Z-Drugs and their use in Drug-Facilitated Crimes: a review of the literature.

Background: Z-Drugs are a category of non-benzodiazepine sedative-hypnotic drugs that include Zolpidem, Zopiclone and Zaleplon. They are all rapidly adsorbed and have a very short half- life, features that make them first-line treatment of insomnia and, in the meantime, first-choice drugs in cases of poisoning for criminal purposes. Z-drugs are frequently use in Drug Facilitated Crime cases (DFC) and Drug Facilitated Sexual Assault (DFSA), namely crimes, robberies, extortion and sexual violence committed after administration of incapacitating substances able to induce sedative-hypnotic effects. In these circumstances, the psychoactive substance is considered as a weapon and constitutes an aggravating circumstance in the criminal act: accordingly, judicial authority legitimates the analytical determination of these substances. Currently, few tests able to detect such drugs are available in daily clinical practice. Aim: The aim of this work is to evaluate the effective utilization of Z-Drugs. Methods: We have analyzed the literature, focusing on cases in which the criminal use of such incapacitating substances has been demonstrated. Relevant scientific articles were identified from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE up to December 2022 using the following keywords: "z-drugs", "drug facilitated crime", "forensic toxicology". The resulting references were screened to exclude duplicates. In addition, non-English papers were excluded. This evaluation left 10 articles (8 case reports and 2 original studies) divided as follows: 1 case report of a DFC (robbery), 6 cases of confirmed DFSA, 3 cases of suspected DFSA, 2 original studies about DFC. Results: The totality of the selected cases showed positive toxicological tests for a single intake of z-drugs. Conclusions: This work has shown the limitations of screening tests currently in use in the emergency rooms. Forensic toxicology tests should be introduced in daily clinical practice.

COVID-19 and its aftermath, new drivers of infertility?

Abstract: Law 40/2004, the Italian piece of legislation governing access to assisted reproductive technologies (ART), is relatively young, compared to the number of years that have passed since the first attempts at ART in the world. Still, such a law has undergone several revisions in recent years, mostly by court rulings, and such changes are indeed necessary in light of the constant evolution in ART innovations. Then, the COVID-19 pandemic struck on a global scale, disrupting virtually all aspects of social and economic life. COVID-19's impact on fertility has to do, although it is not limited to, the distribution and function of ACE2 in the female reproductive system: such receptors are in fact expressed extensively in the ovaries, uterus, vagina and placenta. We point out that overcoming the "demographic winter" Italy has been going through, compounded by the pandemic, will require major adjustments in the way we ensure access to ART services in an equitable, sustainable and affordable fashion for all who wish to fulfill their reproductive potential and have been prevented to do so by legal, regulatory and financial factors.

The importance of updatable analytical screening methods for new psychoactive substances in clinical and forensic toxicology.

Abstract: The continuous emergence of New Psychoactive Substances enter-ing the illegal markets poses always new challenges to forensic and clinical toxicology laboratories facing the lack of analytical methods capable of determining the newer parent compounds and eventual metabolites. More than 50 new molecules have been reported by the European Monitoring Centre for Drugs and Drug Addiction only in 2021, further expanding the panel of target analytes. However, the implementation of new detection methodologies may not be viable due to time constraints and inadequate resources. To this concern, the updatable analytical screening methods constitute a powerful tool for pharmacotoxicological laboratories investigating both non biological seizure materials and conventional and non conventional matrices coming from intoxications and fatalities of drugs consumers.

From the maternal uterus to the "uterus device"? Ethical and scientific considerations on partial ectogenesis.

The article aims to elaborate the progress made in partial ectogenesis research on sheep as well as human embryos. Since the ban on embryos experimentation after the 14-day window is a major roadblock in terms of partial ectogenesis research, the authors have weighed the possibility that such a ban could be reconsidered. In favor of easing such a restriction, it may be argued that: (a) unlike the Catholic approach, prevalent ethics precepts hold that the embryo's interest ought to be balanced against the interests of the other parties involved; (b) an extension of the 14-day deadline would no longer make ethically untenable practices acceptable; hence, the "slippery slope" argument, although generally worthy, would not conclusively apply to partial ectogenesis; (c) in mainstream embryo research efforts, there is a conflict between the lives of embryos and the health of individuals already born; as for partial ectogenesis, however, such a conflict would be between the lives of embryos and the lives of fetuses which would not survive otherwise. Still, in light of the embryo's status as a human being, the authors conclude that such research practices should only be allowed on supernumerary embryos.

Recreational use of GHB and prescribed drugs: the challenge in forensic and clinical toxicology.

ABSTRACT: The dual nature and the double use of γ-hydroxybutyric acid (GHB) are the fundamentals of its spread as recreational drug. Endo-genously, GHB acts as inhibitory neurotransmitter while exogenously it is administered in the form of sodium oxybate to treat cataplexy and to menage alcohol withdrawal. Illicit GHB is extensively used along with prescribed drugs and drugs of abuse for its euphoric and anabolic effects. Since it has been used as incapacitating agent to perpetrate rapes and commit robberies, GHB represents a social and public health issues. The tight window of detectability in biological matrices and the difficultly to read symptoms of polydrug overdose represent the modern challenges in forensic and clinical toxicology.

Increasing diversion of prescribed benzodiazepines and Z-drugs to new psychoactive substances.

ABSTRACT: Over the last few years reports have indicated an increase in the number, type and availability of new psychoactive substances belonging to the benzodiazepine class. These molecules may pose high risks to users, since the majority have never undergone clinical trials or tests so their pharmacology and toxicology is largely unknown. However the new drug scenario emerging from the COVID-19 global pandemic seems to play a role in increasing the diversion of prescribed benzodiazepines and Z-drug. A brief presentation of this phenomenon is hereby presented. The awareness and response activities at national and international levels related to this issue should be enforced.

Floating plastics in Adriatic waters (Mediterranean Sea): From the macro- to the micro-scale.

Macro- and microplastics abundances were determined in the Adriatic Sea following the MSFD TG10 protocol. The studied areas included populated gulfs, river outlets and offshore waters in five Adriatic countries. The use of small ships enabled us to detect small sized plastics (2.5-5 cm) and record average macroplastics densities of 251 ±â€¯601 items km-2, one order of magnitude higher than previously considered. Results from manta net tows for microplastics revealed an average abundance of 315,009 ±â€¯568,578 items km-2 (217 ±â€¯575 g km-2). We found significantly higher microplastics abundances in nearshore (≤4 km) than in offshore waters (>4 km) and this trend seems to affect also the small sized macro plastic fragments (2.5-5 cm). The dominant polymers were polyethylene and polypropylene while the presence of some rare polymers and waxes used in food and dentistry indicated waste water treatment plants as potential sources of microplastics.

Interindividual variability in the expression of surfactant protein A and B in the human lung during development.

The surfactant complex, thanks to its multiple actions including decrease of surface- tension and antimicrobial activity, plays a fundamental role in newborn survival, lowering the risk of respiratory distress syndrome. The aim of this work was to determine if the synthesis of two surfactant proteins (SP), SPA and pro-SPB, shows some inter-individual variability during lung development in the intrauterine life. Immunoreactivity for SPA and pro-SPB was investigated in the lungs of  40 subjects, including 15 fetuses, ranging from 14 to 22 weeks of gestation, and 25 neonates, from 24 to 41 weeks. Lung samples were formalin fixed, paraffin-embedded and routinely processed. SPA and pro-SPB were detected utilizing commercial antibodies.  A semi-quantitative grading system (1 to 4) was applied, based on the number of reactive cells and the intensity of immunostaining. Surfactant protein immunostaining was found in  three compartments: bronchi, bronchioles and alveoli, starting from 14 weeks of gestation in the bronchial epithelium and from the 21st week in the alveolar spaces. Differences were found regarding SPA and pro-SPB expression in the vast majority of subjects: in some lungs, SPA was more expressed whereas in others pro-SPB showed an higher degree of immunoreactivity. The expression of both surfactant proteins was not strictly correlated with gestational age. Whereas the highest levels of reactivity were detected in at term neonates, on the other hand one case with grade 3 was detected at 22 weeks and one negative case for both proteins was observed at 31 weeks. Our data clearly show a marked inter-individual variability regarding the production of SPA and pro-SPB and suggest the existence of other epigenetic factors, acting during gestation, that might influence surfactant production and, consequently, the survival potential of  neonates at birth.

Evaluation of Humoral Response and Protective Efficacy of an Inactivated Vaccine Against Peste des Petits Ruminants Virus in Goats.

Four goats were inoculated with an inactivated peste des petits ruminants virus (PPRV) vaccine. Three unvaccinated goats were kept as controls. After 36 days, the four goats were revaccinated. The immune response was monitored by virus neutralization test showing that two doses of the vaccine were able to stimulate strong immune response in all the vaccinated animals. The vaccinated goat and the controls were challenged with virulent PPRV intranasally. After PPRV challenge, the three control goats showed fever, viremia and virus excretion through mucosal surfaces, whereas the vaccinated goats were fully protected against PPRV infection and replication.

Association between circulating angiotensin-converting enzyme and exercise-induced pulmonary haemorrhage in Thoroughbred racehorses.

Exercise-induced pulmonary haemorrhage has an impact on racehorse performance. Although endoscopic diagnosis (with or without the aid of bronchoalveolar lavage) is considered to be the standard diagnostic method for this condition, the use of biomarkers that could aid in quantifying risk and severity of the condition would represent an advance in equine sport medicine. This preliminary research investigated the use of angiotensin-converting enzyme (ACE) activity in plasma of racehorses and demonstrated that ACE activity is increased in horses with higher degrees of haemorrhage and is a promising biomarker for EIPH in racehorses.

N-Domain angiotensin I-converting enzyme expression in renal artery of Wistar, Wistar Kyoto, and spontaneously hypertensive rats.

One of the most intriguing features in kidney transplantation is the finding that kidneys from hypertensive rats can transfer arterial hypertension on transplantation into normotensive rats. Some evidence also suggest that, in humans undergoing renal transplantation, the genotype of the donor kidney determines the blood pressure in the recipient. The renin-angiotensin-aldosterone system is the major etiological candidate in hypertension because it plays an important role in the control of cardiovascular homeostasis. Angiotensin-converting enzyme (ACE) cleaves the C-terminal from angiotensin I as well as from bradykinin. Thus, by generating the potent vasoconstrictor angiotensin II and by degrading the vasodepressor bradykinin, ACE is considered to play a role in blood pressure regulation. We have previously described the presence of N-domain ACE in urine of Wistar (W), Wistar Kyoto (WKY), and spontaneously hypertensive rats (SHR), all of which can hydrolyze the vasodilator peptide Angiotensin 1-7 and also the N-Acetyl-Ser-Asp-Lys-Pro, two peptides described as specific for N-domain ACE. These findings suggest that the 90 kd ACE isoform found in urine and in tissues of SHR is a possible genetic marker of hypertension. Based on the fact that the renal artery has an important role in the control of renal blood flow, we evaluated the presence of N-domain ACE in the renal artery of hypertensive and normotensive rats. Using Western blotting techniques on the renal arteries of W and WKY rats, we detected the 190-kd ACE (similar to somatic ACE) and also the 65-kd ACE previously described in urine and renal tissue as N-domain ACE. The 65-kd and 90-kd isoforms of ACE were also detected in renal arteries in SHR rats. Further studies are required to understand the role of 90-kd enzyme described as a possible local marker of hypertension, its contribution in angiotensin catabolism, and whether this abnormal form of the enzyme has any link with the development and transfer of hypertension after transplantation.

Thrombocytopenic purpura as adverse reaction to recombinant hepatitis B vaccine.

Three cases of immune thrombocytopenic purpura after the first dose of recombinant hepatitis B vaccine occurred in infants under 6 months of age. Other possible causes of this condition were excluded. Antiplatelet antibodies were present. A defect in platelet production was excluded in two children. Corticosteroid treatment was effective. Subsequent administration of other vaccines (against polio, diphtheria, and tetanus) did not cause relapse of thrombocytopenia.

A neurophysiological study in children and adolescents with Crigler-Najjar syndrome type I.

We studied the neurophysiological features of five patients (age range: 4-20 years) suffering from Crigler-Najjar syndrome type I (CNsI) by means of multimodal (brainstem, somatosensory, motor) evoked potentials and periodic EEG-polygraphic recordings (follow-up: 3 months-4.5 years). Two patients presented with neurological disturbances, consisting mainly of mental slowing, motor impairment and seizures. Both of them presented an abnormal EEG, characterized by slowing of background activity associated with paroxysmal discharges. Liver transplantation was performed in one of these two patients and was followed by improvement of both the neurological picture and EEG activity. In a third patient, clinically normal, after two years of follow-up, the EEG started to show paroxysmal activity during sleep or when evoked by intermittent photic stimulation. In these three patients, multimodal evoked potentials were unremarkable. The remaining two younger subjects did not show any clinical or EEG abnormality. Our findings suggest that, whereas in newborns and infants evoked potentials have been demonstrated as reliable techniques to monitor bilirubin neurotoxicity, in children and adolescents with CNsI, EEG seems to be more sensitive in evaluating patients for neurological damage and effectiveness of therapeutic strategies adopted.

Genetic heterogeneity of Crigler-Najjar syndrome type I: a study of 14 cases.

Crigler-Najjar syndrome type I (CN-I) is an autosomal recessive condition characterized by severe unconjugated hyperbilirubinemia caused by the lack of bilirubin-UDP-glucuronosyltransferase (B-UGT) activity in the liver. Two B-UGTs are coded for by a gene complex (UGT1) that maps to chromosome 2q37 and that also encodes two phenol-UDP-glucuronosyltransferases. Here, we report eleven mutations (including nine novel mutations) of the B-UGT1 gene in a large series of 14 unrelated CN-I children of various geographic origins: France (seven patients: A401P, Q357X, W335X, A368T, 1223insG, A291V, K426E, K437X); Portugal (two patients: G308E); Tunisia (two patients; Q357R); Turkey (one patient: S381R); italy (two siblings: S381R). Interestingly, 6/14 mutant alleles carried by unrelated probands of French ancestry bore the A401P mutation, indicating a founder effect; this effect is probably also present in Portugal, Turkey, and Tunisia. Since mutations occurred in exons 2-5 shared by all mRNAs species of the gene, a combined deficiency of B-UGT and P-UGT was observed in the liver of five patients in whom these activities were measured. The present study confirms that CN-I is genetically heterogeneous and suggests that different founder effects are involved in Western Europe, the Middle East, and North Africa.

[Conservative elective surgery in kidney neoplasms]. / Chirurgia conservativa di elezione nelle neoplasie renali.

After the good results of "necessary" conservative surgery in the treatment of kidney neoplasms (bilateral neoplasms, congenital, acquired or functional solitary kidney), conservative surgery itself has been employed as elective treatment in selected cases presenting without the overmentioned problems. The authors report two cases of elective conservative surgery in kidney neoplasm with good results after 18 and 24 months.

[Interpretation of experimental data in the presence of accidental perturbations: characterization of the bladder]. / Interpretazione di dati sperimentali in presenza di perturbazioni accidentali: la caratterizzazione della vescica.

Some tests are subject to the influence of a special kind of "irreducible" effects which do not satisfy the Central Limit Theorem of statistics, even though they show no systematic character or tendency. These effects especially present when physiological experiments are concerned "in vivo". In such the lack of specific methods to reduce these effects brings about the necessity of special case in minimizing the loss of information. Contained in the experimental data as well as the accumulation of useless information. Recent work has suggested the extensive use of several indexes derived from combination of available variables and their respective mathematic correlation. The information obtained by following this methodology has the character of "working hypothesis" so it needs many favorable confirmation to assess its reliability. It is convenient to analyze a large number of relations in order to emphasize the concordant effects and discord the others. In order to obtain some preliminary indication of the reliability of this procedure we have analyzed some CMG curves in prostatic and non-prostatic subject. The final slope of the curves (urge point) t = dP/dVr has been adapted as an index of the "elasticity" of the bladder; it was compared with the filling volume, the muscular volume and their ratio, i.e. with a geometric index of the bladder shape. The correlation show that the index t can, to some extent significantly represent the mechanical behaviour of the bladder in its physiological condition or when there is a partial obstruction of urine deflection.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pyeloureteral junction syndrome caused by "anomalous vessel"]. / Sindrome del giunto pieloureterale da "vaso anomalo".

In presenting and describing the pathogenesis of the pyeloureteral junction syndrome, the Authors report their recent experience with four cases due to an "abnormal vessel". Symptoms, diagnosis, and surgical techniques are discussed.