Heme-binding-mediated negative regulation of the tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) by IDO2

Indoleamine 2,3-dioxygenases (IDOs) are tryptophan-catabolizing enzymes with immunomodulatory functions. However, the biological role of IDO2 and its relationship with IDO1 are unknown. To assess the relationship between IDO2 and IDO1, we investigated the effects of co-expression of human (h) IDO2 on hIDO1 activity. Cells co-expressing hIDO1 and hIDO2 showed reduced tryptophan metabolic activity compared with those expressing hIDO1 only. In a proteomic analysis, hIDO1-expressing cells exhibited enhanced expression of proteins related to the cell cycle and amino acid metabolism, and decreased expression of proteins related to cell survival. However, cells co-expressing hIDO1 and hIDO2 showed enhanced expression of negative regulators of cell apoptosis compared with those expressing hIDO1 only. Co-expression of hIDO1 and hIDO2 rescued the cell death induced by tryptophan-depletion through hIDO1 activity. Cells expressing only hIDO2 exhibited no marked differences in proteome profiles or cell growth compared with mock-transfectants. Cellular tryptophan metabolic activity and cell death were restored by co-expressing the hIDO2 mutant substituting the histidine 360 residue for alanine. These results demonstrate that hIDO2 plays a novel role as a negative regulator of hIDO1 by competing for heme-binding with hIDO1, and provide information useful for development of therapeutic strategies to control cancer and immunological disorders that target IDO molecules.

Comparison of Antiplatelet Aggregation Effect between the High-Dose and Low-Dose Ticlopidine: A Preliminary Study

BACKGROUND: To investigate the efficacy of antiplatelet activity of low dose ticlopidine, we compared the antiplatelet effect of low dose ticlopidine with a high dose. METHODS: Fourteen healthy volunteers were divided into two series. Volunteers in series I were medicated ticlopidine 250 mg twice a day (group 1) for first 7 days. After drug free interval for another 7 days, single dose of ticlopidine 250 mg a day (group 2) was medicated for the third 7 days. Same medica-tion schedule was taken with different doses in series II, single dose of 250 mg ticlopidine (group 3) for the first 7 days, and divided dose of ticlopidine 250 mg a day (group 4) for the third 7 days after medication free interval of 7 days. Platelet aggregation effect was evaluated by optical method using ADP and collagen reagent at before and after the medication schedule. Differences of platelet aggregation effect between the four groups were analyzed. RESULTS: Five and 4 could accomplish the full medication schedule of two groups in each series. Mean of platelet aggregation effect of group 1 (44.4%) was more decreased than other groups, 61.2% in group 2, 71.0% in group 3, and 62.7% in group 4. However, there was no significant differences of platelet aggregation effect by nonparametric statistical analysis between group 1 and 2, 3 and 4 in each series. CONCLUSIONS: This finding suggests that single low dose ticlopidine may have the similar antiplatelet aggregation effect as the high dose one.

Classification of epileptic seizures according to the international league against epilepsy (ILAE) classifications of epileptic seizures (1981) and epilepsies and epileptic syndromes (1989) in chungnam national university hospital

Classification of epileptic seizures and syndromes is essential in the management of epileptic patients. Both of the classifications proposed by ILAE are still popularly applied in clinical situations. We tried to verify the differences and usefulness of each classification. During the two year period, 385 consecutive patients (248 male, 137 female) of five years of age or more were classified according to the ILAE classimification of epileptic seizures (1981). These patients were independently classified by two neurologists with the ILAE classification (1989) with same clinical informations. We tentatively add three different sub-categories (focal/multifocal structural lesions with generalized epilepsy, isolated and situation-related epilepsy, and unclassified epilepsy) on the ILAE classification (1989) because of some unclassifiable epileptics. In epilepsies and epileptic syndromes, 61.8% were localization related, 21.8% were generalized, 2.9% were undetermined, 10.9% were special syndrome, 2.6% were unclassifed. After the classification of some patients into the three sub-categories, observed amount of agreement was rised as 95.9%. In the classification of epilepsy and epileptic syndromes proposed by ILAE (1989), debatable definition of categories and resulting unclassifiable epileptic seizure limit the clinical application in some patients.

New-onset seizure in hospitalized patients

Systemic illnesses and preexisting disorders affecting the brain may decrease the seizure threshold in some conditions. For the non-neurologist, patient with new-onset seizure (NOS) is troublesome problem to manage properly. To verify the characteristics of patients with NOS, we analyzed their clinical features. From Jan. 1991 to Jul. 1995, 47 patients were consulted to the neurological department because of their NOS during the admission. We retrieved the medical records, laboratory data and consultation sheets. The most common cause of the NOS was a metabolic disorder (18 patients, 38.3%) and was followed by a previous cerebrovasular disease (6 patients, 12.8%). Ceneralized tonic-clonic seizure occurred in more than half of the patients (55.3%). Fifteen out of 26 initial EEGs revealed diffuse slowings only, whereas only four patients showed focal epileptiform discharges. Status epileptics occurred in seven patients and five of them died. Six patients out of 17 patients with metabolic causes died, comparing five patients out of 27 patients with other causes. It is suggested that the NOS associated with metabolic causes are most common in hospitalized patients and were associated with poor prognosis.

Variables Associated with Delayed Hospital Arrival of Stroke Patients Living in Taejon and Its Suburban Areas

Recent stroke researches have re-emphasized the critical therapeutic time window for antithrombotic and neuroprotective trials for the stroke victims. In this prospective study , we tried to reveal the variables that had delayed the presentation time of the acute stroke patients living in Taejon and its suburban areas. The time of stroke onset, distance from the place of stroke occurrence to the Chung-nam National Univorsity Hospital (CNUH), level of consciousness, basic demographic data, place of residence, and referral routes were assessed. During the study period of 8 months, 173 new patients visited the emergency department of the CNLTH.in the acute phase of stroke. Of 173 patients, 122 had cerebral ischemia (CI), 40 intracerebral hemorrhage (ICH), and 11 subarachnoid hemorrhage (SAH). Only 91 patients (52.6%) presented within 6 hours. Fourty-six percent of Cl, 65% of ICH, and 72% of SAH patients presented within 6 hours. There was no correlation between the presentation time and the age, sex, stoke subtype, distance from CNLTH, and place of residence. The vat-la ' bles that had significantly delayed the presentation time included the better initial consciousness level and referral route through the oriental medicine clinics. These findings suggest that the need for prompt management of stroke patient is poorly understood and that the onental medicine is still preferred by the general population. Tlius, we need to develop an education program and public activities as well as an effective patient dehvery system to nunmum the neuronal damage following stroke.

Anton's Syndrome

We report two patients with characteristic behavioral features, which were denial of blindness, indifference to self and environment, severe memory impairment, and confabulation. It seems that transitory functional depression of the right parietal cortex caused by de-afferentation from the occipital lobe is likely to produce unawareness of visual failure. Dysfunction in both temporal lobes secondary to insufficiency of the posterior cerebral arteries may be responsible for memory impairment accompanied with confabulation. It suggest functional depression in parietal and temporal lobes, not occipital lesion perse, is necessary to produce Anton's syndrome in patients with bilateral occipital lesions. To our knowledge, this is the first report on the Anton's syndrome in Korea. But functional brain imaging such as brain SPECT or PET is required to prove my assumptive mechanisms.