Fate of Atrial Myocardium in Severe Mitral Regurgitation in the Aspect of Programmed Cell Death

BACKGROUND AND OBJECTIVES: From the view point of the molecular aspects, the fate of long standing pressure and volume overloaded atrium in severe MR has not been evaluated. This study was performed to elucidate whether apoptosis of right atrial myocytes is related to atrial changes. SUBJECTS AND METHODS: The medical records of 16 patients (M: F=8: 8, mean age=52+/-12), with severe MR having undergone valve replacement surgery, were retrospectively reviewed. The subjects were divided into 2 groups according to the duration of their symptoms (group I, symptom duration less than 12 months, n=10 and group II, more than 12 months, n=6). Using the atrial myocardium specimens obtained during surgery, TUNEL assays and immunohistochemical staining were performed for the expressions of Fas, Bax and the Bcl family. RESULTS: Apoptotic indices of TUNEL assay were 31.1+/-12.6 and 4.9+/-4.3% in groups I and II, respectively (p<0.01). The Fas expressions were 42.1+/-14.4 and 27.8+/-10.5% in groups I and II, respectively (p<0.05), but in group I, with atrial fibrillation (AF), was 49.3+/-6.9%, which was higher than the 29.2+/-12.5% in group I without AF and group II (p<0.001). The Bax expression in group I patients with a left atrial size less than 4 cm was 19.2+/-10.7%, which was higher than the 7.2+/-6.2% in group I with a left atrial size more than 4 cm and group II (p<0.05). CONCLUSION: Programmed cell death of the atrial myocardium, in severe MR, might be an early molecular pathological change rather than the late sequelae. The causality between programmed cell death and electrical and structural changes of the atrium should be further investigated.

Feedback Control of Cyclooxygenase-2 Expression by Prostaglandin E2 in Rheumatoid Synoviocytes

Objective: The role of prostaglandin E2 (PGE2) in the etiopathogenesis of immune and inflammatory diseases has become the subject of recent debate. To determine the role of PGE2 in rheumatoid arthritis (RA), we tested the effect of exogenous PGE2 on the production of cyclooxygenase-2 (COX-2) by rheumatoid synoviocytes. METHODS: Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and cultured in the presence of PGE2. The COX-2 mRNA and protein expression levels were determined by RT-PCR and Western blot analysis, respectively. The PGE2 receptor subtypes in the FLS were analyzed by RT-PCR. Electrophoretic mobility shift assay (EMSA) was used to measure the NF-kappaB binding activity for COX-2 transcription. The in vivoeffect of PGE2 on the development of arthritis was also tested in collagen induced arthritis (CIA) animals. RESULTS: PGE2 (10(-11) to 10(-5) M) dose-dependently inhibited the expression of COX-2 mRNA and the COX-2 protein stimulated with IL-1beta, but not COX-1 mRNA. NS-398, a selective COX-2 inhibitor, displayed an additive effect on PGE2-induced COX-2 downregulation. The FLS predominantly expressed the PGE2 receptor (EP) 2 and EP4, which mediated the COX-2 suppression by PGE2. Treatment with anti-IL-10 monoclonal antibodies partially reversed the PGE2-induced suppression of COX-2 mRNA, suggesting that IL-10 may be involved in modulating COX-2 by PGE2. Experiments using an inducer and an inhibitor of cyclic AMP (cAMP) suggest that cAMP is the major intracellular signal that mediates the regulatory effect of PGE2 on COX-2 expression. EMSA revealed that PGE2 inhibited the binding of NF-kappaB in the COX-2 promoter via a cAMP dependent pathway. In addition, a subcutaneous injection of PGE2 twice daily for 2 weeks significantly reduced the incidence and severity of CIA as well as the production of IgG antibodies to type II collagen. CONCLUSION: Our data suggest that overproduced PGE2 in the RA joints may function as an autocrine regulator of its own synthesis by inhibiting COX-2 production and may, in part, play an anti-inflammatory role in the arthritic joints.

Effect of Endothelin-1 on the Expression of Monocyte Chemoattractant Protein-1 in Cultured Human Proximal Tubular Epithelial Cells / 대한신장학회잡지

BACKGROUND: Monocyte chemoattractant protein- 1 (MCP-1) is produced by renal cells and an important mediator for monocyte/macrophage infiltration in various inflammatory renal diseases. In the process of renal disease, endothelin-1 is known to play an active role in cell growth, inflammation and fibrosis. The aim of this study was to investigate whether endothelin-1 regulates MCP-1 expression in cultured human proximal tubular epithelial cells. METHODS: Primary cultured human proximal tubular epithelial cells (PTEC) were incubated with or without various dose of endothelin-1. MCP-1 concentration in PTEC conditioned medium was measured by sandwich ELISA. MCP-1 mRNA expression was analyzed by Northern blotting. The NF-kB or AP-1 activity in response to endothelin-1 was measured by electrophoretic mobility shift assay. RESULTS: Endothelin-1 (10(-7) M) stimulated MCP- 1 production in PTEC, which was significant at 48 hours and various doses of endothelin-1 (10(-8)-10(-6) M) increased MCP-1 production from PTEC in a dose-dependent manner. Northern blot analysis revealed that endothelin-1 stimulated MCP-1 mRNA expression. Endothelin-1 (10(-7) M) stimulated both AP-1 binding activity and NF-kB binding activity up to 8 hour. Supershift analysis showed that p65 and p50 are major NF-kB subunit bound to the DNA probe and that c-Fos and c-Jun are major AP-1 subunit bound to the DNA probe. CONCLUSION: Our results suggest that endothelin- 1 may stimulate MCP-1 expression in proximal tubular epithelial cells through the activation of NF- kB and AP-1 binding activity.

A Case of Creutzfeldt-Jacob Disease / 신경정신의학

We report a case of Creutzfeldt-Jacob disease and review the relevant literatures. This 56-year-old male patient was admitted to our hospital with a history of rapidly progressing cognitive dysfunction, visual disturbance, gait disturbance, weakness, involuntary movement of lower extremities, and the symptoms of delirium. On mental status examination, he showed psychomotor retardation, speech disturbance, perseveration, disorientation, impairement of short-term and long-term memory, and inability of abstract thinking. He had a rapid downhill course, along with shakiness of trunk, rigidity of the limbs, myoclonus, confusion, and finally, inability to speak or move on the bedside. On electroencephalogram(EEG), continuous multifocal slow delta activities were found in all leads, especially in the right frontal areas. Brain biopsy showed, spongiosis with neuronal loss and gliosis noted at the cerebral cortex. These findings were compatible with Creutzfeldt-jacob disease.

A Case of Eosinophilia Induced by Clozapine / 신경정신의학

Clozapine, one of the dibenzodiazepine derivatives, has potent antipsychotic properties and acts on schizophrenic patients who are nonresponsive to classic neuroleptics without neurologic side effects such as extrapyamidal symptoms, tardive dyskinesia and neuroleptic malignant syndrome. But, several blood dyscrasias associated with clozapine are well known to clinicians. Potentially life-threatening agranulocytosis, leukopenia and leukocytosis are most widely reported. Also eosinophilia has been identified as a potential side effect in some studies or case reports. We report a case of severe eosinophilia associated with the administration of clozapine in a male schizophrenic patient, which improved spontaneously along with clozapine maintenance therapy. We also reviewed previous reports of eosinophilia induced by clozapine adminstration and recognized that eosinophilia is not uncommon and transient side effect of clozapine.

Chronic Antidepressant Administration Increases the Expression of PhosphoCREB(Phosphorylated Cyclic AMP Response Element Binding Protein) in Rat Hippocampus / 신경정신의학

OBJECTIVES: This study designed to assess the expression of phosphoCREB in rat hippocampus after chronic administration of various antidepressants in comparison with chronic administration of antipsychotic and antianxiety drugs. METHODS: Male sprague-Dawley rats(200-300g) were used for this experiment. The subjects were divided into 6groups according to specific treatment agents(paroxetine, desipramine, moclobemide, haloperidol. lorazepam, vehicl) which were administered daily for 1day, 3days, 7days, and 14days by intraperitoneal injection repectively. Brains were removed 15 minutes after the last treatment. PhosphoCREB immunoreactivity was mesured by phosphoCREB(+) cell counts in hippocampus of rats. RESULTS: Expression of phosphoCREB was significantly increased from day 3 in moclobemide group, from day 7 in paroxetine and desipramine groups, and increased most significantly from day 14 in all antidepressant-administered groups, with no increase in other tow groups(lorazepam and haloperidol group) throughout the experiment and even after 14 days of treatment. CONCLUSION: These result suggest that increased expression of phosphoCREB after chronic administration of antidepressants, not of antipsychotic or antianxiety drugs, demonstrates pharmacological specificity of antidepressant treatment in rat hippocampus regardless of their receptor preference.