Molecular mechanisms of Wischnewski spot development on gastric mucosa in fatal hypothermia: an experimental study in rats.

Numerous dark-brown-coloured small spots called "Wischnewski spots" are often observed in the gastric mucosa in the patients dying of hypothermia, but the molecular mechanisms through which they develop remain unclear. We hypothesised that hypothermia may activate the secretion of gastric acid and pepsin, leading to the development of the spots. To investigate this, we performed experiments using organotypic rat gastric tissue slices cultured at 37 °C (control) or 32 °C (cold). Cold loading for 6 h lowered the extracellular pH in the culture medium. The mRNA expression of gastrin, which regulates gastric acid secretion, increased after cold loading for 3 h. Cold loading increased the expression of gastric H+,K+-ATPase pump protein in the apical canalicular membrane and resulted in dynamic morphological changes in parietal cells. Cold loading resulted in an increased abundance of pepsin C protein and an elevated mRNA expression of its precursor progastricsin. Collectively, our findings clarified that cold stress induces acidification by activating gastric H+,K+-ATPase pumps and promoting pepsin C release through inducing progastricsin expression on the gastric mucosa, leading to tiny haemorrhages or erosions of the gastric mucosa that manifest as Wischnewski spots in fatal hypothermia.

Role of activating transcription factor 3 protein ATF3 in necrosis and apoptosis induced by 5-fluoro-2'-deoxyuridine.

Necrosis and apoptosis are the two major forms of cell death. We have studied the mechanisms that regulate the cell death observed during treatment of mouse cancer cell line FM3A with the anticancer drug 5-fluoro-2'-deoxyuridine (FUdR). To detect causal differences between necrosis and apoptosis, we exploited the necrosis in original clone F28-7 and the apoptosis in its variant F28-7-A that occur on treatment with FUdR. Activating transcription factor 3 (ATF3) was strongly induced during necrosis but not apoptosis. In addition, we found that ATF3 expression is regulated by heat shock protein 90 (HSP90) at the mRNA stage. Knockdown of Atf3 by siRNA in the F28-7 cells resulted in apoptotic morphology rather than necrotic morphology. These results suggest that ATF3 is a cell-death regulator in necrosis and apoptosis.

Association of nuclear-intermediate filament lamin B1 with necrotic- and apoptotic-morphologies in cell death induced by 5-fluoro-2'-deoxyuridine.

We report that anticancer 5-fluoro-2'-deoxyuridine (FUdR) shows cytotoxicity against mouse cancer cell line FM3A cells, using a progeny clone F28-7 and its variant F28-7-A. In this process, the cell-death morphology is different between F28-7 and F28-7-A cells, that is, necrosis in F28-7 but apoptosis in F28-7-A cells. Recently we have investigated the gene and protein expression profiles of necrosis and apoptosis induced by FUdR using transcriptomic and proteomic analyses. In the proteomic analysis of these cells before their exposure to FUdR, the nuclear inner-membrane protein lamin B1 is up-regulated in F28-7 but not in F28-7-A, suggesting that lamin B1 may possess a function to regulate the morphology of cell-death. A knockdown of lamin B1 expression in F28-7 cells has now been performed by use of the small interfering RNA technique, resulting in a decrease of the lamin B1-expression level down to the level in F28-7-A. Remarkably, the FUdR-induced death morphology of this knocked-down F28-7 was apoptosis, definitely different from the necrosis that occurs in the FUdR-treated original F28-7. Our present finding provides an interesting possibility that lamin-B1 may have an important role in regulating cell-death morphology.

The present and future situation of "model project for investigation and analysis of medical practice associated deaths" in Osaka, Japan.

To enhance the quality and safety of medical care, the Ministry of Health, Labor and Welfare (MHLW) launched a model project in September 2005 for investigation and analysis of medical practice associated deaths in an attempt to move the existing system in a different direction. The project, initiated in Tokyo, Osaka, Nagoya, and Kobe, has now been implemented in nine prefectures. In the hope that the model project will lead to the nationwide development of medical safety investigating committees, the MHLW has submitted a provisional third plan. Based on our practical experience of the model project in Osaka, we present and discuss practical problems and legal issues involving surgeons' criminal punishment.

Molecular mechanisms in two cell death-types, necrosis and apoptosis, induced by 5-fluoro-2'-deoxyuridine.

We report that anticancer 5-fluoro-2'-deoxyuridine (FUdR) shows cytotoxicity against mouse cancer cell line FM3A cells, using a progeny clone F28-7 and its variant F28-7-A. In this process, the cell-death morphology is different between F28-7 and F28-7-A cells, that is, necrosis in F28-7 but apoptosis in F28-7-A cells. Recently we have investigated the gene and protein expression profiles of necrosis and apoptosis induced by FUdR using transcriptomic and proteomic analysis. In the proteomic analysis of these cells before their exposure to FUdR, the nuclear inner-membrane protein lamin B1 is up-regulated in F28-7 but not in F28-7-A, suggesting that lamin B1 may possess a function to regulate the morphology of cell-death. A knockdown of lamin B1 expression in F28-7 cells has now been performed by use of the small interfering RNA technique, resulting in a decrease of the lamin B1-expression level down to the level in F28-7-A. Remarkably, the FUdR-induced death morphology of this knocked-down F28-7 was apoptosis, definitely different from the necrosis that occurs in the FudR-treated original F28-7. This finding suggests a new role for lamin B1 as a regulator in the cell death.