Bleeding varicose veins' ulcer as a cause of death: a case report and review of the current literature.

ABSTRACT: Chronic venous insufficiency (CVI) and varicose veins (VVs) of the lower limbs are very frequent vascular diseases in Western countri-es. One possible complication of these conditions is skin ulceration and its consequent rupture, which can be spontaneous or due to mild or trivial trauma. In some cases, the resulting hemorrhage is fatal. When the victim is found dead, a large amount of blood around the body might lead to the hypothesis of violent death. The Forensic Pa-thologist needs to be very careful in the corpse's examination, in order to exclude any alternative cause of death. Herein, an illustrative case is reported, as well as a literature review of the literature concerning sudden hemorrhages from VVs. We found 27 scientific papers, the total reported cases of VVs rupture with profuse hemorrhages were 36, 32 of which were fatal. The main characteristics of such forensic scenario have been collected. Corpse examination of the victims showed pallor of the skin and mucous membranes, as well as marked pallor of organs as a sign of hemorrhagic shock, but these pathological findings are unspecific. Usually, the skin near the ulcer presented color alteration (discoloration and atrophy or pigmentation and hyperemia). Besides, the histological examination of the skin could be a valid instrument to demonstrate the presence of the ulcer, even if it could be very difficult to sample, because of its small size. An important limit of our study is the small number of collected cases. More studies in this field are needed to improve evidence concerning death due to VVs rupture.

Physician-Patient Relationship, Assisted Suicide and the Italian Constitutional Court.

In 2017, Italy passed a law that provides for a systematic discipline on informed consent, advance directives, and advance care planning. It ranges from decisions contextual to clinical necessity through the tool of consent/refusal to decisions anticipating future events through the tools of shared care planning and advance directives. Nothing is said in the law regarding the issue of physician assisted suicide. Following the DJ Fabo case, the Italian Constitutional Court declared the constitutional illegitimacy of article 580 of the criminal code in the part in which it does not exclude the punishment of those who facilitate the suicide when the decision has been freely and autonomously made by a person kept alive by life-support treatments and suffering from an irreversible pathology, the source of physical or psychological suffering that he/she considers intolerable, but fully capable of making free and conscious decisions. Such conditions and methods of execution must be verified by a public structure of the national health service, after consulting the territorially competent ethics committee. This statement admits, within strict and regulated bounds, physician assisted suicide, so widening the range of end-of-life decisions for Italian patients. Future application and critical topics will be called into question by the Italian legislator.

Crossbow injuries: A case report with experimental reconstruction study and a systematic review of literature.

In modern times crossbow - a ranged weapon diffused during Middle Ages - is increasing its popularity in recreational hunting and sports; crossbow bolts have a great penetration capacity, despite their low initial velocity. Great concerns emerge when considering that notwithstanding crossbow is a potentially lethal distance weapon, it is easy to obtain without having to undertake any tests on the buyer's mental or physical health. Although rare, crossbow injuries can be challenging for the forensic pathologist due to great similarities with other wounds pattern (gunshots wounds or injury due to sharp force). Especially when the arrow is removed from its original position or the body is decomposed, identification of the weapon can be difficult. According to forensic literature, suicides, homicides and non-lethal injuries by crossbow have been reported up to the present day. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) indications in the identification and selection of studies and reviewed a series of cases of both fatal and non-fatal crossbow injuries, according to the manner of death (homicide, suicide, accidental). The casuistic part of this paper deals with an attempted murder of a 21-year old man: a case of non-lethal crossbow injury of the thorax in which an interdisciplinary approach, involving forensic inspection, ballistic and radiology tests, led to solve the case.

Role of post mortem CT (PMCT) in high energy traumatic deaths.

BACKGROUND: Post Mortem Computed Tomography (PMCT) is being increasingly implemented in forensic field and could be an adjuvant to classic autopsies. In this study we evaluated the feasibility of complementation of conventional autopsy in trauma victims with PMCT. MATERIALS AND METHODS: A total of 21 subjects, who had sustained various types of blunt high-energy trauma, were selected from the casuistry of the Section of Legal Medicine at University of Pisa: before autopsy, a PMCT examination (Toshiba Aquilion 16 CT scanner) was performed, and after the acquisition of the raw images, MPR and VR reconstructions were performed with dedicated software. RESULTS: PMCT is more sensitive than conventional autopsy in detecting skeletal injuries, whilst autopsy constitutes the method of choice for the detection of thoracic and abdominal visceral injuries. CONCLUSIONS: PMCT should be considered a useful tool in addition to conventional autopsy in evaluating trauma victims: it detects further bone fractures in body parts difficult to investigate during autopsy (i.e. posterior regions), facilitating the pathologist in the reconstruction of events and in determining the cause of death.

Oxidative-Nitrosative Stress and Myocardial Dysfunctions in Sepsis: Evidence from the Literature and Postmortem Observations.

BACKGROUND: Myocardial depression in sepsis is common, and it is associated with higher mortality. In recent years, the hypothesis that the myocardial dysfunction during sepsis could be mediated by ischemia related to decreased coronary blood flow waned and a complex mechanism was invoked to explain cardiac dysfunction in sepsis. Oxidative stress unbalance is thought to play a critical role in the pathogenesis of cardiac impairment in septic patients. AIM: In this paper, we review the current literature regarding the pathophysiology of cardiac dysfunction in sepsis, focusing on the possible role of oxidative-nitrosative stress unbalance and mitochondria dysfunction. We discuss these mechanisms within the broad scenario of cardiac involvement in sepsis. CONCLUSIONS: Findings from the current literature broaden our understanding of the role of oxidative and nitrosative stress unbalance in the pathophysiology of cardiac dysfunction in sepsis, thus contributing to the establishment of a relationship between these settings and the occurrence of oxidative stress. The complex pathogenesis of septic cardiac failure may explain why, despite the therapeutic strategies, sepsis remains a big clinical challenge for effectively managing the disease to minimize mortality, leading to consideration of the potential therapeutic effects of antioxidant agents.

The NADPH oxidase NOX2 as a novel biomarker for suicidality: evidence from human post mortem brain samples.

Recent evidence points towards a role of oxidative stress in suicidality. However, few studies were carried out on the sources of reactive oxygen species (ROS) in subjects with suicidal behaviour. We have previously demonstrated that the NADPH oxidase NOX2-derived oxidative stress has a major role in the development of neuropathological alterations observed in an animal model of psychosis. Here, we investigated the possible increase in NOX2 in post mortem brain samples of subjects who died by asphyctic suicide (AS) compared with controls (CTRL) and subjects who died by non-suicidal asphyxia (NSA). We found that NOX2 expression was significantly higher in the cortex of AS subjects than in the other two experimental groups. NOX2 immunostaining was mainly detected in GABAergic neurons, with a minor presence of NOX2-positive-stained cells in glutamatergic and dopaminergic neurons, as well as astrocytes and microglia. A sustained increase in the expression of 8-hydroxy-2'-deoxyguanosine, an indirect marker of oxidative stress, was also detected in the cortex of AS subjects, compared with CTRL and NSA subjects. A significant elevation in cortical interleukin-6 immunoreactivity in AS subjects suggested an involvement of cytokine-associated molecular pathways in NOX2 elevations. Our results suggest that the increase in NOX2-derived oxidative stress in the brain might be involved in the neuropathological pathways leading to suicidal behaviour. These results may open innovative insights in the identification of new pathogenetic and necroscopic biomarkers, predictive for suicidality and potentially useful for suicide prevention.

A Pathophysiological Insight into Sepsis and Its Correlation with Postmortem Diagnosis.

BACKGROUND: Sepsis is among the leading causes of death worldwide and is the focus of a great deal of attention from policymakers and caregivers. However, sepsis poses significant challenges from a clinical point of view regarding its early detection and the best organization of sepsis care. Furthermore, we do not yet have reliable tools for measuring the incidence of sepsis. Methods based on analyses of insurance claims are unreliable, and postmortem diagnosis is still challenging since autopsy findings are often nonspecific. AIM: The objective of this review is to assess the state of our knowledge of the molecular and biohumoral mechanisms of sepsis and to correlate them with our postmortem diagnosis ability. CONCLUSION: The diagnosis of sepsis-related deaths is an illustrative example of the reciprocal value of autopsy both for clinicians and for pathologists. A complete methodological approach, integrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the host response to infectious insults, is mandatory to illuminate the exact cause of death. This would help clinicians to compare pre- and postmortem findings and to reliably measure the incidence of sepsis.

Use of contrast media in diagnostic imaging: medico-legal considerations.

Contrast media (CM) are used in imaging techniques to enhance the differences between body tissues on images. The ideal contrast medium should achieve very high concentration in the tissues without producing any adverse effects. Unfortunately, this has not been possible so far and all CM have adverse effects. The increasing use of CM is likely to give rise to a wide range of pitfalls, including compliance with and appropriateness of indications for the use of CM themselves, the choice of the 'best' contrast agent, off-label use, evaluation of special populations of patients, and competence to tackle emergency scenarios following the administration of CM. Even more prominent, and potentially more important, is the issue of informed consent which brings with it a duty to inform patients awaiting the administration of CM with regard to the nature of the procedure, the existence of alternative procedures, the extent of the risks relating to the use of CM and, finally, the risks relating to refusal of the procedure. All these issues may give rise to concerns about liability for failure to offer adequate information to patients or to carefully evaluate and balance the potential risks and benefits of the procedure or, finally, for being unprepared in the event of adverse reactions to CM, especially when these are severe and life-threatening. Educational and training programmes for radiologists are likely to shape change in the medical liability environment in the coming years.

Gua Sha a traditional Chinese healing technique that could mimick physical abuse: a potential issue with forensic implications. A case study.

Gua Sha (press-stroking) is a traditional Chinese healing technique utilized to combat pain, common cold, heatstroke, and respiratory problems. Patterned ecchymoses may appear due to the action of scraping and scratching repeatedly in a unidirectional manner, with a smooth edge over a lubricated area. They may be very informative, since they, generally, reproduce the shape of the injurious agent. However, many confounding factors can make the identification of the lesions difficult. A case of a 43 year-old Chinese woman, hospitalized for abdominal pain, is reported. An unusual pattern of reddish ecchymoses on the back was present. After a careful investigation, ecchymoses were attributed to Gua Sha. The case demonstrated that clinicians and forensic pathologists should also consider press-stroking, and other similar techniques in adults who present scratch-like marks or ecchymoses on various body districts, even if they have an unusual pattern.

Side effects of cocaine abuse: multiorgan toxicity and pathological consequences.

Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse.

Cardiovascular effects of cocaine: cellular, ionic and molecular mechanisms.

Cocaine is a widely abused drug responsible for the majority of deaths ascribed to drug overdose. Many mechanisms have been proposed in order to explain the various cocaine associated cardiovascular complications. Conventionally, cocaine cardiotoxicity has been thought to be mediated indirectly through its sympathomimetic effect, i.e., by inhibiting the reuptake and thus increasing the levels of neuronal catecholamines at work on adrenoceptors. Increased oxidative stress, reactive oxygen species, and cocaine-induced apoptosis in the heart muscle have suggested a new way to understand the cardiotoxic effects of cocaine. More recent studies have led the attention to the interaction of cocaine and some metabolites with cardiac sodium, calcium and potassium channels. The current paper is aimed to investigate the molecular mechanisms of cocaine cardiotoxicity which have a specific clinical and forensic interest. From a clinical point of view the full knowledge of the exact mechanisms by which cocaine exerts cardio - vascular damage is essential to identify potential therapeutic targets and improve novel strategies for cocaine related cardiovascular diseases. From a forensic point of view, it is to be underlined that cocaine use is often associated to sudden death in young, otherwise healthy individuals. While such events are widely reported, the relationship between cardiac morphological alterations and molecular/cellular mechanisms is still controversial. In conclusion, the study of cocaine cardiovascular toxicity needs a strict collaboration between clinicians and pathologists which may be very effective in further dissecting the mechanisms underlying cocaine cardiotoxicity and understanding the cardiac cocaine connection.

Role of oxidative stress in cocaine-induced cardiotoxicity and cocaine-related death.

Cocaine-induced cardiovascular disorders such as hypertension, thrombosis, myocardial dysfunction, cardiac dysrhythmias and endocarditis have received widespread attention in the context of cocaine abuse. The number of sudden deaths from cardiac causes, including myocardial infarction, ventricular tachyarrhythmia or aortic dissection, is also increasing. This manuscript will highlight the recent employment of study about cocaine cardiotoxicity and oxidative stress. Evidence has revealed that cardiac oxidative stress is a prominent early event of cocaine administration, which severely compromises the cardiac antioxidant cellular system and causes cardiac antioxidant cellular system injuries. Oxidative damage such as peroxidation of membrane phospholipids and depletion of nonenzymatic antioxidants such as glutathione have been found in the myocardium of chronic cocaine-treated animals and in patients. The data indicate that cocaine administration compromised the heart's antioxidant defense system. About the mechanisms involved in the cellular damage, the evidence that cocaine causes apoptosis in the heart comes from in vivo study. In animals model after short-term and long term-cocaine administration, the investigators demonstrates the role of Reactive Oxygen Species as a trigger of cardiac injury induced by cocaine. Cocaine also increased infiltration of inflammatory cells in the heart, and apoptotic cells were predominantly found near inflammatory cells. The role of oxidative stress in cocaine-induced apoptosis in the heart is wide studied and documented.

Retrospective analysis of anaesthesia-related deaths during a 12-year period: looking at the data from a forensic point of view.

Anaesthesia-related death is one of the most complex events to be studied in forensic pathology because of its rarity and its doubtful presentation. Particularly, the difficulties in assessing the cause of deaths in such circumstances are underlined. A scale must be considered in order to determine the causal role of anaesthesia in the process leading to death. Indeed, beyond deaths exclusively explained by anaesthetic care, there are deaths that are not anaesthesia-related and deaths explained by surgery and co-morbidities in which the role of anaesthetic care has to be carefully investigated. A retrospective analysis of 3138 autopsies is presented with the aim of better understanding the patho-physiological process of anaesthesia-related mortality and to determine the causal role of anaesthesiological care in the process leading to death, thus assessing the real incidence of deaths due to anaesthesia (0.16%). In the present study, the number of deaths generically anaesthesia-related (33 cases) accounts for 2.06% of autopsies due to medical malpractice claims and 1.05% of all autopsies. The number of deaths totally related to anaesthesic care is rather low with 0.32% of autopsies due to medical malpractice claims and 0.16% of all autopsies. Anaesthesia-related deaths were due to lack of or delay in intubation (2 cases), acute cardio-respiratory failure (2 cases) and anaesthetic-induced hepatotoxicity (1 case). The importance of a careful forensic investigation (clinical and familial history, medical records, complete autopsy and toxicology), which can lead to a clear understanding of anaesthesia-related deaths, is also stressed.

Acute administration of 3,4-methylenedioxymethamphetamine (MDMA) induces oxidative stress, lipoperoxidation and TNFα-mediated apoptosis in rat liver.

Liver toxicity is one of the consequences of ecstasy (3,4-methylenedioxymethamphetamine MDMA) abuse and hepatocellular damage is reported after MDMA consumption. Various factors probably play a role in ecstasy-induced hepatotoxicity, namely its metabolism, the increased efflux of neurotransmitters, the oxidation of biogenic amines, and hyperthermia. MDMA undergoes extensive hepatic metabolism that involves the production of reactive metabolites which form adducts with intracellular nucleophilic sites. MDMA-induced-TNF-α can promote multiple mechanisms to initiate apoptosis in hepatocytes, activation of pro-apoptotic (BID, SMAC/DIABLO) and inhibition of anti-apoptotic (NF-κB, Bcl-2) proteins. The aim of the present study was to obtain evidence for the oxidative stress mechanism and apoptosis involved in ecstasy-induced hepatotoxicity in rat liver after a single 20 mg/kg, i.p. MDMA administration. Reduced and oxidized glutathione (GSH and GSSG), ascorbic acid (AA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA), an indicator of lipid peroxidation, were determined in rat liver after 3 and 6h after MDMA treatment. The effect of a single MDMA treatment included decrease of GR and GPx activities (29% and 25%, respectively) and GSH/GSSG ratio (32%) with an increase of MDA (119%) after 3h from ecstasy administration compared to control rats. Liver cytosolic level of AA was increased (32%) after 6 h MDMA treatment. Our results demonstrate a strong positive reaction for TNFα (p<0.001) in hepatocytes and a diffuse apoptotic process in the liver specimens (p<0.001). There was correlation between immunohistochemical results and Western blotting which were quantitatively measured by densitometry, confirming the strong positivity for TNF-α (p<0.001) and NF-κB (p<0.001); weak and intense positivity reactions was confirmed for Bcl-2, SMAC/DIABLO (p<0.001) and BID reactions (p<0.001). The results obtained in the present study suggest that MDMA induces loss of GSH homeostasis, decreases antioxidant enzyme activities, and lipoperoxidation that causes an oxidative stress that accompaines the MDMA-induced apoptosis in liver cells.

Immunohistochemical characterisation and TNF-α expression of the granulomatous infiltration of the brainstem in a case of sudden death due to neurosarcoidosis.

Neurosarcoidosis carries a mortality of 10%, over twice that of sarcoidosis overall, although it has been rarely reported as a cause of sudden death. The current evidence suggests that sarcoidosis results from an enhanced immune reaction to a variety of antigens, non-self or self which causes CD4 (helper-inducer) T-cell accumulation with a ratio of helper-inducer T cells to suppressor-cytotoxic T cells usually high in affected organs, activation and release of inflammatory cytokines, and formation of granulomatous lesions. Numerous cytokines and other mediators are produced by both activated macrophages and T lymphocytes bearing the CD4-helper phenotype during the granuloma responses. A number of data suggest that interferon-gamma (IFN-gamma) and cytokines such as TNF-α, IL-2, and IL-18 play a critical role in the formation of granulomas. In this article, we describe the clinical and pathological characteristics of a patient who suddenly died due to acute respiratory failure. Neurosarcoidosis with massive and extensive involvement of the brainstem was established as the cause of death. Western blot analysis in the patient demonstrated the TNF-α presence as a 51-kDa protein in the brain tissue. The immunohistochemical analysis showed a poor positiveness for CD4 in all samples around the granulomas, as well as moderate positiveness for CD8, CD15, and CD20; CD45 and CD68 showed a strong positiveness in all the brain samples. Histological findings, immunohistochemical analysis, and proteomic studies addressed the diagnosis of neurosarcoidosis with involvement of the nucleus of the solitary tract in the brainstem and central hypoventilation as the cause of death.

Anabolic androgenic steroids abuse and liver toxicity.

In the athletes the wide use of Anabolic Androgenic Steroids (AAS) cause series damage in various organs, in particular, analyzing the liver, elevation on the levels of liver enzymes, cholestatic jaundice, liver tumors, both benign and malignant, and peliosis hepatis are described. A prolonged AAS administration provokes an increase in the activities of liver lysosomal hydrolases and a decrease in some components of the microsomal drug-metabolizing system and in the activity of the mitochondrial respiratory chain complexes without modifying classical serum indicators of hepatic function. Liver is a key organ actively involved in numerous metabolic and detoxifying functions. As a consequence, it is continuously exposed to high levels of endogenous and exogenous oxidants that are by-products of many biochemical pathways and, in fact, it has been demonstrated that intracellular oxidant production is more active in liver than in tissues, like the increase of inflammatory cytokines, apoptosis and the inhibitors of apoptosis NF- κB and Heat Shock Proteins.

Heart disease induced by AAS abuse, using experimental mice/rats models and the role of exercise-induced cardiotoxicity.

The anabolic-androgenic steroids (AAS) are all synthetic derivates of testosterone and are commonly used as sport performance enhancers in athletes. The heart is one of the organs most frequently affected by administration of anabolic steroids. A direct myocardial injury caused by AAS is supposed to determine marked hypertrophy in myocardial cells, extensive regional fibrosis and necrosis. A number of excellent studies, using animal models, were performed to evaluate the cardiac effects of AAS. It is known that exogenous administration induced cardiac hypertrophy in vitro and in vivo, and when combined with exercise, anabolic steroid use has been shown to change exercise-induced physiological cardiac hypertrophy to pathophysiological cardiac hypertrophy. However the molecular mechanisms are still poorly understood. It's described that sudden cardiac death, myocardial infarct; ventricular remodelling and cardiomyopathy do to AAS is related to apoptosis and oxidative stress when associated with exercise. Mechanical stimuli and circulating humoral factors (TNF-α, HSP-70, IL-1ß) released by the heart and peripheral organs are responsible. Testosterone and derivates can work through genomic (activation of specific androgen receptor, interaction with coactivators and co-repressors transcription factors, gene regulation) and non-genomic mechanism (membrane-receptor-second messenger cascades). Chronic AAS abuse results in different patterns of pathologic alterations, which depend on type, dose, frequency, and mode of use. The difficulty in interpreting experimental data on animals (mice and rats) lies in the diversity of experiments (the diversity of substances, which show different properties, different mice / rats by sex and age, duration of treatment with AAS, dosages used, type, scope and exercise duration).