Effect of Serum Perampanel Concentration on Sporadic Amyotrophic Lateral Sclerosis Progression

Background@#and Purpose To clarify the effect of perampanel (PER) on sporadic amyotrophic lateral sclerosis (sALS) progression, the relationship between the changes in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores and serum PER concentrations was investigated. @*Methods@#12 patients with sALS from our hospital who agreed to participate and completed the PER for sALS randomized phase 2 study were included. After completing the study, we retrospectively obtained serum PER concentration data from the patients. Based on their mean PER concentrations, we divided the patients who had been taking PER into two groups:four patients with a mean PER concentration of ≥400 ng/mL were assigned to the H group, and three with a mean PER concentration of <400 ng/mL were assigned to the L group. The control group consisted of five patients who had been taking a placebo. We obtained the ALSFRS-R scores of each patient at 36 and 48 weeks after randomization. The differences in ALSFRS-R scores at baseline (0 weeks) and each subsequent week were used in the analysis. @*Results@#At 48 weeks, there were no differences in the degree of deterioration of the bulbar, upper and lower limb, and respiratory ALSFRS-R subscores and total ALSFRS-R score. However, at 36 weeks, the bulbar subscore was significantly lower in the H group than in the control group (p=0.032). @*Conclusions@#Because high PER concentrations may exacerbate bulbar symptoms in patients with sALS, serum PER measurements may be beneficial when patients with sALS are taking PER.

Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model

GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gα i/o and Gα q/11 heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca2+ flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-κB. However, GPR43 shares the same ligands as GPR41, including acetate, propionate, and butyrate, and determination of its precise functions in association with endogenous ligands, such as SCFAs alone, therefore remains a considerable challenge. In this study, we generated novel synthetic agonists that display allosteric modulatory effects on GPR43 and downregulate NF-κB activity. In particular, the potency of compound 187 was significantly superior to that of preexisting compounds in vitro. However, in the colitis model in vivo, compound 110 induced more potent attenuation of inflammation. These novel allosteric agonists of GPR43 clearly display anti-inflammatory potential, supporting their clinical utility as therapeutic drugs.

Prolyl Isomerase Pin1 Expression in the Spinal Motor Neurons of Patients With Sporadic Amyotrophic Lateral Sclerosis

Background@#and Purpose Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Selective deficiency of edited adenosine deaminase acting on RNA 2 (ADAR2), a key molecule in the acquisition of Ca 2+ resistance in motor neurons, has been reported in sporadic ALS (sALS) spinal motor neurons. Since ADAR2 activity is positively regulated by prolyl isomerase Protein never in mitosis gene A interacting-1 (Pin1), a known phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, we investigated Pin1 expression in spinal motor neurons in sALS. @*Methods@#Specimens of the spinal cord were obtained from the lumbar region in eight sALS patients and age-matched five controls after postmortem examinations. The specimens were double stained with anti-Pin1 and anti-TAR DNA-binding protein of 43 kDa (TDP-43) antibodies, and examined under a fluorescence microscope. @*Results@#This study analyzed 254 and 422 spinal motor neurons from 8 sALS patients and 5 control subjects, respectively. The frequency of motor neurons with high cytoplasmic Pin1 expression from the spinal cord did not differ significantly between sALS specimens without cytoplasmic TDP-43 inclusions and control specimens. However, in sALS specimens, neurons for which the Pin1 immunoluminescence intensity in the cytoplasm was at least twice that in the background were more common in specimens with cytoplasmic TDP-43 inclusions (p<0.05 in χ 2 test). @*Conclusions@#In sALS, neurons with higher expression levels of Pin1 levels had more TDP-43 inclusions. Despite the feedback mechanism between Pin1 and ADAR2 being unclear, since Pin1 positively regulates ADAR2, our results suggest that higher Pin1 expression levels in motor neurons with TDP-43 pathology from sALS patients represent a compensatory mechanism.

Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein

BACKGROUND AND PURPOSE: Disruption of nucleoporins has been reported in the motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS). However, the precise changes in the morphology of nucleoporins associated with the pathology of the 43-kDa TAR DNA-binding protein (TDP-43) in the disease process remain unknown. We investigated the expression of nucleoporins that constitute the nuclear pore complex (NPC) in spinal motor neurons that exhibit sALS in relation to TDP-43 pathology, which is a reliable neuropathological hallmark of sALS. METHODS: Paraffin-embedded sections of the lumbar spinal cord were obtained for immunofluorescence analysis from seven control subjects and six sALS patients. Anti-TDP-43 antibody, anti-nucleoporin p62 (NUP62) antibody, and anti-karyopherin beta 1 (KPNB1) antibody were applied as primary antibodies, and then visualized using appropriate secondary antibodies. The sections were then examined under a fluorescence microscope. RESULTS: NUP62 and KPNB1 immunoreactivity appeared as a smooth round rim bordering the nuclear margin in normal spinal motor neurons that exhibited nuclear TDP-43 immunoreactivity. sALS spinal motor neurons with apparent TDP-43 mislocalization demonstrated irregular, disrupted nuclear staining for NUP62 or KPNB1. Some atrophic sALS spinal motor neurons with TDP-43 mislocalization presented no NUP62 immunoreactivity. CONCLUSIONS: Our findings suggest a close relationship between NPC alterations and TDP-43 pathology in the degenerative process of the motor neurons of sALS patients.

Outcomes of Endoscopic Submucosal Dissection for Early Gastric Cancer with Undifferentiated-Type Histology: A Clinical Simulation Using a Non-Selected Surgical Cohort

BACKGROUND/AIMS: Outcomes of endoscopic submucosal dissection (ESD) for undifferentiated-type early gastric cancer (EGC) need to be further evaluated. We aimed to simulate the outcomes of ESD for undifferentiated-type EGC from a surgical database. METHODS: Among 802 patients who underwent gastrectomy with endoscopic biopsy for poorly differentiated adenocarcinoma (PD-type) or signet ring cell carcinoma (SRC-type), ESD candidates meeting the expanded indication (n=280) were selected by reviewing the endoscopic images. According to the surgical pathologic results, the outcomes of the ESD simulation were evaluated. RESULTS: Among the candidates, 104 (37.1%) were PD-type and 176 (62.9%) were SRC-type. The curative resection (CR) rate was 42.1%. Among the patients with CR, three patients (2.5%) showed lymph node metastasis (LNM). Three EGCs with CR and LNM were mucosal cancers ≥1.0 cm in size. The CR rate was higher in the SRC-type than in the PD-type (48.3% vs 31.7%, respectively, p=0.007). In the SRC-type, the CR rate was increased, with a smaller size criterion for the ESD indication, but was similar between the 1.0 cm and 0.6 cm criteria (63.3% and 63.6%, respectively), whereas the CR rate was below 50% in all of the different tumor size criteria (2.0 to 0.6 cm) in the PD-type. CONCLUSIONS: In undifferentiated-type EGC, ESD should be considered in selected patients with tumor sizes < 1 cm and SRC histology.

The Effect of DA-6034 on Intestinal Permeability in an Indomethacin-Induced Small Intestinal Injury Model

BACKGROUND/AIMS: DA-6034 has anti-inflammatory activities and exhibits cytoprotective effects in acute gastric injury models. However, explanations for the protective effects of DA-6034 on intestinal permeability are limited. This study sought to investigate the effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model and its protective effect against small intestinal injury. METHODS: Rats in the treatment group received DA-6034 from days 0 to 2 and indomethacin from days 1 to 2. Rats in the control group received indomethacin from days 1 to 2. On the fourth day, the small intestines were examined to compare the severity of inflammation. Intestinal permeability was evaluated by using fluorescein isothiocyanate-labeled dextran. Western blotting was performed to confirm the association between DA-6034 and the extracellular signal-regulated kinase (ERK) pathway. RESULTS: The inflammation scores in the treatment group were lower than those in the control group, but the difference was statistically insignificant. Hemorrhagic lesions in the treatment group were broader than those in the control group, but the difference was statistically insignificant. Intestinal permeability was lower in the treatment group than in the control group. DA-6034 enhanced extracellular signal-regulated kinase expression, and intestinal permeability was negatively correlated with ERK expression. CONCLUSIONS: DA-6034 may decrease intestinal permeability in an indomethacin-induced intestinal injury model via the ERK pathway.

Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia

Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS) is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation.

Clinical Correlation between Serum Cytokeratin-18 and Metabolic Parameters in Patients with Sonographic Non-alcoholic Fatty Liver Disease / 대한소화기학회지

BACKGROUND/AIMS: The serum cytokeratin-18 (CK-18) has been suggested to be a surrogate marker of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the correlation between CK-18 and metabolic parameter in NAFLD patients. Correlation between CK-18 and macronutrient composition was also assessed. METHODS: A total of 212 subjects were recruited. Blood chemistry including fasting glucose, cholesterol level, AST, ALT, and CK-18 were compared. Data on calorie intake and carbohydrate consumption were acquired by five-day-diet diary using 24 hour recall method. RESULTS: Plasma CK-18 were markedly increased in patient with NAFLD compared with control group (420.4+/-282.3 vs. 313.6+/-179, p<0.001). Plasma CK-18 were positively correlated with systolic blood pressure (r=0.130), ALT (r=0.503) and negatively correlated with HDL cholesterol (r=-0.246). NAFLD patients with metabolic syndrome had higher CK-18 level than those without metabolic syndrome (484.0 vs. 372.1 U/L, p=0.021). When NAFLD patients were subdivided into two groups with CK-18 cut-off value of 400 U/L, patients with CK-18 level over 400 U/L showed higher body mass index (28.0+/-4.5 vs. 25.5+/-4.3), subcutaneous abdominal fat (283.5+/-172.2 vs. 195.7+/-147.8), AST (52.7+/-26.3 vs. 40.7+/-23.5) and ALT (102.0+/-52.6 vs. 61.2+/-32.2). Calorie intake (r=0.301) and carbohydrate intake (r=0.305) also showed positive correlation with CK-18. CONCLUSIONS: Plasma CK-18 showed positive correlation with metabolic parameters as well as calorie and carbohydrate intake when its cut-off value of greater than 400 U/L was used.

Corrigendum: Clinical Correlation between Serum Cytokeratin-18 and Metabolic Parameters in Patients with Sonographic Non-alcoholic Fatty Liver Disease / 대한소화기학회지

This correction is being published to correct the third author's Korean name.

Long-term Successful Treatment of Massive Distal Duodenal Variceal Bleeding with Balloon-occluded Retrograde Transvenous Obliteration / 대한소화기학회지

Duodenal variceal bleeding in patients with portal hypertension due to cirrhosis or other causes is uncommon. We report on a case of a 55-year-old male with an ectopic variceal rupture at the distal fourth part of the duodenum who presented with massive hematochezia and shock. Shortly after achievement of hemodynamic stability, due to the limitation of an endoscopic procedure, we initially attempted to find the bleeding focus by abdominal computed tomography, which showed tortuous duodenal varices that drained into the left gonadal vein. He was treated with first-line balloon-occluded retrograde transvenous obliteration (BRTO), resulting in a favorable long-term outcome without rebleeding three years later. This case suggests that BRTO may be a first-line therapeutic option for control of ruptured duodenal varices, especially at a distal location.

Splenic Hemorrhage with Hemoperitoneum Caused by a Snakebite / 대한구급학회지

In Asia, snakebites are estimated to affect 4 million people every year, and of these, 100,000 people are estimated to die. In Korea, snakebites occur frequently from the spring to the fall, but their importance is often overlooked. Fatal complications, including acute respiratory distress and acute kidney injury, can occur, and in some cases, severe hemorrhage results from coagulopathy. There have been only a few cases of snakebite-induced liver or intestinal bleeding, but to our knowledge, spontaneous bleeding from the spleen has not been previously reported. Here, we report the case of a 61-year-old male who visited the emergency room with abrupt abdominal pain due to hemoperitoneum associated with splenic hemorrhage after a snakebite.

Comparison of the Population Pharmacokinetics and Safety Between Please Orally Soluble Film and VIAGRA(R) in Healthy Male Volunteers

BACKGROUND: The objective of this study was to compare the pharmacokinetics and safety between newly developed sildenafil (Please Orally Soluble Film) and sildenafil citrate (VIAGRA(R)) after single oral administration in healthy Korean male subjects. METHODS: A randomized, open-label, single dose, 2-way crossover study was conducted in 50 healthy male subjects. Each sequence group consisted of 25 subjects, received a single oral 50 mg dose of Please Orally Soluble Film (test formulation) or VIAGRA(R) (reference formulation) by study period. Blood samples were obtained during a 24-hour period after dosing. Sildenafil and its metabolite concentrations were determined using validated LC-MS/MS. A non-compartmental pharmacokinetic analysis was performed. Safety was assessed through monitoring of adverse events, vital sign check-up, physical examination, laboratory tests and electrocardiography. RESULTS: All enrolled participants completed the study. The point estimates and 90% confidence intervals of log transformed C(max) and AUC(last) of the test formulation in comparison to those of reference formulation were 0.9294(0.8353 - 1.0341) and 0.9415 (0.8869 - 0.9994) respectively. The analysis of variance showed no significant influences of formulation, sequence and period on the pharmacokinetic parameters. The frequencies of adverse events were not statistically different between the formulations. No serious adverse event was observed or reported. CONCLUSION: Please Orally Soluble Film could be considered bioequivalent to VIAGRA(R) and had similar safety properties in healthy Korean male subjects.

A Case of Vertebral Osteomyelitis With Epidural Abscess Caused by Mycobacterium intracellulare in a Rheumatoid Arthritis Patient

Mycobacterium avium complex (MAC) is the most common pathogen in nontuberculous mycobacterial lung diseases, but vertebral osteomyelitis caused by MAC is rare. We experienced a case of vertebral osteomyelitis with epidural abscess in a rheumatoid arthritis patient who received immunosuppressive agents. Initial assessment was tuberculous vertebral osteomyelitis, and then treated with antituberculous drugs. Fifty-six days later, Mycobacterium intracellulare was identified from abscess culture and drugs were altered to clarithromycin, rifabutin, and ethambutol. After 3 months of M. intracellulare treatment, the radiological findings showed increases of epidural abscess. According to the suseptibility, the patient received intravenous amikacin for four weeks, and then, oral ciprofloxacin in addition to clarithromycin, rifabutin, and ethambutol. The patient is being treated with the medication for 13 months and currently showing slow improvements.

A Case of Thyroid Papillary Carcinoma With Pulmonary Tumor Embolism

The tumor embolism is defined as tumor cells within the vascular system such as pulmonary artery that is not contiguous with the other metastatic foci. The incidence of tumor embolism varies widely ranging from 3% to 26% among several studies; whereas lung cancer, prostate cancer, colorectal cancer, breast cancer, pancreas cancer are associated with high risks for tumor embolism. However thyroid cancer is rarely associated with tumor embolism. Among the rare cases, tumor embolism was reported as being mostly of follicular carcinoma or undifferentiated carcinoma, but few of papillary carcinoma. We report an unusual presentation that pulmonary tumor embolism from thyroid papillary carcinoma was diagnosed with positron emission tomography/computed tomography (CT) and chest CT.

Actigraph monitor in quantitative evaluation of severity of movement disorders / 中华神经科杂志

Objective To quantitatively assess severity of movement disability by analyzing physical activities recorded by an actigraph monitor in patients with neurology disorders.Methods Eighty-one patients with Parkinson' s disease(PD)and 61 patients with acute cerebral infarction(ACI)accompanying impaired upper limb motor function were included in the study.PD patients and ACI patients were treated using the international PD and ACI treatment guidelines,respectively.The patients were asked to wear an Actigraph monitor for 6 days before the treatment in both PD and ACI patient groups and at 24-38 days post-treatment in PD patients or at 28 days post-treatment in ACI patients.The recorded data was analyzed by power-law exponent(PLE)and detrended fluctuation analysis(DFA).Clinically,before and after the treatments,PD patients were evaluated using the conventional Unified Parkinson Disease Rating Scale (UPDRS),and ACI patients were evaluated by assessing upper limb motor function using Fugl-Meyer Assessment(FMA)and Functional Independence Measure(FIM).The correlation of the UPDRS scores with PLE was analyzed in PD patients,and the correlation of FMA or FIM with DFA in ACI patients.Results Both the UPDRS scores and the PLE values in PD patients were improved after the drug administration(UPDRS total:32.8 ± 16.2 and 28.8 ± 14.7,Z =2.080,P =0.038; UPDRS Ⅲ:18.6 ± 8.2 and 15.7±6.8,Z=2.155,P=0.031; PLE:0.98 ±0.25 and 0.82 ±0.21,Z=2.212,P=0.027,before and after the treatment,respectively).There were a linear correlation coefficient of 0.699 between the improvements of total UPDRS scores and the PLE values,and of 0.823 between the UPDRS Ⅲ and the PLE values.FMA,FIM scores and DFA were improved significantly than before treatment(FMA:12.39 ± 8.21 and 30.28 ±7.29,Z=3.016,P =0.004; FIM:8.98 ±7.29 and 13.21 ±7.6,Z =2.282,P=0.038; DFA:0.86 ±0.31 and 0.98 ±0.27,Z =2.360,P =0.036,before and after the treatment,respectively).It also showed linear correlations between the improvements of FMA scores and DFA(r =0.638),and between FIM scores and DFA(r =0.712,both P ＜0.05).There was no correlation between UPDRS scores and DFA values in PD patients,nor between FIM scores or FMA scores and PLE values in ACI patients.Conclusions Actigraph device can be used to monitor patients activity in movement disorders.Analysis of its PLE can provide a quantitative evaluation in PD while its DFA may provide useful specific assessment of impaired upper limb motor function in ACI patients.It can also be used in quantitatively assessing new drug efficacy.

Association of Serum Gamma Glutamyltransferase and Fasting Blood Glucose among Middle Aged and Elderly in Chuncheon: Hallym Aging Study / 가정의학회지

BACKGROUND: Serum gamma-glutamyltransferase (GGT) was reported to be associated with type 2 diabetes, various cardiovascular disease risk factors, and individual components of metabolic syndrome. We performed a cross-sectional study to elucidate the relations between GGT and impaired fasting glucose (IFG). METHODS: The subject of this study included 693 adults (males 272, females 421) aged 45 years or over who have lived in Chuncheon, a suburban small-sized city. IFG was defined as elevated fasting plasma glucose (FPG) concentration of > or = 100 and or = 75th) were 1.0, 0.56, 1.57, and 2.79, respectively (P-value for trend 0.022). In women, the association between the risk of IFG and GGT was not statistically significant. CONCLUSION: This study suggests that elevated level of GGT within the normal range is an independent predictor of impaired fasting glucose in middle-aged or older men but not in women.

Early Experience with a Stapled TransAnal Rectal Resection for Obstructed Defecation Syndrome

PURPOSE: This study was designed to assess the early outcome of a stapled transanal rectal resection (STARR) in obstructed defecation syndrome (ODS) patients with rectocele and rectal intussusception. METHODS: From January to December in 2005, 41 patients with the symptoms of obstructed defecation and the findings of rectocele and rectal intussusception in defecography, who failed in conservative management, were enrolled in this study. All patients underwent the STARR procedure. Preoperatively all patients received colonoscopy, a colon transit time test, cinedefecography, etc. The constipation score was evaluated by using the Cleveland Clinic Florida (CCF) constipation score preoperatively and at 1 month and 3 months after operation. RESULTS: The mean age of the patients was 55.3 (19~76) years. There were three males and thirty-eight females. The mean operation time was 39.3 (25~80) minutes, and the mean hospital stay was 4.2 (4~6) days. Complications were fecal urgency in 9 cases (21.9%), which improved after 3 months, bleeding in 5 cases (12.2%), and anastomotic stenosis in 1 case (2.4%). At postoperative defecography, both intussusception and rectocele had disappeared in most patients. All constipation symptoms were significantly improved (P < 0.01). The mean CCF constipation score was 17.6 (11~24) preoperatively, and improved to 9.1 after 1 month and 8.2 after 3 months (P < 0.01). The overall patient satisfaction was graded as excellent, good, fairly good and poor in 19 cases (46.3%), 13 cases (31.7%), 4 cases (9.7%), and 5 cases (12.2%), respectively. CONCLUSION: The STARR procedure seems to be a safe and effective procedure in ODS patients with rectocele and rectal intussusception. However, further study of the long-term results is required.

Analysis of Clinicopathological Factors Associated with Lymph Node Metastasis in Early Gastric Cancer Review of 2,137 cases / 대한암학회지

PURPOSE: The majority of patients with early gastric cancer show long-term survival after surgery. So a special attention must be directed to preserving gastric function in these patients. When node-negative early gastric cancer could be diagnosed preoperatively, then minimally invasive surgery can be performed to ensure a postoperative better quality of life. MATERIALS AND METHODS: The pathological records of 2,137 consecutive patients with early gastric cancer who underwent curative operations from January 1986 to December 1998 at Seoul National University Hospital were reviewed. RESULTS: Lymph node metastases were observed in 285 patients (13.3%). In mucosal carcinoma, lymph node metastases were observed in 50 of 1,108 cases (4.5%), and in submucosal carcinoma, in 234 of 1,026 cases (22.8%). The tumor size, depth of invasion and gross appearance were associated with lymph node metastasis. In mucosal carcinoma, the size and histologic differ entiation were associated with lymph node metastasis. In submucosal carcinoma, the size and gross appearance were associated with lymph node metastasis. CONCLUSION: In early gastric cancer, the limited surgery can be applied only to cases satisfying the following criteria; (1) mucosal tumor, (2) size < or =2 cm, (3) elevated type or (4) depressed type which are histologically differentiated and (5) size < or =1 cm among the depressed type his tologically undifferentiated.