Preliminary Metabolomic Profiling of the Vitreous Humor from Hypothermia Fatalities.

The postmortem diagnosis of hypothermia fatalities is often complex due to the absence of pathognomonic lesions and biomarkers. In this study, potential novel biomarkers of hypothermia fatalities were searched in the vitreous humor of known cases of hypothermia fatalities (n = 20) compared to control cases (n = 16), using a targeted metabolomics approach allowing quantitative detection of 188 metabolites. A robust discriminant model with good predictivity was obtained with the supervised OPLS-DA multivariate analysis, showing a distinct separation between the hypothermia and control groups. This signature was characterized by the decreased concentrations of five metabolites (methionine sulfoxide, tryptophan, phenylalanine, alanine, and ornithine) and the increased concentration of 28 metabolites (21 phosphatidylcholines, 3 sphingomyelins, spermine, citrulline, acetylcarnitine, and hydroxybutyrylcarnitine) in hypothermia fatalities compared to controls. The signature shows similarities with already identified features in serum such as the altered concentrations of tryptophan, acylcarnitines, and unsaturated phosphatidylcholines, revealing a highly significant increased activity of methionine sulfoxide reductase, attested by a low methionine sulfoxide-to-methionine ratio. Our results show a preliminary metabolomics signature of hypothermia fatalities in the vitreous humor, highlighting an increased methionine sulfoxide reductase activity.

Age estimation based on the acetabulum using global illumination rendering with computed tomography.

INTRODUCTION: The acetabulum has been reported as a reliable age estimation marker. However, analyzing its morphological changes can be challenging using computed tomography (CT) imaging. Newly introduced global illumination rendering (GIR) applied to CT can improve the visualization of the fine details and thus the method's performance. This study aimed to analyze age estimation using morphological features of the acetabulum using GIR applied to CT. METHODS: We collected 200 postmortem CT scans. A segmentation of the acetabular joint was initially done. Then, three-dimensional (3D) reconstruction of the images was performed using GIR. These images were saved and then analyzed by two operators based on the three morphological criteria described in the Rougé-Maillart method. Reproducibility was assessed by intraclass correlation (ICC). Age estimation was assessed by multiple linear regression. RESULTS: The sample was composed of 155 males and 45 females, with a mean age of 50 ± 18.3 years old. We observed high agreement in both the inter-observer and intra-observer reproducibility for the three variables (ICC of 75.6 to 90.8% and 89.3 to 95.8%, respectively) and the total score (ICC of 93.5% and 95%, respectively). The three variables, as well as the total score, were significantly correlated with age groups. The total score showed a prediction rate higher than 85% for ages under 40 and over 70 years old. We identified three models with two validated models with an adjusted R2 of 85.6% and 84.8%, respectively; a standard error of 0.688 and 0.706, respectively; and a good correlation of all variables and no inter-correlation. The first validated model included the three morphological criteria scores, and the second model was based on the total score. CONCLUSION: GIR applied to CT provides photorealistic images that can be useful for forensic imaging intended for age estimation based on morphological methods.

Pitfalls of toxicological investigations in hair, bones, and nails in extensively decomposed bodies: illustration with two cases.

It is difficult to carry out toxicological investigations in biological samples collected from extensively decomposed bodies and to interpret obtained results as several pitfalls should be considered: redistribution phenomena, degradation of xenobiotics during the postmortem period, contamination by putrefaction fluids, and external contamination. This work aims to present two cases in order to illustrate and discuss these difficulties in this tricky situation. Case#1: the body of a 30-year-old woman was found in a wooded area (1 month after she has been reported missing by her family): hair and a femur section were sampled. Case#2: the decomposed corpse of a 52-year-old man was found in a ditch: hair and nails were sampled. After decontamination steps, toxicological investigations were performed using liquid chromatography with high-resolution mass spectrometry and tandem mass spectrometry detection methods. In case#1, the same drugs or metabolites (benzodiazepines, propranolol, tramadol, acetaminophen, paroxetine, and oxetorone) were detected in hair and in bone specimens. This result combination strongly suggests intakes close to the time of death for three of them (oxazepam, lormetazepam, and propranolol). In case#2, results of toxicological investigations in hair and nails [(hair/nail concentration in ng/mg) nordiazepam (1.12/1.06), oxazepam (0.113/0.042), zolpidem (0.211/< 0.01), hydroxyzine (0.362/< 0.01), and cetirizine (0.872/1.110)] were both consistent with several drug intakes but were not contributory to cause of death determination. In case of positive toxicological results in biological samples collected from extensively decomposed bodies (such as hair, bones, or nails), it is challenging to determine the time, and even more, the level of the dose of exposure(s).

A serum metabolomics signature of hypothermia fatalities involving arginase activity, tryptophan content, and phosphatidylcholine saturation.

INTRODUCTION: Hypothermia is a potentially lethal condition whose postmortem diagnosis is often complex to perform due to the absence of pathognomonic lesions and biomarkers. Our first study of human serum and urinary metabolome in hypothermia fatalities sought novel biomarkers with better diagnostic performances than those already existing. MATERIAL AND METHOD: Thirty-two cases of hypothermia deaths and 16 cases excluding known antemortem exposure to cold or postmortem elements suggesting hypothermia were selected. A targeted metabolomic study allowing the detection and quantitation of 188 metabolites was performed on collected serum and urine using direct flow injection (FIA) and liquid chromatography (LC) separation, both coupled to tandem mass spectrometry (MS/MS). Amino acid quantification was also carried on using an in-house LC-MS/MS method in order to replicate the results obtained with the metabolomic study. RESULTS: A discriminant metabolic signature allowing a clear separation between hypothermia and control groups was obtained in the serum. This signature was characterized by increased arginase activity and fatty acid unsaturation along with decreased levels of tryptophan in hypothermia fatalities compared to controls. By contrast, no discriminant metabolic signature separating hypothermia from control fatalities was found in urines. DISCUSSION: The serum metabolic signature of hypothermia fatalities herein observed pointed toward metabolic adaptations that likely aimed at heat production enhancement, endothelial function, and cell membrane fluidity preservation. Novel biomarkers potentially useful in a hypothermia diagnosis were also identified.

The contribution of Micro-CT to the evaluation of trabecular bone at the posterior part of the auricular surface in men.

AIM: Using multi-slice computed tomography (MSCT), Barrier et al. described the disappearance at the posterior auricular surface of a "central line" (CL) and "juxtalinear cells" (JLCs) belonging to a trabecular bundle, and a trabecular density gradient around the CL that decreased with age. The aim of our study was to use micro-CT to test these findings, referring to the concept of Ascadi and Nemeskeri. METHODOLOGY: The coxal bones of fifteen males were used; age was known. CLs were identified on MSCT-sections using Barrier's method (64 detectors, 0.6 mm slice thickness, 0.1 mm overlap) with two different software programs (Synapse®, Amira®). Then, CLs were researched on microCT slices (pixel size: 36 µm). Three volumes of interest were defined (around, above, and below CL), and 3D morphometric parameters of the trabecular microarchitecture (particularly BV/TV and DA) were calculated. Two-tailed statistical analyses were performed attempting to correlate these parameters with age at death. RESULTS: CLs and JLCs were observed on micro-CT slices, but with moderate agreement between both imaging techniques. Their presence was not correlated with the age of the subjects. Around the CL, BV/TV decreased significantly with age; DA was negatively correlated with BV/TV and had a tendency to increase with age. Between areas above and below the CL, there was a BV/TV gradient and both BV/TVs decreased in parallel with age. CONCLUSION: Our findings regarding the contribution of micro-CT to the evaluation of trabecular bone could be a promising research approach for application in a larger study population.

A diabetic ketoacidosis in a context of hyperglycemia addiction.

We herein present a case of a 20-year-old woman who suffered from type I diabetes mellitus and died from a diabetic ketoacidosis in a context of addiction to hyperglycemia. Diabetic ketoacidosis is a lethal complication of insulin-dependent diabetes mellitus, which can result from insulin therapy stoppage. This can occur voluntarily with suicidal intent or involuntarily due to treatment inaccessibility, forgotten injections, or material deficiency. A new possibility is investigated in our case study: hyperglycemia addiction. The patient was treated by insulin glargine and insulin aspartate. She regularly stopped insulin glargine injections seeking the asthenia sensation produced by hyperglycemia, keeping the insulin aspartate injections to treat the disabling symptom related to hyperketonemia.

Updated review of postmortem biochemical exploration of hypothermia with a presentation of standard strategy of sampling and analyses.

Hypothermia is defined as a core body temperature below 35°C and can be caused by environmental exposure, drug intoxication, metabolic or nervous system dysfunction. This lethal pathology with medico-legal implications is complex to diagnose because macroscopic and microscopic lesions observed at the autopsy and the histological analysis are suggestive but not pathognomonic. Postmortem biochemical explorations have been progressively developed through the study of several biomarkers to improve the diagnosis decision cluster. Here, we present an updated review with novel biomarkers (such as catecholamines O-methylated metabolites, thrombomodulin and the cardiac oxyhemoglobin ratio) as well as some propositional interpretative postmortem thresholds and, to the best of our knowledge, for the first time, we present the most adapted strategy of sampling and analyses to identify biomarkers of hypothermia. For our consideration, the most relevant identified biomarkers are urinary catecholamines and their O-methylated metabolites, urinary free cortisol, blood cortisol, as well as blood, vitreous humor and pericardial fluid for ketone bodies and blood free fatty acids. These biomarkers are increased in response either to cold-mediated stress or to bioenergetics ketogenesis crisis and significantly contribute to the diagnosis by exclusion of death by hypothermia.

Organ Procurement in Forensic Deaths: Specific Features of Nonheart-Beating Donors.

The need for organs has increased in the recent years, and this shortage will only worsen. In addition to the organs procured from brain-dead donors, a procedure for non-heart-beating donors was therefore developed. When deaths involve legal proceedings, the medical examiner makes the decision of whether or not to remove organs. To assist medical examiner in their decision-making, a number of forensic scientific societies aimed to develop recommendations, and legal adjustments were adopted. Nevertheless, these do present certain limits in special cases of procurement: Maastricht class I and II non-heart-beating donors. The peculiarity of this procedure stems from the urgency of the process. Compliance with temporal criteria would require that the deceased subject be removed from the crime scene even before the arrival of the authorities. This is extremely problematic legally and technically because forensic teams must collect evidence at crime scenes. Developments will have to be made to further minimize the restrictions on donations in forensic deaths.

Suicide by skull stab wounds: a case of drug-induced psychosis.

Suicide by stabbing to the head and/or driving sharp objects into the skull is of extreme rarity. This article reports the case of a 27-year-old man, who committed suicide by multiple knife stabs and cuts to the head, the torso, one shoulder and the forearms. Autopsy showed a perforating wound of the skull and the 10-cm long broken blade of the knife being still embedded in the right temporal lobe of the brain. The deceased had no history of psychiatric illness but was currently treated by mefloquine, a quinine derivative associated with a high rate of psychiatric adverse effects. Toxicological examination confirmed a recent intake of mefloquine together with chloroquine, another antimalarial drug. To our knowledge, this is the first report of a completed suicide with very strong evidence of mefloquine implication. Discussion focuses upon mefloquine-induced psychiatric disorders and highlights the importance of performing toxicological investigations in cases of unusual suicides.

Organ donation in France: legislation, epidemiology and ethical comments.

The Bioethics Laws revised in 2004 have defined rules concerning organ donation and transplantation. They have also permitted the creation of the French Biomedicine Agency which guarantees the right of enforcement. In France there are three situations in which organs may be harvested: from cadaveric donors, from living donors and, since 2005, from non heart beating donors. Organ harvesting from cadaveric donors is permissible if the deceased did not make known his refusal during his lifetime (this may be recorded in the national registry set up for this purpose). The rule of presumed consent also applies in the case of organs taken after cardiac arrest. With regard to organ harvesting from living persons, a panel of experts is required to give approval. The recipient's spouse, brothers or sisters, sons or daughters, grandparents, uncles or aunts and first cousins may be authorised to donate organs, as well as the spouse of the recipient's father or mother. The donor may be any person who provides proof of having lived with the recipient for at least two years. Some ethical questions will need to be resolved; for example the relevance of maintaining the EEG for brain death diagnosis, enforcement of the law on presumed consent, the real nature of the will of living donors and the definition of death.

[Thanatobiochemistry: its contribution to the diagnosis of hypothermia fatalities]. / Biochimie thanatologique : ses apports au diagnostic de décès par hypothermie.

Hypothermia is a potentially lethal pathology whose in vivo diagnosis is relatively easy, based on the observation of a body temperature below 35̊C. However, its post mortem diagnosis is much more complex because of a thermal decrease occurring systematically after the death, which renders most often uninterpretable the body temperature as a diagnostic argument for hypothermia. Moreover, none of the macroscopic or microscopic autopsy elements described as suspicious of hypothermia are pathognomonic of a hypothermic death. Currently, this diagnosis arises in the light of an association of concordant arguments including these autopsic and histological elements but also some biomarkers. The aim of this article is to illustrate by a practical case the diagnostic complexity of a death by hypothermia through the evocative elements currently described, by emphasizing the reflection on some biomarkers confirmed or under study.

Practitioner sex abuse: occurrence, prevention and disciplinary sanction.

Studies put forward figures for male practitioner sex abuse of around ten per cent. This practice, which is contrary to medical ethics, is highly reprehensible in ethical terms. The assaults range from uninvited meddling in patients' sexual lives to proven rape and inappropriate touching. The majority of this type of abuse is perpetrated by psychiatrists, but in more recent times a growing number of cases have been uncovered involving general practitioners or obstetric gynaecologists. For the most part, the abusers are men, aged between 45 and 64, who are insufficiently trained in terms of the 'practitioner-patient' relationship, or who are suffering from a mental pathology or who are in a situation of personal or professional crisis. Raising awareness of this issue is the driving force behind the implementation of prevention strategies, based on initial and ongoing training for practitioners in France, whistle-blowing on fellow practitioners in the United States and professional help in Canada. Disciplinary sanctions are more severe than those given within the framework of non-sexual misconduct in the United States. In France, the Order of Practitioners does not appear to be taking its role of defending patients seriously, since it seldom issues anything more substantial than minor penalties.

[The law of March 5, 2007 and the care of persons placed under guardianship]. / La prise en charge médicale des personnes sous tutelle à la lumière de la loi du 5 mars 2007.

The care of persons placed under guardianship has changed considerably since the law of March 5, 2007, as greater autonomy is granted to them. By advocating greater autonomy of protected adults, the French Civil Code is in opposition with the French Public Health Code since the latter states that the systematic consent of the guardian is required in addition to that of the protected adult for so-called general care. In cases of serious injury to bodily integrity, the guardianship judge's opinion must be sought by the guardian. For some specific medical procedures (medically assisted procreation, abortion, etc.), the consent of the guardian does not seem necessary. A protected adult can now, if he/she is able to understand the information, with the agreement of the guardianship judge or the family council, appoint a trusted person and draft advance directives without possible representation by the guardian. The legislator promotes greater autonomy while not neglecting their protection. It also helps relieve the guardian, who is generally trained in asset management, of sometimes difficult medical decisions. Harmony between the Civil Code and the Public Health Code seems essential so as to move towards greater autonomy of the person under guardianship in the care relationship.

Twenty-five years of French jurisprudence in criminal medical liability.

We report on a comprehensive 25-year study on criminal medical liability in France, undertaken to establish trends in the number of cases being brought before the criminal courts. We did this by interrogating the database on the Légifrance website using a Boolean equation (' pénal' (criminal) AND ' médecin' (physician) OR ' docteur' (doctor)). In total 539 cases were selected, in which the status of the physician either influenced the punishment imposed, or was a prerequisite for the commission of the offence. The results of the search produced two outcomes: offences and the dates of the most recent criminal judgements (which had been left blank). Further data were also collected: references to court cases, hearing dates, offence dates, procedural time limits, numbers of accused parties, types of punishments and physician characteristics. The number of court hearings increased from the 1980s until the late 1990s. Since then, it has remained stable at around 25 cases per year. Of the defendants appearing before the courts, 39.2% have been found guilty. On average, 10 to 13 physicians every year - that is, one per month - are punished. Those most often punished are obstetrician-gynaecologists (13%), followed by intensive care anaesthetists (11%) and then by general practitioners (6.7%). The offences most frequently occurring are manslaughter (36.5%), illegal profits (12%), unintentional injuries (11.5%) and sexual offences (10.1%). The results are most reassuring in terms of the risks posed by the practice of medicine in France. Such a risk does indeed exist; however, it is at a low level and stable.

[Spectacular suicide associated with mefloquine]. / Suicide spectaculaire lié à une prise de méfloquine.

INTRODUCTION: We present a case in which suicide was a severe neuropsychiatric reaction to treatment with mefloquine. Physicians must be aware of these serious psychiatric complications and bear them in mind when faced with atypical behavior or suspected suicide. CASE REPORT: The body of a 27-year-old man was discovered at his home, covered with multiple knife wounds. The autopsy report concluded that death was due to a craniocerebral wound from a violent blow. Homicide was initially suspected. Suicide during acute psychosis associated with mefloquine was suggested, and toxicologic analyses confirmed this hypothesis. DISCUSSION: Serious neurologic and psychiatric adverse events associated with mefloquine (Lariam) have been reported since its introduction in 1985. Mefloquine prophylaxis is recommended for travelers to high-risk areas of chloroquine-resistant plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug-associated adverse events. Physicians must nonetheless be aware of these serious psychiatric complications, especially when faced with atypical behavior and atypical suicides. The patient's' family and friends should be asked about a possible trips abroad that might have entailed antimalaria treatment, even several months earlier. Testing for mefloquine during toxicological examinations is then essential. The World Health Organization recommendations and contraindications must be followed in prescribing mefloquine.

Specific Characteristics of Injuries Inflicted by Claw Hammer.

Claw hammers have the specific characteristic of having two distinct ends: one a flat head of variable form, the other bifurcated. So the use of this tool as a blunt instrument will cause varying injuries. The authors present two clinical cases of assault with a claw hammer. Examinations revealed two types of wound. A first injury composed of integumentary lacerations and underlying bone injuries in terms of "shape" suggested the use of a blunt instrument. A second injury made up of damage showing two parallel wounds or two wounds located one in the extension of the other suggested the use of an object with a bifurcated end. The combination of both types of injury should alert examiners to the possibility of the use of a claw hammer in causing the injuries in order to help direct investigators in their investigations and in the search for the weapon used.

Left Diaphragm Laceration Due to Cardiopulmonary Resuscitation.

External cardiac massage is the essential life-saving gesture for the management of any cardiac arrest. Since the 1960s, many recommendations have been published to improve the effectiveness of chest compressions alongside the development of automated systems intended to maximize the chances of survival. The use of these manual and/or instrumental techniques can cause secondary injuries, of which rib fractures are the most commonly observed by forensic pathologists. However, a comprehensive review of the literature seldom highlights reports of injuries to the abdomen, even less so to the diaphragm. In this observation, an iatrogenic left diaphragmatic laceration for the first time is described, as a result of manual and instrumental cardiopulmonary resuscitation, in a victim from an intrathoracic wound caused by a bladed weapon.

Anal lesions presenting in a cohort of child gastroenterological examinations. Implications for sexual traumatic injuries.

The purpose of this study was to describe the anal lesions found in children during a pediatric gastroenterology consultation when the reason for the complaint was related to a digestive disease. This prospective descriptive study included 100 children under 15 years of age over a 13-month period, consulting due to digestive symptoms. The children were under 8 years old (90%) and 25% were under 3.1 years old. Constipation was the most frequent reason for consultation (69%). Fifty-one anal lesions were observed, of which 58.8% were anal fissures, 15.7% were skin tags and 5.8% were venous congestions related to straining. Anal fissures and skin tags were located at the median line, according to the clock-face method in supine position. No child had more than two anal lesions. No anal dilatation, sphincter hypotonia, anal scars, anal lacerations or bruises were found. The two most common anal lesions were anal fissures and skin tags. These anal lesions were mainly observed at the median line and were due to constipation. No cases of multiple anal lesions were found in terms of common digestive diseases.

The determination of male adult age at death by central and posterior coxal analysis--a preliminary study.

In forensic anthropological analysis, the pelvis is of particular interest as it is often a comparatively well-preserved part of the skeleton. This study in age determination uses the acetabulum, the central element of the pelvis, as a complement to the examination of the auricular surface. The test sample consisted of 30 individuals. First, the authors studied the auricular surface using the Lovejoy criteria. Second, they isolated four criteria based on chronological changes in the acetabulum. Third, they conducted an evaluation of each of these variables. The study examines the correlation between these criteria and the age of the individuals. A significant correlation was found between the acetabular criteria and age, and between the acetabular criteria and the Lovejoy criteria of the auricular surface. For forensic purposes, the acetabulum is an effective predictor in the determination of age. This newly proposed method explores the same criteria of ageing as the Lovejoy method. The combination of the two methods produces relatively consistent results in the estimation of age.

Liability for pharmaceutical products: a difficult attempt at harmonisation.

On the 25 July 1985, the European Community adopted a Directive on liability for defective products. Doctors are very affected by this law because an injured person will possibly be able to take action against them. This directive had several aims: to harmonise member states' legislation concerning the legal protection of victims and to subject producers to the same framework of liability and competition rules. However, this directive currently remains relatively ineffective. Several reasons can be put forward to explain this failure. First, by leaving it open to member states to decide whether to opt for one or more derogations, the Directive has made it easier for different interpretations to emerge. Secondly, several ideas proposed by the Directive have not been defined. As a result, the different legal terminology used in different states makes the interpretation of these concepts more difficult. Our paper concludes that the Directive was soundly based. However, Member States must enquire about the solutions adopted in neighbouring countries, and the ECJ (European Court of Justice) should try to impress on states the importance of a community vision. Without an adequate level of convergence, the differences between national laws will encourage 'forum shopping' on the part of a claimant and the situation will become more difficult for prescribers.