Sudden death due to butane abuse - An overview.

Volatile Solvents Abuse (VSA) poses major health risks, especially for young people and those living in precarious socio-economic conditions. Such substances can in fact bring about psychoactive effects such as euphoria, and even lead to sudden death from cardiac arrhythmias, respiratory depression, myocardial infarction, laryngospasm, encephalopathy, and rhabdomyolysis. The present case report is centered around a 23-year-old man who died in prison due to inhalation of a cooker gas mixture (n-butane, propane, and isobutane) inside a plastic bag. External examination and autopsy showed non-specific signs of asphyxia associated with edema and brain swelling. Histological signs of early myocardial damage and hypoxic-ischemic injury (HII) were highlighted in the brain and cerebellum, as well as activated macrophages and anthracotic-like material in the lungs. Toxicological investigations revealed the presence of propane, isobutane and n-butane in liquids and biological samples. Besides the cardiotoxic effect, there was an asphyctic component due to the plastic bag that may have facilitated death. The assessment of cerebral HII and cardiopulmonary damage in acute cases is very important to prove death by butane inhalation. In the forensic field, it may be useful to shed more light on intoxications, deaths, and butane encephalopathies, as the latter can be mistaken for a hypoxic-ischemic encephalopathy.

Heparan Sulfate and Enoxaparin Interact at the Interface of the Spike Protein of HCoV-229E but Not with HCoV-OC43.

It is known that the spike protein of human coronaviruses can bind to a secondary receptor, or coreceptor, to facilitate the virus entry. While HCoV-229E uses human aminopeptidase N (hAPN) as a receptor, HCoV-OC43 binds to 9-O-acetyl-sialic acid (9-O-Ac-Sia), which is linked in a terminal way to the oligosaccharides that decorate glycoproteins and gangliosides on the surface of the host cell. Thus, evaluating the possible inhibitory activity of heparan sulfate, a linear polysaccharide found in animal tissues, and enoxaparin sodium on these viral strains can be considered attractive. Therefore, our study also aims to evaluate these molecules' antiviral activity as possible adsorption inhibitors against non-SARS-CoV. Once the molecules' activity was verified in in vitro experiments, the binding was studied by molecular docking and molecular dynamic simulations confirming the interactions at the interface of the spike proteins.

Fourth generation of synthetic cannabinoid receptor agonists: a summary on the latest insights.

BACKGROUND AND AIM: From few years, an emerging number of new psychoactive substances (NPS) entered the illicit market. NPS are designed to be similar to the effects of classical drugs of abuse, with increased effects and duration. Synthetic cannabinoids are cannabinoid receptor agonists (SCRAs), some of the most abused NPS. METHODS: We have herein briefly highlighted current relevant available information on the newest SCRAs generation, with relevant structural remarks as to the distinctive traits of such substances. RESULTS: Compared to the previous SCRAs generations, the structures of the last generation result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be mainly responsible for the psychoactive effects of THC and its analogues. Accordingly, these more potent cannabimimetic effects may increase the number of adverse reactions such as neurological disorders, psychiatric episodes and deaths. In the last decade, more than a hundred SCRAs from different chemical classes emerged on the illicit web market. SCRAs have been thoroughly studied and the last generations include increasingly potent and toxic compounds, posing a potentially daunting health threat to consumers. CONCLUSIONS: From November 2017 to February 2021, at least 20 new "fourth-generation" SCRAs were formally reported to international drug agencies. Our understanding about the neurotoxicity of these compounds is still limited, due to the lack of global data, but their potency and their toxicity are likely higher than those of the previous generations.

Uterus Transplantation and the redefinition of core bioethics precepts.

To the Editor, The first uterus transplantation (UTx) to be successfully carried out in Italy occurred at the Transplant Center of the Policlinico di Catania, on 21st August 2020. The patient, a 30-year-old woman with absolute uterine factor infertility (AUFI) due to Rokitansky syndrome, is now set to undergo a medically assisted reproductive procedure aimed at implanting her own oocytes, which had been stored via cryopreservation, following in vitro fertilization. Only UTx from deceased donors has been approved in Italy, although most UTx attempts and live births worldwide have been achieved from live donors, mostly closely related to the recipient (1). If UTx becomes a mainstream surgical practice for women who could not otherwise experience pregnancy, such an option will mark a point where the set of moral and ethical precepts which we espouse could soon become obsolete. Still, UTx is undoubtedly a milestone bound to give rise to even more complex bioethical issues. In fact, it encompasses the ethical complexities inherent in MAP as well as those arising from its status as a non-life saving transplantation, but rather a "life-giving" one (2). Moreover, since the development of UTx was primarily motivated by the potential to allay dissatisfaction and unhappiness stemming from the discrepancy between procreative ability and reproductive aspirations, it can be viewed as "life-enhancing" as well. An important framework providing perspective is the revised version of the Montreal Criteria for the Ethical Feasibility of Uterine Transplantation (3). Nevertheless, such a set of criteria is emblematic of how fast scientific innovation can outpace fundamental bioethics standards, and may itself be already outdated, in that it requires the recipient to be a "genetic female", whereas research on the possibility to perform UTx on transgender women is already in progress. That future scenario goes to the heart of UTx and its fundamental purpose: not life-saving but, as far as transgender women are concerned, life-enhancing. Research has clarified the primary motivation for which transgender women would opt for UTx. Findings from a recent survey unequivocally reflect the "life-enhancing" purpose: an overwhelming 90% majority of respondents expressed the belief that having a transplanted, functioning uterus and vagina would benefit their sex life and perceived sense of femininity, improving quality of life overall (4). Such findings are rather similar to those regarding the perceptions of biological women with AUFI: 95% of respondents in a UK study exploring the attitudes of women toward uterus transplant stated that, despite the additional risks posed, they would choose uterus transplant over surrogacy and adoption (5). Hence, it is not unreasonable to assume that in transgender women, UTx may go a long way towards the achievement of reproductive aspirations, benefit quality of life overall, and be effective in allaying dysphoric symptoms. After all, gender dysphoria entails discomfort and even distress with one's biological sex. It has the potential to severely affect quality of life overall. Treating gender dysphoria in transgender women relies on a multidisciplinary approach involving medical, psychological, and surgical specialists. Psychological input, hormonal therapy, or gender affirmation surgery are all potential options according to a highly individualized assessment for each patient. Nonetheless, UTx intended as a means for transgender women to foster their sense of femininity does present considerable contraindications. UTx is in fact ephemeral in nature: following childbirth, the graft has to be removed in order to eliminate the need for immunosuppressive medications. If on the other hand UTx were performed for reasons other than reproduction, i.e. to improve dysphoric symptoms, the duration of the graft would have to be significantly longer, hence a worse risk-benefit ratio. From a merely reproductive perspective, however, it is worth bearing in mind that transgender women may deem pregnancy as the final and conclusive stage in the process of reconfiguring their life aspirations according to the gender with which they psychologically identify. Certainly, the safety of the procedure into a biologically male body will likely be more complicated and risky than performing UTx in a female body. One of the pioneer scientists who first mastered UTx has acknowledged that transgendered pregnancy may be feasible, but in addition to the anatomical barriers, he has expressed ethical concerns (6). The fundamental ethical question that needs an answer is: if UTx becomes mainstream, safe and effective for biological women with AUFI, would there be any morally tenable grounds as to why transgender women should be denied such an opportunity for gestation? In countries where transgendered women who have transitioned are granted the same legal rights as their female counterparts, this will become a relevant question if UTx is offered as clinical treatment in women. Arguably, UTx and ever more innovative MAP procedures pose ethical quandaries bound to grow as such practices become available on a large scale (7). Already, in vitro fertilization entails the separation between sexuality and procreation, which has made it possible for same-sex couples and singles to have children through heterologous fertilization (8). Such practices are governed with varying degrees of restrictions by each country, which reflects the diversity of approaches in terms of ethical acceptability (9). Advances in embryo manipulation through genome editing could soon pave the way for the eradication of diseases before birth, or even the enhancement of humans yet to be born (10), a whole new frontier in beginning of life bioethics for which we are unprepared. Ultimately, we feel it may all go down to whether procreative liberty ought to be deemed as entailing an absolute right to gestate, and whether transgender women can be denied such a right without infringing upon ethical precepts of equality and non-discrimination. Current bioethics approaches need to undergo a radical update if we are to successfully meet the challenges posed by fast-growing scientific advances, set to shape and mold our lives ever more dramatically.

Are carboxyhaemoglobin levels and distance of the corpse from the site of explosion linked? Results from the retrospective analysis of a terroristic attack.

We present a retrospective analysis of a terrorist attack with incendiary grenades. We tried to analyse the correlation between carboxyhaemoglobin levels and distance of the corpse from the explosion site to check whether there is a direct relationship between them. In most fatal cases caused by grenade explosions reported in literature, death results from disruptive injuries or following multiorgan complications of the trauma, but here the terrorists used incendiary grenades causing serious burns to the victims with flames at the site of explosion. As a result, the external injuries were not fatal for most victims, especially those further from the explosion site where the flames and carbon monoxide from the fire played a significant role in causing death. The convergence of circumstantial data, autopsy results, and toxicological data led us to conclude that a direct link between the carboxyhaemoglobin level and distance from the site of explosion could not be made. Understanding the limitation of the value of linking such data is important both for police and forensic pathologists as this can reduce potential errors in reconstructing the dynamics of the event.

CRISPR-Cas and Its Wide-Ranging Applications: From Human Genome Editing to Environmental Implications, Technical Limitations, Hazards and Bioethical Issues.

The CRISPR-Cas system is a powerful tool for in vivo editing the genome of most organisms, including man. During the years this technique has been applied in several fields, such as agriculture for crop upgrade and breeding including the creation of allergy-free foods, for eradicating pests, for the improvement of animal breeds, in the industry of bio-fuels and it can even be used as a basis for a cell-based recording apparatus. Possible applications in human health include the making of new medicines through the creation of genetically modified organisms, the treatment of viral infections, the control of pathogens, applications in clinical diagnostics and the cure of human genetic diseases, either caused by somatic (e.g., cancer) or inherited (mendelian disorders) mutations. One of the most divisive, possible uses of this system is the modification of human embryos, for the purpose of preventing or curing a human being before birth. However, the technology in this field is evolving faster than regulations and several concerns are raised by its enormous yet controversial potential. In this scenario, appropriate laws need to be issued and ethical guidelines must be developed, in order to properly assess advantages as well as risks of this approach. In this review, we summarize the potential of these genome editing techniques and their applications in human embryo treatment. We will analyze CRISPR-Cas limitations and the possible genome damage caused in the treated embryo. Finally, we will discuss how all this impacts the law, ethics and common sense.

New Psychoactive Substances: Evolution in the Exchange of Information and Innovative Legal Responses in the European Union.

At the end of 2019, the European Monitoring Centre for Drugs and Drug Addiction was monitoring around 790 new psychoactive substances, more than twice the total number of controlled substances under the United Nations Conventions. These substances, which are not subject to international drug controls, include a wide range of molecules, including the assortment of drugs such as synthetic cannabinoids, stimulants, opiates, and benzodiazepines. Most of them are sold as "legal" substitutes for illicit drugs, while others are intended for small groups willing to experiment with them in order to know their possible new effects. At the national level, various measures have been taken to control new substances and many European countries have responded with specific legislation in favor of consumer safety and by extending or adapting existing drug laws to incorporate the new psychoactive substances. Moreover, since 1997, an early warning system has been created in Europe for identifying and responding quickly to the risks of new psychoactive substances. In order to establish a quicker and more effective system to address the criminal activities associated with new dangerous psychoactive substances, the European legal framework has considerably changed over the years.

A novel LC-MS/MS analytical method for detection of articaine and mepivacaine in blood and its application to a preliminary pharmacokinetic study.

Local anaesthetics (LAs) are commonly used in surgery, especially in dentistry. They cause a transitory inhibition of nerve signal due to the blockade of the voltage-gated sodium channels. LAs are administrated alone or with vasoconstriction agents, such as adrenaline. Toxicity of LAs is associated to neurological and cardiovascular alterations. Tachycardia, arrhythmia, tremors, tonic-clonic seizure and respiratory depression (at high doses) are the main symptoms of intoxication by LAs. Lidocaine, articaine and mepivacaine are among the most used anaesthetics. This study aimed to fully validated a new method for the simultaneous detection of articaine and mepivacaine in whole blood. Sample treatment consisted in a liquid-liquid extraction with phosphate buffer (pH 8, 0.1 M) and ethyl-acetate. Analysis was performed by liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode (transitions: articaine, 285→8658 m/z; mepivacaine, 247→9870 m/z; lidocaine - internal standard -, 235→8658 m/z). The method proved to be highly sensitive with limit of quantifications for articaine and mepivacaine of 0.8 and 0.1 ng/mL, respectively. Accuracy and precision were always within the acceptance criteria. The new procedure was also successfully applied to a preliminary pharmacokinetics study.

Evidence of Natural GHB Presence in Energy Drinks: Caution in Data Interpretation in Suspected DFSA Cases.

Gamma-hydroxybutyric acid (GHB), usually reported as rape drug in drug-facilitated sexual assaults (DFSA), is an endogenous substance in human body and is also found in many beverages. This may lead to data misinterpretation in forensic cases. Herein, we aimed to collect evidence about natural GHB presence in 13 energy drinks (ED). After a liquid-liquid extraction with acidic ethyl acetate, samples were derivatized with BSTFA 1% TMCS. Analyses were carried out by a GC-MS system in SIM mode (GHB, 233, 234, 143 and 147 m/z; GHB-d6, 239, 240, 120 and 206 m/z). GHB was present in all the samples at very low concentrations ranging from 98 to 197 ng/mL. Thus, GHB presence in ED is not exclusively related to exogenous addition. Since the GHB levels are far lower than the minimum active dose (i.e., 0.5 g), it is not expected to induce any effect.

Ethyl Glucuronide Concentration in Hair of Detainees: A Preliminary Study.

Through the measurement of ethyl glucuronide in hair (hETG), it is possible to assess chronic alcohol abuse over time. In this paper, we present a study on hETG in Italian prison inmates. Analyses were performed by LC-MS according to a previously published method. Results were evaluated using the cut-offs established by the Society of Hair Testing. Positives samples (ETG > 30 pg/mg) accounted for 6% of all subjects, with concentrations ranging from 42 pg/mg up to 270 pg/mg, abstinent subjects (ETG < 7 pg/mg) accounted for 88%, and moderate alcohol consumption (7 < ETG < 30 pg/mg) for 6% of the subjects. No females displayed ETG values above 30 pg/mg. Among positive samples, only two subjects did not declare heavy alcohol consumption and were found strongly positive at 210 and 270 pg/mg. To the best of our knowledge, this represents the first study on ETG hair concentration on prison inmates.

Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form.

Modified-release oral dosage forms are commonly used in pharmaceutics to delay or sustain the release of drugs. Nowadays, they are only marketed as solid dosage forms such as capsules or tablets. Therefore, the development of a liquid oral dosage form with modified-release properties has been keenly awaited to increase the compliance of patients with a swallowing impairment, such as paediatric, older or critically ill patients. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup, using omeprazole as a model drug. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a mean diameter below 500 µm. Eudragit® E100 and Eudragit® L100-55 were used to prevent the early release of omeprazole in the syrup and in the acidic environment of the stomach, respectively. These polymers allowed the stability of the coated particles to be ensured when dispersed in a liquid and the enteric release of the drug to be targeted. It was demonstrated that our new system presented similar release performances to existing marketed enteric dosage forms. It is able to protect omeprazole for 2 h in acidic medium at pH 1.2, while omeprazole was entirely released at pH 6.8 within 45 min. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days).

Psychotropic substance abuse and fitness to hold a driving license in Italy.

Objective: Driving under the influence (DUI) of psychotropic substances is a serious and widespread problem in road safety. All countries try to reduce the impact with legislative controls over the criteria to regain a driver's license after suspension. In many European countries there are mandatory clinical and toxicological examinations required before a license is regranted. In Italy, individuals convicted of driving under the influence of drugs and/or alcohol must undergo a mandatory medico-legal and forensic toxicological examination prior to regranting of a license. This article reports on the prevalence, trends, and implications of psychotropic substances detected in more than 5,000 subjects submitted to driving license reissuance in the period 2011-2016. Methods: The study involved taking a clinical history, medical examination, and toxicological analysis of both urine and hair samples. Results: There was no change in the prevalence of psychoactive substances in the period 2011-2016. Cocaine was found most often (60%), followed by cannabinoids (15%) and opiates (9%). Methadone and amphetamine stimulants accounted for less than 5% each. Benzodiazepines were present in 15% of samples throughout the period. Conclusion: Cocaine and cannabinoids were the most used substances in the analyzed population, alone and in combination. Benzodiazepines were the most commonly detected prescription medication, raising questions about prescribed medication and driving risk that are not addressed by current legislation.

Drug-related deaths with evidences of body packing: Two case reports and medico-legal issues.

Body packing is a general term used to indicate the internal transportation of drug packages, mainly cocaine, heroin, amphetamines, and methamphetamine, within the gastrointestinal tract. We described two cases of accidental drug intoxication, observed over the last year period, with evidence of intracorporeal drug concealment. The first case concerned a body packer transporting 69 drug packages of heroin adulterated with piracetam. The second body packer transported 16 drug packages of cocaine adulterated with levamisole. For both cases, forensic examination and toxicological analysis of drug packages and biological samples were carried out. Authors also wants to highlight the main medico-legal issues that commonly arise in cases of suspected or ascertained body packers.

Development and Validation of a GC-MS Method for the Detection and Quantification of Clotiapine in Blood and Urine Specimens and Application to a Postmortem Case.

Introduction. Clotiapine is an atypical antipsychotic of the dibenzothiazepine class introduced in a few European countries since 1970, efficient in treatment-resistant schizophrenic patients. There is little published data on the therapeutic and toxic concentrations of this drug. Aims. The aim of the present study is the development and validation of a method that allows the detection and quantification of clotiapine in blood and urine specimens by gas chromatography-mass spectrometry (GC-MS). Methods. Validation was performed working on spiked postmortem blood and urine samples. Samples were extracted with liquid-liquid extraction (LLE) technique at pH 8.5 with n-hexane/dichloromethane (85/15 v/v) and analysis was followed by GC-MS. Methadone-d9 was used as internal standard. Results. The limit of detection (LOD) was 1.2 and 1.3 ng/mL for urine and blood, respectively, while the lower limit of quantification (LLOQ) was 3.9 and 4.3 ng/mL, respectively. Linearity, precision, selectivity, accuracy, and recovery were also determined. The method was applied to a postmortem case. The blood and urine clotiapine concentrations were 1.32 and 0.49 µg/mL, respectively. Conclusions. A reliable GC-MS method for the detection and quantification of clotiapine in blood and urine samples has been developed and fully validated and then applied to a postmortem case.

[Some Italian research on the phenomenon of filicide]. / Alcune ricerche italiane sul fenomeno del figlicidio.

In this work on the phenomenon of filicide, structured on the basis of the examination of hundreds of cases from 1880 to 2010, the five causes were taken into account: the altruistic filicide, the high psychotic component, that of the unwanted child, accidental filicide, and the spouse revenge filicide. Following the observation of Resnick's (1969) 530 psycho-biographiesss, a more structured typing was developed which on the basis of their motive and/or psychopathology divides mother infanticide into 20 categories: the first 10 imply full imputability, stessor events, for piety, immaturity of the mother, hyperactivity of the child, the son of the blame, Medea syndrome, disturbance dependent, narcissistic, or histrionic personality, unwanted child, depression, behavioral disorders involved in the recruitment of drugs. The remaining 10 are those where there may be impairment of traceability for postpartum psychosis (Brief psychotic disorder), Fundus hysterical plus precipitating factors, major depression, schizophrenia, twilight state, psychotic disorder due to a general medical condition, epilepsy, oligophrenia, multiple sclerosis and multiple personality, which however appears to be quite rare. An examination of the causes of death concludes the work.