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.

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.

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.

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.

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.

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.

C3a, TNF-alpha and interleukin myocardial expression in a case of fatal sudden cardiac failure during clinic reactivation of systemic lupus erythematosus.

Isolated myocarditis, or dilated cardiomyopathy, is a rare and usually late clinical manifestation of systemic lupus erythematosus (SLE). Increased levels of complement split products are associated with disease activity. Injury of the vascular endothelium due to complement activation and immune complexes may contribute to the vasculopathy in SLE. We present a case of sudden cardiac failure and death in a 28-year-old Caucasian man, during reactivation of SLE. To explain the sudden cardiac failure, we looked for anti-tumour necrosis factor (TNF)- proportional, variant and anti-interleukin (IL) expression in cardiac cells, and anti-complement (anti-C)3a in small cardiac vessels. The immunohistochemical examination of heart specimens revealed a strong positive reaction in cardiac myocytes for antibodies anti-TNF- proportional, variant and IL-8, and a milder positive reaction for antibodies anti-IL-15 and IL-10. A strong positive reaction of C3a in small cardiac vessels was observed in all specimens. Furthermore, the expression of CD4 and CD8 showed a strong positive reaction in pericardium and valvular endocardium, and a lesser positivity in myocardial specimens. TNF appears to have played a major proinflammatory role in this fatal 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.

Preimplantation genetic diagnosis: a step by step guide to recent Italian ethical and legislative troubles.

OBJECTIVE: To analyse legislation and medical professionals' position concerning the doctor's role in assisted reproduction techniques in Italy, and to discuss the implications for physicians of preimplantation genetic diagnosis (PGD). BACKGROUND: Until recently a strict interpretation of the assisted reproduction law (40/2004) and the guidelines subsequently issued, lead to denying infertile couples affected by genetic diseases the right to resort to PGD. In October 2006 the Constitutional Court ruled regarding the question of the constitutional legitimacy of the prohibition of PGD. DISCUSSION: The Constitutional Court declared the manifest inadmissibility of the question of the constitutional legitimacy of article 13 of law 40/2004. The debate has become very animated since the ruling. After the negative sentence of the Constitutional Court, three further sentences recognised the right of couples to obtain PGD, representing a hard blow to law 40/2004 and to the ministerial guidelines; a further confirmation of the untenability of a law that violates fundamental principles such as the right to healthcare for women and the unborn child, the right to responsible motherhood and to informed consent. CONCLUSION: It seems that in Italy the legislative inadequacy for medically assisted procreation is reprieved by the courageous decisions of the judges, which refer to the values of the Italian Constitution, in defence of the fundamental rights of the citizens.

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 systematic study of a myocardial lesion: colliquative myocytolysis.

BACKGROUND: The term "myocytolysis" was first used to define the repair process of contraction band necrosis associated with an acute myocardial infarction. On the other hand, in the latter condition a "myofibrillolysis," presenting edematous myocardial cells not involved by infarct necrosis, and without evidence of repair process was reported. The objective of this study is to establish the frequency, extent and meaning of this myocardial lesion. MATERIALS AND METHODS: In 12 groups of patients for a total of 432 cases with and without coronary heart disease, "colliquative myocytolysis"--i.e., progressive vacuolization by loss of myofibrils until their total or subtotal disappearance associated with intramyocellular edema in absence of any cellular reaction--was graded in 16 histological slides of the different cardiac regions in each pathological case. RESULTS: Colliquative myocytolysis (CM) was present in more than 90% with a maximal extent in cases of irreversible congestive heart failure followed by transplanted heart cases (67%) with a survival greater than 1 week. In all other groups, the lesion was absent or minimal. CONCLUSIONS: No correlation was found between CM and contraction band necrosis, gender, age, heart weight, myocardial fibrosis, coronary artery stenosis, clinical data. Colliquative myocytolysis is a specific histological marker of congestive heart failure, without relation to coronary blood flow, heart weight and myocardial fibrosis. Vacuolization of myocardial cells may be due to other causes (e.g., storage disease, etc.) or may be an artifact. There is no support for the belief that coronary ischemia or myocardial hypoxia is its causes.

Myocardial disarray: an architectural disorganization linked with adrenergic stress?

BACKGROUND: Myocardial disarray is a structural abnormality found in specific zones of the normal heart. In some conditions, such as hypertrophic cardiomyopathy (HCM), its occurrence represents a pathological process leading to myocardial asynergy. The incidence of "pathological" myocardial disarray in humans is still not known. It has been suggested that a link exists between adrenergic overactivity and myocardial disarray. The aim of the present study is to compare heart findings in conditions with and without chronic sympathetic overtone for evidence of possible linkage in humans. MATERIALS AND METHODS: A total of 340 hearts were studied. They were divided into seven groups: sudden/unexpected coronary death; sudden/unexpected death in silent Chagas' disease; brain haemorrhage following berry aneurysm rupture; transplanted hearts; congestive heart failure, AIDS and cocaine abuse. Findings in these hearts were compared with anatomic changes in 92 control hearts, where the decedent had died from head trauma, electrocution, or carbon monoxide intoxication. The frequency and presence of myocardial disarray were recorded and correlated to heart weight, extent of myocardial fibrosis, and contraction band necrosis (CBN). RESULTS: Hearts from patients with conditions that increased sympathetic tone showed an association of myocardial disarray and contraction band necrosis without any relationship to heart weight. CONCLUSIONS: Myocardial disarray was observed in cardiac areas where it is not found normally. It was associated with adrenergic myocardial stress morphologically expressed by a higher number of foci (p<0.01) and myocells (p<0.001) with CBN versus findings in normal subjects. The condition deserves further study as a possible myocardial asynergic and arrhythmogenic factor especially in sudden/unexpected death.

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.

Anabolic steroid abuse and cardiac sudden death: a pathologic study.

CONTEXT: Androgenic anabolic steroids (AAS) used for improving physical performance have been considered responsible for acute myocardial infarction and sudden cardiac death. OBJECTIVE: To establish the relationship between AAS and cardiac death. DESIGN: Case report. PATIENTS: Two young, healthy, male bodybuilders using AAS. MAIN OUTCOME MEASURES: Pathologic cardiac findings associated with AAS ingestion. RESULTS: The autopsy revealed normal coronary arteries. In one case, we documented a typical infarct with a histologic age of 2 weeks. A segmentation of myocardial cells at the intercalated disc level was observed in the noninfarcted region. This segmentation was the only anomaly detected in the second case. No other pathologic findings in the heart or other organs were found. Urine in both subjects contained the metabolites of nortestosterone and stanozolol. COMMENT: A myocardial infarct without vascular lesions is rare. To our knowledge, its association with AAS use, bodybuilding, or both lacks any evidence of a cause-effect relationship. The histologic findings in our 2 cases and in the few others reported in medical literature are nonspecific and do not prove the cardiac toxicity of AAS. A better understanding of AAS action on the neurogenic control of the cardiac function in relation to regional myocardial contraction and vascular regulation is required.