Future policy directions for planning of national responsibility for dementia care

Dementia is one of the biggest global public health challenges facing our generation today. By 2030, Korea is projected to have the highest life expectancy in the world. The government's new plans regarding national responsibility for dementia care are well-timed strategies for patients and family members suffering from dementia and should be welcomed. The newly designed national dementia strategy of Korea may set new standards for dementia welfare policies. However, these plans should be modified after careful consideration of following aspects: financial sustainability, issues related with long-term care systems for other critical diseases, and instantaneous nationwide implementation without a period of trial-and-error learning. More gradual and steady policy initiatives is preferred. Through consensus we should strategically develop the optimal quality control system for dementia care and education program for training physicians, dementia-care professionals, and workers to be deployed in both specialized 72 public dementia care hospitals and nationwide 252 regional dementia centers. In addition, these care plans should also include health policy aiming the primary prevention to reduce future dementia prevalence while creating dementia-friendly communities and emphasizing clinical and basic research for dementia. Modifying the current plans for the Korean national dementia strategy using stepwise, well-integrated, and systematic approaches will lead to successful dementia welfare policy.

Optimization of Extraction Conditions for Active Compounds of Herbal Medicinal Formula, DF, by Response Surface Methodology

DF formula is comprised of three traditional herbs, Ephedra intermedia, Rheum palmatum and Lithospermum erythrorhizon, and locally used for treating of the metabolic diseases, such as obesity and diabetes in Korea. We tried to optimize the extraction conditions of two major components, (−)-ephedrine and (+)-pseudoephedrine, in DF formula using response surface methodology with Box-Behnken design (BBD). The experimental conditions with 70% for EtOH concentrations, 4.8 hour for extraction hours and 8.7 times for the solvent to material ratio were suggested for the optimized extraction of DF formula with the highest amounts of (−)-ephedrine and (+)-pseudoephedrine in the designed model.

Preclinical safety assessment of Angelica acutiloba using a 13-week repeated dose oral toxicity study in rats / 한국실험동물학회지

Angelica acutiloba (AA), a Japanese species of Danggui, has been used worldwide as a traditional herbal medicine with several bioactivities including anti-diabetic, anti-allergic, anti-inflammatory, anti-tumor, and anti-obesity. However, there is lack of toxicological data available to evaluate potential long-term toxicity and the no-observed-adverse-effect level (NOAEL) of AA extract in accordance with the test guidelines published by the Organization for Economic Cooperation and Development. In the 14-day repeat-dose toxicity study, no adverse effects on mortality, body weight change, clinical signs, and organ weights was found following repeat oral administration to rats for 14 days (125, 250, 500, 1000, and 2000 mg/kg body weight), leading that 2000 mg/kg is the highest recommended dose of AA extract for the 13-week repeat-dose oral toxicity study. In the 13-week repeat-dose oral toxicity study, the AA extract was orally administered to groups of rats for 13 weeks (125, 250, 500, 1000, and 2000 mg/kg body weight) to compare between control and AA extract groups. The administration of AA extract did not produce mortality or remarkable clinical signs during this 13-week study. And, the data revealed that there were no significant differences in food/water consumption, body weight, hematological parameters, clinical chemistry parameters, gross macroscopic findings, organ weight and histopathology in comparison to the control group. On the basis of these results, the subchronic NOAEL of the AA extract was more than 2000 mg/kg/day when tested in rats. And, the AA extract is considered safe to use orally as a traditional herbal medicine.

Evaluation of in vitro and in vivo genotoxicity of Angelica acutiloba in a standard battery of assays / 한국실험동물학회지

Among three representative species of Angelica found in Asian countries, including Korea, China, and Japan, Angelica acutiloba (AA) has been used as traditional herbal medicine with antitumor, anti-inflammatory, anti-obesity, and anti-diabetes activities. In this study, the potential genotoxicity and mutagenicity of the AA extract were examined in a battery of in vitro and in vivo tests (bacterial reverse mutation assay, in vitro chromosomal aberrations assay, and in vivo micronucleus assay) in accordance with the test guidelines for toxicity testing developed by the Organization for Economic Cooperation and Development. Upon testing in the bacterial mutation assay (Ames test) using five Salmonella typhimurium TA98, TA100, TA102, TA1535 and TA1537, no significant increase the number of revertant colonies in the metabolic activation system and non-activation system was noted in the AA extract groups. Also, in the chromosome aberration test, the AA extract did not cause chromosomal aberration with or without metabolic activation by S9 mix. A bone marrow micronucleus test of mice demonstrated that the incidence of micronucleated polychromatic erythrocytes in the AA extract groups (500, 1000 and 2000 mg/kg BW) was equivalent to that of the negative control group. Based on these results from a standard battery of assays, the AA extract was concluded to have no genotoxic at the proper dose.

A Novel F45S SOD1 Mutation in Amyotrophic Lateral Sclerosis Coexisting with Bullous Pemphigoid

BACKGROUND: The coexistence of an autoimmune disease and amyotrophic lateral sclerosis (ALS) has led to the hypothesis that immune-mediated pathological mechanisms are overlapping in the two diseases. We report herein a rare coexistence of bullous pemphigoid (BP) in a novel mutation (F45S) of the gene encoding Cu/Zn superoxide dismutase (SOD1) in an ALS patient, and discuss a role for the SOD1 mutation in this unusual overlap. CASE REPORT: A 57-year-old male with familial ALS, including vesicles and tense bullae on erythematous bases, was diagnosed with BP. Direct immunofluorescence revealed deposits of C3 and immunoglobulin G in the basement membrane zone. Direct sequencing of SOD1 in the patient revealed a novel mutation (c.137T>C; F45S). CONCLUSIONS: We report a novel SOD1 mutation in ALS, which was combined with BP. This novel SOD1 mutation could affect the phenotype of a combined autoimmune disease and matrix metalloproteinase-9. There may therefore be common factors linking BP and ALS with the SOD1 mutation.

Effects of Long-Term Combination Treatment with Valproate and Atypical Antipsychotics on Bone Mineral Density and Bone Metabolism in Premenopausal Patients with Bipolar Disorder: A Preliminary Study

OBJECTIVE: We investigated bone mineral density (BMD) and bone metabolism in female bipolar patients who were undergoing long-term treatment with valproate combined with a low-dose atypical antipsychotic. METHODS: Nineteen premenopausal women with bipolar disorder who were treated with valproate combined with atypical antipsycho-tics for at least 2 years were evaluated. The BMD was measured at lumbar spine and femur sites using dual-energy X-ray absorptiometry (DE-XA). The biochemical markers of bone turnover and circulating levels of gonadal hormones were assessed. Subjects with abnormal DEXA scans were compared to those with normal scans. RESULTS: Nine (47%) of nineteen subjects showed osteopenia or osteoporosis. The T-score for subjects with abnormal DEXA scans was -1.988. Decreased BMD was more prominent in the proximal femur than in the lumbar spine. Subjects with abnormal DEXA scans had high phosphorus and low testosterone levels relative to subjects with normal scans (p=0.008 and p=0.028, respectively). There was a significant negative correlation between phosphorus, osteocalcin, and femur neck BMD (p<0.05). However, multivariate analysis did not show a significant association between femur and lumbar BMD and biochemical markers of bone turnover. CONCLUSION: Long-term treatment with valproate combined with low-dose atypical antipsychotics may adversely affect BMD in premenopausal women with bipolar disorder. A prospective, controlled-study with a larger population is warranted, and assessment of BMD and bone metabolism should be taken into consideration in long-term therapy with valproate and atypical antipsychotics.

Changes of Serum Cytokines After the Long Term Immunotherapy with Japanese Hop Pollen Extracts

Japanese hop (Hop J) pollen has been considered as one of the major causative pollen allergens in the autumn season. We developed a new Hop J immunotherapy extract in collaboration with Allergopharma (Reinbeck, Germany) and investigated immunologic mechanisms during 3 yr immunotherapy. Twenty patients (13 asthma with rhinitis and 7 hay fever) were enrolled from Ajou University Hospital. Sera were collected before, 1 yr, and 3 yr after the immunotherapy. Changes of serum specific IgE, IgG1 , and IgG4 levels to Hop J pollen extracts and serum IL-10, IL-12, TGF-beta1 and soluble CD23 levels were monitored by ELISA. Skin reactivity and airway hyper-responsiveness to methacholine were improved during the study period. Specific IgG1 increased at 1 yr then decreased again at 3 yr, and specific IgG4 levels increased progressively (p<0.05, respectively), whereas total and specific IgE levels showed variable responses with no statistical significance. IL-10, TGF-beta1 and soluble CD23 level began to decrease during first year and then further decreased during next two years with statistical significances. (p<0.05, respectively). In con-clusion, these findings suggested the favorable effect of long term immunotherapy with Hop J pollen extracts can be explained by lowered IgE affinity and generation of specific IgG4 , which may be mediated by IL-10 and TGF-beta1.

IgE sensitization to the potato allergen in adult allergy patients and identification of IgE binding components: comparison between the wild and genetically modified potato / 대한내과학회지

BACKGROUND: The aim of this study was to evaluate the prevalence of IgE sensitization and allergic risk of genetically modified (GM) potato compared with wild one in adult patients with various allergic diseases. METHODS: One thousand eight hundred eighty eight allergy patients visited Ajou University hospital and 38 healthy controls were enrolled. Skin prick tests were performed with wild and GM extracts. Phosphinothricin N-acetyltransferase (PAT) and neomycin phosphotransferase (NPT) gene was inserted in GM potato. Serum specific IgE level to the two potato extracts was measured by ELISA and their binding specificities were confirmed by ELISA inhibition test. IgE binding components in both wild and GM potato extracts were identified by SDS-PAGE and IgE-immunoblot. RESULTS: One hundred eight patients (5.7%) showed positive responses (A/H >or= 2+) on skin prick test to both wild and GM potatoes. Serum specific IgE was detectable in 50~88% among the positive reactors on skin prick test. ELISA inhibition tests showed similar inhibition pattern between wild and GM. Fourteen IgE binding components within wild potato and nine IgE binding components within GM potato with similar binding patterns, of which three major allergens in wild (26, 34, 45 kDa) and one (45 kDa) in GM one were noted.. CONCLUSIONS: The sensitization rates to wild and GM potato extracts were 5.7% respectively, in adult allergy patients and one common major allergen (45 kDa) was identified. It is speculated that genetic manipulation of the potato did not increase allergenic risk.

Chestnut as a Food Allergen: Identification of Major Allergens

Chestnut as a Food Allergen: Identification of Major Allergens To evaluate the clinical significance of chestnut as a food allergen in Korea, skin prick test and ELISA were done in 1,738 patients with respiratory allergies. To identify the IgE binding components, IgE-immunoblotting, 2D IgE-immunoblotting and MALDITOF were performed. To observe the effects of digestive enzymes and a boiling treatment, simulated gastric fluid (SGF) and simulated intestinal fluids (SIF) were incubated with chestnut extracts, and IgE-immunoblotting were then repeated. Skin prick test revealed that 56 (3.2%) patients showed more than 2+ of allergen to histamine ratio to chestnut. Among the 21 IgE binding components, 9 bands were found in more than 50% of the sera tested and the 24 kDa protein had the highest binding intensity. The amino acid sequence of the 24 kDa protein (pI 6.3) had homology with legume protein of oak tree. SGF, SIF and boiling treatment were able to suppress the IgE binding components. In conclusion, chestnut ingestion was shown to induce IgE mediated responses with a 3.2% sensitization rate. Twenty one IgE binding components and one new allergen (the 24 kDa protein) were identified. Digestive enzymes and boiling treatment were able to decrease the allergenic potency.

A Case of Osmotic Myelinolysis Confined to Central Pons and Pyramidal Tracts

Osmotic myelinolysis is a distinctive clinical syndrome with a characteristic "bat wing" MRI lesion in the central pons, which is also called central pontine myelinolysis (CPM). However, demyelinating lesions are not only limited to the central pons, but also may be involved in the extrapontine regions including the basal ganglia, thalamus, and cerebellum (extrapontine myelinolysis; EPM). We report an atypical case of osmotic myelinolysis confined to the pyramidal tract from the precentral gyrus to the central pons via the corona radiata and internal capsule in a MR image.

Diallyl Disulfide Inhibits Cytochrome c-Mediated Apoptosis in H2O2 Induced Death of Neuronal-differentiated PC12 Cells

BACKGROUND: The effects of diallyl disulfide (DADS), a garlic derived compound, on the viability and cell signaling- like the downstream signaling through cytochrome c, caspase-3, poly (ADP-ribose) polymerase (PARP) during an oxidative-stress induced injury were studied using H2O2 treated neuronal-differentiated PC12 cells by a nerve growth factor. METHODS: To evaluate the toxicity of the DADS itself, the viability of the differentiated PC12 cells treated with several concentrations of DADS was evaluated with 3, (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. To evaluate the protective effect of the low concentration of DADS from oxidative stress, the viability of the cells (DADS pretreated vs. not pretreated) was evaluated following the exposure to 100 micro M H2O2. Additionally, the expression of caspase-3, PARP, and cytochrome c was examined using western blot analyses. RESULTS: The viability was not affected at low concentrations of DADS, up to 20 micro M, but, over this concentration, it was decreased. Compared with the cells treated with only 100 micro M H2O2, the pretreatment with low concentrations of DADS before exposure to 100 micro M H2O2 increased the viability and induced the inhibition of caspase-3 activation, PARP cleavage, and cytochrome c release. CONCLUSIONS: These results show that low concentrations of DADS shows neuroprotective effects by affecting the downstream signaling through cytochrome c, caspase-3, and PARP pathway and may be a new potential therapeutic strategy for neurodegenerative diseases associated with oxidative injury.

Electrophysiological Analysis of Deafferentation Effect on Visual Cortex in Rats

PURPOSE: Temporary deafferentation (TD) by local anesthesia in small parts of the body induces an immediate and reVersible reorganization of the receptive field (RF). It is thought that an adaptation for deafferentation would occur in the visual system. Therefore, in this study, simultaneous multi-single unit recording (SMSUR) from visual cortex (VI cortex) of rats have been carried out to characterize; 1) the TD-induced changes in the populational activities of single neurons, 2) the alteration of the neural network among neurons in each area during TD and 3) the synaptic mechanism underlying the neuronal plasticity of the visual system. METHODS: Using four channels of a multi-electrode made from tungsten microwire, the neuronal activities (evoked responses and spontaneous activities) and networks in the VI cortex of anesthetized rats have been investigated. In this study, TD was induced by a retrobulbar injection of lidocaine (2%, 0.1 ml). RESULTS: After the induction of TD, the cortical neurons showed reversed changes in their evoked reoponses. The induction of TD suppressed the activities of the target cells in the VI cortex. However, TD also caused facilitation of the activities of the neighboring neurons. The spontaneous activities of the neighboring neurons were also gradually facilitated after the induction of TD and then gradually recovered to their initial control period values. CONCLUSIONS: The results from the present study suggest that; 1) TD-induced plasticity of the central visual system involving the VI cortex may be due to disinhibition of the lateral inhibition and 2) the spontaneous activities of the VI cortical neurons, as well as evoking responses, may be involved in the TD-induced visual plasticity of anesthetized rats.

Effect of Thiamine Deficiency on the Glial Fibrillary Acidic Protein ( GFAP ) Immunoreacitivity of the Astrogial Cells in Rat Forebrain

BACKGROUND: Diverse injury to central nervous system results in proliferation and hypertrophy of astrocytes. The hallmark of this response is enhanced expression of the major intermediate filament protein of astrocyte, glial fibrillary acidic protein(GFAP). These obsevations suggested that GFAP may be a useful biochemical indicator of neurotoxicity. This study is designed for investigating the chronological effects of the thiamine deficiency on the astrogrial GFAP immunoreactivity in the rat forebrain, and for comparing the difference between time-sequenital morphological changes of luxol fast blue-cresyl violet stain reported in previous study and GFAP immunoreactivity. METHODS: A total of 40 healthy Sprague-Dawley strain rats, weighing about 200gm were used as experimental animals(10 control, 30 thiamine deficient rats). Pyrithiamine was injected intraperitonially for 9 days and thiamine deficient diet was continuously supplied until sacrifice. Thiamine deficient rats were subdivided into 3 groups according to thiamine deficient state. Immunohistochemical stains for GFAP in the regions of thalamus, medial mammillary nucleus and CA1 sector in hippocampus were performed by free floating method in cell culture plate. All preperations were observed with light microscope. RESULTS: GFAP immunoactivities at thalamus were tracely positive(+) in controls, strongly positive(+++) in group I, and moderately positive(++) in group II and III. But GFAP immunoactivities at medial mammillary nucleus were tracely positive( ) in controls, moderately positive(++) in group I and III , and strongly positive(+++) in group II. At the CA1 region of hippocampus, the immunoactivities were weakly positive in controls , strongly positive(+++) in group I and II, and moderately positive(++) in group III. The diverse patterns of GFAP immunoreactivities in each vulnerable site were different from the previous morphological study. In luxol-fast and cresyl violet staining, the neuronal damage and necrosis were marked in group III, group II, and group I, in that order, which findings are consistent in all regions. CONCLUSIONS: Different patterns of time-sequential GFAP immunoactivities at each vulnerable site suggest that there are regional differences in sensitivity and resistance to thiamine deficiency.

MELAS syndrome: Point mutation at nt 3243 (A3243G) in tRNALeu(UUR) gene of mtDNA

MELAS (Mitochondrial Encephalomyopathy with Lactic acidosis, and Stroke-like episodes) is a major maternally inherited mitochondrial(mt) encephalopathy, a disease in which 80% of cases are associated with mtDNA point mutation (nt A3243G in tRNALeu(UUR)). We report a case of MELAS syndrome confirmed by typical clinical presentation, muscle biopsy, and molecular genetic diagnosis. A patient was 14-year-old male presenting repeated episode of right hemiparesis and visual field defect. He is exhibited a short stature with dull appearance. On neurologic examination, right homonymous hemianopsia, right hemiparesis, and right side hypesthesia are noted. Brain MRI showed multiple signal changes lesion in left thalamus, right occipital and both temporal regions. Level of lactic acid in serum and CSF was highly increased. Ragged red fibers were shown in the modified Gomori-Trichrome staining, and electromicroscopic finding showed on accumulation of variable sized mitochondrias and glycogen particles in some areas of subsarcolemmal and interfibrillar areas. The mitochondrial tRNALeu(UUR) 3243 A to G mutation was identified by PCR/restriction endonuclease and sequencing. The ratio of mutation in leukocytes of proband and proband's mother was 50% and 10%, respectively. We report a case of MELAS syndromes showing mitochondrial tRNALeu(UUR) 3243 A to G mutation.

Neuro-Behcet diseases showing pseudotumoral presentation

BACKGROUND AND SIGNIFICANCE: Because of the diverse clinical and radiologic manifestations of Neuro-Behcet disease, it is sometimes difficult to differentiate with multiple sclerosis or tumorous condition. We report two cases of Neuro-Behcet disease underwent by stereotaxic biopsy showing vasculitis without any evidence of malignancy, initially misdiagnosed as solitary tumor and metastatic tumor, respectively. CASE: A 35-year-old male admitted due to right hemiparesis. Brain CT showed low density mass shadow in left thalamus. Under the impression of low grade astrocytoma, stereotaxic biopsy was performed. Dense perivascular lymphocytic infiltration with petechial microhemorrhage mixed with hemosiderin pigment was noted in thalamic region. The other patient (male, 44yrs old) admitted due to seizure. On MRI, there are multiple inhomogenous signals on right occipital and left frontal lobe and left thalamus. Under the impression of metastatic tumor, work-up about the primary tumor was done without any positive findings. To determine the primary focus, stereotaxic biopsy was performed. Only reactive gliosis and mild perivascular lymphocytic infiltration was noted in pathologic specimen. With the retrospective careful history taking and follow-up image study, two patients were confirmed as having a Behcet's disease.

Morphologic Studies on Forebrain of Thiamine Deficient Rats Induced by Thiamine eficient Diet and Pyrithiamine

OBJECTIVE: This study was designed for developing a new experimental animal model of Wernicke's encephalopathy, and for investigating the timesequential morphological changes in the thiamine deficient rat brain by thiamine deficient diet with short term treatment of pyrithiamine. METHODS: A total of 40 healthy Sprague-Dawley strain rats, weighing about 2OOgm were used as experimental animals, divided into 10 control rats and 30 thiamine deficient experimental rats. Pyrithiamine (50mg/lOOgm/day) was injected intraperitonially for 9 days and thiamine deficient diet (20gm/rat/day) was continuously supplied until sacrifice. Then thiamine deficient experimental rats were subdivided into 3 groups according'to the exposure time of thiamine deficiency. For observing the morphological features in thalamus, medial mammillary nucleus and CA, sector in hippocampus, luxol-fast blue-cresy violet stain was performed. RESULTS: Treatment with pyrithiamine and thiamine deficient diet results in weight loss and decrement of body temperature on the 12th-14th day, followed by various neurologic manifestations, such as ataxia, hypotonia, circling movement, opisthotonus and loss of righting reflex, on the 16th-20th day, and then died on the 23th-25th, day. Chromatolysis and nuclear condensation of neurons in thalamus, medial mammillary nucleus and CA1 region of hippocampus are observed in group I. Mild edematous changes with neuronal necrosis in group II, and marked neuronal loss with severe edematous necrosis in group III are noted in same regions. CONCLUSION: These time sequential consistent morphological changes suggest that our experimental method could be used as a new animal model of Wernicke's encephalopathy in studying the sequential changes of thiamine deficient rat brain.