Purpose: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels. Materials and Methods: We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results: Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders. Conclusion Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor.

Background: Lipopolysaccharide (LPS) exerts cytotoxic effects on brain cells, especially on those belonging to the oligodendrocyte lineage, in preterm infants. The susceptibility of oligodendrocyte lineage cells to LPS-induced inflammation is dependent on the developmental stage. This study aimed to investigate the effect of LPS on oligodendrocyte lineage cells at different developmental stages in a microglial cell and oligodendrocyte coculture model. Methods: The primary cultures of oligodendrocytes and microglia cells were prepared from the forebrains of 2-day-old Sprague–Dawley rats. The oligodendrocyte progenitor cells (OPCs) co-cultured with microglial cells were treated with 0 (control), 0.01, 0.1, and 1 µg/mL LPS at the D3 stage to determine the dose of LPS that impairs oligodendrocyte differentiation. The co-culture was treated with 0.01 µg/mL LPS, which was the lowest dose that did not impair oligodendrocyte differentiation, at the developmental stages D1 (early LPS group), D3 (late LPS group), or D1 and D3 (double LPS group). On day 7 of differentiation, oligodendrocytes were subjected to neural glial antigen 2 (NG2) and myelin basic protein (MBP) immunostaining to examine the number of OPCs and mature oligodendrocytes, respectively. Results: LPS dose-dependently decreased the proportion of mature oligodendrocytes (MBP+ cells) relative to the total number of cells. The number of MBP+ cells in the early LPS group was significantly lower than that in the late LPS group. Compared with those in the control group, the MBP+ cell numbers were significantly lower and the NG2+ cell numbers were significantly higher in the double LPS group, which exhibited impaired oligodendrocyte lineage cell development, on day 7 of differentiation. Conclusion Repetitive LPS stimulation during development significantly inhibited brain cell development by impairing oligodendrocyte differentiation. In contrast, brain cell development was not affected in the late LPS group. These findings suggest that inflammation at the early developmental stage of oligodendrocytes increases the susceptibility of the preterm brain to inflammation-induced injury.

BACKGROUND: While gait disturbance is an important feature of idiopathic normal pressure hydrocephalus (NPH), there are only tentative theories explaining its pathophysiology. The mesencephalic locomotor region has been suggested as the anatomical substrate for the development of hypokinetic gait. We evaluated the correlation between gait disturbance and midbrain diameter to investigate the role of mesencephalic locomotor region in development of NPH gait. METHODS: We enrolled 21 patients with NPH and 20 age-matched control subjects. Maximal diameter of midbrain and pons and the width of lateral and third ventricle were measured at midsagittal T1-weighted MRI and axial T2-weighted MRI, respectively. Gait disturbance, cognitive dysfunction, and incontinence were semi quantified. RESULTS: Maximal midbrain diameter was significantly smaller in NPH group, as compared to the controls (14.8 +/- 0.9 vs. 17.1 +/- 0.7 mm, p<0.001). There was an inverse correlation between the midbrain diameter and the ventricular width (r=-0.562, p=0.008 in third ventricle and r=-0.510, p=0.018 in lateral ventricle). Severity of gait disturbance were negatively correlated with midbrain diameter (r=-0.598, p=0.004), but degree of cognitive dysfunction and incontinence showed no significant correlation with brainstem diameter nor ventricular width. CONCLUSIONS: This study suggests that midbrain atrophy is significantly associated with gait disturbance in NPH. Furthermore, this study implies the possible role of midbrain structures including mesencephalic locomotor region in the genesis of NPH gait.
Atrophy ; Brain Stem ; Gait* ; Humans ; Hydrocephalus, Normal Pressure* ; Magnetic Resonance Imaging ; Mesencephalon* ; Pons ; Third Ventricle

BACKGROUND: This study compared the bronchodilator efficacy and safety of tiotropium inhalation capsules (18microgram once daily) with a ipratropium metered dose inhaler (2 puffs of 20microgram q.i.d.) in patients with chronic obstructive pulmonary disease (COPD). METHOD: After the initial screening assessment and a two-week run-in period, patients received either tiotropium 18microgram once daily or ipratropium 40microgram four times daily over a period of 4 weeks in a double blind, double dummy, parallel group study. The outcome measures were the lung function, the daily records of the peak expiratory flow rate (PEFR), the patients' questionnaire, and the use of concomitant salbutamol. The forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC) were measured 5 minutes before inhalation, and 0.5, 1, 2 and 3 hours after inhaling the study drug on days 0, 14 and 28. RESULT: In 16 centers, 134 patients with a mean (SD) age of 66 (7) years and a predicted FEV1 of 42 (12)% were analyzed. The trough FEV1 response was significantly higher in the tiotropium group than in the ipratropium group after a four-week treatment period. The weekly mean morning PEFR of the tiotropium group was consistently higher than that of the ipratropium group during the 4-week treatment period with differences ranging from 12.52 to 13.88 l/min, which were statistically significant. Tiotropium was well tolerated by the COPD patients during the 4-week treatment period and had a similar safety profile to ipratropium. CONCLUSION: This study shows that tiotropium administrated once daily has a superior bronchodilator effect with a similar safety profile in treating COPD patients compared with ipratropium, inhaled four times daily.
Adult* ; Albuterol ; Bronchodilator Agents ; Capsules ; Forced Expiratory Volume ; Humans ; Inhalation ; Ipratropium* ; Lung ; Mass Screening ; Metered Dose Inhalers ; Outcome Assessment (Health Care) ; Peak Expiratory Flow Rate ; Pulmonary Disease, Chronic Obstructive* ; Surveys and Questionnaires ; Vital Capacity ; Tiotropium Bromide

KMAP (Korean Medication Algorithm Project for Major Psychiatric Disorders) was established to develop Korean algorithm for major psychiatric disorders. KMAP developed the draft of Korean medication algorithm for schizophrenia and assessed the level of satisfaction and fitness in the Review Committee using questionnaire about this draft. The members of Review Committee were medical doctors of psychiatry who were interested in the research of psychiatric drugs or were experienced in psychiatric pharmacotherapy in college of medicine, mental hospital or private psychiatric clinic. 57 psychiatrists were appointed as committee of re-examination of algorithm and 48 (84.2%) answered the questionnaire. The Korean medication algorithm draft for schizophrenia was based upon Korean clinical research, clinical experience of Korean professionals and clinical guidelines of other countries. The draft of this algorithm was categorized into 32 items, then we made a questionnaire according to these items. The answers of each question were consist of 5 levels of satisfaction, and the committee members could propose free opinion about these questions. The results of questionnaire were presented and discussed in an open forum. In most items except two, over half of committee members answered that `correction unnecessary of draft'. The 2 items showing low level of satisfaction were `trial of atypical antipsychotics at level 1', `trial of typical antipsychotics at level 4'. These items were revised from the draft after having discussion in an open forum. And then we published the first edition of `Korean Medication Algorithm for Schizophrenia'.
Advisory Committees ; Antipsychotic Agents ; Committee Membership ; Drug Therapy ; Hospitals, Psychiatric ; Psychiatry ; Surveys and Questionnaires* ; Schizophrenia*

As a solution about many problems of pharmacotherapy for Korean patients with major psychiatric disorders, Korean Medication Algorithm Project for Major Psychiatric Disorders (KMAP) was launched. Recently, a medication algorithm for schizophrenic patients was developed and distributed. This review article showed the designs, processes and methods for developing this algorithm. Also we compared the development of Korean algorithm for schizophrenics with other foreign representative algorithms or clinical practice guidelines. We hope that this review elicit the productive criticism about the rigour, the system of development and the objectivity of content. The limitations and problems of Korean algorithm are also discussed in this review.
Drug Therapy ; Hope ; Humans ; Schizophrenia

In this special article we present Korean medication algorithm development project for major psychiatric disorder (KMAP), basic plan, organization, basic principles of algorithm developments, methods of development, limitations and cautions of using this algorithm. The Korean Society of Psychopharmcology and Korean Academy of Schizophrenia as a co-worker started to make Korean algorithm project that is helpful to treat major mental disorder (schizophrenia, bipolar disorder) patients by the better psychopharmacologic treatments. In spite of many advantages of algorithm, these projects have many limitations and problems simultaneously; we needed to introduce the goal of algorithm, details of development methods in this special article. KMAP have employed the latest survey techniques and reflect only the most current clinical standards. The results are a practical reference tool not only for clinicians but also for mental health educators and other healthcare professionals involved in the care of patients who have major mental disorders. This algorithm projects can have problems and shortcomings. but we will revise this issues by correction and amendment.
Bipolar Disorder ; Delivery of Health Care ; Humans ; Mental Disorders ; Mental Health ; Schizophrenia

OBJECTIVES: We tested the reliability and validity of the Korean version of the PANSS (PANSS-KV). METHODS: The PANSS ratings were obtained from 101 subjects with DSM-IV diagnoses of schizophrenia or schizophreniform disorder. To study the concurrent validity, the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) were also administrated in 38 patients. Using these data, inter-rater reliability, test-retest reliability, internal consistency, criterion validity and concurrent validity were evaluated. Factor structure was analyzed by the principal axis factoring. RESULTS: The inter-rater reliability of the Korean version of the PANSS was satisfactory in positive (r=0.92) and negative syndrome subscales(r=0.86), but somewhat low in general psychopathology subscale (r=0.78). The test-retest correlations for the 3 PANSS subscales ranged between 0.89 and 0.95, so it showed excellent test-retest reliability. The Cronbach's alpha for the positive, negative and general psychopathology subscales were 0.73, 0.84 and 0.74, respectively and thus the 3 subscales of the PANSS had good internal consistencies. All separate items revealed significant corrected item-total correlations in the positive and negative syndrome subscales, but some items of the general psychopathology subscale showed no or low corrected item-total correlations. The positive and negative syndrome subscales held a high concurrent validity in relation to the SAPS and the SANS. It was confirmed that positive and negative syndromes were independent constructs. The factor analysis by the principal axis factoring produced 5 components: cognitive, excitement, depression, positive and negative. CONCLUSION: These findings prove that the reliability and validity of the PANSS-KV are comparable to those of the original PANSS. So, the PANSS-KV can be widely and extensively used in researches for schizophrenia.
Axis, Cervical Vertebra ; Depression ; Diagnosis ; Diagnostic and Statistical Manual of Mental Disorders ; Humans ; Psychopathology ; Psychotic Disorders ; Reproducibility of Results* ; Schizophrenia

OBJECTIVES: Regional cerebral blood flow(rCBF)in schizophrenics is confounded by various factors including medication status. Previously, there have been numerous studies regarding the effects of antipsychotics on rCBF. However, these works have shown contradictory and inconsistent findings due to the different of type, dose and exposed duration of antipsychotics. The aim of this study was to observe the effect of antipsychotic medication on rCBF and exposed duration of antipsychotics under control. METHODS: Eighteen drug-naive schizophrenics and 19 schizophrenics medicated with haloperidol were included in the study. Regional cerebral blood flow was assessed with the singlephoton emission computed tomography(SPECT)under a resting state. Relative rCBF was compared between two groups. Haloperidol was selected as the antipsychotic drug as it has relatively selective action at the D2 receptor and less active metabolites. Exposed duration was limited from one to three weeks. RESULTS: Haloperidol-medicated schizophrenic patients had a significantly greater increase of relative cerebral perfusion in the right inferior temporal lobe, left inferior frontal lobe, both basal ganglia, left thalamus, both parieto-occipital lobes, and right parietal lobe than drug-naive schizophrenic patients. Haloperidol-medicated schizophrenic patients had a significant decrease of relative cerebral perfusion in left inferior temporal lobe. However, no significant differences in relative rCBF were found between drug-naive and haloperidol-medicated schizophrenic patients in right inferior frontal lobe, right thalamus, both superior temporal lobes, both superior frontal lobes, and left parietal lobe. CONCLUSION: These findings suggest that antipsychotics affect regional cerebral blood flow, and antipsychotic medication status must be considered in the relative rCBF studies of schizophrenic patients.
Antipsychotic Agents ; Basal Ganglia ; Frontal Lobe ; Haloperidol* ; Humans ; Parietal Lobe ; Perfusion ; Schizophrenia ; Temporal Lobe ; Thalamus ; Tomography, Emission-Computed, Single-Photon*

OBJECTIVES: In schizophrenics, regional cerebral blood flow(rCBF) are affected by various confounding variables, i.e., age, sex, duration of illness, and clinical status. The pharmacological condition of patients is also a particular important variable to be taken into consideration. However, few data are available regarding the differences between the relative rCBF findings in drug-free and drug-naive schizophrenic patients. Currently, numerous studies have included drug-free and drug-naive schizophrenic patients in the same 'unmedicated' group under the assumption that the rCBF is identical between drug-free and drug-naive cases. Therefore, the aim of this study was to compare the rCBF between a group of drug-free schizophrenic patients and a group of drug-naive schizophrenic patients about the effects of age, sex, duration of illness, and clinical status(positive and negative symptoms) under control. METHODS: Eighteen drug-naive schizophrenics and fifteen drug-free schizophrenics were in-cluded in the study. Regional cerebral blood flow was studied with the single-photon emission computed tomography(SPECT) under resting state. Symptoms were assessed with Positive and Negative Syndrome Scale(PANSS). Regions of interest were both inferior temporal lobe, inferior frontal lobe, superior temporal lobe, thalamus, basal ganglia, parieto-occipital lobe, superior frontal lobe, and parietal lobe. RESULTS: No significant differences of relative rCBF were found between drug-free and drug-naive schizophrenic patients in left inferior temporal lobe, right inferior frontal lobe, both superior temporal lobe, both thalamus, both basal ganglia, right parieto-occipital lobe, and both superior frontal lobe. But, drug-free schizophrenic patients had a significant increase of perfusion in the right inferior temporal lobe and left inferior frontal lobe and a significant decrease of perfusion in both parietal lobes and left parieto-occipital lobe. CONCLUSIONS: Relative rCBF in drug-free schizophrenic patients is different from that in drug-naive schizophrenic patients. So, in the relative rCBF studies of schizophrenic patients, it must be considered whether the patients were previously medicated or not.
Basal Ganglia ; Confounding Factors (Epidemiology) ; Frontal Lobe ; Humans ; Parietal Lobe ; Perfusion ; Schizophrenia ; Temporal Lobe ; Thalamus ; Tomography, Emission-Computed, Single-Photon*