[Diagnosis of a rare and severe inflammatory bowel disease in an infant with peri-orificial ulcerations]. / Diagnostic d'une maladie inflammatoire rare et sévère de l'intestin chez un nourrisson présentant des ulcérations péri-orificielles.

We report the case of an infant aged 8 and a half months, who had an apparent life-threatening event and died despite optimal resuscitation management. The medical history was marked by mild symptoms, mainly feeding difficulties and progressively settling skin lesions. Parents were related (first cousins) and the patient had two healthy older sisters. Autopsy showed growth delay, symmetrical erythematous and ulcerated periorificial lesions associated with punctiform erythematous lesions of the face and alopecia. Microscopic examination revealed deep bronchial inhalation with the onset of infectious pneumopathy, major inflammatory ulceration of the gastrointestinal tract, hepatic steatosis, brain stem and pancreas abnormalities. We conclude that the cause of death was a multi-visceral failure with inhalation pneumopathy, in a context of very early onset inflammatory bowel disease (VEO-IBD). Genetic consultation, into a rare disease reference center, allowed to orient the analysis, to identify a homozygous pathogenic variant in the IL10RA gene, confirming the diagnostic of an autosomal recessive very early onset inflammatory bowel disease (inflammatory bowel disease 28, early-onset, autosomal recessive, #613148).

[Neuropathology of sudden infant death syndrome: Review of the literature and proposal of a protocol for neuropathological examination]. / Neuropathologie du syndrome de la mort inattendue du nourrisson : revue de la littérature et proposition d'un protocole pour l'examen neuropathologique.

According to the French High Authority for Health, sudden unexpected death in infants (SUDI) is defined as "a sudden death that occurs in an infant, whereas nothing in its known history could have predicted it". This is an exclusion diagnosis. There are great interregional disparities despite the professional recommendations established in February 2007. For the examination of the brain, instructions are not adapted to current and research practice. The role of the pathologist, like anyone involved in SUDI, is to eliminate an abuse head trauma and to determine the cause of death. Major neuropathological lesions by definition do not exist. Lesions of hypoxia/ischemia are the most frequent but not specific. The accessibility of anti-APP immunoblotting has highlighted the role of anoxia in the development of axonal diffuse damages. Many studies are looking for a neurological substratum of the SUDI (neuropathological and/or neurobiochinic). This article aims to define a detailed sampling protocol based on foreign consensus and current data of science in order to assist pathologists and to promote a homogeneous data bank in France.

[Sudden death of a young man as late sequelae complicating a pediatric disease: About a case]. / Mort subite d'un homme jeune dans le cadre de séquelles tardives d'une pathologie pédiatrique : à propos d'un cas.

In France, sudden death is responsible every year for 40,000 deaths. The most frequent etiology is cardiac disease. Atheromatous-related pathology is the most common etiology beyond 35, but cardiomyopathies and channelopathies are responsible for a significant number of deaths in young adults. Some acquired disorders can also cause sudden cardiac death. We report the case of a 17-year-old man who died suddenly after sport. Autopsy and pathological study found multiple giant coronary aneurysms. Thrombosis and fibrous scar of myocardial ischemic events were observed. These lesions were in favor of late sequelae of Kawasaki disease. Kawasaki disease is a rare but not exceptional cause of sudden cardiac death in young adults. In the lack of known clinical history, some aspects, even not specific, should evoke this diagnosis. Even in front of apparent good clinical tolerance, these sequelae require appropriate follow-up because of a significant risk of sudden death.

Bone beveling caused by blunt trauma: a case report.

The authors report a fatal case of blunt trauma to the skull caused by a rib of a beach umbrella. The skull displayed a round hole in the right temporal bone with typical internal beveling. Blunt trauma mimicking a gunshot wound (round perforation of the skull with internal beveling) is very rarely reported in the forensic literature.

Postmortem CT appearance of gas collections in fatal diving accidents.

OBJECTIVE. The purpose of our study was to define the postmortem CT semiology of gas collections linked to putrefaction, postmortem "off-gassing," and decompression illness after fatal diving accidents and to establish postmortem CT diagnostic criteria to distinguish the different causes of death in diving. SUBJECTS AND METHODS. A 4-year prospective study was conducted including cases of death during diving. A hyperbaric physician analyzed the circumstances of death and the dive profile, and an autopsy was performed. Subjects were divided into three groups according to the analysis from their dive profile: decompression illness, death after decompression dive without decompression illness, and death after nondecompression dive without decompression illness. Full-body postmortem CT was performed before autopsy. RESULTS. The presence of intraarterial gas associated with death by decompression illness had a negative predictive value (NPV) of 100%, but the positive predictive value (PPV) was only 54% because of postmortem off-gassing. The PPV reached 70% when considering pneumatization of the supraaortic trunks. Pneumothorax, subcutaneous emphysema, and intraarterial gas, all of which are classic criteria for decompression illness diagnosis, are not specific for decompression illness. CONCLUSION. This study is the first to show that pneumothorax, subcutaneous emphysema, and intraarterial gas, all of which are classic criteria for decompression illness diagnosis, are not specific for decompression illness. Complete pneumatization of supraaortic trunks is the best postmortem CT criteria to detect a fatal decompression illness when CT is performed within 24 hours after death.

Traumatic axonal injury: Clinic, forensic and biomechanics perspectives.

Identification of Traumatic axonal injury (TAI) is critical in clinical practice, particularly in terms of long-term prognosis, but also for medico-legal issues, to verify whether the death or the after-effects were attributable to trauma. Multidisciplinary approaches are an undeniable asset when it comes to solving these problems. The aim of this work is therefore to list the different techniques needed to identify axonal lesions and to understand the lesion mechanisms involved in their formation. Imaging can be used to assess the consequences of trauma, to identify indirect signs of TAI, to explain the patient's initial symptoms and even to assess the patient's prognosis. Three-dimensional reconstructions of the skull can highlight fractures suggestive of trauma. Microscopic and immunohistochemical techniques are currently considered as the most reliable tools for the early identification of TAI following trauma. Finite element models use mechanical equations to predict biomechanical parameters, such as tissue stresses and strains in the brain, when subjected to external forces, such as violent impacts to the head. These parameters, which are difficult to measure experimentally, are then used to predict the risk of injury. The integration of imaging data with finite element models allows researchers to create realistic and personalized computational models by incorporating actual geometry and properties obtained from imaging techniques. The personalization of these models makes their forensic approach particularly interesting.

Head injury: Importance of the deep brain nuclei in force transmission to the brain.

Finite element modeling provides a digital representation of the human body. It is currently the most pertinent method to study the mechanisms of head injury, and is becoming a scientific reference in forensic expert reports. Improved biofidelity is a recurrent aim of research studies in biomechanics in order to improve earlier models whose mechanical properties conformed to simplified elastic behavior and mechanic laws. We aimed to study force transmission to the brain following impacts to the head, using a finite element head model with increased biofidelity. To the model developed by the Laboratory of Applied Biomechanics of Marseille, we added new brain structures (thalamus, central gray nuclei and ventricular systems) as well as three tracts involved in the symptoms of head injury: the corpus callosum, uncinate tracts and corticospinal tracts. Three head impact scenarios were simulated: an uppercut with the prior model and an uppercut with the improved model in order to compare the two models, and a lateral impact with an impact velocity of 6.5 m/s in the improved model. In these conditions, in uppercuts the maximum stress values did not exceed the injury risk threshold. On the other hand, the deep gray matter (thalamus and central gray nuclei) was the region at highest risk of injury during lateral impacts. Even if injury to the deep gray matter is not immediately life-threatening, it could explain the chronic disabling symptoms of even low-intensity head injury.

Resuscitation and Forensic Factors Influencing Outcome in Penetrating Cardiac Injury.

BACKGROUND: Cardiac injury caused by a sharp object is a medical and surgical therapeutic challenge. Mortality risk factors have been identified but there are major discrepancies in the literature. The aim of this study was to analyse the management of victims of penetrating cardiac injuries before and after admission to hospital and the anatomical characteristics of these injuries in order to facilitate diagnosis of the most critical patients. METHODS: To carry out this study, we conducted a retrospective analytical study with epidemiological data on victims of penetrating cardiac injuries. We included two types of patients, with those who underwent autopsy in our institution after death from sharp injury to the heart or great vessels and those who survived with treatment in the emergency department or intensive care unit between January 2015 and February 2022. RESULTS: We included 30 autopsied patients and 12 survivors aged between 18 and 73 years. Higher mortality was associated with prehospital or in-hospital cardiorespiratory arrest (OR = 4, CI [1.71-9.35]), preoperative mechanical ventilation (OR = 10, CI [1.53-65.41]), preoperative catecholamines (OR = 7, CI [1.12-6.29]), preoperative and perioperative adrenaline (OR = 13, CI [1.98-85.46] and [1.98-85.46]), penetrating cardiac injury (OR = 14, CI [2.10-93.22]), multiple cardiac injuries (OR = 1.5, CI [1.05-2.22]) and an Organ Injury Scaling of the American Association for the Surgery of Trauma (AAST-OIS) score of 5 (OR = 2.9, CI [1.04-8.54]; p = 0.0329) with an AUC-ROC curve value of 0.708 (CI [0.543-0.841]). CONCLUSIONS: This study identified risk mortality factors in penetrating cardiac injury patients. These findings can help improve the diagnosis and management of these patients. The AAST-OIS score may be a good tool to diagnose critical patients.

Identification of soluble CD146 as a regulator of trophoblast migration: potential role in placental vascular development.

Both vasculogenesis and angiogenesis occur during normal placental vascular development. Additionally, the placenta undergoes a process of vascular mimicry (pseudo-vasculogenesis) where the placental extravillous trophoblast (EVT) that invade the spiral arteries convert from an epithelial to an endothelial phenotype during normal pregnancy. As soluble CD146 (sCD146) constitutes a new physiological factor with angiogenic properties, we hypothesized that it could be involved in the regulation of placental vascular development by acting on EVT. Using placental villous explants, we demonstrated that sCD146 inhibits EVT outgrowth. Consistently, we showed that sCD146 inhibits the ability of EVT cells (HTR8/SVneo) to migrate, invade and form tubes in Matrigel, without affecting their proliferation or apoptosis. The involvement of sCD146 in human pregnancy was investigated by evaluation of sCD146 levels in 50 pregnant women. We observed physiological down-regulation of sCD146 throughout pregnancy. These results prompted us to investigate the effect of prolonged sCD146 administration in a rat model of pregnancy. Repeated systemic sCD146 injections after coupling caused a significant decrease of pregnancy rate and number of embryos. Histological studies performed on placenta evidenced a reduced migration of glycogen cells (analogous to EVT in rat) in sCD146-treated rats. We propose that in human, sCD146 could represent both an attractive biomarker of placental vascular development and a therapeutic target in pregnancy complications associated with pathological angiogenesis.

Effects of fall conditions and biological variability on the mechanism of skull fractures caused by falls.

In a forensic investigation, there is considerable difficulty in distinguishing between different mechanisms that could explain the head injury sustained. The key question is often whether the injury was the consequence of a fall, a blow, or a fall caused by a blow. Better understanding of the parameters influencing the mechanism of skull fracture could be of use when attempting to distinguish between different causes of injury. Numerous parameters concerning fall conditions and biological variability are reported in the literature to influence the mechanism of skull fracture. At the current time, there are no studies that investigate both the effect of a fall and biological parameters. The aim of this paper is to study the influence of these parameters on the mechanism of skull fracture using a numerical approach. We focused on accidental falls from a standing height. A multibody model was used to estimate head impact velocities and a finite element model was used to investigate the effect of the fall conditions and of biological variability on skull fracture. The results show that the mechanism of skull fractures is influenced by a combination of at least four parameters: impact velocity, impact surface, cortical thickness and cortical density.

Can subclavian blood be equated with a peripheral blood sample? A series of 50 cases.

If femoral blood is not available at autopsy, toxicological analyses, in particular blood ethanol measurements, are carried out on cardiac blood. This is known to be subject to major redistribution. We aimed to determine whether subclavian blood can be equated with a peripheral blood sample and could be used if femoral blood is not available. The study was based on 50 medicolegal autopsies in which we compared ethanol concentrations between subclavian blood, the different heart blood compartments (right and left cardiac blood), and femoral blood. Mechanisms that could lead to variations in concentration, i.e., postmortem redistribution and/or endogenous production, were also taken into account in interpreting the results. Ethanol concentrations were determined by headspace gas chromatography with a flame ionization detector. In each case, we recorded the circumstances of death, resuscitation attempts if any, degree of putrefaction, chest or abdominal trauma, and/or inhalation of gastric fluid in the airways. Ethanol concentrations in subclavian blood were found to be close to those in peripheral blood (p = 0.948) and were not influenced by the degree of putrefaction (r = 0.017, p = 0.904), gastric ethanol concentration (r = -0.011, p = 0.940), inhalation of gastric contents in the airways (p = 0.461), or cardiac resuscitation attempts (p = 0.368). We discuss the possible explanations for these findings and stress the value of sampling subclavian blood when femoral blood is not obtainable at autopsy.

Soluble CD146 displays angiogenic properties and promotes neovascularization in experimental hind-limb ischemia.

CD146, an endothelial molecule involved in permeability and monocyte transmigration, has recently been reported to promote vessel growth. As CD146 is also detectable as a soluble form (sCD146), we hypothesized that sCD146 could stimulate angiogenesis. Experiments of Matrigel plugs in vivo showed that sCD146 displayed chemotactic activity on endogenous endothelial cells, and exogenously injected late endothelial progenitor cells (EPCs). Recruited endothelial cells participated in formation of vascular-like structures. In vitro, sCD146 enhanced angiogenic properties of EPCs, with an increased cell migration, proliferation, and capacity to establish capillary-like structures. Effects were additive with those of vascular endothelial growth factor (VEGF), and sCD146 enhanced VEGFR2 expression and VEGF secretion. Consistent with a proangiogenic role, gene expression profiling of sCD146-stimulated EPCs revealed an up-regulation of endothelial nitric oxide synthase, urokinase plasminogen activator, matrix metalloproteinase 2, and VEGFR2. Silencing membrane-bound CD146 inhibited responses. The potential therapeutic interest of sCD146 was tested in a model of hind limb ischemia. Local injections of sCD146 significantly reduced auto-amputation, tissue necrosis, fibrosis, inflammation, and increased blood flow. Together, these findings establish that sCD146 displays chemotactic and angiogenic properties and promotes efficient neovascularization in vivo. Recombinant human sCD146 might thus support novel strategies for therapeutic angiogenesis in ischemic diseases.

[Loss of chance in compensation for non-accidental bodily injury: inventory]. / Perte de chance en réparation du préjudice corporel hors accident : état des lieux.

Loss of chance in compensation for non-accidental bodily injury: inventory The main problem with this notion is the hypothetical nature of the loss of chance, insofar as it is impossible to take for sure if the hoped-for event would actually haved occurred. This this is the main difficulty encountered when estimating a loss of chance. The aim of this work is to identify a number of tools that will serve as a basis for the assessment of loss of chance damage. The contribution of data from the literature, the use of abacuses depending on the terrain and the pathology and the contribution of sapients will be described. The calculation methodology will also be discussed in the context of the cumulative loss of chances suffered by the patient.

Perte de chance en réparation du préjudice corporel hors accident : état des lieux La problématique de la notion de perte de chance est son caractère hypothétique, dans la mesure où il est impossible de savoir avec certitude si le fait espéré se serait réellement réalisé. C'est là toute la difficulté qui incombe au calcul de la perte de chance. Il est cependant possible de distinguer ou d'envisager un certain nombre de moyens permettant d'évaluer le préjudice de perte de chance. Les données de la littérature, les abaques, en fonction du terrain et de la pathologie, et les experts y contribuent. La méthodologie de calcul, dans le cadre du cumul de pertes de chances subies par le patient, mérite aussi d'être discutée.

[A rare cause of sudden cardiac failure: histiocytoid cardiomyopathy]. / Une cause rare de défaillance cardiaque brutale chez le nourrisson : la cardiomyopathie histiocytoïde.

Histiocytoid cardiomyopathy is a rare disease which occurs predominantly in the first two years of life, with a female preponderance. We report the cases of two girls (11 and 15-month-old) which were respectively referred to our institution for ventricular tachycardia and ventricular fibrillation without prodroma. Etiologic findings only showed mild cardiomyopathy. Autopsy and histologic examination led to the diagnosis of histiocytoid cardiomyopathy. Furthermore, in the first observation, agenesis of the corpus callosum was found.

Cyclosporin A: A Repurposable Drug in the Treatment of COVID-19?

Coronavirus disease 2019 (COVID-19) is now at the forefront of major health challenge faced globally, creating an urgent need for safe and efficient therapeutic strategies. Given the high attrition rates, high costs, and quite slow development of drug discovery, repurposing of known FDA-approved molecules is increasingly becoming an attractive issue in order to quickly find molecules capable of preventing and/or curing COVID-19 patients. Cyclosporin A (CsA), a common anti-rejection drug widely used in transplantation, has recently been shown to exhibit substantial anti-SARS-CoV-2 antiviral activity and anti-COVID-19 effect. Here, we review the molecular mechanisms of action of CsA in order to highlight why this molecule seems to be an interesting candidate for the therapeutic management of COVID-19 patients. We conclude that CsA could have at least three major targets in COVID-19 patients: (i) an anti-inflammatory effect reducing the production of proinflammatory cytokines, (ii) an antiviral effect preventing the formation of the viral RNA synthesis complex, and (iii) an effect on tissue damage and thrombosis by acting against the deleterious action of angiotensin II. Several preliminary CsA clinical trials performed on COVID-19 patients report lower incidence of death and suggest that this strategy should be investigated further in order to assess in which context the benefit/risk ratio of repurposing CsA as first-line therapy in COVID-19 is the most favorable.

Homicides and suicides by firearm in Marseille: An 8-year review.

The regions of Provence-Alpes-Côte d'Azur and Corsica in south-east France are regularly affected by firearm deaths, and a large amount of data has been collected by our forensic institute. We carried out a single-center retrospective descriptive study of the records of our institute between January 1, 2011, and 31 December, 2018, relating to firearm deaths (homicides and suicides). There were 302 cases (218 homicides and 84 suicides). The anatomic locations most frequently involved were the thorax, abdomen and head, in that order, in homicides and the head in suicides. More than 80% of the homicides in our series had more than one wound complex and nearly one in four homicides had more than 7. The weapon most frequently used in suicides was a hunting smooth bore gun, followed by the 9mm Luger and then by the .22 Long Rifle. In homicides, the caliber most frequently used was the 7.62 × 39 (29.6%), followed by the 9mm Luger (29%) and lastly by hunting calibers (27%). More than 10% of cases involved two weapons of two different calibers. Our study, which used a dual forensic and ballistic approach, was carried out in one of the most heavily populated regions of metropolitan France. We observed very few similarities with the literature regarding type of caliber and wound complexes. This may be explained, among other factors, by differences in political, societal or cultural contexts.

The Role of the Adhesion Receptor CD146 and Its Soluble Form in Human Embryo Implantation and Pregnancy.

CD146 is an adhesion molecule essentially located in the vascular system, which has been described to play an important role in angiogenesis. A soluble form of CD146, called sCD146, is detected in the bloodstream and is known as an angiogenic factor. During placental development, CD146 is selectively expressed in extravillous trophoblasts. A growing body of evidence shows that CD146 and, in particular, sCD146, regulate extravillous trophoblasts migration and invasion both in vitro and in vivo. Hereby, we review expression and functions of CD146/sCD146 in the obstetrical field, mainly in pregnancy and in embryo implantation. We emphasized the relevance of quantifying sCD146 in the plasma of pregnant women or in embryo supernatant in the case of in vitro fertilization (IVF) to predict pathological pregnancy such as preeclampsia or implantation defect. This review will also shed light on some major results that led us to define CD146/sCD146 as a biomarker of placental development and paves the way toward identification of new therapeutic targets during implantation and pregnancy.

Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction.

Recent studies showed that mesenchymal stem cells (MSCs) transplantation significantly decreased cardiac fibrosis; however, the mechanisms involved in these effects are still poorly understood. In this work, we investigated whether the antifibrotic properties of MSCs involve the regulation of matrix metalloproteinases (MMPs) and matrix metalloproteinase endogenous inhibitor (TIMP) production by cardiac fibroblasts. In vitro experiments showed that conditioned medium from MSCs decreased viability, alpha-smooth muscle actin expression, and collagen secretion of cardiac fibroblasts. These effects were concomitant with the stimulation of MMP-2/MMP-9 activities and membrane type 1 MMP expression. Experiments performed with fibroblasts from MMP2-knockout mice demonstrated that MMP-2 plays a preponderant role in preventing collagen accumulation upon incubation with conditioned medium from MSCs. We found that MSC-conditioned medium also decreased the expression of TIMP2 in cardiac fibroblasts. In vivo studies showed that intracardiac injection of MSCs in a rat model of postischemic heart failure induced a significant decrease in ventricular fibrosis. This effect was associated with the improvement of morphological and functional cardiac parameters. In conclusion, we showed that MSCs modulate the phenotype of cardiac fibroblasts and their ability to degrade extracellular matrix. These properties of MSCs open new perspectives for understanding the mechanisms of action of MSCs and anticipate their potential therapeutic or side effects.

Buprenorphine-related deaths: unusual forensic situations.

The success of high-dose buprenorphine (HDB) as substitution therapy for major opioid dependence is related to its partial agonist effect on opioid receptors, which in theory makes it very safe to use. However, numerous deaths directly attributable to buprenorphine have been described in the literature. These deaths are generally related to misuse of HDB with intravenous administration and/or concomitant use of benzodiazepines, and they usually occur in patients on HDB substitution therapy for opioid dependence. We present three deaths attributed to HDB which arose from uncommon mechanisms and led to unusual forensic situations. The first death was that of a patient admitted to hospital after simultaneous prescription of HDB, clonazepam, oxazepam, and cyamemazine. The second death followed forcible administration of a very low dose of HDB to a patient with post-hepatitis C cirrhosis and heart failure. The third death was subsequent to an HDB overdose, probably with suicidal intent, in a young woman who had not been prescribed the drug as opiate substitute. Such deaths raise the question of the mechanisms involved and draw attention to the resulting unusual forensic situations.