Hereditary Spastic Paraplegia in Koreans: Clinical Characteristics and Factors Influencing the Disease Severity

Background@#and Purpose Hereditary spastic paraplegia (HSP) progresses over time and is associated with locomotive dysfunction. Understanding the factors affecting disease severity and locomotive function is important in HSP. This study investigated the factors influencing disease severity and ambulation status of HSP. @*Methods@#We consecutively enrolled 109 Korean patients (64 males, and 45 females)from 84 families with a clinical diagnosis of HSP. HSP was primarily diagnosed based on clinical criteria including clinical findings, family history, and supported by genetic studies. Epidemiological and clinical features of the patients were analyzed, and the Spastic Paraplegia Rating Scale (SPRS) score and ambulatory status were used to evaluate disease severity. @*Results@#Ninety-two (84.4%) patients had pure HSP, and 55 (50.4%) had a dominant family history. Thirty-one (28.4%) patients required a mobility aid for locomotion. A Kaplan-Meier analysis showed that HSP patients lost their independent gait ability after a median disease duration of 34 years. Those with an age at onset of ≤18 years had a longer median independent walking time. Pure HSP is characterized by predominant bilateral lower extremity weakness and spasticity, whereas complicated HSP presents more complex neurological findings such as ocular and bulbar symptoms, ataxia, and cognitive impairment. Complicated HSP was significantly correlated with the SPRS mobility score (β=3.70, 95% confidence interval=0.45–6.94). The age at onset and disease duration were significantly correlated with disease severity, and they were significant predictors of the use of a mobility aid (p<0.05). @*Conclusions@#These findings suggest that a later age at onset and longer disease duration are significant factors affecting the disease severity and ambulatory function in patients with HSP. These findings can help clinicians to identify subjects at risk of locomotive impairment.

Altered Gene Expression Profiles in Neural Stem Cells Derived from Duchenne Muscular Dystrophy Patients with Intellectual Disability

Intellectual disability (ID) is a neurodevelopmental disorder defined by below-average intelligence (intelligence quotient of <70) accompanied by adaptive behavior deficits. Defects in the functions of neural stem cells during brain development are closely linked to the pathogenesis of ID. To understand the molecular etiology of ID, we examined neural stem cells from individuals with Duchenne muscular dystrophy (DMD), a genetic disorder in which approximately one-third of the patients exhibit ID. In this study, we generated induced pluripotent stem cells from peripheral blood mononuclear cells from a normal individual and DMD patients with and without ID to identify ID-specific functional and molecular abnormalities. We found defects in neural ectoderm formation in the group of DMD patients with ID. Our transcriptome analysis of patient-derived neural stem cells revealed altered expression of genes related to the hippo signaling pathway and neuroactive ligand-receptor interaction, implicating these in the pathogenesis of ID in patients with DMD.

Altered Gene Expression Profiles in Neural Stem Cells Derived from Duchenne Muscular Dystrophy Patients with Intellectual Disability

Intellectual disability (ID) is a neurodevelopmental disorder defined by below-average intelligence (intelligence quotient of <70) accompanied by adaptive behavior deficits. Defects in the functions of neural stem cells during brain development are closely linked to the pathogenesis of ID. To understand the molecular etiology of ID, we examined neural stem cells from individuals with Duchenne muscular dystrophy (DMD), a genetic disorder in which approximately one-third of the patients exhibit ID. In this study, we generated induced pluripotent stem cells from peripheral blood mononuclear cells from a normal individual and DMD patients with and without ID to identify ID-specific functional and molecular abnormalities. We found defects in neural ectoderm formation in the group of DMD patients with ID. Our transcriptome analysis of patient-derived neural stem cells revealed altered expression of genes related to the hippo signaling pathway and neuroactive ligand-receptor interaction, implicating these in the pathogenesis of ID in patients with DMD.

Methodology of revision of Korean national cancer screening guideline

The National Cancer Screening Program (NCSP) was established to provide cancer screening services for low-income Medicaid recipients in 1999. Since then, the NCSP has expanded its target population to include National Health Insurance beneficiaries. Currently, the program targets the five most common types of cancer in Korea: stomach, liver, colorectal, breast, and cervical cancer. The National Cancer Center has been involved in developing and revising the practice guidelines for the NCSP in collaboration with the Ministry of Health and Welfare and related academic societies. The main methodological principles of development were determined as follows: an evidence-based approach to the development of recommendations on cancer screening was used, that the recommendation could be drawn by an adaptation process if evidence-based current reliable clinical practice guidelines were available, and that the level of evidence was assessed by methodologies. The process of recommendation development was divided into planning, development, and finalization steps. Planning tasks consisted of selection of clinical practice guideline topics, organization of a clinical practice guideline development group, reviewing the existing clinical practice guidelines, establishment of development plans, and definition of key questions. Development tasks consisted of steps including searching the literature evidence base, assessment of the quality of evidence, integration of evidence, and formulation of recommendations and deciding on the recommendation grade. The finalization tasks included external review, up-dating of the plan, and publication of the clinical practice guidelines.

The Korean guideline for breast cancer screening

Breast cancer is the second most common malignancy among Korean women. The 2002 National Cancer Center screening guideline breast cancer was revised via an evidence-based approach to provide medical personnel with a standard protocol of screening breast cancer. There is moderate-level evidence that biennial screening mammography in asymptomatic women aged 40 to 69 reduces breast cancer mortality, while low-level evidence suggests that screening mammography in women 70 years or older does not reduce breast cancer mortality. The committee concluded that the current evidence is insufficient to assess the benefits and harms of either ultrasonography or clinical breast examination as screening modalities for breast cancer. Future researches about the benefits and harms of the National Breast Cancer Screening Program in Korea are strongly required because the characteristics of breast cancer in Korea are different from those in the West, especially regarding dense breast. In conclusion, the committee recommends biennial screening mammography in asymptomatic women aged 40 to 69 years (grade B recommendation). The committee recommends selective screening mammography in women 70 years or older according to individual risk and preference (grade C recommendation). The committee neither recommends nor opposes ultrasonography and clinical breast examination as screening modalities (grade I recommendation). Symptomatic and high-risk women, however, should be offered complementary measures including ultrasonography and clinical breast examination under clinical supervision.

Assessment of the Quality of Clinical Practice Guidelines in Korea Using the AGREE Instrument

The objective of this study was to conduct the systematic evaluation of methodological quality of clinical practice guidelines (CPGs) in Korea. The authors conducted a very comprehensive literature search to identify potential CPGs for evaluation. CPGs were selected which were consistent with a predetermined criteria. Four reviewers evaluated the quality of the CPGs using the Appraisal of Guidelines, Research and Evaluation (AGREE) Instrument. AGREE item scores and standardized domain scores were calculated. The inter-rater reliability of each domain was evaluated using the intra-class correlation coefficient (ICC). Consequently, 66 CPGs were selected and their quality evaluated. ICCs for CPG appraisal using the AGREE Instrument ranged from 0.626 to 0.877. Except for the "Scope and Purpose" and "Clarity and Presentation domains", 80% of CPGs scored less than 40 in all other domains. This review shows that many Korean research groups and academic societies have made considerable efforts to develop CPGs, and the number of CPGs has increased over time. However, the quality of CPGs in Korea were not good according to the AGREE Instrument evaluation. Therefore, we should make more of an effort to ensure the high quality of CPGs.

Factors associated with diabetes outpatient use of tertiary or general hospitals as their usual source of care in Korea

Deterioration in the health care delivery system has been a growing problem in Korea. The concentration of mild patients with chronic disease in tertiary care centers or general hospitals other than in clinics results in the distortion of functional differentiation among various types of providers. This brings about not a coordination of care through well-organized a referral system but an undesirable competition between clinics and hospitals. In this study, we used a multivariate binary logistic model to estimate the factors associated with the diabetes outpatients' choice of tertiary care centers (TCCs) or general hospitals as their usual source of care. Data were collected from the 2008 Korean Health Panel. The unit of analysis was a diabetes outpatient (n=910). Our study results showed that 56% of all of the diabetes outpatients studied only used clinics for their care during the year of 2008 followed by general hospitals (16%), mixed (12%), TCCs (10%) and hospitals (6%). Among the various types of providers, TCC or general hospital users had the highest out-of-pocket payments per visit, but the lowest number of visits, tests, and prescriptions during the year of 2008. According to our regression analysis, patients with higher education, income, and Charlson Comorbidity Index levels were more likely to use TCCs or general hospitals. Compared with patients who enrolled in the National Health Insurance program, Medical Aid program enrollees were more likely to visit TCCs or general hospitals. In addition, being enrolled in private health insurance or having any disability was also positively associated with the greater use of TCCs or general hospitals. Our findings suggest that policy-makers should take into consideration the characteristics of patients in implementing policies related to the healthcare delivery system. It is also necessary to employ diverse approaches, such as regulation and incentives considering patent characteristics to reform the current defective aspects of health care utilization and provision.

Association Between Prophylactic Antibiotic Use and Surgical Site Infection Based on Quality Assessment Data in Korea / 예방의학회지

OBJECTIVES: To examine the prophylactic antibiotic use in reducing surgical site infection. METHODS: This was a retrospective study for patients aged 18 years and older who underwent gastrectomy, cholecystectomy, colectomy, cesarean section and hysterectomy. The data source was quality assessment data of the Health Insurance Review & Assessment Service gathered from medical records of 302 national hospitals. Prophylactic antibiotic use was defined as: timely antibiotic administration or inappropriate antibiotic selection. We performed hierarchical logistic regression to examine the association between prophylactic antibiotic use and surgical site infection with adjustment for covariates. RESULTS: The study population consisted of 16 348 patients (1588 gastrectomies, 2327 cholecystectomies, 1,384 colectomies, 3977 hysterectomies and 7072 cesarean sections) and surgical site infection was identified in 351 (2.1%) patients. The rates of timely antibiotic administration and inappropriate antibiotic selection varied according to procedures. Cholecystectomy patients who received timely prophylactic antibiotic had a significantly reduced risk of surgical site infection compared with those who did not receive a timely prophylactic antibiotics (OR 0.64, 95% CI=0.50-0.83), but no significant reduction was observed for other procedures. When inappropriate prophylactic antibiotics were given, the risk of surgical site infection significantly increased: 8.26-fold (95% CI=4.34-15.7) for gastrectomy, 4.73-fold (95% CI=2.09-10.7) for colectomy, 2.34-fold (95% CI=1.14-4.80) for cesarean section, 4.03-fold (95% CI=1.93-8.42) for hysterectomy. CONCLUSIONS: This study examines the association among timely antibiotic administration, inappropriate antibiotic selection and surgical site infection. Patients who received timely and appropriate antibiotics had a decreased risk of surgical site infection. Efforts to improve the timing of antibiotic administration and use of appropriate antibiotic are needed to lower the risk of surgical site infection.

Expression Profiling of Calcium Induced Genes in Cultured Human Keratinocytes

Terminal differentiation of skin keratinocytes is a vertically directed multi-step process that is tightly controlled by the sequential expression of a variety of genes. To examine the gene expression profile in calcium-induced keratinocyte differentiation, we constructed a normalized cDNA library using mRNA isolated from these calcium-treated keratinocytes. After sequencing about 10,000 clones, we were able to obtain 4,104 independent genes. They consisted of 3,699 annotated genes and 405 expressed sequence tags (ESTs). Some were the genes involved in constituting epidermal structures and others were unknown genes that are probably associated with keratinocytes. In particular, we were able to identify genes located at the chromosome 1q21, the locus for the epidermal differentiation complex, and 19q13.1, another probable locus for epidermal differentiation-related gene clusters. One EST located at the chromosome 19q13.1 showed increased expression by calcium treatment, suggesting a novel candidate gene relevant to keratinocyte differentiation. These results demonstrate the complexity of the transcriptional profile of keratinocytes, providing important clues on which to base further investigations of the molecular events underlying keratinocyte differentiation.

Regulation of glucose metabolism-related genes and VEGF by HIF-1alpha and HIF-1beta, but not HIF-2alpha, in gastric cancer

Hypoxia-inducible factors (HIFs) are transcription factors that activate the transcription of target genes involved in crucial aspects of cancer development. This study investigated the expression of HIFs and their contribution to the regulation of target genes related to angiogenesis and glucose metabolism in gastric cancer. The data showed that HIFs were over-expressed in gastric cancer and that activation of the target genes was observed mainly in the early stages. Moreover, the results of the present study revealed that only HIF-1alpha, but not HIF-2alpha dimerizes with HIF-1beta and then regulates expression of target genes in response to hypoxia. The results of the present study demonstrate that HIF-1alpha and HIF-1beta enhances expression of VEGF and glucose metabolism-related genes in response to hypoxia in gastric cancer. These data offer important information regarding HIF pathways in the development of gastric cancer.

The Expression of Estrogen Receptors in Hepatocellular Carcinoma in Korean Patients

Expression of estrogen receptors (ER)-alpha and -beta, as well as androgen receptor (AR), in hepatocellular carcinoma (HCC) is thought to be correlated with prognosis, survival, and male prevalence of HCC. These hypotheses are based on investigations of European patients; however the expression patterns of these receptors in Asian patients are largely unknown. In this study, we collected liver carcinoma and peritumor tissues from 32 patients (9 females and 23 males) in South Korea. The expression of ERs and ARs was studied using RT-PCR. Wild-type ER-alpha and AR were expressed in all of the samples investigated, and their expression was independent of the causal virus or patient sex. Expression of the ER-alpha variant was independent of sex (100% female vs. 91.3% male) and HCV and HBV status (91.3% vs. 100%). Wild-type ER-beta was expressed more often in HCV patients than in HBV patients (95.7% vs. 44.4%; p < 0.05). In conclusion, the stronger ER-alpha variant expression in HCC tissues implies that this variant has an important role in HCC development. However, at least in Korean patients, expression of the ER-alpha variant (vER-alpha) is not related to male HCC prevalence. In addition, the predominant expression of ER-beta in HCV patients suggests that it plays an important role in HCV-induced liver disease.

Expression of the RERG Gene is Gender-Dependent in Hepatocellular Carcinoma and Regulated by Histone Deacetyltransferases

Ras-related, estrogen-regulated, and growth-inhibitory gene (RERG) is a novel gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types. In this study, RERG expression was analyzed in hepatocellular carcinomas of human patients using reverse transcriptase PCR analysis. In addition, the possible regulation of RERG expression by histone deacetyltransferases (HDACs) was studied in several cell lines. Interestingly, the expression of RERG gene was increased in hepatocellular carcinoma (HCC) of male patients (57.9%) but decreased in HCC of females (87.5%) comparison with paired peri-tumoral tissues. Moreover, RERG gene expression was increased in murine hepatoma Hepa1-6 cells, human breast tumor MDA-MB-231 cells, and mouse normal fibroblast NIH3T3 cells after treated by HDAC inhibitor, trichostatin A. Our results suggest that RERG may function in a gender-dependent manner in hepatic tumorigenesis and that the expression of this gene may be regulated by an HDAC-related signaling pathway.

Identification of Novel Genes with Proapoptotic Activity

In order to identify novel proapoptotic genes, we screened approximately 1,000 hypothetical genes whose functions are completely unknown. After these genes were transiently expressed in HeLa cells, their nuclei images were captured using automated high-speed fluorescence microscope, through which the ratio of apoptotic nuclei was estimated. We selected genes that induce greater than 3-fold increase in apoptotic nuclei compared to that of the vector control. The candidate proapoptotic genes were sequenced and their effects on cell death were further confirmed by the additional assay, DNA fragmentation ELISA. Finally, we were able to identify 4 full-length hypo-thetical genes with proapoptotic activity.

Evaluation of Consistency, Generalizability, Applicability of Recommendations about Pharmacological Treatment of Osterarthritis using RAND Method

BACKGROUND: When research based evidence is not sufficient, clinical practice guidelines can be based on opinions. In such situations, formal consensus development methods, often based on the modified nominal group techniques are widely used. It can be used to evaluate consistency, generalizability, applicability of recommendation when evidence comes from other countries. METHODS: To develop evidence based guidelines for osterarthritis pharmacotherapy, a consensus expert panel consisting of internists, family physicians, methodologists, and orthopedic surgeons were convened. After an extensive structured literature searching and evaluation, evidence statements for key question were developed. Rating methods for consistency, generalizability, applicability of statement were adopted from those jointly developed by Rand and the University of California, Los Angeles. RESULTS: We developed 27 evidence statements in 17 question domains. Among 72 rating items, 62 items reached agreement. Among 15 recommendations, 10 recommendation grading were A, 2 were B, and 3 were C. CONCLUSION: When research based evidence is not sufficient, clinical practice guidelines can be based on formal consensus of experts, especially modified nominal group techniques. It can be used to evaluate consistency, generalizability, applicability of recommendation when evidence comes from other countries.

Gene Expression Analysis of Cultured Amniotic Fluid Cell with Down Syndrome by DNA Microarray

Complete or partial triplication of human chromosome 21 results in Down syndrome (DS). To analyze differential gene expressions in amniotic fluid (AF) cells of DS, we used a DNA microarray system to analyze 102 genes, which included 24 genes on chromosome 21, 28 genes related to the function of brain and muscle, 36 genes related to apoptosis, 4 genes related to extracellular matrix, 8 genes related to other molecular function and 2 house-keeping genes. AF cells were collected from 12 pregnancies at 16-18 weeks of gestation in DS (n=6) and normal (n=6) subjects. Our DNA microarray experiments showed that the expressions of 11 genes were altered by at least 2-folds in DS, as follows. Ten genes, COL6A1, CASP5, AKT2, JUN, PYGM, BNIP1, OSF-2, PRSS7, COL3A1, and MBLL were down-regulated and GSTT1 was only up-regulated. The differential expressions of GSTT1 and COL3A1 were further confirmed by semi-quantitative RT-PCR for each sample. The gene dosage hypothesis on chromosome 21 may explain the neurological and other symptoms of DS. However, our results showed that only two genes (COL6A1 and PRSS7), among 24 genes on chromosome 21, were down-regulated in the AF cells of DS. Our data may provide the basis for a more systematic identification of biological markers of fetal DS, thus leading to an improved understanding of pathogenesis for fetal DS.

KBUD: The Korea Brain UniGene Database

Human brain EST data provide important clues for our understanding of the molecular biology associated with the function of the normal brain and the molecular pathophysiology with brain disorders. To systematically and efficiently study the function and disorders of the human brain, 45,773 human brain ESTs were collected from 27 human brain cDNA libraries, which were constructed from normal brains and brain disorders such as brain tumors, Parkinson's disease (PD) and epilepsy. An analysis of 45,773 human brain ESTs using our EST analysis pipeline resulted in 38,396 high-quality ESTs and 35,906 ESTs, which were coalesced into 8,246 unique gene clusters, showing a significant similarity to known genes in the human RefSeq, human mRNAs and UniGene database. In addition, among 8,246 gene clusters, 4,287 genes (52%) were found to contain full-length cDNA clones. To facilitate the extraction of useful information in collected these human brain ESTs, we developed a user-friendly interface system, the Korea Brain Unigene Database (KBUD). The KBUD web interface allows access to our human brain data through three major search modes, the BioCarta pathway, keywords and BLAST searches. Each result when viewed in KBUD offers comprehensive information concerning the analyzed human brain ESTs provided by our data as well as data linked to various other public databases. The user-friendly developed KBUD, the first world-wide web interface for human brain EST data with ESTs of human brain disorders as well as normal brains, will be a helpful system for developing a better understanding of the underlying mechanisms of the normal brain well as brain disorders. The KBUD system is freely accessible at http://kugi.kribb.re.kr/KU/cgi-bin/brain.pl.

Understanding the Culture of Antibiotics Prescribing of Primary Physicians for Acute Upper Respiratory Infection

BACKGROUND: To understand why primary physicians prescribe antibiotics for some cases of acute upper respiratory infections and to explore the factors that influence their prescribing. METHODS: Qualitative analysis of semi-structured interviews. Participants were 12 primary physicians in the maximum variety sample. RESULTS: Interviewees were identified the problems of antibiotics abuse and misuse in Korea. Primary physicians were certain that patients will benefit from antibiotics and prescribe for the patients' expectation of fast relief. Doctors are mostly comfortable with their prescribing decisions by their clinical experiences. They are also more likely to prescribe antibiotics in pressures of time and in competitive clinical environment. CONCLUSION: Multiple factors are involved in primary physicians' decision of their prescribing for acute upper respiratory infections. Further interventions to reduces prescribing would need to improve identification of patients at risk of complications and be workable in busy clinical situations. Repeating evidence for lack of effectiveness and lack of efficiency in general might be helpful.

The Study of X Chromosome Inactivation Mechanism in Klinefelter's Syndrome by cDNA Microarray Experiment

To investigate the XIST gene expression and its effect in a Klinefelter''s patient, we used Klinefelter''s syndrome (XXY) patient with azoospermia and also used a normal male (XY) and a normal female (XX) as the control, We were performed cytogenetic analysis, Y chromosomal microdeletion assay (Yq), semi-quantitative RT-PCR, and the Northern blot for Klinefelter''s syndrome (KS) patient, a female and a male control, We extracted total RNA from the KS patient, and from the normal cells of the female and male control subjects using the RNA prep kit (Qiagen), cDNA microarray contained 218 human X chromosome-specific genes was fabricated. Each total RNA was reverse transcribed to the first strand cDNA and was labeled with Cy-3 and Cy-5 fluorescein, The microarray was scanned by ScanArray 4000XL system. XIST transcripts were detected from the Klinefelters patient and the female by RT-PCR and Northern blot analysis, but not from the normal male, In the cDNA microarray experiment, we found 24 genes and 14 genes are highly expressed in KS more than the normal male and females, respectively. We concluded that highly expressed genes in KS may be a resulted of the abnormal X inactivation mechanism.

An improved method for constructing a full-length enriched cDNA library using small amounts of total RNA as a starting material

We have developed an improved method for constructing a full-length cDNA library using small quantity of material by modifying the original oligo-capping method. In our devised method, total RNAs are used in sequential oligo-capping steps directly without preliminary mRNA purification. Using this method, we constructed full- length cDNA libraries from 100 microg of total RNA. These libraries contained 8x10(5) to 8x10(6) independent clones with average insert sizes of 2.0 kb. Moreover, the number of full-length cDNAs containing the translation initiation codon ATG in the constructed libraries was estimated to 60-70%. In addition, 54% of the known cDNAs had a longer 5' end than the corresponding genes in the public database. Our results show that the method can be effectively used to construct full-length enriched cDNA libraries, especially, if starting material is limited.

Socioeconomic Costs of Obesity for Korean Adults / 예방의학회지

OBJECTIVE: To estimate the socioeconomic costs of obesity in Korea, 1998. METHODS: The 1998 National Health and Nutrition Examination Survey (1998 NHNES) data was used and 10,880 persons who had taken health examinations were selected for study. Essential hypertension, NIDDM (non insulin-dependent diabetes mellitus), dyslipidemia, osteoarthritis, coronary heart disease, stroke were included as obesity related disease. The data of direct costs of obesity was obtained from the National Federation of Medical Insurance. The category of indirect costs was the loss of productivity caused by premature death and admission, time costs, traffic costs, nursing fees due to obesity. Multiple logistic regression model was developed to estimate prevalence odds ratio by obesity class adjusted demographic and socio-ecnomic factors and calculate PAF (Population Attributable Fraction) of obesity on obesity related disease. And we finally calculated the socioeconomic costs of obesity in relation to BMI with PAF. RESULTS: The direct costs of obesity were 2,126 billion~965 billion Won in considering out of pocket payment to uninsured services, and the indirect costs of obesity were 2,099 billion~1,086 billion Won. Consequently, in considering out of pocket payment to uninsured services, the socioeconomic costs of obesity were 4,225 billion~2,050 billion Won, which corresponded to about 0.094% ~0.046% of GDP and 1.88%~0.91 of total health care costs in Korea. CONCLUSIONS: Obesity represents a major health problem with significant economic implications for the society. This results are conservative estimates as far as all obesity related disease and all health care and indirect costs were not included due to missing information. Further studies are needed to caculate socioeconomic costs of obesity more exactly.