Epigenetically Upregulated T-Type Calcium Channels Contribute to Abnormal Proliferation of Embryonic Neural Progenitor Cells Exposed to Valproic Acid

Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.

T-Type Calcium Channels Are Required to Maintain Viability of Neural Progenitor Cells

T-type calcium channels are low voltage-activated calcium channels that evoke small and transient calcium currents. Recently, T-type calcium channels have been implicated in neurodevelopmental disorders such as autism spectrum disorder and neural tube defects. However, their function during embryonic development is largely unknown. Here, we investigated the function and expression of T-type calcium channels in embryonic neural progenitor cells (NPCs). First, we compared the expression of T-type calcium channel subtypes (CaV3.1, 3.2, and 3.3) in NPCs and differentiated neural cells (neurons and astrocytes). We detected all subtypes in neurons but not in astrocytes. In NPCs, CaV3.1 was the dominant subtype, whereas CaV3.2 was weakly expressed, and CaV3.3 was not detected. Next, we determined CaV3.1 expression levels in the cortex during early brain development. Expression levels of CaV3.1 in the embryonic period were transiently decreased during the perinatal period and increased at postnatal day 11. We then pharmacologically blocked T-type calcium channels to determine the effects in neuronal cells. The blockade of T-type calcium channels reduced cell viability, and induced apoptotic cell death in NPCs but not in differentiated astrocytes. Furthermore, blocking T-type calcium channels rapidly reduced AKT-phosphorylation (Ser473) and GSK3β-phosphorylation (Ser9). Our results suggest that T-type calcium channels play essential roles in maintaining NPC viability, and T-type calcium channel blockers are toxic to embryonic neural cells, and may potentially be responsible for neurodevelopmental disorders.

A Case of Pure Red Cell Aplasia Associated with B-cell Chronic Lymphocytic Leukemia / 대한혈액학회지

Pure red cell aplasia (PRCA) is a rare disorder, which is characterized by severe anemia associated with reticulocytopenia and absence of erythroid precursor cells in the bone marrow. Recently we experienced a patient with B-cell chronic lymphocytic leukemia associated with PRCA, which was successfully treated with prednisone. A 50-year-old man was admitted because of lymphocytosis. The leukocyte count was 26,800/nL with 82% abnormal mature lymphocytes. Neither anemia nor thrombocytopenia was present. Many abnormal lymphocytes and erythroblasts were seen in the bone marrow. The surface markers of these cells were positive for CD5, CD19, CD20, CD22, and surface immunoglobulin. The patient was diagnosed of B-CLL in Binet-Rai stage A (II), and was treated with chlorambucil. Six months later, severe anemia (hemoglobin 5.9g/dL) with reticulocytopenia developed. In the bone marrow at that time, neutrophils and megakaryocytes besides leukemic cells were preserved, but marked decrease of erythroblasts, a pattern of PRCA was observed. After one-month's observation, we prescribed prednisone. After four weeks of such therapy the patient's hemoglobin reached 10.9g/dL, and he needed no further transfusion.

A Case of Postpartum Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome / 대한혈액학회지

The postpartum thrombotic thrombocytopenic purpura-hemolytic uremic syndrome is a rare complication of normal pregnancy and delivery that is described as a constellation of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. We report a case in patient with postpartum thrombotic thrombocytopenic purpura-hemolytic uremic syndrome who was successfully treated with plasama exchange and prednisolone. Relevant literature was reviewed.

The Effect of Granulocyte-Colony Stimulating Factor in Remission Induction Chemotherapy of Acute Myelogenous Leukemia / 대한혈액학회지

BACKGROUND: Colony stimulating factors have been shown to accelerate recovery from severe neutropenia after intensive chemotherapy. To prove its clinical effectiveness, we conducted this study of administration of G- CSF in acute myelogenous leukemia after remission induction chemotherapy. METHODS: Thirty six patients with acute myelogenous leukemia were assigned to one of two groups (21 to G-CSF treated group, 15 to control group) after remission induction che motherapy administration. Treatment with G-CSF (lenograstim, 200ng/m2/d) was started 5 days after the end of chemotherapy and continued until the neutrophil count rose above 1,500/mm3. RESULTS: Treatment with G-CSF shortened neutropenic period after chemotherapy. The median time to recovery to neutrophil counts more than 500/mm3 from the end of chemotherapy was 19 days in G-CSF treated group and 25 days in control group. The incidence of infection was 19 cases in G-CSF treated group and 13 cases in control group and febrile periods were 12 days in G-CSF treated group and 15 days in control group, but there were no statistically significant differences. The duration of antibiotics treatment in G-CSF treated group was shorter than that of control group. There was no evidence that G-CSF could increase remission duration and overall survival. CONCLUSION: Recombinant G-CSF is safe and useful in patients after intensive chemotherapy, accelerating neutrophil recovery and thereby reducing the duration of antibiotics administration.

A case of Hydroxyurea-induced fever / 대한내과학회지

A patient with idiopathic hypereosinophilic syndrome is reported who developed a drug fever that may be related to the administration of hydroxyurea. Typically, this form of fever develops after a few weeks of exposure to the drug and disappears with withdrawal of the drug and recurs on reexposure to the drug. The mechanism of hydroxyurea-induced fever remains unclear.

Brain metastasis: Clinical characteristics and prognosis / 대한내과학회지

BACKGROUND: Brain metastasis is a common complication in cancer patients. We evaluated the clinical characteristics, treatment outcome and prognostic factors for patients with metastatic brain tumor. METHODS: The records of 97 patients with metastatic brain tumor during the period from January 1991 to November 1997 were reviewed retrospectively. RESULTS: The most common primary tumor is lung cancer (61 cases, 63%) followed by metastatic cancer unknown primary site (15 cases, 16%), gastrointestinal cancer (13 cases, 13%), breast cancer (6 cases, 6%) and renal cancer (2 cases, 2%). There were 44 patients with a single brain metastasis and 53 patients with multiple brain metastases. The median survival was 3.0 months and one-year survival rate was 8% irrespective of treatment. Favorable prognostic factors which affect survival were ambulatory status (p<0.01) and functional neurologic class 1, 2 (p<0.01). Median survival was 3.7 months for patients with steroid therapy and 1.1 months with no therapy (p<0.01). Median survival was 4.8 months for patients with steroid therapy plus whole brain radiotherapy (WBRT) and 2.2 months with steroid therapy alone (p<0.01). Additional chemotherapy did not appear to affect the survival. The patients treated with surgery had median survival time of 8.8 months compared with 2.5 months for patients treated with steroid therapy plus WBRT (p<0.05). CONCLUSION: In present study, we confirmed that whole brain irradiation and corticosteroid administration are effective palliative treatment for patients with metastatic brain tumor. Initial performance status and neurological function were identified as important prognostic factors. Although confounded by the limitations of retrospective study, more aggressive treatments including surgery and chemotherapy could be regarded to have a significant role to achieve better treatment outcome in some selected cases.

Therapeutic Results of Two Regimens for Childhood Acute Myelogenous Leukemia / 대한소아혈액종양학회지

PURPOSE: The purpose of this study was to compare the therapeutic results between the two groups of children with acute myelogenous leukemia (AML) who were treated either by 3-year Okayama regimen or by 2-year KSBRM regimen. METHODS: The subjects were 38 newly diagnosed AML patients at Chonnam University Hospital from Apr. 1991 to Dec. 1998. Until April, 1994, 10 patients were treated by the Okayama regimen for 3 years while 28 patients received KSBRM regimen for 2 years thereafter. The remission induction rate, relapse rate, and survival rate were compared retrospectively between the two groups. RESULTS: 1) The remission induction rate was 78.9% (30/38): Okayama group, 80.0% (8/10); KSBRM group, 78.6% (22/28). 2) The relapse rate after remission in the Okayama group was 37.5% (3/8) while that in the KSBRM group was 27.3% (6/22). 3) Deaths were encountered in 16 patients (42.1%): 60.0% (6/10) of Okayama group vs 35.7% (10/28) of KSBRM group (P=0.27). 4) Kaplan-Meier 3-year disease free survival (DFS) for all of the patients was 45.2%. The 3-year DFS was 40.0% for Okayama group and 48.2% for KSBRM group, respectively. The remission induction rate, relapse rate and DFS rate were not different between the two groups. CONCLUSION: The current study showed that KSBRM regimen was as equivalent as Okayama regimen for remission induction rate, relapse rate and 3-year Kaplan-Meier DFS despite the advantage of shortening of treatment duration by 1 year.