The Sarin-like Organophosphorus Agent bis(isopropyl methyl)phosphonate Induces Apoptotic Cell Death and COX-2 Expression in SK-N-SH Cells

Organophosphorus compounds, such as sarin, are highly toxic nerve agents that inhibit acetylcholinesterase (AChE), but not cholinesterase, via multiple mechanisms. Recent studies have shown that organophosphorus compounds increase cyclooxygenase-2 (COX-2) expression and induce neurotoxicity. In this study, we examined the toxicity of the sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate (BIMP) and the effects of BIMP on COX-2 expression in SK-N-SH human neuroblastoma cells. Exposure to BIMP changed cell morphology and induced caspase-dependent apoptotic cell death accompanied by cleavage of caspase 3, caspase 9, and poly (ADP-ribose) polymerase (PARP). It also increased COX-2 expression, while pretreatment with a COX inhibitor, ibuprofen, decreased BIMP-dependent cell death and COX-2 expression in SK-N-SH cells. Thus, our findings suggest that BIMP induces apoptotic cell death and upregulates COX-2 expression

Autopsy Findings Involving Murderous Intent: Comparison between Positive and Negative Murderous Intent Cases in Japan

The presence or absence of murderous intent is an important fact during criminal trials. To verify autopsy findings that were considered as evidence of murderous intent, we compared autopsy findings in homicide cases committed with and without murderous intent (n = 12 and n = 11, respectively). Although the number of wounds may only be limited to one or two, stab wounds on the trunk of the body from a sharp instrument can be a significant evidence of murderous intent. Bruise or petechial haemorrhage at the back or limbs caused by blunt instruments or without any weapons do not indicate the presence of murderous intent. Although results in this study should be carefully interpreted in other jurisdictions, statistical analysis comparing cases with and without murderous intents might be a valuable methodology to understand autopsy findings involving murderous intent in Japan

Replication study of the association of SNPs in the LHX3-QSOX2 and IGF1 loci with adult height in the Japanese population; wide-ranging comparison of each SNP genotype distribution

Adult height is a highly heritable trait involving multiple genes. Recent genome-wide association studies have identified that SNP rs12338076 in the LHX3-QSOX2 locus, and rs1457595 and rs17032362 in the IGF1 locus are associated with human height in the Japanese population (Okada et al. (2010)[9]). We performed a replication study to examine the associations between these three SNPs and adult height in the Japanese population based on autopsy cases. However, it was not possible to confirm that all these SNPs influenced adult height in the study population. We first conducted a wide-ranging survey of these three SNPs in the above genes using nine different populations including Asians, Africans and Caucasians, and demonstrated that the genotypes of rs12338076 and rs17032362 were distributed in an ethnicity-dependent manner; even within Asian populations, the genotype distributions of the SNPs differed widely. Although there are differences in height distribution between different populations, possibly due to genetic factors and/or gene-environmental interactions, the contradictory results of the association study and ethnic differences in genotype distribution allow us to assume that these height-related SNPs in the genes may contribute to adult height to a slight extent, at least in the Japanese population. It is anticipated that the present information will be useful for developing a reliable tool for personal identification through elucidation of the genetic basis of human height

Smoothened as a new therapeutic target for human osteosarcoma

<p>Abstract</p> <p>Background</p> <p>The Hedgehog signaling pathway functions as an organizer in embryonic development. Recent studies have demonstrated constitutive activation of Hedgehog pathway in various types of malignancies. However, it remains unclear how Hedgehog pathway is involved in the pathogenesis of osteosarcoma. To explore the involvement of aberrant Hedgehog pathway in the pathogenesis of osteosarcoma, we investigated the expression and activation of Hedgehog pathway in osteosarcoma and examined the effect of SMOOTHENED (SMO) inhibition.</p> <p>Results</p> <p>To evaluate the expression of genes of Hedgehog pathway, we performed real-time PCR and immunohistochemistry using osteosarcoma cell lines and osteosarcoma biopsy specimens. To evaluate the effect of SMO inhibition, we did cell viability, colony formation, cell cycle <it>in vitro </it>and xenograft model <it>in vivo</it>. Real-time PCR revealed that osteosarcoma cell lines over-expressed <it>Sonic hedgehog</it>, <it>Indian hedgehog</it>, <it>PTCH1</it>, <it>SMO</it>, and <it>GLI</it>. Real-time PCR revealed over-expression of <it>SMO, PTCH1</it>, and <it>GLI2 </it>in osteosarcoma biopsy specimens. These findings showed that Hedgehog pathway is activated in osteosarcomas. Inhibition of SMO by cyclopamine, a specific inhibitor of SMO, slowed the growth of osteosarcoma in vitro. Cell cycle analysis revealed that cyclopamine promoted G1 arrest. Cyclopamine reduced the expression of accelerators of the cell cycle including cyclin D1, cyclin E1, SKP2, and pRb. On the other hand, p21^cip1wprotein was up-regulated by cyclopamine treatment. In addition, knockdown of <it>SMO </it>by <it>SMO </it>shRNA prevents osteosarcoma growth in vitro and in vivo.</p> <p>Conclusions</p> <p>These findings suggest that inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma.</p

Gender Differences in D-Aspartic Acid Content in Skull Bone

In forensic medicine, the personal identification of cadavers is one of the most important tasks. One method of estimating age at death relies on the high correlation between racemization rates in teeth and actual age, and this method has been applied successfully in forensic odontology for several years. In this study, we attempt to facilitate the analysis of racemized amino acids and examine the determination of age at death on the basis of the extent of aspartic acid (Asp) racemization in skull bones.　　 The specimens were obtained from 61 human skull bones (19 females and 42 males) that underwent judicial autopsy from October 2010 to May 2012. The amount of D-Asp and L-Asp, total protein, osteocalcin, and collagen I in the skull bones was measured. Logistic regression analysis was performed for age, sex, and each measured protein.　　 The amount of D-Asp in the female skull bones was significantly different from that in the male skull bones (p = 0.021), whereas the amount of L-Asp was similar. Thus, our study indicates that the amount of D-Asp in skull bones is different between the sexes

Effects of age on suicide attempts by medication in patients transferred to the emergency rooms of two advanced medical centers: A retrospective chart review of the DJ project

Abstract Aims The means of suicide vary, but in cases of impaired consciousness, it is often difficult to determine the initial treatment because it is not known whether a patient has overdosed or used pesticides or poisons. Therefore, we investigated the clinical characteristics of suicide by medication in patients with suicide attempts who were brought to the emergency department, especially the influence of age. Methods Patients with suicide attempts were transported to the two hospitals. There were 96 males (38.4%) and 154 females (61.6%). The mean age was 43.5 ± 20 years, and both males and females were most often in their 20s. Data on sex, age, motive for suicide, means of suicide attempt, psychiatric diagnosis, length of hospital stay, and place of discharge were retrospectively analyzed. Results The average age of the patients by means of suicide attempt was 40.5 years for “prescription drugs,” 30.2 years for “over‐the‐counter drugs,” and 63.5 years for “pesticide/poison.” For each means of suicide attempt, there was a significant difference in age among patients with suicide attempts using “prescription drugs,” “over‐the‐counter drugs” and “pesticides/poisons.” There was a statistical bias in the means and reasons for each suicide attempt. Conclusion The results showed that the age of patients who used over‐the‐counter medicines and pesticides and poisons varied significantly. It was thought that pesticide use should be considered first, especially when patients aged 50 years and over are brought to the hospital with impaired consciousness due to suicide attempts

TIMP-1 c.T372C Genetic Polymorphism as a Possible Predictor for Acute Aortic Dissection

While single nucleotide polymorphisms (SNP) have been extensively researched in atherosclerotic aortic aneurysms, there are too few data about acute aortic dissection (AAD). The matrix metalloproteinase regulation system has shown a high biological relevance to the development of aortic aneurysms and AAD. The TIMP-1 c.T372C (rs4898, nt+434) SNP was previously associated with the onset of abdominal aortic and other aneurysms. Therefore, we chose this SNP to search for a connection with AAD and to find its place among the other risk factors. 115 patients with AAD were studied for their TIMP-1 c.T372C genotype by means of conventional restrictase analysis. To confirm the biological relevance of our findings, immunohistochemistry for TIMP-1 was performed on tissue samples from the same patients with AAD and compared with a control group of 23 autopsy cases. The TIMP-1 c.T372C showed a significant difference in allele frequency in the AAD patients compared to the general population (p < 0.0001 for both sexes). This genotype did not show any association with any other co-morbid condition, nor with age. The immunohistochemistry results also showed significantly lower TIMP-1 expression in the dissected aortas. The C allele of TIMP-1 c.T372C shows a strong association with the onset of AAD