Publications by authors named "Adriano Tagliabracci"

63 Publications

Visceral fat inflammation and fat embolism are associated with lung's lipidic hyaline membranes in subjects with COVID-19.

Int J Obes (Lond) 2022 05 26;46(5):1009-1017. Epub 2022 Jan 26.

Center for the Study of Obesity, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Tronto 10A, Ancona, Italy.

Background: Preliminary data suggested that fat embolism could explain the importance of visceral obesity as a critical determinant of coronavirus disease-2019 (COVID-19).

Methods: We performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissue (VAT), lungs and livers of 19 subjects with COVID-19 (COVID-19+), and 23 people without COVID-19 (controls). Human adipocytes (hMADS) infected with SARS-CoV-2 were also studied.

Results: Although there were no between-group differences in body-mass-index and adipocytes size, a higher prevalence of CD68+ macrophages among COVID-19+ VAT was detected (p = 0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV-2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution by ORO. Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19+ (p < 0.001). Notably, signs of fat embolism were more prevalent among people with obesity (p = 0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication exacerbated by SARS-CoV-2 infection. Importantly, all infected subjects' lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control patient with non-COVID-19-related pneumonia. Importantly, transition aspects between embolic fat and hyaline membranes were also observed.

Conclusions: This study confirms the lung fat embolism in COVID-19+ patients and describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in people with COVID-19 and obesity.
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http://dx.doi.org/10.1038/s41366-022-01071-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790008PMC
May 2022

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks.

Pharmaceuticals (Basel) 2021 Jun 11;14(6). Epub 2021 Jun 11.

Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Via Tronto 10, 60126 Ancona, Italy.

The rising use of designer benzodiazepines (DBZD) is a cat-and-mouse game between organized crime and law enforcement. Non-prohibited benzodiazepines are introduced onto the global drug market and scheduled as rapidly as possible by international authorities. In response, DBZD are continuously modified to avoid legal sanctions and drug seizures and generally to increase the abuse potential of the DBZD. This results in an unpredictable fluctuation between the appearance and disappearance of DBZD in the illicit market. Thirty-one DBZD were considered for review after consulting the international early warning database, but only 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam had sufficient data to contribute to this scoping review. A total of 49 reports describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 emergency department (ED) admissions, 63 driving under the influence of drugs (DUID) and 141 deaths reported between 2008 and 2021 are included in this study. Etizolam, flualprazolam flubromazolam and phenazepam were implicated in the majority of adverse-events, drug offenses and deaths. However, due to a general lack of knowledge of DBZD pharmacokinetics and toxicity, and due to a lack of validated analytical methods, total cases are much likely higher. Between 2019 and April 2020, DBZD were identified in 48% and 83% of postmortem and DUID cases reported to the UNODC, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances. DBZD toxicology, public health risks and adverse events are reported.
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http://dx.doi.org/10.3390/ph14060560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230725PMC
June 2021

Mycobacterium chimaera: a report of 2 new cases and literature review.

Int J Legal Med 2021 Nov 29;135(6):2667-2679. Epub 2021 Jun 29.

Section of Legal Medicine, Department of Excellence SBSP-Biomedical Sciences and Public Health, Università Politecnica delle Marche of Ancona, Conca 71, Street, Ancona, Italy.

Mycobacterium chimaera is a non-tuberculous mycobacterium, member of the Mycobacterium avium complex (MAC), which has become a global public health concern due to infection following cardiac surgery performed with contaminated heater-cooler units. M. chimaera infection is characterized by a long latency, non-specific signs and symptoms and high mortality rates. Thus, the diagnosis is still challenging both for forensic pathologists and for clinicians. Clinical manifestations of M. chimaera infection include endocarditis, hepatitis, nephritis, encephalitis and chorioretinitis. A constant histopathologic finding is the presence of non-caseating granulomas, with multinucleated giant cells and histiocytes. Hereby, we present two cases of fatal disseminated M. chimaera infection following aortic valve surgery reporting clinical history and post-mortem findings. Further, we provide a brief overview of the literature with a special focus on histopathological characteristics of M. chimaera infection. The aim of this article is to provide a complete synopsis of histopathological characteristics useful for forensic pathologists.
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http://dx.doi.org/10.1007/s00414-021-02630-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523431PMC
November 2021

Death following extreme temperature exposure: Histological, biochemical and immunohistochemical markers.

Med Sci Law 2021 Jan;61(1_suppl):36-41

Università Politecnica delle Marche, Dipartimento di Scienze Biomediche e Sanità Pubblica, Italy.

Introduction: Defining extreme temperatures as the cause of death remains challenging. It is mostly based on circumstantial, macroscopic and microscopic features.

Methods: We retrospectively compared groups of cases of fatal hypothermia, fatal hyperthermia and non-extreme temperature-related deaths. We analysed specific histological findings, focusing on samples from the liver, pancreas and kidney.

Results: Between 1 January 2013 and 31 December 2016, 15 autopsies were performed for deaths related to extreme temperatures. They included 11 cases of fatal hypothermia (group A), four cases of fatal hyperthermia (group B) and eight controls (group C). Perinuclear hepatocyte vacuolisation was observed in seven cases of hypothermia, one case of hyperthermia and four controls. Pancreatic cytoarchitecture was well preserved in two cases of hypothermia, one case of hyperthermia and two controls. No particular microscopic feature was found in pancreatic samples. Renal epithelial tubular cell vacuolisation was observed in seven cases of hypothermia and one case of hyperthermia, while it was absent in all controls. Chromogranin A (CgA) was markedly positive in the pancreatic tissue of five cases of fatal hypothermia and one control, and mildly positive in one case of fatal hyperthermia. No significant -values were observed for any comparisons ( > 0.05), except when hypothermia cases group were compared to the control group for the Armanni-Ebstein phenomenon test ( = 0.0078).

Conclusions: Although our study did not find a specific microscopic marker, hepatocyte vacuolisation, the Armanni-Ebstein phenomenon and pancreatic CgA positivity, taken together, may be useful tools to confirm hypo- and hyperthermia-related deaths, in addition to circumstantial and macroscopic findings.
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http://dx.doi.org/10.1177/0025802420942423DOI Listing
January 2021

UHPLC-MS/MS analysis of cannabidiol metabolites in serum and urine samples. Application to an individual treated with medical cannabis.

Talanta 2021 Feb 14;223(Pt 2):121772. Epub 2020 Oct 14.

Department of Excellence-Biomedical Sciences and Public Health, University Politecnica Delle Marche, Ancona, Italy.

No analytical assay is currently available for the simultaneous determination of CBD major metabolites in serum or urine samples of individuals treated with medical cannabis or CBD-based pharmaceuticals. We developed and validated a method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) for quantifying cannabidiol (CBD) and its metabolites, cannabidiol-7-oic acid (7-COOH-CBD), 7- hydroxycannabidiol (7-OH-CBD), 6-alpha-hydroxycannabidiol (6-α-OH-CBD) and 6-beta-hydroxycannabidiol (6-β-OH-CBD) in serum and urine samples of an individual treated with medical cannabis. The ionization was performed by electrospray in negative mode to reach the sensitivity required to detect trace amounts, with limits of quantification ranging from 0.05 to 0.1 ng/mL. The method is accurate (average inter/intra-day error, <15%), precise (inter/intra-day imprecision, <15%) and fast (8 min run time) and it is an essential tool to investigate CBD pharmacokinetics and pharmacodynamics in individuals treated with medical cannabis or with CBD-based medical preparations.
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http://dx.doi.org/10.1016/j.talanta.2020.121772DOI Listing
February 2021

Application of aquatic decomposition scores for the determination of the Post Mortem Submersion Interval on human bodies recovered from the Northern Adriatic Sea.

Forensic Sci Int 2021 Jan 16;318:110599. Epub 2020 Nov 16.

Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy. Electronic address:

Purpose: The decomposition process of human bodies in marine environment is not well understood, and it is influenced by external variables related to the geographical area where the body is submerged. We report the application of two decomposition scores, the Heaton's score and the van Daalen's score, on a casuistry of human bodies recovered from the Northern Adriatic Sea. The aims of this study are to verify whether the marine environment of a Mediterranean climate area may affect the applicability of both scores and to develop a prediction model that can be applied on bodies recovered in salt water.

Methods: A retrospective study was performed on 61 human bodies recovered between 2005 and 2019 from coastal water of the Northern Adriatic Sea nearby the Italian regions Emilia-Romagna and Marche. For each of the 61 cases included, the Total Aquatic Decomposition Score (TADS) was calculated with the Heaton's score and the Van Daalen's score. The prediction model was assessed through multiple regression analyses, and the determination coefficients (r) between TADS and PMSI (expressed in days) and between TADS and Accumulate Degrees Days (ADD) were studied. The prediction model was applied to the entire case sample, to bodies recovered during the warm season and to bodies recovered during the cold season.

Results: All bodies were recovered floating, and a very poor scavenging activity was observed. The regression analyses showed a strong correlation between the TADS and the total case sample using both scores and both independent variables (PMSI and ADD). The determination coefficients were greater than 0.95 also when considering the total case sample.

Discussion: The proposed prediction models are not significantly influenced by seasonality, contrarily to what observed on bodies recovered in fresh water in the same climate area. However, the ADD model, which also consider the water temperature, should be preferred for higher decomposition stages. This study helps increase the accuracy of PMSI estimation in bodies recovered from a marine environment of the Northern Adriatic Sea.
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http://dx.doi.org/10.1016/j.forsciint.2020.110599DOI Listing
January 2021

Assessment of the Precision ID Identity Panel kit on challenging forensic samples.

Forensic Sci Int Genet 2020 11 3;49:102400. Epub 2020 Oct 3.

Department of Medicine, Surgery and Health, University of Trieste, Italy. Electronic address:

The performance of the Precision ID Identity Panel (Thermo Fisher Scientific) was assessed on a set of 87 forensic samples with different levels of degradation for which a reference sample from the "same donor" or from a "first degree relative" was available. PCR-MPS analysis was performed with DNA input ranging from 1 ng to 12 pg and through 21-26 PCR cycles, in replicate tests, and a total number of 255 libraries were sequenced on the Ion Personal Genome Machine™ (PGM™) System. The evaluation of the molecular data allowed to set a fix threshold for locus call at 50 x which suitably worked even when low amounts of degraded DNA (12 pg) were investigated. In these analytical conditions, in fact, 25 PCR cycles allowed the genotyping of about 50 % and 35 % of the autosomal and the Y-specific markers on average, respectively, for each single amplification with a negligible frequency of drop ins (0.01 %). On the other hand, drop out artefacts reached 18-23 % when low copy number and degraded DNA samples were studied, with surviving alleles showing more than 600 reads in 2.9 % of the cases. Our data pointed out that the Precision ID Identity Panel allowed accurate typing of almost any amount of good quality/moderately degraded DNA samples, in duplicate tests. The analysis of low copy number DNAs evidenced that the same allele of a heterozygous genotype could be lost twice, thus suggesting that a third amplification could be useful for a correct genotype assignment in these peculiar cases. Using the consensus approach, a limited number of genotyping errors were computed and about 37 % of the autosomal markers was finally typed with a corresponding combined random match probability of at least 1.6 × 10, which can be considered an excellent result for this kind of challenging samples. In the end, the results presented in this study emphasize the crucial role of the expert opinion in the correct evaluation of artefacts arising from PCR-MPS technology that could potentially lead to genetic mistyping.
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http://dx.doi.org/10.1016/j.fsigen.2020.102400DOI Listing
November 2020

Searching the undetected mtDNA variants in forensic MPS data.

Forensic Sci Int Genet 2020 11 28;49:102399. Epub 2020 Sep 28.

Section of Legal Medicine, Department of Excellence of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy - Via Tronto, 60126 Torrette Ancona, Italy. Electronic address:

The efficiency of MPS in forensic mtDNA analysis has been thoroughly proven, although a reliable and well established data evaluation still remains a critical point. Numerous bioinformatics tools have been developed, but most of them require specific operating systems and high costs, while free open-source programs with user-friendly interfaces are few. In this study, 43 full mtGenomes were sequenced using the Ion Personal Genome Machine™ (PGM™) System and analyzed utilizing the plug-in Variant Caller (TVC) of the Ion Torrent Software Suite and the mtDNA-Server (mDS), a free web-based mitochondrial analysis tool for MPS data. The outcomes of these two different analysis tools were compared to variants noted after manual inspection of the aligned reads performed using Integrative Genomics Viewer (IGV). The comparison highlighted the presence of thirty-nine discordant variant calls, which were resolved by Sanger sequencing that confirmed the presence of all variants, except for 7 deletions. The combined adoption of IGV and Sanger type sequencing confirmatory steps, in addition of TVC and mDS analysis, resulted in a more accurate variants assignment with the detection of 32 additional true polymorphisms, which were noted in the final dataset. Regarding the heteroplasmy issue, out of a total of thirty heteroplasmic variants, twenty-eight were detected by the TVC, while the mDS detected twenty-two. Overall, none of the used bioinformatics tools were the perfect choice and a secondary analysis with an expert's opinion in complete mtGenome MPS data evaluation is still required in forensic genetic analysis.
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http://dx.doi.org/10.1016/j.fsigen.2020.102399DOI Listing
November 2020

A Review of Synthetic Cathinone-Related Fatalities From 2017 to 2020.

Ther Drug Monit 2021 02;43(1):52-68

Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania.

Background: Synthetic cathinones (SCs) are designer analogs of the natural active principle of khat. Since their appearance on the black market in 2003, their popularity has increased annually, and they have become the most seized class of new psychoactive substances reported to the UNODC Early Warning Advisory system. The constant introduction of newly synthesized molecules makes this issue difficult to monitor. The authors reviewed the most recent SC-related fatalities worldwide to highlight new trends of consumption, reporting acute pharmacological and toxicological symptoms, scene investigations, analytical methods, and reported SC concentrations in diverse biological matrices.

Methods: A literature search was performed using scientific databases such as PubMed, Scopus, Science Direct, Web of Science, and Research Gate to identify relevant scientific publications from 2017 to 2020. In addition, a search was conducted through the EU EWS.

Results: From 2017 to 2020, 31 different SCs were identified in 75 reported fatal intoxications in the literature, alone or in combination with other substances. The most abused SCs were N-ethylpentylone, N-ethylhexedrone, and 4-chloromethcathinone. The EU EWS included less detail on 72 additional SC-related fatalities from 2017 to 2020.

Conclusions: New SCs continuously replace older natural and synthetic stimulant drugs, making determining the cause of death difficult. Analytical methods and high-performance mass spectrometry instruments are essential to detect the low concentrations of these potent new SCs. Little data are available on the pharmacology of these new drugs; the evaluation of toxicological antemortem and postmortem findings provides critical data on the drug's pharmacology and toxicology and for the interpretation of new SC cases.
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http://dx.doi.org/10.1097/FTD.0000000000000808DOI Listing
February 2021

Evaluation of the Ion AmpliSeq SARS-CoV-2 Research Panel by Massive Parallel Sequencing.

Genes (Basel) 2020 08 12;11(8). Epub 2020 Aug 12.

Virology Unit, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Torrette, 60126 Ancona, Italy.

Deep knowledge of the genetic features of SARS-CoV-2 is essential to track the ongoing pandemic through different geographical areas and to design and develop early diagnostic procedures, therapeutic strategies, public health interventions, and vaccines. We describe protocols and first results of the Ion AmpliSeq™ SARS-CoV-2 Research Panel by a massively parallel sequencing (MPS) assay. The panel allows for targeted sequencing by overlapping amplicons, thereby providing specific, accurate, and high throughput analysis. A modified reverse transcription reaction, which consists of the use of a SARS-CoV-2 specific primers pool from the Ion AmpliSeq SARS-CoV-2 Research Panel, was assessed in order to promote viral RNA specific reverse transcription. The aim of this study was to evaluate the effectiveness of the Ion AmpliSeq™ SARS-CoV-2 Research Panel in sequencing the entire viral genome in different samples. SARS-CoV-2 sequence data were obtained from ten viral isolates and one nasopharyngeal swab from different patients. The ten isolate samples amplified with 12 PCR cycles displayed high mean depth values compared to those of the two isolates amplified with 20 PCR cycles. High mean depth values were also obtained for the nasopharyngeal swab processed by use of a target-specific reverse transcription. The relative depth of coverage (rDoC) analysis showed that when 12 PCR cycles were used, all target regions were amplified with high sequencing coverage, while in libraries amplified at 20 cycles, a poor uniformity of amplification, with absent or low coverage of many target regions, was observed. Our results show that the Ion AmpliSeq SARS-CoV-2 Research Panel can achieve rapid and high throughput SARS-CoV-2 whole genome sequencing from 10 ng of DNA-free viral RNA from isolates and from 1 ng of DNA-free viral RNA from a nasopharyngeal swab using 12 PCR cycles for library amplification. The modified RT-PCR protocol yielded superior results on the nasopharyngeal swab compared to the reverse transcription reaction set up according to the manufacturer's instructions.
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http://dx.doi.org/10.3390/genes11080929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463572PMC
August 2020

Molecular Tracing of SARS-CoV-2 in Italy in the First Three Months of the Epidemic.

Viruses 2020 07 24;12(8). Epub 2020 Jul 24.

Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, 20157 Milan, Italy.

The aim of this study is the characterization and genomic tracing by phylogenetic analyses of 59 new SARS-CoV-2 Italian isolates obtained from patients attending clinical centres in North and Central Italy until the end of April 2020. All but one of the newly-characterized genomes belonged to the lineage B.1, the most frequently identified in European countries, including Italy. Only a single sequence was found to belong to lineage B. A mean of 6 nucleotide substitutions per viral genome was observed, without significant differences between synonymous and non-synonymous mutations, indicating genetic drift as a major source for virus evolution. tMRCA estimation confirmed the probable origin of the epidemic between the end of January and the beginning of February with a rapid increase in the number of infections between the end of February and mid-March. Since early February, an effective reproduction number (R) greater than 1 was estimated, which then increased reaching the peak of 2.3 in early March, confirming the circulation of the virus before the first COVID-19 cases were documented. Continuous use of state-of-the-art methods for molecular surveillance is warranted to trace virus circulation and evolution and inform effective prevention and containment of future SARS-CoV-2 outbreaks.
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http://dx.doi.org/10.3390/v12080798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472216PMC
July 2020

Corrigendum to "Fatal inhalation of nitrogen inside a closed environment: toxicological issues about the cause of death" [Forensic Sci. Int. 302C (2019) 109871].

Forensic Sci Int 2020 Sep 25;314:110421. Epub 2020 Jul 25.

Section of Legal Medicine, Università Politecnica delle Marche, Ancona, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.forsciint.2020.110421DOI Listing
September 2020

Use of Methylphenidate Analogues as Cognitive Enhancers: The Prelude to Cosmetic Neurology and an Ethical Issue.

Front Psychiatry 2019 23;10:1006. Epub 2020 Jan 23.

Department of Anatomical, Histological, Forensic, and Orthopedic Sciences, Sapienza University, Rome, Italy.

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http://dx.doi.org/10.3389/fpsyt.2019.01006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989549PMC
January 2020

Mechanism of miR-222 and miR-126 regulation and its role in asbestos-induced malignancy.

Int J Biochem Cell Biol 2020 04 4;121:105700. Epub 2020 Feb 4.

Department of Clinical and Molecular Sciences, Section of Experimental and Occupational Medicine, Polytechnic University of Marche, Via Tronto 10/A, 60020, Ancona, Italy. Electronic address:

MiR-222 and miR-126 are associated with asbestos exposure and the ensuing malignancy, but the mechanism(s) of their regulation remain unclear. We evaluated the mechanism by which asbestos regulates miR-222 and miR-126 expression in the context of cancer etiology. An 'in vitro' model of carcinogen-induced cell transformation was used based on exposing bronchial epithelium BEAS-2B cells to three different carcinogens including asbestos. Involvement of the EGFR pathway and the role of epigenetics have been investigated in carcinogen-transformed cells and in malignant mesothelioma, a neoplastic disease associated with asbestos exposure. Increased expression of miR-222 and miR-126 were found in asbestos-transformed cells, but not in cells exposed to arsenic and chrome. Asbestos-mediated activation of the EGFR pathway and macrophages-induced inflammation resulted in miR-222 upregulation, which was reversed by EGFR inhibition. Conversely, asbestos-induced miR-126 expression was affected neither by EGFR modulation nor inflammation. Rather than methylation of the miR-126 host gene EGFL7, epigenetic mechanism involving DNMT1- and PARP1-mediated chromatin remodeling was found to upregulate of miR-126 in asbestos-exposed cells, while miR-126 was downregulated in malignant cells. Analysis of MM tissue supported the role of PARP1 in miR-126 regulation. Therefore, activation of the EGFR pathway and the PARP1-mediated epigenetic regulation both play a role in asbestos-induced miRNA expression, associated with in asbestos-induced carcinogenesis and tumor progression.
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http://dx.doi.org/10.1016/j.biocel.2020.105700DOI Listing
April 2020

Interpreting GHB concentrations in hair: can a cut-off be established?

Forensic Sci Int 2020 Jan 23;306:110009. Epub 2019 Oct 23.

Section of Legal Medicine - Department of Excellence SBSP - University "Politecnica delle Marche" of Ancona, Italy.

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http://dx.doi.org/10.1016/j.forsciint.2019.110009DOI Listing
January 2020

Biomedical analysis of New Psychoactive Substances (NPS) of natural origin.

J Pharm Biomed Anal 2020 Feb 30;179:112945. Epub 2019 Oct 30.

Department of Excellence of Biomedical Sciences and Public Health, University "Politecnica delle Marche" of Ancona, Via Tronto 71, Ancona, Italy. Electronic address:

New psychoactive substances (NPS) can be divided into two main groups: synthetic molecules and active principles of natural origin. With respect to this latter group, a wide range of alkaloids contained in plants, mainly from Asia and South America, can be included in the class of NPS of natural origin. The majority NPS of natural origin presents stimulant and/or hallucinogenic effects (e.g. Catha edulis and Ayahuasca, respectively) while few of them show sedative and relaxing properties (e.g. kratom). Few information is available in relation to the analytical identification of psychoactive principles contained in the plant material. Moreover, to our knowledge, scarce data are present in literature, about the characterization and quantification of the parent drug in biological matrices from intoxication and fatality cases. In addition, the metabolism of natural active principles has not been yet fully investigated for most of the psychoactive substances from plant material. Consequently, their identification is not frequently performed and produced metabolites are often unknown. To fill this gap, we reviewed the currently available analytical methodologies for the identification and quantification of NPS of natural origin in plant material and, whenever possible, in conventional and non-conventional biological matrices of intoxicated and dead subjects. The psychoactive principles contained in the following plants were investigated: Areca catechu, Argyreia nervosa, Ayahuasca, Catha edulis, Ipomoea violacea, Mandragora officinarum, Mitragyna speciosa, Pausinystalia yohimbe, Piper methisticum, Psilocybe, Rivea corymbosa, Salvia divinorum, Sceletium tortuosum, Lactuca virosa. From the results obtained, it can be evidenced that although several analytical methods for the simultaneous quantification of different molecules from the same plants have been developed and validated, a comprehensive method to detect active compounds from different natural specimens both in biological and non-biological matrices is still lacking.
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http://dx.doi.org/10.1016/j.jpba.2019.112945DOI Listing
February 2020

Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication.

Cancer Lett 2019 Oct 7;463:27-36. Epub 2019 Aug 7.

Department of Clinical and Molecular Sciences, Section of Experimental and Occupational Medicine, Polytechnic University of Marche, Via Tronto 10/A, 60126, Ancona, Italy. Electronic address:

MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVEC), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM.
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http://dx.doi.org/10.1016/j.canlet.2019.08.001DOI Listing
October 2019

Letter: The Indusium Griseum: Anatomic Study with Potential Application to Callosotomy.

Neurosurgery 2019 09;85(3):E621-E622

Department of Experimental and Clinical Medicine Section of Neuroscience and Cell Biology School of Medicine Università Politecnica delle Marche Ancona, Italy.

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http://dx.doi.org/10.1093/neuros/nyz236DOI Listing
September 2019

Letter: The Indusium Griseum: Anatomic Study with Potential Application to Callosotomy.

Neurosurgery 2019 09;85(3):E621-E622

Department of Experimental and Clinical Medicine Section of Neuroscience and Cell Biology School of Medicine Università Politecnica delle Marche Ancona, Italy.

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http://dx.doi.org/10.1093/neuros/nyz236DOI Listing
September 2019

Editorial: The Challenge Posed by New Synthetic Opioids: Pharmacology and Toxicology.

Front Pharmacol 2019 21;10:563. Epub 2019 May 21.

Section of Legal Medicine, Department of Excellence SBSP - University "Politecnica delle Marche", Ancona, Italy.

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http://dx.doi.org/10.3389/fphar.2019.00563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536647PMC
May 2019

Is etizolam a safe medication? Effects on psychomotor perfomance at therapeutic dosages of a newly abused psychoactive substance.

Forensic Sci Int 2019 Aug 18;301:137-141. Epub 2019 May 18.

Section of Legal Medicine, Università Politecnica delle Marche, Ancona, Italy.

Etizolam is a drug from the thienotriazoldiazepine class, widely prescribed as anxiolytic due to its apparently secure toxicological profile. Nevertheless, some recent cases of etizolam dependence, intoxications and fatalities associated to its abuse have been reported in the international literature. For this reason, the drug listed as new psychoactive substance (NPS) by the World Health Organization (WHO) since 2015. Euphoric effect at high dosage is the first cause of its recreational use that has determined a wider distribution in the illicit market. An experimental study was performed to obtain evidence that etizolam at low therapeutic dosages is a drug with negligible influence on the psychomotor performances involved in driving. The psychomotor performance was assessed by performing different tests, such as critical tracking task (CTT), critical flicker fusion (CFF), choice reaction time (CRT), visual vigilance task (VVT), response competition test (RCT) in a group of 16 healthy volunteers after a single administration of etizolam at two different dosages (0.25 mg or 1.00 mg) in comparison to placebo. The test results showed that etizolam at 0.25 mg and 1.00 mg had no significant effect on vigilance, short term memory, psychomotor coordination or speed in decision making. Differently, abuse of etizolam to obtain the euphoric effects at presumably high dosages or in combination with other psychoactive substances could be fatal. The negligible side effects on mental and behavioral function demonstrated by this study, could represent an incitement to abuse, which can be strongly discouraged with correct information on differences between its correct use and its misuse.
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http://dx.doi.org/10.1016/j.forsciint.2019.05.018DOI Listing
August 2019

Evaluation of a microhaplotypes panel for forensic genetics using massive parallel sequencing technology.

Forensic Sci Int Genet 2019 07 1;41:120-127. Epub 2019 May 1.

Section of Legal Medicine, Department of Excellence of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy - Via Tronto, 60126, Torrette, Ancona (AN), Italy.

Massive parallel DNA sequencing (MPS) makes it possible to explore a new type of genetic marker, known as microhaplotypes or microhaps. These loci were recently introduced in the landscape of forensic genetic and appear to be useful for identification purposes, reconstruction of family relationships, ancestry prediction and DNA mixtures deconvolution. Microhaplotypes loci, based on 89 loci in ALFRED, were selected and their genetic variations in 100 Italian individuals were evaluated by using MPS, in order to make inference about utility of a set of microhaps in forensic genetics. After MPS, the panel was reduced to 87 microhaps, comprised of 266 different SNPs and spread across 22 human autosomes. Genotype and haplotype frequencies were estimated, as well as the effective number of alleles at each locus (A), which relates to the usefulness of the locus in resolution of relationships and deconvolution of DNA mixtures. Overall, the A values for the 87 microhaps range from 1.010 to 8.344, with about 80% showing values greater than 2.0. Noteworthy, 32 microhaps display A values greater than 3.0 and 18 loci A above 4.0. To explore the suitability of microhaplotypes in mixture deconvolution, the probability of detecting a mixture, as a function of A, was inferred for different groups of loci. Considering the fourteen loci with A between 3.0 and 3.999 the probability of detecting a mixture was at least 0.99973, while considering the ten loci with Ae between 4.0 and 4.999 the probability was at least 0.99998. Moreover, when considering just the six loci with A between 5.0 and 5.999 the probability of detecting a mixture was at least 0.99984, while when considering just the two loci with A above 6 the probability was 0.97228. Combining these 32 MH loci, the theoretical probability of detecting a mixture was 0.999999999999973. These results make the subset of 32 loci with A above three informative for mixture resolution. The individual matching probabilities (PI) of the 87 microhaps ranged from 0.032 to 0.9802. Considering the 32 microhap loci with A greater than 3.0, the cumulative PI value was 1.6 × 10, while considering the 18 microhap loci with A above 4.0, the cumulative PI value was 2.34 × 10. Overall the results of this study confirmed the utility of microhaps in forensic genetics.
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http://dx.doi.org/10.1016/j.fsigen.2019.04.009DOI Listing
July 2019

Metabolic Pathways and Potencies of New Fentanyl Analogs.

Front Pharmacol 2019 5;10:238. Epub 2019 Apr 5.

National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy.

Up to now, little is known about the metabolic pathways of new fentanyl analogs that have recently emerged on the drug markets worldwide with high potential for producing addiction and severe adverse effects including coma and death. For some of the compounds, limited information on the metabolism has been published, however, for others so far no information is available. Considering the well characterized metabolism of the pharmaceutically used opioid fentanyl and the so far available data, the metabolism of the new fentanyl analogs can be anticipated to generally involve reactions like hydrolysis, hydroxylation (and further oxidation steps), - and -dealkylation and -methylation. Furthermore, phase II metabolic reactions can be expected comprising glucuronide or sulfate conjugate formation. When analyzing blood and urine samples of acute intoxication cases or fatalities, the presence of metabolites can be crucial for confirmation of the uptake of such compounds and further interpretation. Here we present a review on the metabolic profiles of new fentanyl analogs responsible for a growing number of severe and fatal intoxications in the United States, Europe, Canada, Australia, and Japan in the last years, as assessed by a systematic search of the scientific literature and official reports.
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http://dx.doi.org/10.3389/fphar.2019.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461066PMC
April 2019

Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry Assay for Quantifying Fentanyl and 22 Analogs and Metabolites in Whole Blood, Urine, and Hair.

Front Chem 2019 2;7:184. Epub 2019 Apr 2.

National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy.

Recently, synthetic opioid-related overdose fatalities, led by illicitly manufactured fentanyl and analogs, increased at an alarming rate, posing a global public health threat. New synthetic fentanyl analogs have been constantly emerging onto the drug marked for the last few years, to circumvent the laws and avoid analytical detection. Analytical methods need to be regularly updated to keep up with the new trends. In this study, we aimed to develop a new method for detecting the newest fentanyl analogs with a high sensitivity, in whole blood, urine, and hair. The method is intended to provide to clinical and forensic toxicologists a tool for documenting consumption. We developed a comprehensive ultra-high-performance liquid chromatography-tandem mass spectrometry method for quantifying fentanyl and 22 analogs and metabolites. Urine samples were simply diluted before injection; a liquid-liquid extraction was performed for blood testing; and a solid phase extraction was performed in hair. The chromatographic separation was short (8 min). The method was validated with a high sensitivity; limits of quantifications ranged from 2 to 6 ng/L in blood and urine, and from 11 to 21 pg/g in hair. The suitability of the method was tested with 42 postmortem blood, urine, or hair specimens from 27 fatalities in which fentanyl analogs were involved. Average blood concentrations (±SD) were 7.84 ± 7.21 and 30.0 ± 18.0 μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, respectively ( = 8), 4.08 ± 2.30 μg/L for methoxyacetylfentanyl, ( = 4), 40.2 ± 38.6 and 44.5 ± 21.1 μg/L for acetylfentanyl and acetyl norfentanyl, respectively ( = 3), 33.7 and 7.17 μg/L for fentanyl and norfentanyl, respectively ( = 1), 3.60 and 0.90 μg/L for furanylfentanyl and furanyl norfentanyl, respectively ( = 1), 0.67 μg/L for sufentanil ( = 1), and 3.13 ± 2.37 μg/L for 4-ANPP ( = 9). Average urine concentrations were 47.7 ± 39.3 and 417 ± 296 μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, respectively ( = 11), 995 ± 908 μg/L for methoxyacetylfentanyl, ( = 3), 1,874 ± 1,710 and 6,582 ± 3,252 μg/L for acetylfentanyl and acetyl norfentanyl, respectively ( = 5), 146 ± 318 and 300 ± 710 μg/L for fentanyl ( = 5) and norfentanyl ( = 6), respectively, 84.0 and 23.0 μg/L for furanylfentanyl and furanyl norfentanyl, respectively ( = 1), and 50.5 ± 50.9 μg/L for 4-ANPP ( = 10). Average hair concentrations were 2,670 ± 184 and 82.1 ± 94.7 ng/g for fentanyl and norfentanyl, respectively ( = 2), and 10.8 ± 0.57 ng/g for 4-ANPP ( = 2).
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http://dx.doi.org/10.3389/fchem.2019.00184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454115PMC
April 2019

THC and CBD concentrations in blood, oral fluid and urine following a single and repeated administration of "light cannabis".

Clin Chem Lab Med 2020 04;58(5):682-689

Lambert Center for the Study of Medicinal Cannabis and Hemp, Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, USA.

Background "Light cannabis" is a product legally sold in Europe with Δ9-tetrahydrocannabinol (THC) concentration lower than 0.2% and variable cannabidiol (CBD) content. We studied THC and CBD excretion profiles in blood, oral fluid (OF) and urine after smoking one or four light cannabis cigarettes. Methods Blood, OF and urine samples were obtained from six healthy light cannabis consumers after smoking one 1 g cigarette containing 0.16% THC and 5.8% CBD and from six others after smoking four 1 g cigarettes within 4 h. Sample collection began 0.5 and 4.5 h after smoking one or four cigarettes, respectively. Cannabinoid concentrations were quantified by gas chromatography-mass spectrometry (GC-MS). Results At the first collection, the highest THC and CBD concentrations occurred in blood (THC 7.0-10.8 ng/mL; CBD 30.2-56.1 ng/mL) and OF (THC 5.1-15.5 ng/mL; CBD 14.2-28.1 ng/mL); similar results occurred 0.5 h after the last of four cigarettes in blood (THC 14.1-18.2 ng/mL, and CBD 25.6-45.4 ng/mL) and OF (THC 11.2-24.3 ng/mL; CBD 14.4-37.0 ng/mL). The mean OF to blood ratio ranged from 0.6 to 1.2 after one and 0.6 to 1.9 after four light cannabis cigarettes. THC/CBD ratios in blood and OF were never greater than 2. Urinary 11-nor-9-carboxy-THC concentrations peaked 8 h after one and four cigarettes. Conclusions OF was a valuable alternative to blood in monitoring consumption of light cannabis. Blood and OF THC/CBD concentration ratios, never exceeded 2, possibly providing a useful biomarker to identify light cannabis vs illegal higher THC cannabis use, where THC/CBD ratios are generally greater than 10.
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http://dx.doi.org/10.1515/cclm-2019-0119DOI Listing
April 2020

Environmental microbiology: Perspectives for legal and occupational medicine.

Leg Med (Tokyo) 2018 Nov 24;35:34-43. Epub 2018 Sep 24.

Carabinieri, Reparto Investigazioni Scientifiche di Roma, V.le di Tor di Quinto, 119, 00191 Roma, Italy. Electronic address:

The analysis of microorganism population is crucial in several medical fields. This is especially true in legal and occupational medicine, where the specialist can be asked to perform an evaluation of several environmental matrices. In these two medical fields an accurate microbiological analysis is part of a wide process aimed to the definition of the interactions between human beings and environment. In legal medicine it is important to deserve attention to the identification of microbiological traces in order to better understand past events, while in occupational and preventive medicine the microbiological evaluation of environmental samples is crucial for an effective risk management and the definition of safety procedures. The achievement of these objectives requires the comprehension of microbial biodiversity and not only the identification of few biomarkers. In the present paper, the complexity of this process is highlighted through the presentation of typical scenarios where microorganism population analyses are relevant in legal medicine and occupational medicine. The similarities between the microbiological approach in legal and occupational medicine lead to the sharing of laboratory approaches. A description of technological evolution shows how new protocols and procedures are supporting a wider microbiological comprehension of specimens. The development of molecular tools has opened new opportunities, but it has underlined the need for the implementation of new standardized procedures dedicated to these medical fields, where science and medicine interact with the law. In addition, the rapid evolution of massive parallel sequencing technologies requires the implementation of new bioinformatic tools with a user-friendly interface.
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http://dx.doi.org/10.1016/j.legalmed.2018.09.014DOI Listing
November 2018

MiR-126 in intestinal-type sinonasal adenocarcinomas: exosomal transfer of MiR-126 promotes anti-tumour responses.

BMC Cancer 2018 Sep 17;18(1):896. Epub 2018 Sep 17.

Department of Clinical and Molecular Sciences, Section of Occupational Medicine, Polytechnic University of Marche, Via Tronto 10/a, 60020, Ancona, Italy.

Background: Intestinal-type sinonasal adenocarcinomas (ITACs) are aggressive malignancies related to wood dust and leather exposure. ITACs are generally associated with advanced stage at presentation due to the insidious growth pattern and non-specific symptoms. Therefore, biomarkers that can detect the switch from the benign disease to malignancy are needed. Essential for tumour growth, angiogenesis is an important step in tumour development and progression. This process is strictly regulated, and MiR-126 considered its master modulator.

Methods: We have investigated MiR-126 levels in ITACs and compared them to benign sinonasal lesions, such as sinonasal-inverted papillomas (SIPs) and inflammatory polyps (NIPs). The tumour-suppressive functions of MiR-126 were also evaluated.

Results: We found that MiR-126 can significantly distinguish malignancy from benign nasal forms. The low levels of MiR-126 in ITACs point to its role in tumour progression. In this context, restoration of MiR-126 induced metabolic changes, and inhibited cell growth and the tumorigenic potential of MNSC cells.

Conclusions: We report that MiR-126 delivered via exosomes from endothelial cells promotes anti-tumour responses. This paracrine transfer of MiRs may represent a new approach towards MiR-based therapy.
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http://dx.doi.org/10.1186/s12885-018-4801-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142309PMC
September 2018

Delayed Intracerebral Hemorrhage After Pseudoaneurysm of Middle Meningeal Artery Rupture: Case Report, Literature Review, and Forensic Issues.

World Neurosurg 2018 Sep 30;117:394-410. Epub 2018 Jun 30.

Section of Legal Medicine, Polytechnic University of Marche, Ancona, Italy.

Background: Traumatic pseudoaneurysm of the middle meningeal artery (PMMA) is rare. Its rupture is associated with high mortality, so an early diagnosis is recommended for this risky condition. In the absence of a specific guideline, computed tomography (CT), digital subtraction angiography, and CT angiography (CTA) are proposed for its diagnosis. CTA is the technique of choice even if it is almost never performed, especially in mild head injury. We report a rare case of a delayed rupture of PMMA, analyzed from a forensic point of view.

Methods: Fifteen days after mild blunt head trauma, characterized by temporal fracture and a small hemorrhage near the rim, a wide intraparenchymal hemorrhage (IPH) occurred. The onset of IPH was marked by neurologic deterioration and arm paralysis. Immediate head CT showed IPH, and CTA showed PMMA. Prompt surgery could not help patient survival. The goal of autopsy was to formulate the cause of death and to individuate potential medical negligence.

Results: In the literature, 16 cases of 54 are related to PMMA (26%) and are associated with IPH. IPH can be acute or delayed. Eight cases of acute IPH and 8 cases of delayed IPH (including our case), both coexisting with PMMA, are described. The literature review showed that the association of temporal rim fracture and a small hemorrhage nearby is highly predictive of PMMA formation.

Conclusions: Therefore, in the presence of these 2 risk factors after heat trauma, CTA is strongly suggested.
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http://dx.doi.org/10.1016/j.wneu.2018.06.158DOI Listing
September 2018

Investigation on genetic thrombophilic factors in FFPE autopsy tissue from subjects who died from pulmonary embolism.

Int J Legal Med 2017 Mar 9;131(2):447-458. Epub 2016 Dec 9.

Section of Legal Medicine, Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Ancona, Italy.

Venous thromboembolism (VTE) is a multifactorial disease determined by a combination of inherited and acquired factors. Inherited factors include mutations in the genes coding for coagulation factors, some of which seem to exert a differential influence on the risk of developing deep vein thrombosis (DVT) and pulmonary embolism (PE). In post-mortem studies of subjects who have died from pulmonary embolism (PE), the analysis of the factors that may have augmented the VTE risk is often limited to acquired factors. This is due to the complexity-and sometimes the unfeasibility-of analyzing genetic factors and to insufficient knowledge of their individual roles in PE development. The present study used formalin-fixed paraffin-embedded (FFPE) tissue to investigate a panel of 12 polymorphisms-the largest ever studied-that affect the VTE risk. Tissue samples came from post-mortem examinations performed by the specialists of the Section of Legal Medicine of the Department of Pathology of Marche's Polytechnic University, and by the specialists of Health Care District Hospital of Imola, on 44 subjects who died from PE in the period 1997-2014. All individuals were found to have at least one mutation affecting the VTE risk. The present study demonstrates that genetic analysis can be performed post-mortem and the results are useful for forensic investigations, especially from MTHFR C677T and PAI-1 4G/5G polymorphisms. Broader studies using the techniques described herein are needed to determine the relative influence of the individual polymorphisms and their interaction in PE deaths.
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http://dx.doi.org/10.1007/s00414-016-1508-zDOI Listing
March 2017

When "Chems" Meet Sex: A Rising Phenomenon Called "ChemSex".

Curr Neuropharmacol 2017 ;15(5):762-770

Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome. 0.

Background: The term "chemsex" was coined to indicate the voluntary intake of psychoactive and non psychoactive drugs in the context of recreational settings to facilitate and/or to enhance sexual intercourses mostly among men who have sex with other men (MSM).

Objective: The authors aimed to review the mechanisms of action, the toxicity and the pattern of use and abuse of substances involved in "chemsex" practice together with the sociocultural background underlying it and the health-related consequences that they may have.

Results: Gamma-hydroxybutyrate, gamma-butyrolactone,1,4-butanediol, mephedrone, methamphetamine, sildenafil, tadalafil, vardenafil and alkyl nitrites have been described in their role of "chemsex drugs" including pharmacological action and in their implication to impair capacities to chose sexual partners and consensual sex. Moreover, it has been demonstrated that sexual activity over protracted length of time under the influence of chemsex drugs can result in rectal trauma or penile abrasions and a significant increase of the risk of transmission of sexual transmitted diseases, especially in case of condomless intercourses, which are frequent in this context, representing therefore a serious health threat.

Conclusion: One of the major problems to establish health policy priority interventions for chemsex is the lack of available epidemiological data on the issue. Finally, social actions should be taken in order to break down the barriers that currently exist among chemsex drug users in accessing services, including the shame and stigma often associated with drug use. In conclusion, more specific resources to face high risks of infections and HIV transmission are required in bisexual and homosexual individuals having SUID: sex under the influence of drugs.
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http://dx.doi.org/10.2174/1570159X15666161117151148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771052PMC
March 2018
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