residence in urban (prevalent ratio, 1.37, 95% CI, 1.23–1.52) and admission to tertiary hospital (prevalent ratio, 2.07, 95% CI, 1.85–2.31) were important factors associated with treatment underutilization. Patients not given evidence-based treatment were more likely to experience dementia, reside in rural areas, and have less-specialized healthcare providers and were less likely to have coexisting cardiovascular diseases or concomitant medications than patients in the evidence-based treatment group.
Conclusions
Healthcare system factors, such as hospital type, healthcare provider factors, such as specialty, and patient factors, such as comorbid cardiovascular disease, systemic disease with concomitant medications, together influence the underutilization of evidence-based pharmacologic treatment for patients with heart failure.
doi:10.1186/1471-2261-12-60
PMCID: PMC3468388  PMID: 22849621
Congestive heart failure; Drug utilization evaluation; Elderly; Type 2 angiotensin receptor antagonists; Angiotensin-converting enzyme antagonists; Beta-adrenergic blockers
17.  Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease 
Archives of Neurology  2010;67(1):27-32.
Background
Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood.
Objective
To examine the effects of a dopamine agonist on the motor response to levodopa.
Design
Double-blind, randomized, placebo-controlled, crossover clinical trial.
Setting
Ambulatory academic referral center.
Patients
Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia.
Interventions
Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment.
Main Outcome Measures
Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to “ON” (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC.
Results
Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute×minutes (P=.006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P=.02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion.
Conclusions
Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.
Trial Registration
clinicaltrials.gov Identifier: NCT00666653
doi:10.1001/archneurol.2009.287
PMCID: PMC3390306  PMID: 20065126
18.  WDR46 is a Genetic Risk Factor for Aspirin-Exacerbated Respiratory Disease in a Korean Population 
Purpose
The human WD repeat-containing protein 46 (WDR46; also known as C6orf11), located at the disease-relevant centromere side of the class II major histocompatibility complex region, is hypothesized to be associated with risk of aspirin-exacerbated respiratory disease (AERD) as well as a decline in forced expiratory volume in the first second (FEV1), an important diagnostic marker of asthma.
Methods
To investigate the association between WDR46 and AERD, five single-nucleotide polymorphisms (SNPs) were genotyped in 93 AERD cases and 96 aspirin-tolerant asthma controls of Korean ethnicity. Three major haplotypes were inferred from pairwise comparison of the SNPs, and one was included in the association analysis. Differences in the frequency distribution of WDR46 SNPs and haplotype were analyzed using logistic and regression models via various modes of genetic inheritance.
Results
Depending on the genetic model, the logistic and regression analyses revealed significant associations between rs463260, rs446735, rs455567, rs469064, and WDR46_ht2 and the risk of AERD (P=0.007-0.04, Pcorr=0.01-0.04) and FEV1 decline after aspirin provocation (P=0.006-0.03, Pcorr=0.01-0.03). Furthermore, functional analysis in silico showed that the G>A allele of rs463260 located in the 5' untranslated region potentially matched a nucleotide sequence within an upstream open reading frame of WDR46.
Conclusions
These findings show for the first time that WDR46 is an important genetic marker of aspirin-induced airway inflammation and may be useful for formulating new disease-management strategies.
doi:10.4168/aair.2012.4.4.199
PMCID: PMC3378926  PMID: 22754713
Aspirin exacerbated respiratory disease; WDR46; FEV1; haplotype; single-nucleotide polymorphism
19.  Prevalence Rate and Associated Factors of Sarcopenic Obesity in Korean Elderly Population 
Journal of Korean Medical Science  2012;27(7):748-755.
This study was conducted to estimate the prevalence rates and to explore associated factors of sarcopenic obesity (SO) in 2,221 Koreans over 60 yr-of age from the Fourth Korea National Health and Nutrition Examination Survey (2009). Participants were assessed by dual energy X-ray absorptiometry. Appendicular skeletal muscle mass divided by body weight was used to define sarcopenia and waist circumference was used to define obesity. We estimated the prevalence rates of SO according to age-groups, sex and region. In addition, each group was compared by demographic characteristics, metabolic status, nutrition, and physical activity. The prevalence rates of SO were 6.1% (95% confidential interval [CI] = 6.1-6.2) for men and 7.3% (95% CI = 7.3-7.3) for women, respectively. SO was positively associated with no current working and the number of combined medical conditions. High serum insulin level was positively associated with SO, whereas vitamin D was negatively associated with SO in both men and women. In conclusion, the prevalence rates of SO are 6.1% in men and 7.3% in women. SO is associated with insulin resistance, inappropriate nutrition, and low physical activity.
doi:10.3346/jkms.2012.27.7.748
PMCID: PMC3390722  PMID: 22787369
Sarcopenia; Obesity; Aging; Prevalence; Epidemiology
20.  Zolpidem Use and Risk of Fracture in Elderly Insomnia Patients 
Objectives
To evaluate the risk of fractures related with zolpidem in elderly insomnia patients.
Methods
Health claims data on the entire South Korean elderly population from January 2005 to June 2006 were extracted from the Health Insurance Review and Assessment Service database. We applied a case-crossover design. Cases were defined as insomnia patients who had a fracture diagnosis. We set the hazard period of 1 day length prior to the fracture date and four control periods of the same length at 5, 10, 15, and 20 weeks prior to the fracture date. Time independent confounding factors such as age, gender, lifestyle, cognitive function level, mobility, socioeconomic status, residential environment, and comorbidity could be controlled using the casecrossover design. Time dependent confounding factors, especially co-medication of patients during the study period, were adjusted by conditional logistic regression analysis. The odds ratios and their 95% confidence intervals (CIs) were estimated for the risk of fracture related to zolpidem.
Results
One thousand five hundred and eight cases of fracture were detected in insomnia patients during the study period. In our data, the use of zolpidem increased the risk of fracture significantly (adjusted odds ratio [aOR], 1.72; 95% CI, 1.37 to 2.16). However, the association between benzodiazepine hypnotics and the risk of fracture was not statistically significant (aOR, 1.00; 95% CI, 0.83 to 1.21). Likewise, the results were not statistically significant in stratified analysis with each benzodiazepine generic subgroup.
Conclusions
Zolpidem could increase the risk of fracture in elderly insomnia patients. Therefore zolpidem should be prescribed carefully and the elderly should be provided with sufficient patient education.
doi:10.3961/jpmph.2012.45.4.219
PMCID: PMC3412984  PMID: 22880153
Zolpidem; Bone fractures; Case-crossover design; Aged; Hypnotic; Sleep initiation and maintenance disorders
21.  Korean Brain Rehabilitation Registry for Rehabilitation of Persons with Brain Disorders: Annual Report in 2009 
Journal of Korean Medical Science  2012;27(6):691-696.
This first annual report provides a description of patients discharged from rehabilitation facilities in Korea based on secondary data analysis of Korean Brain Rehabilitation Registry V1.0 subscribed in 2009. The analysis included 1,697 records of patients with brain disorders including stroke, traumatic brain injury, brain tumor and other disorders from 24 rehabilitation facilities across Korea. The data comprised 1,380 cases of stroke, 104 cases of brain injury, 55 cases of brain tumor, and 58 cases of other brain diseases. The functional status of each patient was measured using the Korean version of the Modified Barthel Index (KMBI). The average change in the KMBI score was 15.9 for all patients in the inpatient rehabilitation facility. The average length of stay for inpatient rehabilitation was 36.9 days. The transfer rates to other hospitals were high, being 62.4% when all patients were considered. Patients with brain disorders of Korea in 2009 and measurable functional improvement was observed in patients. However, relatively high percentages of patients were not discharged to the community after inpatient rehabilitation. Based on the results of this study, consecutive reports of the status of rehabilitation need to be conducted in order to provide useful information to many practitioners.
doi:10.3346/jkms.2012.27.6.691
PMCID: PMC3369458  PMID: 22690103
Registries; Rehabilitation; Korea; Brain
22.  Yoga Training Improves Metabolic Parameters in Obese Boys 
Yoga has been known to have stimulatory or inhibitory effects on the metabolic parameters and to be uncomplicated therapy for obesity. The purpose of the present study was to test the effect of an 8-week of yoga-asana training on body composition, lipid profile, and insulin resistance (IR) in obese adolescent boys. Twenty volunteers with body mass index (BMI) greater than the 95th percentile were randomly assigned to yoga (age 14.7±0.5 years, n=10) and control groups (age 14.6±1.0 years, n=10). The yoga group performed exercises three times per week at 40~60% of heart-rate reserve (HRR) for 8 weeks. IR was determined with the homeostasis model assessment of insulin resistance (HOMA-IR). After yoga training, body weight, BMI, fat mass (FM), and body fat % (BF %) were significantly decreased, and fat-free mass and basal metabolic rate were significantly increased than baseline values. FM and BF % were significantly improved in the yoga group compared with the control group (p<0.05). Total cholesterol (TC) was significantly decreased in the yoga group (p<0.01). HDL-cholesterol was decreased in both groups (p<0.05). No significant changes were observed between or within groups for triglycerides, LDL-cholesterol, glucose, insulin, and HOMA-IR. Our findings show that an 8-week of yoga training improves body composition and TC levels in obese adolescent boys, suggesting that yoga training may be effective in controlling some metabolic syndrome factors in obese adolescent boys.
doi:10.4196/kjpp.2012.16.3.175
PMCID: PMC3394919  PMID: 22802698
Yoga (asana); Obesity; Body composition; Lipid profile; HOMA-IR
23.  Independent beneficial effects of aged garlic extract intake with regular exercise on cardiovascular risk in postmenopausal women 
Nutrition Research and Practice  2012;6(3):226-231.
The purpose of the study was to assess the effects of a 12 weeks aged garlic extract (AGE) regimen with regular exercise on cardiovascular disease (CVD) risk in postmenopausal women. A total of 30 postmenopausal women (54.4 ± 5.4 years) were randomly divided into the following four groups: Placebo (Placebo; n = 6), AGE intake (AGEI; n = 8), exercise and placebo (Ex + Placebo; n = 8), exercise and AGE (Ex + AGE; n = 8) groups. The AGE group consume 80 mg per day, and exercise groups performed moderate exercise (aerobic and resistance) three times per week. After 12 weeks of treatment, body composition, lipid profile, and CVD risk factors were analyzed. Body weight was significantly decreased in AGEI, Ex + Placebo, and Ex + AGE groups compared to baseline. Body fat % was significantly decreased in the AGEI and Ex + Placebo groups. Body mass index (BMI) was significantly decreased in the AGEI, Ex + Placebo, and Ex + AGE groups. Fat-free mass was significantly decreased in the AGEI group. Total cholesterol (TC) was significantly lower in the Ex + Placebo compared to the Placebo group. AGE supplementation or exercise effectively reduced low-density lipoprotein (LDL-C). Triglyceride (TG) was significantly increased in the AGEI group. Malondialdehyde (MDA) levels were significantly decreased in the AGEI, Ex + Placebo, and Ex + AGE compared to the placebo group. AGE supplementation reduced homocysteine levels regardless of whether the women also exercised. The present results suggest that AGE supplementation reduces cardiovascular risk factors independently of exercise in postmenopausal women.
doi:10.4162/nrp.2012.6.3.226
PMCID: PMC3395788  PMID: 22808347
Aged garlic extract; exercise; postmenopausal women; cardiovascular risk factor; homocysteine
24.  Analyzing large biological datasets with association networks 
Nucleic Acids Research  2012;40(17):e131.
Due to advances in high-throughput biotechnologies biological information is being collected in databases at an amazing rate, requiring novel computational approaches that process collected data into new knowledge in a timely manner. In this study, we propose a computational framework for discovering modular structure, relationships and regularities in complex data. The framework utilizes a semantic-preserving vocabulary to convert records of biological annotations of an object, such as an organism, gene, chemical or sequence, into networks (Anets) of the associated annotations. An association between a pair of annotations in an Anet is determined by the similarity of their co-occurrence pattern with all other annotations in the data. This feature captures associations between annotations that do not necessarily co-occur with each other and facilitates discovery of the most significant relationships in the collected data through clustering and visualization of the Anet. To demonstrate this approach, we applied the framework to the analysis of metadata from the Genomes OnLine Database and produced a biological map of sequenced prokaryotic organisms with three major clusters of metadata that represent pathogens, environmental isolates and plant symbionts.
doi:10.1093/nar/gks403
PMCID: PMC3458522  PMID: 22638576
25.  Long-Term Effects of Neonatal Methamphetamine Exposure on Cognitive Function in Adolescent Mice 
Behavioural brain research  2011;219(1):159-164.
Exposure to methamphetamine during brain development impairs cognition in children and adult rodents. In mice, these impairments are greater in females than males. Adult female, but not male, mice show impairments in novel location recognition following methamphetamine exposure during brain development. In contrast to adulthood, little is known about the potential effects of methamphetamine exposure on cognition in adolescent mice. As adolescence is an important time of development and is relatively understudied, the aim of the current study was to examine potential long-term effects of neonatal methamphetamine exposure on behavior and cognition during adolescence. Male and female mice were exposed to methamphetamine (5 mg/kg) or saline once a day from postnatal day 11-20, the period of rodent hippocampal development. Behavioral and cognitive function was assessed during adolescence beginning on postnatal day 30. During the injection period, methamphetamine-exposed mice gained less weight on average compared to saline-exposed mice. In both male and female mice, methamphetamine exposure significantly impaired novel object recognition and there was a trend towards impaired novel location recognition. Anxiety-like behavior, sensorimotor gating, and contextual and cued fear conditioning were not affected by methamphetamine exposure. Thus, neonatal methamphetamine exposure affects cognition in adolescence and unlike in adulthood equally affects male and female mice.
doi:10.1016/j.bbr.2011.01.015
PMCID: PMC3062671  PMID: 21238498
Methamphetamine; cognition; adolescence; hippocampus; postnatal

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