Acute myeloid leukemia (AML) is a fatal hematological malignancy which is resistant to a variety of chemotherapy drugs. Extracellular signal-regulated kinase 5 (ERK5) plays a novel role in chemoresistance in some cancer cells and this pathway is a central mediator of cell survival and apoptotic regulation. The aim of this study was to investigate the effect of ERK5 inhibitor, XMD8-92, on proliferation and apoptosis in AML cell lines. Findings showed that XMD8-92 inhibited the activation of ERK5 by G-CSF and decreased the expression of c-Myc and Cyclin D1. The treatment of XMD8-92 reduced the phosphorylation of ERK5 leading to a distinct inhibition of cell proliferation and increased apoptosis in Kasumi-1 and HL-60 cells. Taken together, our study suggests that the inhibition of ERK5 by XMD8-92 can trigger apoptosis and inhibit proliferation in AMLs. Therefore, the inhibition of ERK5 may be an effective adjuvant in AML chemotherapy.
Apoptosis ; Cell Cycle ; Cell Line ; Cell Proliferation ; Cell Survival ; Cyclin D1 ; Drug Therapy ; Granulocyte Colony-Stimulating Factor ; Hematologic Neoplasms ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute ; Mitogen-Activated Protein Kinase 7 ; Phosphorylation

We report a 48-year-old man with laryngeal cancer who received a massive cisplatin toxic overdose without intravenous prehydration through an error in prescription. He received 400 mg/m2 of cisplatin over a 4-day period. On day 4, he exhibited a broad range of cisplatin toxicities and emergency plasma exchange was started. From day 5 through 19, he underwent 9 cycles of plasma exchange and his plasma cisplatin concentration decreased from 2,470 ng/ml to 216 ng/ml. He completely recovered without any sequelae. No previous reports exist in the English literature of survival without complication after the administration of such a high cisplatin dosage without prehydration.
Antineoplastic Agents/*poisoning ; Case Report ; Cisplatin/*poisoning ; Human ; Male ; Middle Age ; Overdose/therapy ; *Plasma Exchange

No abstract available.
Capsid Proteins* ; Capsid* ; Humans* ; Insects*

BACKGROUND: Semantic dementia (SD) is a temporal variant of frontotemporal lobar degeneration (FTLD), which is characterized by naming difficulty, decreased comprehension of words, prosopagnosia and object visual agnosia. We report clinical features, neuropsychological and neuroimaging findings of 4 patients with SD. METHODS: Of 55 patients diagnosed as having FTLD between Jan 1995 and May 2001 at Samsung Medical Center, four patients fulfilled the diagnostic criteria of SD proposed by consensus on FTLD diagnostic criteria. We investigated their clinical features such as presenting symptoms and abnormal behaviors, neuropsychological and neuroimaging findings. Neuropsychological tests included the Seoul Neuropsychological Screening Battery, the Korean-version of Western Aphasia Battery and Hanja reading and writing. All patients underwent brain MRI and FDG-PET. RESULTS: All of the patients showed naming difficulty as a presenting symptom. Language assessments showed severe naming and compre-hension difficulties with preserved fluency and repetition, which were compatible with transcortical sensory aphasia. Whereas Hangul reading aloud and writing were intact, three patients were impaired at Hanja reading and writing. Other neuropsychological tests were remarkable for prosopagnosia, object visual agnosia and memory loss. Brain MRI showed asymmetric temporal atrophies, mainly left antero-inferior temporal cortices. FDG-PET also showed hypome-tabolism in bilateral anterior temporal lobes, more severe on the left. CONCLUSIONS: Our SD patients had characteristic neuropsychological and neuroimaging findings, which can be differentiated from other neurodegenerative diseases. We also found Hanja alexia and agraphia in SD patients, which has not been reported yet.
Agnosia ; Agraphia ; Aphasia ; Aphasia, Wernicke ; Atrophy ; Brain ; Comprehension ; Consensus ; Dyslexia ; Frontotemporal Dementia* ; Frontotemporal Lobar Degeneration ; Humans ; Magnetic Resonance Imaging ; Mass Screening ; Memory Disorders ; Neurodegenerative Diseases ; Neuroimaging* ; Neuropsychological Tests ; Prosopagnosia ; Semantics* ; Seoul ; Temporal Lobe ; Writing

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.
Cell Proliferation ; Cell Survival ; Gene Expression ; HEK293 Cells ; Heme/*metabolism ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics/*metabolism ; Protein Binding ; Tryptophan/*metabolism ; Up-Regulation

Butylated hydroxytoluene (BHT) can inhibit experimental atherosclerosis in animals. Although the agent is an antioxidant, the exact mechanism of the reaction in atherosclerosis is still unknown. To investigate the effects of BHT on expression of P-selectin (PADGEM, GMP-140), intercellular adhesion molecule-1 (ICAM-1) and class II MHC (Ia) antigen, we proposed an experiment on rats. Male rats (n=18 per group) were fed either a normal cholesterol control diet, a normal cholesterol diet containing 0.5% BHT (BD), a high cholesterol diet containing 1.5% cholesterol and 0.1% sodium cholate (CD), or the CD diet containing 0.5% BHT (BCD). Rats were sacrificed after 3 days, and after 1, 2, 4, 10, and 17 weeks of dietary treatment. Although there was no gross or light microscopic atherosclerotic lesions, scanning electron microscopy revealed monocytic adhesion to aortic endothelium and mild endothelial injuries in CD and BCD groups. Immunohistochemically, the addition of BHT to a high cholesterol diet inhibited P-selectin expression but not in ICAM-1 and Ia antigen. These findings suggest that in rats, high cholesterol diets induce expression of ICAM-1, P-selectin and Ia antigen. In addition, the antiatherogenic effect of BHT may play a role in the inhibition of P-selectin.
Animal ; Antioxidants/pharmacology ; Antioxidants/metabolism* ; Aorta, Abdominal/ultrastructure ; Aorta, Abdominal/pathology ; Aorta, Thoracic/ultrastructure ; Aorta, Thoracic/pathology ; Butylated Hydroxytoluene/pharmacology ; Butylated Hydroxytoluene/metabolism* ; Cholesterol/metabolism ; Cholesterol, Dietary/metabolism* ; Male ; Microscopy, Electron, Scanning ; P-Selectin/biosynthesis* ; Rats ; Rats, Sprague-Dawley

BACKGROUND: We have recently shown that lipopolysaccharide (LPS), a major biologically active component of Gram-negative bacteria, mediate the activation of human keratinocytes by CD14 and Toll-like receptor (TLR 4). However, the mechanism of activation of keratinocytes by Gram-positive bacterial toxins remains unclear. OBJECTIVE: We investigated the mechanism of activation of human keratinocytes by lipoteichoic acid (LTA), a main stimulatory component of Gram-positive bacteria. METHODS: The effects of LTA on CD14, TLR2 and TLR4 mRNA expression were measured by quantitative RT-PCR in cultured human keratinocytes. To determine whether the effects of LTA on CD14, TLR2 and TLR4 expressions of the human keratinocytes were biologically functional, NF-kappaB nuclear translocation and IL-1alpha secretion were measured by immunofluorescence staining and ELISA, respectively. Furthermore, to determine whether these effects by LTA were specific for CD14, TLR2 and TLR4, some cells were pretreated with anti-CD14, anti-TLR2, or anti-TLR2 monoclonal antibodies prior to the addition of LTA. RESULTS: TLR4 mRNA expression on keratinocytes was augmented by exposure to LTA. LTA binding to keratinocytes resulted in NF-kappaB nuclear translocation and secretion of interleukin-1alpha. These responses by LTA were effectively abrogated by preincubating cells with anti-TLR4 monoclonal antibody, but not with anti-CD14 or anti- TLR2 monoclonal antibodies. CONCLUSION: These results indicate that, similar to LPS, LTA induces activation of human keratinocytes mainly through TLR4, however, in contrast to LPS signaling, LTA-induced keratinocyte activation is CD14-independent.
Antibodies, Monoclonal ; Bacterial Toxins ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Gram-Negative Bacteria ; Gram-Positive Bacteria ; Humans* ; Interleukin-1alpha ; Keratinocytes* ; NF-kappa B ; RNA, Messenger ; Toll-Like Receptor 4* ; Toll-Like Receptors*

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder characterized by a severe impairment of gastrointestinal propulsion in the absence of mechanical obstruction. We experienced a case of chronic pseudo-obstruction in the initial phase mimicking acute pseudo-obstruction, which was treated medically. This ongoing case was compared to another recurrent and intractable case successfully treated with surgery and diagnosed as hypoganglionosis. These two cases showed different clinical features and therapeutic approaches for CIPO; one with the first episode of CIPO mimicking Ogilvie's syndrome; the other with recurrent episodes of CIPO with typical features. In conclusion, CIPO is a difficult disorder with various clinical manifestations and different treatment modalities, therefore individualized diagnostic and therapeutic approaches are needed.
Colon ; Intestinal Pseudo-Obstruction

Recent studies indicate that several Toll-like receptors (TLRs) are implicated in recognizing viral structures and instigating immune responses against viral infections. The aim of this study is to examine the expression of TLRs and proinflammatory cytokines in viral skin diseases such as verruca vulgaris (VV) and molluscum contagiosum (MC). Reverse transcription-polymerase chain reaction and immunostaining of skin samples were performed to determine the expression of specific antiviral and proinflammatory cytokines as well as 5 TLRs (TLR2, 3, 4, 7, and 9). In normal human skin, TLR2, 4, and 7 mRNA was constitutively expressed, whereas little TLR3 and 9 mRNA was detected. Compared to normal skin (NS), TLR3 and 9 mRNA was clearly expressed in VV and MC specimens. Likewise, immunohistochemistry indicated that keratinocytes in NS constitutively expressed TLR2, 4, and 7; however, TLR3 was rarely detected and TLR9 was only weakly expressed, whereas 5 TLRs were all strongly expressed on the epidermal keratinocytes of VV and MC lesions. In addition, the mRNA expression of IFN-beta and TNF-alpha was upregulated in the VV and MC samples. Immunohistochemistry indicated that IFN-beta and TNF-alpha were predominately localized in the granular layer in the VV lesions and adjacent to the MC bodies. Our results indicated that VV and MC skin lesions expressed TLR3 and 9 in addition to IFN-beta and TNF-alpha. These viral-induced proinflammatory cytokines may play a pivotal role in cutaneous innate immune responses.
Cytokines/metabolism ; *Gene Expression Regulation ; Humans ; Immunohistochemistry/methods ; Inflammation ; Interferon-beta/biosynthesis ; Keratinocytes/cytology ; Models, Biological ; Molluscum Contagiosum/*metabolism ; Toll-Like Receptor 3/biosynthesis ; Toll-Like Receptor 9/biosynthesis ; Toll-Like Receptors/*biosynthesis ; Tumor Necrosis Factor-alpha/biosynthesis ; Warts/*metabolism

BACKGROUND: Neglect dyslexia is a type of neglect syndrome, in which patients with unilateral hemisphere injury omit or misread the contralateral side of a text or the initial letters of a word. Hangul can be arrayed vertically (vertical reading, VR) as well as horizontally (horizontal reading, HR). Thus, HR and VR can be differentially affected in neglect dyslexia. We conducted an experiment in a 66 year-old woman who suffered from neglect dyslexia after a right cerebral infarction. We compared HR with VR in terms of error frequencies and patterns. METHODS: Stimuli for neglect dyslexia consisted of 227 words. The 227 words were written horizontally or vertically (total 554 words) and were pre-sented in random order. The patient was asked to read the words and the examiner recorded the patient's responses and reaction times. RESULTS: The differences in HR and VR were as follows: 1) the error frequency in HR (59.0%) was higher than the error frequency in VR (20.3%), 2) the most frequent error in HR was syllabic deletion (79.1%) whereas phonemic substitution (89.1%) predominated in VR, 3) the error rate was highest at the first syllabic position in HR whereas no position effect was noted in VR. CONCLUSIONS: Patients with neglect dyslexia make less error in VR than in HR. The neural processing of HR may be different from that of VR. VR may be an alternative reading strategy that may be useful during the recovery stage of neglect dyslexia.
Aged ; Cerebral Infarction ; Dyslexia* ; Female ; Humans ; Reaction Time