Three Cases of Reversible Agranulocytosis after Treatment with Lamotrigine

Several psychotropic drugs, including clozapine, are known to cause agranulocytosis and this may lead to a fatal condition. Lamotrigine is an anticonvulsant that the Food and Drug Administration (FDA) has approved for the depression of bipolar disorder. A few cases of lamotrigine-induced agranulocytosis have been previously reported on, but the pathophysiology and clinical manifestations are not yet known. This case series reports on 3 patients with different medical conditions who experienced agranulocytosis during treatment with lamotrigine. In these cases, the agranulocytosis occurred a few weeks after initiation of lamotrigine and it rapidly disappeared after discontinuation. We also discuss several characteristics of lamotrigine-induced agranulocytosis

Role of Transcription Factor Modifications in the Pathogenesis of Insulin Resistance

Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver not due to alcohol abuse. NAFLD is accompanied by variety of symptoms related to metabolic syndrome. Although the metabolic link between NAFLD and insulin resistance is not fully understood, it is clear that NAFLD is one of the main cause of insulin resistance. NAFLD is shown to affect the functions of other organs, including pancreas, adipose tissue, muscle and inflammatory systems. Currently efforts are being made to understand molecular mechanism of interrelationship between NAFLD and insulin resistance at the transcriptional level with specific focus on post-translational modification (PTM) of transcription factors. PTM of transcription factors plays a key role in controlling numerous biological events, including cellular energy metabolism, cell-cycle progression, and organ development. Cell type- and tissue-specific reversible modifications include lysine acetylation, methylation, ubiquitination, and SUMOylation. Moreover, phosphorylation and O-GlcNAcylation on serine and threonine residues have been shown to affect protein stability, subcellular distribution, DNA-binding affinity, and transcriptional activity. PTMs of transcription factors involved in insulin-sensitive tissues confer specific adaptive mechanisms in response to internal or external stimuli. Our understanding of the interplay between these modifications and their effects on transcriptional regulation is growing. Here, we summarize the diverse roles of PTMs in insulin-sensitive tissues and their involvement in the pathogenesis of insulin resistance

The effects of MK-801 on the phosphorylation of Ser338-c-Raf-MEK-ERK pathway in the rat frontal cortex

MK-801 induces psychotomimetic behavioural changes in animals. ERKs play an important role in the pathogenesis of schizophrenia and in the action of antipsychotics and psychotomimetics. We observed phosphorylation of ERK-signalling-pathway-associated molecules in the rat frontal cortex and their association with rat behaviour after MK-801 administration. After injecting 0.25-1 mg/kg MK-801, ERK phosphorylation decreased compared to vehicle treatment, and rats showed increased locomotion. After 2 mg/kg treatment, ERK phosphorylation increased and rat motility started to decrease. After treating with 4-8 mg/kg, ERK phosphorylation once again decreased and rats showed hypomotility and ataxia. ERK phosphorylation levels were maintained from 15 min to 90 min after 1 or 2 mg/kg treatment. Ser338-c-Raf and MEK phosphorylation showed similar dose-dependent and temporal patterns to those of ERK. Taken together, Ser338-c-Raf-MEK-ERK phosphorylation by MK-801 in the rat frontal cortex showed a specific pattern and may be associated with behavioural changes induced by MK-801

PCR for Diagnosis of Male Trichomonas vaginalis Infection with Chronic Prostatitis and Urethritis

The aim of this study was to assess the usefulness of PCR for diagnosis of Trichomonas vaginalis infection among male patients with chronic recurrent prostatitis and urethritis. Between June 2001 and December 2003, a total of 33 patients visited the Department of Urology, Hanyang University Guri Hospital and were examined for T. vaginalis infection by PCR and culture in TYM medium. For the PCR, we used primers based on a repetitive sequence cloned from T. vaginalis (TV-E650). Voided bladder urine (VB1 and VB3) was sampled from 33 men with symptoms of lower urinary tract infection (urethral charge, residual urine sensation, and frequency). Culture failed to detect any T. vaginalis infection whereas PCR identified 7 cases of trichomoniasis (21.2%). Five of the 7 cases had been diagnosed with prostatitis and 2 with urethritis. PCR for the 5 prostatitis cases yielded a positive 330 bp band from bothVB1 and VB3, whereas positive results were only obtained from VB1 for the 2 urethritis patients. We showed that the PCR method could detect T. vaginalis when there was only 1 T. vaginalis cell per PCR mixture. Our results strongly support the usefulness of PCR on urine samples for detecting T. vaginalis in chronic prostatitis and urethritis patients

An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERRγ

The estrogen receptor-related receptor gamma (ERRγ/ERR3/NR3B3) is a member of the nuclear receptor superfamily that activates transcription in the absence of ligand. However, the detailed mechanism of gene regulation by ERRγ is not fully understood. In this study we have found that the orphan nuclear receptor ERRγ activates the DAX-1 promoter, which, in turn, represses transactivation by ERRγ. Serial deletions of mouse DAX-1 (mDAX-1) gene promoter have revealed that the region responding to ERRγ is located between −129 and −121 bp and −334 and −326 bp. Gel shift assays and chromatin immunoprecipitation (ChIP) assays demonstrated that ERRγ binds directly to the mDAX-1 promoter. Site-directed mutagenesis results demonstrated that ERRE1 (−129 to −121 bp) is more important than ERRE2 (−334 to −326 bp) which is not conserved in the human DAX-1 promoter. In addition, adenovirus-mediated overexpression of ERRγ induced DAX-1 gene expression in MCF-7 breast cancer cells that co-expressed ERRγ and DAX-1. Moreover, yeast two-hybrid and glutathione S-transferase (GST)-pull down assays demonstrated that DAX-1 physically interacted with ERRγ and inhibited ERRγ transactivation, and that this interaction was dependent on the AF-2 domain of ERRγ. In addition, in vitro competition assays showed that DAX-1 inhibited PGC-1α mediated ERRγ transactivation, via competition between these two factors for the AF-2 binding domain. We thus propose a novel autoregulatory loop that controls DAX-1 gene expression by ERRγ

Increased phosphorylation of Ser473-Akt, Ser9-GSK-3beta and Ser133-CREB in the rat frontal cortex after MK-801 intraperitoneal injection

GSK-3beta is regarded as playing an important part in the pathogenesis of schizophrenia and the action of psychotomimetic agents. We observed phosphorylation of molecules associated with the GSK-3beta signalling pathway in the rat brain after MK-801 injection, which induces a schizophrenia-like state in humans. Ser9-GSK-3beta phosphorylation was increased after injection of 1 mg/kg MK-801 in the rat frontal cortex but not in the hippocampus or cerebellum. This increase peaked at 30 min and was maintained until 90 min after injection. The phosphorylation showed a dose-dependent increase up to 1 mg/kg MK-801, followed by a decrease at higher dosage. Furthermore, phosphorylation of Ser473-Akt and Ser133-CREB showed similar temporal, dose-dependent and regionally specific patterns with those of Ser9-GSK-3beta. However, phosphorylation of Dvl and Ser33-beta-catenin was not affected by MK-801. These results suggest that GSK-3beta phosphorylation by MK-801 may be associated with the Akt-GSK-3beta pathway rather than with the Wnt-Dvl-GSK3beta pathway

Erratum: Nation-Wide Korean Breast Cancer Data from 2008 Using the Breast Cancer Registration Program

nation-wide breast cancer data and analyzed the data using their online registration program biannually. The purpose of this study was to evaluate the characteristics of Korean breast cancer from 2008 and examine chronological based patterns. Methods: Data were collected from 38 medical schools (67 hospitals), 20 general hospitals, and 10 private clinics. The data on the total number, gender, and age distribution were collected through a questionnaire as well as other detailed data analyzed via the online registration program. Results: In 2008, there were 13,908 patients who were newly diagnosed with breast cancer. The crude incidence rate of female breast cancer was 57.3 among 100,000 and the median age was 49 years. The age distribution had not changed since the initial survey; however the proportion of postmenopausal patients had increased and median age was older than the past. In staging distribution, the proportion of early breast cancer (stage 0, I) was 47.2 % with, breast-conserving surgery performed in 58 % and mastectomy in 39.5%. Conclusion: Compared to past data, the incidence of breast cancer in Korea continues to rise. Furthermore, the proportion of those detected by screening and breast conservation surgery has increased remarkably. To understand the patterns of Korean breast cancer, the nation-wide data should continuously investigated

The effects of repeated administrations of MK-801 on ERK and GSK-3beta signalling pathways in the rat frontal cortex

Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, Bax, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801