Pharmacogenetics and Forensic Toxicology: A New Step towards a Multidisciplinary Approach

Pharmacogenetics analyzes the individual behavior of DNA genes after the administration of a drug. Pharmacogenetic research has been implemented in recent years thanks to the improvement in genome sequencing techniques and molecular genetics. In addition to medical purposes, pharmacogenetics can constitute an important tool for clarifying the interpretation of toxicological data in post-mortem examinations, sometimes crucial for determining the cause and modality of death. The purpose of this systematic literature review is not only to raise awareness among the forensic community concerning pharmacogenetics, but also to provide a workflow for forensic toxicologists to follow in cases of unknown causes of death related to drug use/abuse. The scientific community is called on to work hard in order to supply evidence in forensic practice, demonstrating that this investigation could become an essential tool both in civil and forensic contexts. The following keywords were used for the search engine: (pharmacogenetics) AND (forensic toxicology); (pharmacogenetics) AND (post-mortem); (pharmacogenetics) AND (forensic science); and (pharmacogenetics) AND (autopsy). A total of 125 articles were collected. Of these, 29 articles were included in this systematic review. A total of 75% of the included studies were original articles (n = 21) and 25% were case reports (n = 7). A total of 78% (n = 22) of the studies involved deceased people for whom a complete autopsy was performed, while 22% (n = 6) involved people in good health who were given a drug with a subsequent pharmacogenetic study. The most studied drugs were opioids (codeine, morphine, and methadone), followed by antidepressants (tricyclic antidepressants and venlafaxine). Furthermore, all studies highlighted the importance of a pharmacogenetics study in drug-related deaths, especially in cases of non-overdose of drugs of abuse. This study highlights the importance of forensic pharmacogenetics, a field of toxicology still not fully understood, which is of great help in cases of sudden death, deaths from overdose, deaths after the administration of a drug, and also in cases of complaint of medical malpractice

Effectiveness of antipsychotics in reducing suicidal ideation: Possible physiologic mechanisms

Background: The aim of this study is to evaluate whether any specific antipsychotic regi-men or dosage is effective in managing suicidal ideation in schizophrenia. Four comparisons were conducted between: (1) clozapine and other antipsychotics; (2) long-acting injectable and oral antipsy-chotics; (3) atypical and typical antipsychotics; (4) antipsychotics augmented with antidepressants and antipsychotic treatment without antidepressant augmentation. Methods: We recruited 103 participants diagnosed with schizophrenia spectrum disorders. Participants were followed for at least six months. The Beck Scale for Suicidal Ideation (BSS) was used to assess the severity of suicidal ideation at each visit. We performed a multiple linear regression model controlling for BSS score at study entry and other confounding variables to predict the change in the BSS scores between two visits. Results: Overall, there were 28 subjects treated with clozapine (27.2%), and 21 subjects with depot antipsychotics (20.4%). In our sample, 30 subjects experienced some suicidal ideation at study entry. When considering the entire sample, there was a statistically significant decrease in suicidal ideation severity in the follow-up visit compared to the study entry visit (p = 0.043). Conclusions: To conclude, our preliminary analysis implies that antipsychotics are effective in controlling suicidal ideation in schizophrenia patients, but no difference was found among alternative antipsychotics’ classes or dosages

Risk management and recommendations for the prevention of fatal foreign body aspiration: Four cases aged 1.5 to 3 years and mini-review of the literature

(1) Background: Foreign body aspiration (FBA) is a significant public health concern among the pediatric population, and fatalities are dramatic for families. It typically involves organic foreign bodies (mainly food) aspirated by children under three years old, usually at home or school. This review aimed to focus on the preventive measures around four actual cases of fatal foreign body aspiration, emphasizing the correct execution of the Heimlich maneuver and cardiopulmonary resuscitation, supervised mealtimes, and high-risk foods. (2) Methods: Four fatal cases of foreign body aspiration in children are presented here. The children were in a free environment, such as school, home, and the countryside, and were in the presence of teachers, parents, and a grandmother who did not supervise the children adequately. A literature review was performed via the MEDLINE database using the key terms: “foreign body aspiration,” “infant choking, 1.5 to 3 years,” “food and foreign body aspiration,” “common household,” “prevention of foreign body aspiration,” “guidelines,” “recommendations,” “training of caregivers (parents, educators),” “resuscitation,” “Heimlich maneuver,” and “disengagement of the upper airways.” We focused on the prevention of foreign body aspiration. (3) Results: a complete postmortem examination was performed. In three cases, the foreign bodies were food (mozzarella cheese, pear, or raw bean), while in one case, the foreign body was a pebble. (4) Conclusions: This review aimed to discuss recent scientific literature and provide a perspective on the benefits of a dedicated approach to the management of fatal foreign body aspiration in children by caregivers who usually have no experience with the best ways of supervising children in a safe environment, especially regarding the correct execution of resuscitation maneuvers, such as the Heimlich maneuver. Recommendation updates could improve healthcare quality in a pediatric setting and reduce medico-legal implications

Do we really need hazard prevention at the expense of safeguarding death dignity in covid-19?

To date, little is known regarding the transmission risks of SARS-CoV-2 infection for subjects involved in handling, transporting, and examining deceased persons with known or suspected COVID-19 positivity at the time of death. This experimental study aims to define if and/or how long SARS-CoV-2 persists with replication capacity in the tissues of individuals who died with/from COVID-19, thereby generating infectious hazards. Sixteen patients who died with/from COVID-19 who underwent autopsy between April 2020 and April 2021 were included in this study. Based on PMI, all samples were subdivided into two groups: ‘short PMI’ group (eight subjects who were autopsied between 12 to 72 h after death); ‘long PMI’ (eight subjects who were autopsied between 24 to 78 days after death). All patients tested positive for RT-PCR at nasopharyngeal swab both before death and on samples collected during post-mortem investigation. Moreover, a lung specimen was collected and frozen at −80◦ C in order to perform viral culture. The result was defined based on the cytopathic effect (subjective reading) combined with the positivity of the RT-PCR test (objective reading) in the supernatant. Only in one sample (PMI 12 h), virus vitality was demonstrated. This study, supported by a literature review, suggests that the risk of cadaveric infection in cases of a person who died from/with COVID-19 is extremely low in the first hours after death, becoming null after 12 h after death, confirming the World Health Organization (WHO) assumed in March 2020 and suggesting that the corpse of a subject who died from/with COVID-19 should be generally considered not infectious

Anaphylactic death: A new forensic workflow for diagnosis

Anaphylaxis is a life-threatening or fatal clinical emergency characterized by rapid onset, and death may be sudden. The margin of certainty about the diagnosis of anaphylactic death is not well established. The application of immunohistochemical techniques combined with the evaluation of blood tryptase concentrations opened up a new field of investigation into anaphylactic death. The present study investigated eleven autopsy cases of anaphylactic death, carried out between 2005 and 2017, by the Departments of Forensic Pathology of the Universities of Foggia and Catania (Italy). An analysis of the medical records was carried out in all autopsies. Seven autopsies were carried out on males and four on females. Of the eleven cases, one showed a history of asthma, one of food ingestion, two of oral administration of medications, six did not refer any allergy history, and one subject was unknown. All cases (100%) showed pulmonary congestion and edema; 7/11 (64%) of the cases had pharyngeal/laryngeal edema and mucus plugging in the airway; only one case (9%) had a skin reaction that was found during external examination. Serum tryptase concentration was measured in ten cases, and the mean value was 133.5 µg/L ± 177.9. The immunohistochemical examination using an anti-tryptase antibody on samples from the lungs, pharynx/larynx, and skin site of medication injection showed that all cases (100%) were strongly immunopositive for anti-tryptase antibody staining on lung samples; three cases (30%) were strongly immunopositive for anti-tryptase antibody staining on pharyngeal/laryngeal samples; and eight cases (80%) were strongly immunopositive for anti-tryptase antibody staining on skin samples. We conclude that a typical clinical history, blood tryptase level >40 µg/L, and strongly positive anti-tryptase antibody staining in the immunohistochemical investigation may represent reliable parameters in the determination of anaphylactic death with the accuracy needed for forensic purposes

Nandrolone decanoate: Use, abuse and side effects

Background and Objectives: Androgens play a significant role in the development of male reproductive organs. The clinical use of synthetic testosterone derivatives, such as nandrolone, is focused on maximizing the anabolic effects and minimizing the androgenic ones. Class II anabolic androgenic steroids (AAS), including nandrolone, are rapidly becoming a widespread group of drugs used both clinically and illicitly. The illicit use of AAS is diffused among adolescent and bodybuilders because of their anabolic proprieties and their capacity to increase tolerance to exercise. This systematic review aims to focus on side effects related to illicit AAS abuse, evaluating the scientific literature in order to underline the most frequent side effects on AAS abusers’ bodies. Materials and Methods: A systematic review of the scientific literature was performed using the PubMed database and the keywords “nandrolone decanoate”. The inclusion criteria for articles or abstracts were English language and the presence of the following words: “abuse” or “adverse effects”. After applying the exclusion and inclusion criteria, from a total of 766 articles, only 148 were considered eligible for the study. Results: The most reported adverse effects (found in more than 5% of the studies) were endocrine effects (18 studies, 42%), such as virilization, gynecomastia, hormonal disorders, dyslipidemia, genital alterations, and infertility; cardiovascular dysfunctions (six studies, 14%) such as vascular damage, coagulation disorders, and arteriosus hypertension; skin disorders (five studies, 12%) such as pricking, acne, and skin spots; psychiatric and mood disorders (four studies, 9%) such as aggressiveness, sleep disorders and anxiety; musculoskeletal disorders (two studies, 5%), excretory disorders (two studies, 5%), and gastrointestinal disorders (two studies, 5%). Conclusions: Based on the result of our study, the most common adverse effects secondary to the abuse of nandrolone decanoate (ND) involve the endocrine, cardiovascular, skin, and psychiatric systems. These data could prove useful to healthcare professionals in both sports and clinical settings

Sudden cardiac death in anabolic-androgenic steroid users: A literature review

Background and objectives: Anabolic-androgenic steroids (AASs) are a group of synthetic molecules derived from testosterone and its related precursors. AASs are widely used illicitly by adolescents and athletes, especially by bodybuilders, both for aesthetic uses and as performance enhancers to increase muscle growth and lean body mass. When used illicitly they can damage health and cause disorders affecting several functions. Sudden cardiac death (SCD) is the most common medical cause of death in athletes. SCD in athletes has also been associated with the use of performance-enhancing drugs. This review aimed to focus on deaths related to AAS abuse to investigate the cardiac pathophysiological mechanism that underlies this type of death, which still needs to be fully investigated. Materials and Methods: This review was conducted using PubMed Central and Google Scholar databases, until 21 July 2020, using the following key terms: “((Sudden cardiac death) OR (Sudden death)) AND ((androgenic anabolic steroid) OR (androgenic anabolic steroids) OR (anabolic-androgenic steroids) OR (anabolic-androgenic steroid))”. Thirteen articles met the inclusion and exclusion criteria, for a total of 33 reported cases. Results: Of the 33 cases, 31 (93.9%) were males while only 2 (61%) were females. Mean age was 29.79 and, among sportsmen, the most represented sports activity was bodybuilding. In all cases there was a history of AAS abuse or a physical phenotype suggesting AAS use; the total usage period was unspecified in most cases. In 24 cases the results of the toxicological analysis were reported. The most detected AASs were nandrolone, testosterone, and stanozolol. The most frequently reported macroscopic alterations were cardiomegaly and left ventricular hypertrophy, while the histological alterations were foci of fibrosis and necrosis of the myocardial tissue. Conclusions: Four principal mechanisms responsible for SCD have been proposed in AAS abusers: the atherogenic model, the thrombosis model, the model of vasospasm induced by the release of nitric oxide, and the direct myocardial injury model. Hypertrophy, fibrosis, and necrosis represent a substrate for arrhythmias, especially when combined with exercise. Indeed, AAS use has been shown to change physiological cardiac remodeling of athletes to pathophysiological cardiac hypertrophy with an increased risk of life-threatening arrhythmias

Short-term physiological effects of a very low-calorie ketogenic diet: Effects on adiponectin levels and inflammatory states

Adipose tissue is a multifunctional organ involved in many physiological and metabolic processes through the production of adipokines and, in particular, adiponectin. Caloric restriction is one of the most important strategies against obesity today. The very low-calorie ketogenic diet (VLCKD) represents a type of caloric restriction with very or extremely low daily food energy consumption. This study aimed to investigate the physiological effects of a VLCKD on anthropometric and biochemical parameters such as adiponectin levels, as well as analyzing oligomeric profiles and cytokine serum levels in obese subjects before and after a VLCKD. Twenty obese subjects were enrolled. At baseline and after eight weeks of intervention, anthropometric and biochemical parameters, such as adiponectin levels, were recorded. Our findings showed a significant change in the anthropometric and biochemical parameters of these obese subjects before and after a VLCKD. We found a negative correlation between adiponectin and lipid profile, visceral adipose tissue (VAT), C-reactive protein (CRP), and pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), which confirmed the important involvement of adiponectin in metabolic and inflammatory diseases. We demonstrated the beneficial short-term effects of a VLCKD not only in the treatment of obesity but also in the establishment of obesity-correlated diseases

The human microbiota and prostate cancer: Friend or foe?

The human microbiome is gaining increasing attention in the medical community, as knowledge on its role not only in health but also in disease development and response to therapies is expanding. Furthermore, the connection between the microbiota and cancer, especially the link between the gut microbiota and gastrointestinal tumors, is becoming clearer. The interaction between the microbiota and the response to chemotherapies and, more recently, to immunotherapy has been widely studied, and a connection between a peculiar type of microbiota and a better response to these therapies and a different incidence in toxicities has been hypothesized. As knowledge on the gut microbiota increases, interest in the residing microbial population in other systems of our body is also increasing. Consequently, the urinary microbiota is under evaluation for its possible implications in genitourinary diseases, including cancer. Prostate cancer is the most common cancer in the male population; thus, research regarding its etiology and possible factors correlated to disease progression or the response to specific therapies is thriving. This review has the purpose to recollect the current knowledge on the relationship between the human microbiota and prostate cancer