Diffuse axonal injury and oxidative stress: A comprehensive review

Traumatic brain injury (TBI) is one of the worldâ\u80\u99s leading causes of morbidity and mortality among young individuals. TBI applies powerful rotational and translational forces to the brain parenchyma, which results in a traumatic diffuse axonal injury (DAI) responsible for brain swelling and neuronal death. Following TBI, axonal degeneration has been identified as a progressive process that starts with disrupted axonal transport causing axonal swelling, followed by secondary axonal disconnection and Wallerian degeneration. These modifications in the axonal cytoskeleton interrupt the axoplasmic transport mechanisms, causing the gradual gathering of transport products so as to generate axonal swellings and modifications in neuronal homeostasis. Oxidative stress with consequent impairment of endogenous antioxidant defense mechanisms plays a significant role in the secondary events leading to neuronal death. Studies support the role of an altered axonal calcium homeostasis as a mechanism in the secondary damage of axon, and suggest that calcium channel blocker can alleviate the secondary damage, as well as other mechanisms implied in the secondary injury, and could be targeted as a candidate for therapeutic approaches. Reactive oxygen species (ROS)-mediated axonal degeneration is mainly caused by extracellular Ca2+. Increases in the defense mechanisms through the use of exogenous antioxidants may be neuroprotective, particularly if they are given within the neuroprotective time window. A promising potential therapeutic target for DAI is to directly address mitochondria-related injury or to modulate energetic axonal energy failure

Regulation of miRNAs as new tool for cutaneous vitality lesions demonstration in ligature marks in deaths by hanging

This study aims to demonstrate that the application of miRNA expression in forensic pathology, in cases of hanging, applying the method on skin samples. The proposed investigative protocol allowed us to highlight a different miRNA expression in the skin ligature marks of subjects who died by hanging compared to healthy skin control samples. The results obtained showed an increase in the expression of miRNAs recognized as regulators of the inflammatory response in skin lesions such as miR125a-5p and miR125b-5p. Furthermore, overexpression of additional miRNAs – miR214a-3p, miR128-3p, miR130a-3p, and miR92a-3p – with anti-inflammatory activity was highlighted. It was possible to document a statistical significance to control skin samples only for miR103a-3p (p < 0.05), miR214-3p and miR92a-3p (p < 0.01) The upregulation of miR222-3p and miR150-5p, respectively related to mast-cell activation and neutrophils after the application of traumatic stimuli supports the immunohistochemical data showed in literature. The diagnostic accuracy of miRNAs could expand the range of diagnostic tools available in the assessment of the vitality of a lesion

A Mix-up During Assisted Reproductive Technique: What is in the Best Interest of the New-Born?

A woman, after undergoing fertility treatment in hospital in Rome, became pregnant but three months later she was informed that she was carrying he twins of another couple. The error had gone unnoticed until the mother had a genetic test revealing that neither she nor her husband were the genetic parents. In December 2013 an embryo exchange took place, because embryos belonging to one couple, who had undergone a treatment of homologous fertilization, were erroneously implanted in another woman's uterus. This other couple had undertaken the same kind of treatment. The genetic parents urgently appealed to stop the new-born registration practices and to give the newborn twins to their genetic parents. On August 8(th), 2014, the Civil Court of Rome issued a judgement, which rejected the appeal, stating that the uterine mother and her husband must be considered the legal parents of the twins. In the present paper, the Authors will explore the grounds of this judgment, moreover, taking into account this serious adverse event, which raises numerous issues from a human, ethical and legal point of view, several considerations will be made

Micrornas: the new challenge for traumatic brain injury diagnosis

The acronym TBI refers to traumatic brain injury, an alteration of brain function, or an evidence of brain pathology, that is caused by an external force. TBI is estimated to become the third leading cause of permanent disability and mortality worldwide. TBI-related injuries can be classified in many ways, according to the degree of severity or the pathophysiology of brain injury (primary and secondary damage). Numerous cellular pathways act in secondary brain damage: excitotoxicity (mediated by excitatory neurotransmitters), free radical generation (due to mitochondrial impairment), neuroinflammatory response (due to central nervous system and immunoactivation) and apoptosis. In this scenario, microRNAs are implicated in the regulation of almost all genes at the post-transcriptional level. Several microRNAs have been demonstrated to be specifically expressed in particular cerebral areas; moreover, physiological changes in microRNA expression during normal cerebral development upon the establishment of neural networks have been characterized. More importantly, microRNAs show profound alteration in expression in response to brain pathological states, both traumatic or not. This review summarizes the most important molecular networks involved in TBI and examines the most recent and important findings on TBI-related microRNAs, both in animal and clinical studies. The importance of microRNA research holds promise to find biomarkers able to unearth primary and secondary molecular patterns altered upon TBI, to ultimately identify key points of regulation, as a valuable support in forensic pathology and potential therapeutic targets for clinical treatment

The Impact of Nandrolone Decanoate on the Central Nervous System

Nandrolone is included in the class II of anabolic androgenic steroids (AAS) which is composed of 19-nor-testosterone-derivates. In general, AAS is a broad and rapidly increasing group of synthetic androgens used both clinically and illicitly. AAS in general and nandrolone decanoate (ND) in particular have been associated with several behavioral disorders. The purpose of this review is to summarize the literature concerning studies dealing with ND exposure on animal models, mostly rats that mimic human abuse systems (i.e. supraphysiological doses). We have focused in particular on researches that have investigated how ND alters the function and expression of neuronal signaling molecules that underlie behavior, anxiety, aggression, learning and memory, reproductive behaviors, locomotion and reward

Searching for highly sensitive and specific biomarkers for sepsis: state-of-the-art in post-mortem diagnosis of sepsis through immunohistochemical analysis

he autoptical observations commonly ascribed to sepsis deal with unspecific general and local signs of inflammation or ischemia, such as myocardial inflammation, pulmonary edema and infiltration, cerebral swallowing, and tubular necrosis in the kidney. In the two last decades, some studies have been carried out to implement immunohistochemical markers for post-mortem diagnosis. All of these target molecules are specifically up-regulated or down-regulated during systemic inflammatory responses, especially for infective causes. Among these, we found some antigens expressed on leukocyte surfaces (very late antigen-4 (VLA-4), cluster differentiation-15 (CD15)), enzyme contained in neutrophils granules (lysozyme (LZ), lactoferrin (LF)), endothelial markers and junctions (E-selectin, vascular endothelial cadherin (VE-cadherin)), and soluble factors (vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (s-TREM-1)). All of these showed potential reliability in differentiating sepsis cases from controls. Further studies are needed to provide a concrete validation for a combination of markers on specific organ samples in order to reach a post-mortem diagnosis of sepsis also in the absence of clinical records

Acute Spinal Cord Injury: A Systematic Review Investigating miRNA Families Involved

Acute traumatic spinal cord injury (SCI) involves primary and secondary injury mechanisms. The primary mechanism is related to the initial traumatic damage caused by the damaging impact and this damage is irreversible. Secondary mechanisms, which begin as early as a few minutes after the initial trauma, include processes such as spinal cord ischemia, cellular excitotoxicity, ionic dysregulation, and free radical-mediated peroxidation. SCI is featured by different forms of injury, investigating the pathology and degree of clinical diagnosis and treatment strategies, the animal models that have allowed us to better understand this entity and, finally, the role of new diagnostic and prognostic tools such as miRNA could improve our ability to manage this pathological entity. Autopsy could benefit from improvements in miRNA research: the specificity and sensitivity of miRNAs could help physicians in determining the cause of death, besides the time of death

Corpse dismemberment: A case series. Solving the puzzle through an integrated multidisciplinary approach

The finding of corpse parts poses several challenges for the forensic pathologist presenting implications for identification, diagnosis of death and determination of wounds vitality. Further interpretative difficulties in cases of cadaveric dismemberment derive from the scarcity of tanatochronological parameters useful to estimate the post-mortem interval (PMI) and the absence of uniform investigative protocols in the different centres of forensic pathology. The present study proposes an investigation protocol for the cadaveric dismemberment through the discussion of a case series. The study group consisted of cases in which the dismemberment was performed after the murder. For all cases, a study protocol based on crime scene investigation, post-mortem computed tomog- raphy (PMCT), autopsy, toxicological, histological, immunohistochemical and genetic investigations was implemented. In particular, the standardised use of radiographic study before the autopsy allows all to have information that can guide the forensic pathologist during the autopsy. The use of immunohistochemistry allows an assessment of the vitality of the lesions possibly involved in the determinism of death, as well as of the surfaces of dismemberment, representing a tool of considerable utility for forensic purposes. The genetic in- vestigations allow the identification of the victims, while the toxicological ones highlight the possible abuse of substances. The implemented protocol presents a demonstrated usefulness in improving diagnostic accuracy in corpse dismemberment cases

miR-1, miR-499 and miR-208 are sensitive markers to diagnose sudden death due to early acute myocardial infarction

MicroRNAs (miRNAs) are strongly up-regulated under pathological stress and in a wide range of diseases. In recent years, miRNAs are under investigation for their potential use as biomarkers in cardiovascular diseases. We investigate whether specific cardio-miRNAs are overexpressed in heart samples from subjects deceased for acute myocardial infarction (AMI) or sudden cardiac death (SCD), and whether miRNA could help differentiate between them. Forty four cases of death due to cardiovascular disease were selected, respectively, 19 cases categorized as AMI and 25 as SCD. Eighteen cases of traumatic death without pathological cardiac involvement were selected as control. Immunohistochemical investigation was performed for CD15, IL-15, Cx43, MCP-1, tryptase, troponin C and troponin I. Reverse transcription and quantitative real-time PCR were performed for miR-1, miR-133, miR-208 and miR-499. In AMI group, stronger immunoreaction for the CD15, IL-15 and MCP-1 antibodies was detectable compared with SCD and control. Cx43 showed a negative reaction with respect to the other groups. Real-time PCR results showed a down-regulation of all miRNAs in the AMI group compared with SCD and control. The selected miRNAs presented high accuracy in discriminating SCD from AMI (miR-1 and miR-499) and AMI from control (miR-208) representing a potential aid for both clinicians and pathologists for differential diagnosis

Myocardial oxidative damage is induced by cardiac Fas-dependent and mitochondria-dependent apoptotic pathways in human cocaine-related overdose

The aim of this study is to analyse cardiac specimens from human cocaine-related overdose, to verify the hypothesis that cardiac toxicity by acute exposure to high dosage of cocaine could be mediated by unbalanced myocardial oxidative stress, and to evaluate the apoptotic response. To address these issues, biochemical and immunohistological markers of oxidative/nitrosative stress were evaluated. We found that i-NOS, NOX2 and nitrotyrosine expression were significantly higher in the hearts of subjects who had died from high doses of cocaine, compared to the control group. Increase of these markers was associated with a dramatic increase in 8-OHdG, another marker of oxidative stress. A high number of TUNEL-positive apoptotic myocells was observed in the study group compared to the control group. The immunoexpression of TNF-α was significantly higher in the cocaine group compared to the control group. Furthermore, we detected a significantly stronger immunoresponse to anti-SMAC/DIABLO in our study group compared to control cases. Both cardiac Fas-dependent and mitochondria-dependent apoptotic pathways appeared to be activated to a greater extent in the cocaine group than in the control group. Our results highlight the central role of oxidative stress in cocaine toxicity. High levels of NOS can promote the oxidation process and lead to apoptosis