Yoko Nishitani

Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway

OBJECTIVES Osteonecrosis of the femoral head is observed in patients treated with steroids. However, the pathogenesis of femoral head osteonecrosis remains unclear. We established a rat model with femoral head osteonecrosis by injecting lipopolysaccharide (LPS) and steroid, and assessed the consequences of this on femoral head histology, the systemic immune response and lipid synthesis. METHODS Male Wistar rats were injected intravenously on days 0 and 1 with 2 mg/kg LPS and intramuscularly with 20 mg/kg methylprednisolone on days 3, 4 and 5. The animals were sacrificed 1, 2, 3 or 4 weeks after the last methylprednisolone injection. Histopathological and biochemical analyses were performed every week. RESULTS Osteonecrosis of the femoral head was observed in the rats. The plasma triglyceride concentrations had decreased significantly by weeks 2 and 3. The total plasma cholesterol concentrations had increased significantly by week 1 but then decreased significantly by week 4. The plasma concentrations of IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma and TNF-alpha had increased significantly by week 1. These cytokines can all be induced by toll-like receptor 4 (TLR4) signalling. CONCLUSIONS LPS and methylprednisolone induced osteonecrosis of the femoral head in rats and this was associated with a disruption of the innate immune system and lipid synthesis. These findings suggest that the TLR4 signalling pathway plays an important role in the pathogenesis of femoral head osteonecrosis.

Ethanol rapidly causes activation of JNK associated with ER stress under inhibition of ADH

Acute ethanol loading causes oxidative stress to activate cell‐death signaling via c‐Jun NH2‐terminal kinase (JNK) in livers. JNK are stimulated under conditions of endoplasmic reticulum (ER) stress which causes programmed cell death. However, no remarked cell death was observed in acute ethanol intoxication. Akt, one of the cell survival protein kinases, may be activated under ethanol loading. The aim of this study was to estimate activation of JNK and ER stress, role of ethanol metabolism on the activation, and association of JNK with Akt under acute ethanol loading using the perfused rat liver system. Activation of JNK or Akt and association of JNK and Akt with JNK interacting protein 1 were estimated by immunoprecipitation and immunoblotting. Expression of 78 kDa glucose‐regulated protein (GRP78) mRNA, a biomarker of ER stress, was detected by quantitative real‐time RT‐PCR. Activations of JNK and Akt were enhanced by co‐treatment with ethanol and a classical inhibitor of alcohol dehydrogenase (ADH). Addition of an antioxidant reduced the activation of JNK. Ethanol loading with ADH inhibition causes down‐regulation of GRP78 mRNA levels. Therefore, these findings suggest first revelation that inhibition of ethanol metabolism complicates oxidative and ER stresses produced by ethanol.

Prior ethanol injection promotes brain edema after traumatic brain injury

Alcohol consumption prior to traumatic brain injury (TBI) promotes morbidity and mortality although the mechanisms involved remain unclear. The morbidity and mortality caused by TBI, especially brain contusion, are known to be closely associated with brain edema. Here we examined the effects of ethanol pretreatment on brain edema, inflammatory responses, and oxidative stress after brain contusion. Male Wistar rats were given 3 g/kg ethanol intraperitoneally and 1 h later were subjected to brain contusion. The ethanol-pretreated group had a significantly decreased survival rate. Magnetic resonance imaging showed ethanol pretreatment significantly augmented the volume of cytotoxic brain edema after contusion. In the ethanol-pretreated rat, the activities of NF-kappaB and AP-1 were reduced 6 h after contusion and COX-2 mRNA expression was increased 24 h after contusion. These findings suggest that ethanol augmented cerebral edema and mortality in rats with brain contusion, possibly through actions on cell survival pathways or COX-2 expression. In addition, antioxidant treatment at 3 h post-injury significantly attenuated some markers of oxidative stress, mortality, and volume of edema at 24 h after ethanol treatment and contusion.

The discrepant severity of external and internal injuries in a traffic accident: The cushioning effect via a human body against direct impact: Autopsy cases

Traffic accidents cause unexpectedly severe injuries of internal organs despite tiny injuries observed on the external body. A 51-year-old woman (subject 1) and a 54-year-old man (subject 2) were found dead on a road. Subject 1 had subcutaneous and intramuscular bleeding with décollement on the posterior aspect of her body, including upper cervical spine dislocation. Subject 2 did not exhibit any apparent findings on autopsy that were indicative of a direct injury by a motor vehicle, but had severe internal organ injuries, including the transection at the pontomedullary junction. We surmise that subjects 1 and 2 were walking in line with the vehicle which collided with them from behind, and then the body of subject 1 cushioned the direct impact of the vehicle against subject 2. This report illustrates the need of forensic autopsy for victims with no severe external injuries.

Decapitation by force to the body: a case report and a review of the literature

Decapitation is rarely experienced for forensic pathologists except for the putrefaction corpus decomposed by invaders. However, it has been very important for forensic pathologists to think of the cause of death, antemortem or post-mortem decapitation, and the instrument for decapitation. Postmortem decapitation is often caused after hanging. Rarely, victim is murdered and the corpse is unlawfully disposed after death for the purpose of hiding or carrying easily. Antemortem decapitation is divided into suicide, homicide and accident by classification of the cause of death. Antemortem decapitation is generally performed by a lot of instruments, such as knife, saw, guillotine, rope, chain, and so on (Table 1). In most of the cases, these objects act around the neck directly. The force for decapitation by blunt instrument is strongish, such as vehicle-assisted ligature strangulation [1-8], suicidal hanging [9-12], rarely, attacks by animal such as dog and so on [13,14], and explosion [15]. However, any strong force is not necessary for decapitation by sharp instrument [16,17]. Most of suicidal decapitations can be performed by hanging rope [1,2,6,8-12], wheels of train [4], and sharp instrument [16]. Homicidal decapitation can be mostly performed by sharp instruments such as knife, saw and scissors [17]. Turk et al. reported four cases of homicidal decapitation, which decapitation was inflicted at postmortem after killing the victim in three cases and decapitation was inflicted during survival in one case [17]. Ihama et al. reported an accidental decapitation by the movement of the chain [5]. Buschmann et al. reported that the dogs attacked the neck of 3-week-old male infant and swallowed his head [13]. Therefore, decapitation can be caused by the force to the narrow width in the neck directly and strongly. Indirect force to the neck may be difficult to cause decapitation. In this report, we experienced rare case of decapitation due to the force to the body. Decapitation is caused by indirect force to the neck. Language: en

Effect of acute ethanol administration on histone acetylation in mouse brain

drugs, was shown to increase extracellular levels of 5HT in the nucleus accumbens (ACC), the frontal cortex, and the ventral hippocampus in rat. For elucidation of relationship between alcohol-addiction and 5HT system, we produced chronic alcohol treatment mice by the exposure to alcohol vapor for 20 days. C57BL/6J mice showed a significant increase in alcohol drinking behavior after alcohol exposure, whereas there was no significant difference in alcohol drinking of C3H/HeJ, another inbred strain. We then examined expression levels of 5HT receptor family and found that expression of 5HT2C receptor (5HT2CR) was significantly increased in the ACC and the dorsal raphe nucleus (DRN) by chronic alcohol exposure, suggesting that 5HT2CR might be involved in alcohol addiction. 5HT2CR was known to undergo premRNA editing at five sites (site A-E) within exon 5 by deaminating enzymes. As a result of RNA-editing, amino acid substitution occurs at three sites, which alters the ability of the receptor to activate phospholipase C. Here, we investigated RNA-editing changes in alcohol vapor inhalation mice. Either C57BL/6J or C3H/HeJ was exposed to alcohol vapor, followed by the determination of 5HT2CR isoform frequency. C57BL/6J mice exhibited a 1.5-fold increase in site D editing by exposure to alcohol vapor, resulting that 5HT2CR-VXV isoforms were 92% in the ACC. On the other hand, unedited INI-isoform was the most prevalent in C3H/HeJ mice, in spite of alcohol exposure. Furthermore, it was demonstrated that an increase of RNA-editing frequency by alcohol exposure was dependent on the expression level of ADAR1 and ADAR2, RNAediting enzymes. These findings suggest that difference in RNA-editing of 5HT2CR may be associated with alcohol-addiction and -response.