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The epidemic of obesity and its complications is rapidly increasing worldwide. Recent drug discoveries established the utility of prolyl hydroxylase domain (PHD) inhibitors as stabilizers of hypoxia-inducible factors (HIFs) in vivo, which are currently in human clinical studies for the treatment of anemia in chronic kidney disease (CKD). These studies suggest a role for PHD inhibitors in ameliorating obesity and hyperlipidemia. We hypothesized that HIF activation using a PHD inhibitor, JTZ-951, protects from obesity-related diseases in the white adipose tissue (WAT), liver, and kidney in mice fed with high-fat diet (HFD). Eight-week-old, C57BL/6J mice were fed with HFD for 20 weeks with or without JTZ-951(0.005%; mixed in chow). Body weight and plasma non-high-density lipoprotein (HDL) cholesterol levels were significantly lower in the JTZ-951 group as compared with the vehicle group. PHD inhibition improved liver steatosis, macrophage infiltration into WAT and adipocyte fibrosis. In the kidney, PHD inhibition reduced albuminuria. Histologically, the number of F4/80- positive infiltrating macrophages and mesangial expansion were milder in the JTZ-951 group. Relative mRNA expression of adiponectin in WAT was higher in the JTZ-951-treated group and inversely correlated with hepatic steatosis score, adipocyte macrophage aggregation, and albuminuria. Activation of HIF ameliorates multiple obesity-related consequences in mice with HFD. The results of the present study offer the promising view that pharmacological PHD inhibition may be beneficial for the treatment of obesity-related diseases that can be ameliorated by weight loss.

Introduction:In Japan, victims of large-scale disasters are usually identified by non-objective means. In the case of the 2011 Great East Japan Earthquake, ~90% of the bodies were identified based on nonobjective means such as facial features or belongings, which resulted in misidentification. At present, the situation remains the same. However, according to global standards, a method referred to as “disaster victim identification” (DVI; individual identification of disaster victims) is recommended by the International Criminal Police Organization; in this method, a multidisciplinary investigation team integrates objective information such as dental charts and DNA. Furthermore, recently, there has been a movement to employ postmortem computed tomography (CT) for personal identification, and radiologists are expected to be included in the DVI team.Method:In the Department of Legal Medicine of Chiba University in Japan, individual identification via CT or magnetic resonance imaging was conducted in forensic autopsy cases of unknown identities when there was an assumed person for the body and the antemortem image of the person could be acquired. Two certified radiologists interpreted and compared the antemortem CT with the postmortem CT taken prior to autopsy and assessed whether the two images were compatible to indicate the same person.Results:A total of 20 cases were judged. In all cases, two images were compatible, indicating the same person. Image-based identification was particularly useful when dental findings or fingerprints were unavailable for comparison and there were no family members available for DNA testing.Conclusion:In the future, this method will be applied to large-scale disasters.

Obesity is a risk factor for many diseases including diabetes, cancer, cardiovascular disease, and chronic kidney disease. Obesity is characterized by the expansion of white adipose tissue (WAT). Hypertrophy and hyperplasia of adipocytes cause tissue hypoxia followed by inflammation and fibrosis. Its trigger, preadipocyte differentiation into mature adipocytes, is finely regulated by transcription factors, signal molecules, and cofactors. We found that echinomycin, a potent HIF-1 inhibitor, completely inhibited adipogenesis in 3T3-L1 WAT preadipocytes by affecting the early phase of mitotic clonal expansion. The dose required to exert the effect was surprisingly low and the time was short. Interestingly, its inhibitory effect was independent of HIF-1 pathways. Time-course DNA microarray analysis of drug-treated and untreated preadipocytes extracted a major transcription factor, CCAAT/enhancer-protein β, as a key target of echinomycin. Echinomycin also inhibited adipogenesis and body weight gain in high fat diet mice. These findings highlight a novel role of echinomycin in suppressing adipocyte differentiation and offer a new therapeutic strategy against obesity and diabetes.

We aimed to reproduce the anthropometrical measurement of femoral dimensions using multi-planar reconstruction computed tomography (CT), assess the correlation between stature and femoral measurements obtained by this approach, and establish a regression equation for estimating stature in the modern Japanese population. We used data regarding 224 cadavers (116 males, 108 females) that were subjected to postmortem CT and subsequent forensic autopsy at our department between October 2009 and July 2016. To simulate the placement of the femur on the osteometric board using reconstructed CT images, we defined a virtual horizontal plane (VHP) based on the three most dorsal points of the femur (lateral condyle, medial condyle, and greater trochanter). Five femoral measurements including the maximum femoral length (MFL) were obtained. The correlations between stature and each femoral measurement were expressed in terms of the coefficient of determination (R2). On regression analysis, MFL provided the lowest value for the standard error of the estimation (SEE); the SEE values in all subjects, males, and females, respectively, were 3.783 cm (R2 = 0.832), 3.850 cm (R2 = 0.653), and 3.340 cm (R2 = 0.760) for MFL on the left side and 3.747 cm (R2 = 0.835), 3.847 cm (R2 = 0.650), and 3.290 cm (R2 = 0.687) for MFL on the right side. Multiple regression equations using MFL and femoral epicondylar breadth were slightly superior to simple regression equations in males and in all subjects (SEE = 3.44–3.55 cm), whereas no effective equation could be obtained in females. To our knowledge, this is the first multiple regression equation for stature estimation using only femoral measurements.

•FEB and MHD measurements are more accurate predictors for sex estimation.•FEB and MHD are better predictors for body size in Japanese cadavers.•Though AFT is significantly higher in women, it has low accuracy in sex estimation. We aimed to reproduce the anthropometrical measurements of femoral dimensions using multi-planar reconstruction (MPR) computed tomography (CT); to assess the feasibility of sex estimation using femoral measurements through this approach, and to establish the corresponding sex estimation thresholds in the modern Japanese population. We used data on 224 cadavers (116 male and 108 female) that were subjected to postmortem CT and subsequent forensic autopsy at our department between October 2009 and July 2016. Four femoral measurements were obtained. Receiver operating characteristic (ROC) curve analysis was performed to test the overall ability of the variables in sex estimation, while the accuracy of the sex estimation was measured by the area under the ROC curve (AUC). The femoral bicondylar breadth showed the largest AUC values (left; 0.973, right; 0.974), followed by the maximum head diameter (left; 0.951, right; 0.955), and maximum femoral length (left; 0.885, right; 0.887). To the best of our knowledge, this is the first report to assess sex estimation based on femoral measurements, using MPR CT images.

Although electrolyte analysis of pleural effusion at autopsy is useful for the diagnosis of water aspiration (i.e., drowning), the method of comparing each level of sodium (Na+), potassium (K+), and chloride (Cl−) ions does not clearly differentiate between freshwater drowning, seawater drowning, and non-drowning. Therefore, here we introduce the summation of Na+, K+, and Cl− levels, that is SUMNa+K+Cl, as a modified diagnostic indicator. In 21 autopsy cases of freshwater drowning, 32 cases of seawater drowning, and 43 non-drowning controls (with pleural effusion), mean SUMNa+K+Cl differed significantly between the groups (188.8±33.2, 403.5±107.9, and 239.3±21.7mEq/L, respectively). We defined a SUMNa+K+Cl cut-off value of <195.9mEq/L as strongly suggestive of freshwater aspiration and that of >282.7mEq/L as strongly suggestive of seawater aspiration. When these values were applied to the two drowning groups, 15 cases (71%) of freshwater drowning and 29 cases (91%) of seawater drowning were diagnosed correctly. This new approach may be more valid than previous methods in cases found >2 days after death or those with substantial pleural effusion (>100mL). For an additional 15 bathtub deaths, mean SUMNa+K+Cl was 198.8±40.0mEq/L, and in 14 of these cases (93%) the relationship between cause of death and SUMNa+K+Cl could be explained using this method. Forensic pathologists should not depend exclusively on chemical findings and should consider also typical pathological indicators of drowning. This new method may be useful as a supplementary diagnostic tool when used alongside consideration of the pathological findings.

The identification of vomit stains may be helpful for crime scene reconstruction. However, there is no specific and convenient method for identifying vomit stain. Therefore, to establish the procedure for forensic identification of vomit stains, we focused on four gastric mucosa-expressing proteins, pepsinogen I (PGA), pepsinogen II (PGC), gastrin (GAST), and mucin 5AC (MUC5AC). We developed enzyme-linked immunosorbent assay (ELISA) procedures for the detection of these four candidate proteins. The specificity and sensitivity of ELISA detection of these proteins were analyzed, and applicability for the identification of vomit in forensic casework samples was also investigated. We found the sensitivities of ELISA for detection of PGA, PGC, GAST, and MUC5AC from the standard protein (peptide) and from diluted gastric mucosa extract were 10.0–100.0 ng/ml and 1:200–1:1600, respectively. PGA and PGC were successfully detected in stomach contents and gastric mucosa samples; however, these also cross-reacted with some urine and semen samples, respectively, because of low level expression in these fluids. MUC5AC was positive for most gastric mucosa samples; however, it was difficult to detect in stomach contents. ELISA detection of GAST was not suitable for the identification of vomit. All aged samples stored up to 90 days gave positive results for ELISA procedures for PGA, PGC, and MUC5AC. Therefore, ELISA detection of these proteins might be applicable to aged samples. PGA was also detected in all actual vomit samples tested. These results suggest that ELISA for the detection of gastric mucosa-expressing proteins, especially PGA, could be an effective tool for the forensic identification of vomit.

Diagnosis of traumatic subarachnoid hemorrhage (SAH), although relatively rare, is important in forensic medicine. It is mostly associated with rupture of the vertebrobasilar artery. Traumatic aneurysm of the intracranial part of the internal carotid artery (ICA) is also rare but has been reported in several studies. It is thought that the intracranial ICA is injured by blunt force to the head, neck, and chest. However, traumatic SAH with fatal acute course resulting from rupture of the ICA is especially uncommon: only two fatal cases without an associated aneurysm have been reported in the English-language literature. Although detecting the arterial lesion is required to make a precise diagnosis, this is sometimes impossible by macroscopic examination at autopsy or by investigation after formalin-fixation according to the position of the lesion. We report a rare case of fatal traumatic SAH associated with intracranial ICA rupture. Postmortem computed tomography angiography was useful to confirm the lesion.

Recent epidemiologic studies revealed a correlation between acute kidney injury (AKI) episodes and the progression to chronic kidney disease (CKD). Although the severity and duration of the initial insult likely predict the development of CKD, information regarding tissue markers predictive of early development of renal fibrosis is limited. We investigated key markers in fibrotic kidney in rats and mice. Seven‐ to eight‐week‐old male Sprague–Dawley rats underwent bilateral ischemia–reperfusion injury (IRI). Kidney tissues were collected to determine the markers correlated with the severity of kidney fibrosis. In a separate set, a specific chemokine (C‐C motif) receptor 2 (CCR2) inhibitor, RS‐102895, was administered to 9‐week‐old male C57BL/6J mice that underwent unilateral IRI (9.2 mg/kg/day in drinking water for 17 days) to investigate whether blockade of the monocyte chemotactic protein‐1 (MCP‐1) signaling was sufficient to prevent fibrosis. Among candidate tissue markers, neutrophil gelatinase‐associated lipocalin (NGAL) and MCP‐1 mRNA expressions were correlated with kidney fibrosis. Studies on macrophage polarity showed that mRNA expression of M2, but not M1 macrophage markers, were correlated with acute‐phase serum creatinine and fibrosis. Pharmacological blockade of the MCP‐1–CCR2 signaling downregulated CCR2, which was insufficient to improve fibrosis in mouse unilateral IRI model, suggesting that additional, redundant pathways contribute to fibrosis. These findings suggested that tissue NGAL expression and M2 macrophage markers are promising markers that show severity of kidney fibrosis. Mechanistic involvement of these markers in CKD pathogenesis warrant additional investigation. NGAL and MCP‐1 mRNA expression of rat kidneys subjected to ischemia‐reperfusion injury was correlated with the level of acute‐phase of serum creatinine and the extent of kidney fibrosis.

ObjectivesWe aimed to examine the validity of the quick Sequential Organ Failure Assessment (qSOFA) score for mortality and bacteraemia risk assessment in Japanese haemodialysis patients.DesignThis is a retrospective multicentre cohort study.SettingThe six participating hospitals are tertiary-care institutions that receive patients on an emergency basis and provide primary, secondary and tertiary care. The other participating hospital is a secondary-care institution that receives patients on an emergency basis and provides both primary and secondary care.ParticipantsThis study included haemodialysis outpatients admitted for bacteraemia suspicion, who had blood drawn for cultures within 48 hours of their initial admission.Primary and secondary outcome measuresThe primary outcome measure was overall in-hospital mortality. Secondary outcomes included 28-day in-hospital mortality and the incidence of bacteraemia diagnosed based on blood culture findings. The discrimination, calibration and test performance of the qSOFA score were assessed. Missing data were handled using multiple imputation.ResultsAmong the 507 haemodialysis patients admitted with bacteraemia suspicion between August 2011 and July 2013, the overall in-hospital mortality was 14.6% (74/507), the 28-day in-hospital mortality was 11.1% (56/507) and the incidence of bacteraemia, defined as a positive blood culture, was 13.4% (68/507). For predicting in-hospital mortality among haemodialysis patients, the area under the receiver operating characteristic curve was 0.61 (95% CI 0.56–0.67) for a qSOFA score ≥2. The Hosmer-Lemeshow χ2 statistics for the qSOFA score as a predictor of overall and 28-day in-hospital mortality were 5.72 (p=0.02) and 7.40 (p<0.01), respectively.ConclusionOn external validation, the qSOFA score exhibited low diagnostic accuracy and miscalibration for in-hospital mortality and bacteraemia among haemodialysis patients.