Increased expression of mRNAs for microtubule disassembly molecules during nerve regeneration

The mRNA expression of the microtubule disassembly molecules (SCG10, stathmin, SCLIP and RB3) in response to nerve injury was examined using a rat hypoglossal nerve injury model. After nerve injury prominent increase in mRNA expression of SCG10, stathmin and RB3 was observed, while only slight increase in SCLIP mRNA was observed in injured motor neurons. The increase in SCG10 and RB3 mRNA expression was quicker than that of stathmin and SCLIP. All the elevated signals decreased gradually to control levels by 4 weeks after nerve injury.     

The Effect of Human Gammaglobulin Derivatives on Human Lymphoblastoid Cell Lines Persistently Infected with Herpes Simplex Virus

Human lymphoblastoid cells (NC-37) were infected with two strains of herpes simplex virus type 1 (HSV-1). Persistent infections with two strains (a freshly isolated strain, Seike strain, and Miyama strain) of HSV-1 were established in NC-37 cells. In NC-37 cells infected with HSV-1 (Seike), the growth of cells was inhibited, 6–72% of viable cells were positive for HSV-antigen by fluorescent antibody technique, and the percentage of HSV-antigen positive cells seemed to be inversely related to that of viable cells. Growth of cells and infectious viruses was seen for more than 396 days without external support. NC-37 cells infected with HSV-1 were subcultured with fresh medium containing human gammaglobulin derivatives. The percentage of HSV-antigen positive cells decreased and no infectious viruses were detected in the treated cells and cultured fluids after more than 16 days. It is thought that HSV continues to associate with T-lymphocytes stimulated in vivo for a long period of time after the appearance of circulating antibody, at least for two weeks, and lymphocytes persistently infect with HSV have a relation to the patho-genesis of herpesvirus encephalitis in oider children and adults similar to the pathogenesis of SSPE. (Acta Paediatr Jpn 23(2): 201–207 1981)     

Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis

Aurora kinases are known to play a key role in maintaining mitotic fidelity, and overexpression of aurora kinases has been noted in various tumors. Overexpression of aurora kinase activity is thought to promote cancer development through a loss of centrosome or chromosome number integrity. Here we observed augmentation of G12V-mutated HRAS-induced neoplastic transformation in BALB/c 3T3 A31-1-1 cells transfected with Aurora-A. Aurora-A-short hairpin RNA (shRNA) experiments showed that the expression level of Aurora-A determines susceptibility to transformation. Aurora-A gene amplification was noted in human patients with tongue or gingival squamous carcinoma (4/11). Amplification was observed even in pathologically normal epithelial tissue taken at sites distant from the tumors in two patients with tongue cancer. However, overexpression of Aurora-A mRNA was observed only within the tumors of all patients examined (11/11). Our data indicate that Aurora-A gene amplification and overexpression play a role in human carcinogenesis, largely due to the effect of Aurora-A on oncogenic cell growth, rather than a loss of maintenance of centrosomal or chromosomal integrity.     

Aurora-B/AIM-1 kinase activity is involved in Ras-mediated cell transformation

Aurora-B, previously known as AIM-1, is a conserved eukaryotic mitotic protein kinase. In mammals, this kinase plays an essential role in chromosomal segregation processes, including chromosome condensation, alignment, control of spindle checkpoints, chromosome segregation, and cytokinesis. Aurora-B is overexpressed in various cancer cells, suggesting that the kinase activity perturbs chromosomal segregation processes. Its forced overexpression induces chromosomal number instability and progressive tumorigenicity in rodent cells in vitro and in vivo. Nevertheless, based on focus formation in BALB/c 3T3 A31-1-1 cells, Aurora-B is not oncogenic. Here, we show that Aurora-B kinase activity augments Ras-mediated cell transformation. RNA interference with short hairpin RNA inhibits transformation by Ras and its upstream oncogene Src, but not by the downstream oncogene Raf. In addition, the inner centromere protein, which is a passenger protein associated with Aurora-B, has a similar ability to potentiate the activity of oncogenic Ras. These data indicate that elevated Aurora-B activity promotes transformation by oncogenic Ras by enhancing oncogenic signaling and by converting chromosome number-stable cells to aneuploid cells.     

The role of HMGB-1 on the development of necrosis during hepatic ischemia and hepatic ischemia/reperfusion injury in mice

BACKGROUND: High-mobility group 1 (HMGB-1) is a late mediator of endotoxin lethality in mice. The release of HMGB-1 is delayed compared to other proinflammatory cytokines that mediate shock and tissue injury. The purpose of this study was to investigate the role of HMGB-1 levels in response to hepatic ischemia, hepatic I/R injury, and the relationship between changes in HMGB-1 and other cytokines. MATERIALS AND METHODS: Three murine models were employed: our robust model of segmental hepatic warm ischemia (SHWI), a model of partial hepatic ischemia/reperfusion injury (PHIRI), and a model of total hepatic ischemia/reperfusion injury (THIRI). Over a 48-h period following ischemic insult and reperfusion using these models, serum HMGB-1 concentrations, concentrations of HMGB-1 in ischemic and nonischemic lobes, and serum concentrations of TNF-alpha and IL-6 levels were determined in mice. An anti-HMGB-1 antibody treatment was used in SHWI and THIRI to evaluate what aspects of response to ischemia and reperfusion were potentially mediated by HMGB-1. RESULTS: Hepatic HMGB-1 tissue concentrations exhibited biphasic changes in SHWI mice, which were increased in the ischemic lobes relative to nonischemic lobes at 12 h but decreased relative to nonischemic lobes at 24 h after ischemic insult. These results suggested that HMGB-1 was released into the systemic circulation by necrotic cells over the first 12 h but this process may be complete by 24 h postischemia. By 6 to 12 h after SHWI, serum TNF-alpha began to increase significantly and continued to increase for 18 h, followed by a sudden decline. Similarly, serum IL-6 increased over 1-3 h after SHWI and then decreased over the next 6 h. Treatment with an anti-HMGB-1 antibody significantly prolonged survival time in SHWI and THIRI. CONCLUSIONS: HMGB-1 plays a significant role in the response to hepatic ischemia and hepatic ischemia/reperfusion injury. The present study demonstrated a time-dependent production of HMGB-1 following hepatic warm ischemia in mice. The inherent HMGB-1 in ischemic areas was exhausted and HMGB-1 may be released by necrotic cells. HMGB-1 activation is involved in immediate proinflammatory stress response to I/R and anti-HMGB-1 antibody treatment remarkably improved survival. We demonstrated that systemic HMGB-1 accumulation was measured at an earlier phase of the hepatic ischemia and ischemia/reperfusion injury model than LPS-induced endotoxemia.     

Platypnea-orthodeoxia syndrome combined with multiple congenital heart anomalies

A 71-year-old woman was admitted for paralysis on the left side of her body. She developed dyspnea and hypoxemia after admission. Although pulmonary embolism was suspected, hypoxemia and dyspnea occurred repeatedly in spite of anticoagulation therapy. Transesophageal echocardiography revealed a patent foramen ovale (PFO), an atrial septal aneurysm (ASA), and a right-to-left shunt that appeared in an upright position. She was diagnosed with platypnea-orthodeoxia syndrome. Moreover, cardiac catheterization showed congenital anomalies, such as unroofed coronary sinus, partial anomalous pulmonary venous return and persistent left superior vena cava. Simple surgical closure of the ASA and PFO improved all of her symptoms.     

Zonisamide at clinically relevant concentrations inhibits field EPSP but not presynaptic fiber volley in rat frontal cortex

We investigated the effect of Zonisamide (ZNS), a newer anti-epileptic drug, on field potentials and neuropropagation in rat frontal cortex, with the aid of the 64-channel multi-electrode dish (MED64) system. The amplitude and propagation of field potentials were expressed dimensionally in the MED64 system. ZNS (3-100 microM) inhibited the amplitude and propagation of field excitatory postsynaptic potentials (fEPSP) in a concentration dependent manner. In contrast, ZNS could not suppress the amplitude and propagation of the presynaptic fiber volley (PrV) at clinically relevant concentrations (10-30 microM). Stimulating dependency with reduction fEPSP was seen in the presence of ZNS at clinically relevant concentrations, but not with PrV. The reduction of fEPSP amplitude was not accompanied by a change in paired-pulse facilitation. These data suggest that at clinically relevant concentrations of ZNS, the suppression of neuronal propagation is at least partially due to the postsynaptic mechanism, probably through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.