Molecular mechanism of empagliflozin cardioprotection in 5-fluorouracil (5-FU)-induced cardiotoxicity via modulation of SGLT2 and TNFα/TLR/NF-κB signaling pathway in rats.

One of the commoly used chemotherapeutic agents is 5-Fluorouracil (5-FU). Unfortunately, the clinical administration of 5-FU is complicated with serious cardiotoxic effects and the safe use becomes an urgent task in cardio-oncology. Till now, there are no studies discussed the role of empagliflozin (EMP) against 5-FU cardiotoxicity. Thus, we investigated this effect and the involved mechanisms in 5-FU induced heart injury. Forty male rats of Wistar albino species were used and divided randomly into four groups. Group I is the control group, group II is EMP given group, group III is 5-FU cardiotoxic group and group IV is 5-FU plus EMP group. 5-FU (150 mg/kg) was administered as a single intraperitoneal (i.p.) dose on 1st day to induce cardiotoxicity with or without EMP (30 mg/kg/d) orally for 5 days. The dose of 5-FU is relevant to the human toxic dose. Our data showed that 5-FU given group caused cardiotoxicity with significant increase of serum cardiac enzymes, toll like receptors, enhancement of nuclear factor kappa B (NF-κB), interleukin1ß (IL1ß), IL6, myeloid-differentiation-factor 88 (MYD88), heart weight, malondialdehyde (MDA), tumor-necrosis-factor-alpha (TNFα), sodium glucose co-transporter 2 (SGLT2), P53 and caspase3 expression with clear histopathological features of cardiotoxicity. Moreover, there is a significant decrease in reduced glutathione (GSH) and total antioxidant capacity (TAC). Interestingly, co-administration of EMP could ameliorate 5-FU induced biochemical and histopathological changes. This effect may be due to modulation of SGLT2, decreasing inflammation, oxidative stress and apoptosis with downregulation of an essential inflammatory cascade that mediates 5-FU cardiotoxicity; TNFα/TLR/NF-κB. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00204-1.

Scorpion sting: N-terminal fragment of proB-type natriuretic peptide as an early predictor of pediatric cardiotoxicity.

AIM OF THE WORK: This prospective study was conducted to evaluate the clinical reliability of N-terminal fragment of proB-type natriuretic peptide (NT-proBNP) in identifying patients with cardiotoxicity in the early hours following scorpion sting. SUBJECTS AND METHODS: This study involved 483 children aging between 2-17 years who were admitted to Minia University Poisoning Control Center from 1st January 2010 to 31st December 2019 with a history of scorpion sting, and on clinical evaluation symptoms were manifested. All subjects were clinically examined, investigated for NT-proBNP and CPK-MB on admission, 6 h and 24 h post-envenomation; and subjected to 24 h cardiac monitoring with periodic ECG every 6 h. RESULTS: Assessment of CPK-MB levels showed a significant increase in all moderate to severe cases 6 h post-envenomation. Assessment of NT-proBNP levels showed a significant increase in all moderate to severe cases on admission and 6 h post-envenomation. Moreover, there was a significant decrease in the NT-proBNP level after 24 h compared with that measured on admission. The sensitivity of NT-proBNP for the diagnosis of myocardial injury at hospital admission was significantly higher than that of CPK-MB. CONCLUSION: NT-proBNP may be a valuable and sensitive laboratory biomarker to predict cardiotoxicity of scorpion sting in the early hours.

Virtual computed tomography morphometry of the patella for estimation of sex using postmortem Japanese adult data in forensic identification.

In forensic anthropological identification of human remains and single bones, computed tomography (CT) data analysis facilitates volumetric and radiographic density analyses, and a recently developed automated analysis system markedly improved the performance, accuracy, and reproducibility of three-dimensional (3-D) reconstruction. The present study aimed to investigate virtual CT morphometry of the patella for the estimation of sex using postmortem CT data of forensic autopsy cases of Japanese individuals aged ≥18 years (total n=220; 110 males and 110 females; estimated postmortem interval <88h), especially with regard to the efficacy of 3-D bone volumetry. Sex-related differences were detected for all parameters (males>females; p<0.0001), but the differences were the most notable for bone mass volume; the estimated cut-off values (cm3) for discriminating males and females were 20.35 with a sensitivity and specificity of 0.85 and 0.91 for the left side and 19.96 with a sensitivity and specificity of 0.83 and 0.92 for the right side, respectively. The mean CT value showed an age-dependent decrease and was particularly low in females aged >60years. These findings indicate the efficacy of virtual CT morphometry of the patella using an automated analyzer for sex estimation.

Virtual CT morphometry of lower limb long bones for estimation of the sex and stature using postmortem Japanese adult data in forensic identification.

The application of computed tomography (CT) is useful for the documentation of whole-body anatomical data on routine autopsy, virtual reconstruction of skeletal structure, objective measurements, and reassessment by repetitive analyses. In addition, CT data processing facilitates volumetric and radiographic density analyses. Furthermore, a recently developed automated analysis system markedly improved the performance and accuracy of three-dimensional (3D) reconstruction. The present study investigated virtual CT morphometry of lower limb long bones, including the femur, tibia, fibula, and first metatarsus, to estimate the sex and stature using postmortem CT data of forensic autopsy cases of Japanese over 19 years of age (total n = 259, 150 males and 109 females). Bone mass volumes, lengths, and total CT attenuation values of bilateral femurs, tibias, and fibulas correlated with the stature; however, the mean CT attenuation (HU) values showed age-dependent decreases. Correlations with the stature were similar for the lengths and mass volumes of the femur, tibia, and fibula (r = 0.77-0.85) but were higher for the mass volume of the first metatarsus (r = 0.77 for right and r = 0.58 for left). In addition, the ratio of the bone volume to the length of each bone showed the most significant sex-related differences (males > females with accuracy of 75.8-98.1 %). These findings indicate the usefulness of virtual CT morphometry of individual lower limb long bones, including volumetry, to estimate the sex and stature in identification.

Efficacy of drug screening in forensic autopsy: retrospective investigation of routine toxicological findings.

Toxicological analysis is indispensable in forensic autopsy laboratories, but often depends on the limitations of individual institutions. The present study reviewed routine drug screening data of forensic autopsy cases (n=2996) during an 18.5-year period (January 1996-June 2014) at our institute to examine the efficacy of the procedures and findings in autopsy diagnosis and interpretation. Drug screening was performed using on-site immunoassay screening devices and gas chromatography/mass spectrometry (GC/MS) in all cases, followed by re-examination using GC/MS and liquid chromatography/tandem mass spectrometry (LC/MS/MS) at a cooperating institute in specific cases in the last 4 years. GC/MS detected drugs in 486 cases (16.2%), including amphetamines (n=160), major tranquilizers (n=72), minor tranquilizers (n=294), antidepressants (n=21), cold remedies (n=77), and other drugs (n=19). Among these cases, fatal intoxication (n=123) involved amphetamines (n=73), major tranquilizers (n=37), minor tranquilizers (n=86), antidepressants (n=3), and cold remedies (n=9); most cases involved self-administration, alleged suicide and accidental overdose, while homicide was not included. These drugs were also identified in other manners of death, including homicide (n=40/372), suicide (n=34/226), accidental falls (n=27/129), and natural death (n=72/514). In these cases, on-site immunoassay screening of drugs of abuse showed negative findings in 2440 cases (81.4% in all cases), while GC/MS detected other drugs in 218 cases (7.3% in all cases), including several antipsychotic drugs, acetaminophen and salicylic acid. Further analysis using LC/MS/MS detected low concentrations of benzodiazepines in 32 cases, and also anti-diabetic and hypertensive drugs in a case of fatal abuse. These observations indicate the efficacy of systematic routine toxicological analysis to investigate not only the cause of death but also the background of fatalities in forensic autopsy. The provision of extensive drug screening is needed for forensic and social risk management, considering the marked diversity of medical and illicit drugs.

Postmortem CT morphometry with a proposal of novel parameters for sex discrimination of the mandible using Japanese adult data.

Major human sex differences in the mandible after adolescence include the overall size as well as the shape of the chin and mandibular angle; however, objective interpretation of discrimination accuracy is difficult for these morphological indicators. The present study investigated measurements of the mandible for sex discrimination using postmortem CT morphometry in forensic autopsy cases of Japanese subjects after adolescence (age>16 years; male, n=116, and female, n=106), including the proposal of novel parameters representing the overall mandibular size and shape. The distance between the gnathion and condylus (gn-cdl), and bigonial width (go-go), as well as the angle formed by bilateral gn-cdl lines (Agn-cdl), correlated with bicondylar breadth (cdl-cdl), independent of the body height, showing no significant sex difference. The distance from the gn to the cdl-cdl line (oblique length), the ratio of Agn-cdl to cdl-cdl, and the oblique triangular area formed by bilateral gn-cdl and cdl-cdl lines (Δobl), which were proposed as indicators of chin protrusion, showed significant sex differences (p<0.001). Overall sensitivity and specificity at respective discriminating points for sex estimation were 0.72 and 0.78 at 105.0mm for the oblique length, 0.73 and 0.83 at 0.49 for the Agn-cdl to cdl-cdl ratio, and 0.82 and 0.78 at 643 mm(2) for Δobl; the efficacy for females was greater in younger subjects. Although these parameters weakly depended on the body height (p<0.0001), the correlations were insufficient for stature estimation. These findings suggest the efficacy of CT morphometry of the mandible for sex discrimination with quantitative assessment.

Efficacy of automated three-dimensional image reconstruction of the femur from postmortem computed tomography data in morphometry for victim identification.

Besides conventional radiology, postmortem computed tomography (PM-CT) is nowadays widely used for victim identification in forensic routines to detect anatomical characteristics and specific pathologies as well as to estimate the stature and sex. A major advantage of PM-CT is virtual reconstruction of skeletal structures independent of the status of recovered remains. The present study investigated the efficacy of a recently provided automated analyzer to reconstruct three-dimensional (3-D) images using CT data for skeletal morphometry, measuring the whole bone mass volume of the femur (60 bones in 30 cases) as an index of reproducibility. Manual cursoring could reconstruct bilateral femurs with high reproducibility, showing mass volume fluctuations by repetition and between two independent observers of 0.2-2.1% and 3.5-6.7%, respectively, partly depending on the data analysis system, but was time-consuming, while automated reconstruction was very rapid and highly reproducible virtually without detectable fluctuation; there was a high correlation between bone mass volumes reconstructed by manual and automated procedures (r=0.9976, p<0.0001). The reproducibility of the automated procedure was 98.64-100.81% in 5 cases scanned twice under the same CT conditions. Preliminary analysis showed a substantial correlation of the whole femur mass volume with the body height and a significant sex-related difference in the femur mass volume/body height ratio (males>females). These findings indicate the accuracy and practical feasibility of the automated procedure to reconstruct single bone 3-D CT images for virtual skeletal morphometry in victim identification.