Eperisone hydrochloride is a centrally acting muscle relaxant prescribed for muscle stiffness that acts by depressing the activities of ? and ? efferent neurons in the spinal cord and supraspinal structures. Although a case of eperisone-induced severe QT prolongation had been reported, the relationship between serum eperisone concentration and QT interval remains obscure.
Technologies for the transfection of antigen-encoding genes into the dendritic cells, and subsequent immune-activation are both prerequisites for a successful DNA vaccine. We herein report on the density-dependent enhancement of transgene expression by the simple modification by stearyl-conjugated KALA, an ?-helical peptide (STR-KALA), onto a lipid envelope-type nanoparticle (the R8-MEND, an octaarginine-modified multifunctional envelope-type nano device). The enhanced transgene expression in the KALA-modified R8-MEND (R8/KALA-MEND) cannot be explained by cellular uptake and nuclear delivery efficacy. Thus, the post-nuclear delivery process (i.e. transcription), but not intracellular trafficking processes attributed the enhanced transfection efficacy. Microarray analyses revealed that transfection with the R8/KALA-MEND resulted in a greater perturbation in host genes expression in comparison with the R8-MEND and that this effect was time-dependent. Further pathway analyses in the category of transcription-related genes and a gene ontology analysis indicated that the R8/KALA-MEND stimulated the expression of transcription factors that are closely related to immune-activation (i.e. NF-kB and STAT). Inhibition of the transfection efficacy by blockage of the STAT pathways revealed that the enhanced transcription activity is the result of immune-stimulation. Collectively, the R8/KALA-MEND mounts a "switch-on" function that triggers signal transduction forward to the immune-stimulation analogous to an adjuvant, and consequently elicits active transcription.
Fatty liver is one of the typical manifestations in homocysteinemia/homocystinuria patients and their genetic animal model, mice lacking cystathionine ?-synthase (Cbs(-/-)). The vast majority of Cbs(-/-) die within 4 weeks after birth via yet unknown mechanisms, whereas a small portion survive to adulthood, escaping fatty degeneration of the liver during lactation periods, through regeneration. To investigate the molecular basis of such fatty changes, we analyzed lipid components in fatty livers of 2-week-old Cbs(-/-) and regenerated non-fatty livers of 8-week-old Cbs(-/-) survivors using a chip-based nanoESI (electrospray ionization)-MS system, which allows quantitative detection of triacylglycerol/phospholipid molecular species. Hepatic levels of all major triacylglycerol species were much higher in Cbs(-/-) than in wild-type mice at 2 weeks, although not at 8 weeks. Levels of some phospholipid species were either up- or downregulated in 2-week-old Cbs(-/-); e.g. saturated (16:0 and 18:0) or mono-unsaturated (16:1 and 18:1) fatty acids-containing phosphatidylcholine/phosphatidylethanolamine species were upregulated, while poly-unsaturated fatty acids-containing phosphatidylcholine (18:2-18:2 and 18:2-20:5), phosphatidylethanolamine (18:1-20:4), and phosphatidylinositol (18:0-20:4) were downregulated. Capillary electrophoresis-MS analysis identified high-level accumulation of S-adenosylmethionine and S-adenosylhomocysteine in fatty livers of 2-week-old Cbs(-/-) but much less in non-fatty livers of 8-week-old Cbs(-/-). Although hepatic S-adenosylmethionine/S-adenosylhomocysteine ratios were comparable between 2-week-old Cbs(-/-) and wild-type, global protein arginine methylation was disturbed in fatty livers of Cbs(-/-). Our results suggest that cellular signaling mediated by altered phospholipid contents might be involved in pathogenesis of fatty liver in Cbs(-/-).
Performing angiography in the prone position is a difficult technique; however it is useful in some emergency situation. We experienced a 60 years old male who was performed lipoma excision on his back in his family doctors clinic. Since massive arterial bleeding could not be controlled with manual astriction, he transferred to our hospital in prone position with hemodynamic instability. Operating field was not kept because of massive bleeding; therefore surgical treatment was impossible. We planed emergency arterial embolization (AE) in prone position. Hence we chose the left radial artery for vascular access. The left subclavicle arteriography showed many major and minor feeding arteries from left subclavicular and axillary arteries and a massive extravasation of the contrast medium. Three major feeding arteries were performed AE with gelatin sponge and steel coils. After AE, massive bleeding was controlled. He could discharge from our hospital on the 5th hospital day without any complication. Arterial embolization for life-threatening bleeding from subcutaneous hypervascular tumor in the prone position is first report to our knowledge, and it is extremely rare. However we thought that this technique is useful for patients who could not turn in the supine position, e.g. massive bleeding during renal biopsy and penetrating trauma from back.
In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.
A previously healthy 21-year-old woman, transported to our medical emergency center for excluding organic brain disease, had undergone medical examination 9 days before for trembling in her left hand, which was caused by stress. The patient exhibited fever and strange behaviors, e.g., wandering around, babbling, and making smoking gestures; hence, psychiatric examination was performed. The patients Glasgow Coma Scale score was 4-3-5, and involuntary movement was observed. Cerebrospinal fluid examination revealed increased cell count; hence, we suspected anti-N-methyl-d-aspartate (NMDA) receptor encephalitis. We conducted an abdominal CT scan, which revealed a neoplastic lesion with calcification in the right ovary. Early steroid pulse therapy was started. On hospital day 25, she tested positive for anti-NMDA receptor antibodies; hence, anti-NMDA receptor encephalitis and concomitant ovarian teratoma was diagnosid. She underwent right adnexectomy; subsequently, immunotherapy was performed. The patient recovered and was discharged on hospital day 105. Anti-NMDA receptor encephalitis is not uncommon; however, this disease must be considered for young encephalitis patients exhibiting psychiatric symptoms. If patients (aged ? 30 years) presents with encephalitis of uncertain etiology, psychiatric symptoms, seizures, movement disorders, or psychosis, clinicians should consider anti-NMDA encephalitis as a possible diagnosis. Clinical diagnosis should be waged early to ensure timely treatment.
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