miRNA Dysregulation in Cardiovascular Diseases: Current Opinion and Future Perspectives.

MicroRNAs (miRNAs), small noncoding RNAs, are post-transcriptional gene regulators that can promote the degradation or decay of coding mRNAs, regulating protein synthesis. Many experimental studies have contributed to clarifying the functions of several miRNAs involved in regulatory processes at the cardiac level, playing a pivotal role in cardiovascular disease (CVD). This review aims to provide an up-to-date overview, with a focus on the past 5 years, of experimental studies on human samples to present a clear background of the latest advances to summarize the current knowledge and future perspectives. SCOPUS and Web of Science were searched using the following keywords: (miRNA or microRNA) AND (cardiovascular diseases); AND (myocardial infarction); AND (heart damage); AND (heart failure), including studies published from 1 January 2018 to 31 December 2022. After an accurate evaluation, 59 articles were included in the present systematic review. While it is clear that miRNAs are powerful gene regulators, all the underlying mechanisms remain unclear. The need for up-to-date data always justifies the enormous amount of scientific work to increasingly highlight their pathways. Given the importance of CVDs, miRNAs could be important both as diagnostic and therapeutic (theranostic) tools. In this context, the discovery of "TheranoMIRNAs" could be decisive in the near future. The definition of well-setout studies is necessary to provide further evidence in this challenging field.

New Insight into Mechanisms of Cardiovascular Diseases: An Integrative Analysis Approach to Identify TheranoMiRNAs.

MiRNAs regulate both physiological and pathological heart functions. Altered expression of miRNAs is associated with cardiovascular diseases (CVDs), making miRNAs attractive therapeutic strategies for the diagnosis and treatment of heart diseases. A recent publication defined, for the first time, the term theranoMiRNA, meaning the miRNAs that may be used both for diagnosis and treatment. The use of in silico tools may be considered fundamental for these purposes, clarifying several molecular aspects, suggesting future directions for in vivo studies. This study aims to explore different bioinformatic tools in order to clarify miRNA interactions with candidate genes, demonstrating the need to use a computational approach when establishing the most probable associations between miRNAs and target genes. This study focused on the functions of miR-133a-3p, miR-21-5p, miR-499a-5p, miR-1-3p, and miR-126-3p, providing an up-to-date overview, and suggests future lines of research in the identification of theranoMiRNAs related to CVDs. Based on the results of the present study, we elucidated the molecular mechanisms that could be linked between miRNAs and CVDs, confirming that these miRNAs play an active role in the genesis and development of heart damage. Given that CVDs are the leading cause of death in the world, the identification of theranoMiRNAs is crucial, hence the need for a definition of in vivo studies in order to obtain further evidence in this challenging field of research.

Autopsy Tool in Unknown Diseases: The Experience with Coronaviruses (SARS-CoV, MERS-CoV, SARS-CoV-2).

In the last two decades, three unknown pathogens have caused outbreaks, generating severe global health concerns. In 2003, after nucleic acid genotyping, a new virus was named severe acute respiratory syndrome coronavirus (SARS-CoV). After nine years, another coronavirus emerged in the middle east and was named MERS-CoV (Middle East Respiratory Syndrome-Coronavirus). Finally, in December 2019, a new unknown coronavirus was isolated from a cluster of patients and was named SARS-CoV-2 (COVID-19, coronavirus disease 2019). This review aims to propose a complete overview of autopsy in the three coronaviruses over the past two decades, showing its pivotal role in the management of unknown diseases. A total of 116 studies fulfilled the inclusion criteria: 14 studies were collected concerning SARS-CoV (87 autopsy reports, from Asian and American countries), 2 studies for MERS-CoV (2 autopsy reports, from Middle-East Asian countries), and 100 studies on SARS-CoV-2 (930 autopsy reports). Analyzing the data obtained on COVID-19, based on the country criterion, a large number of post-mortem investigation were performed in European countries (580 reports), followed by American countries (251 reports). It is interesting to note that no data were found from the Oceanic countries, maybe because of the minor involvement of the outbreak. In all cases, autopsy provided much information about each unknown coronavirus. Despite advanced technologies in the diagnostic fields, to date, autopsy remains the gold standard method to understand the biological features and the pathogenesis of unknown infections, especially when awareness of a pathogen is restricted and the impact on the healthcare system is substantial. The knowledge gained through this technique may positively influence therapeutic strategies, ultimately reducing mortality.

Human Brain Injury and miRNAs: An Experimental Study.

Brain damage is a complex dysfunction that involves a variety of conditions whose pathogenesis involves a number of mediators that lead to clinical sequelae. For this reason, the identification of specific circulating and/or tissue biomarkers which could indicate brain injury is challenging. This experimental study focused on microRNAs (miRNAs), a well-known diagnostic tool both in the clinical setting and in medico-legal investigation. Previous studies demonstrated that specific miRNAs (miR-21, miR-34, miR-124, miR-132, and miR-200b) control important target genes involved in neuronal apoptosis and neuronal stress-induced adaptation. Thus, in this experimental setting, their expression was evaluated in three selected groups of cadavers: drug abusers (cocaine), ischemic-stroke-related deaths, and aging damage in elder people who died from other neurological causes. The results demonstrated that the drug abuser group showed a higher expression of miR-132 and miR-34, suggesting a specific pathway in consumption-induced neurodegeneration. Instead, miR-200b and miR-21 dysregulation was linked to age-related cognitive impairment, and finally, stroke events and consequences were associated with an alteration in miR-200b, miR-21, and miR-124; significantly higher levels of this last expression are strongly sensitive for ischemic damage. Moreover, these results suggest that these expression patterns could be studied in other biological samples (plasma, urine) in subjects with brain injury linked to aging, drug abuse, and stroke to identify reliable biomarkers that could be applied in clinical practice. Further studies with larger samples are needed to confirm these interesting findings.

Neuropsychiatric and Behavioral Involvement in AAS Abusers. A Literature Review.

Background and Objectives: Anabolic androgenic steroids (AASs) are a complex group of molecules that include both steroidal androgens and synthetic compounds, derived from testosterone. AASs are commonly used to support pharmacological therapy in cases of primary or secondary hypogonadism, major burns, and neoplastic cachexia. Their prolonged and supra-physiological consumption can provoke several adverse effects on various organs and systems. Among these, the physiopathological mechanisms that induce neuropsychiatric disorders related to AAS abuse are poorly known. For this reason, the proposed review aims to retrace the pathway of action of testosterone to focus on the effects on the central nervous system and specifically highlight the effects of AASs on neuropsychiatric and behavioral functions, as well as on lifestyle. Materials and Methods: This review was conducted using PubMed and Google Scholar databases. On these database websites, we searched for articles from 1 January 1980 to March 2019 using the key terms: "AAS," "Anabolic Androgenic Steroids," "brain," and "neurology." Results: The use of AASs through self-administration yields circulating androgens levels, inducing neuron apoptosis, which is linked to thinner cortex and, in general, less cortical volume. The same alterations affect the putamen. These differences were more evident when correlated with longer use. From a functional point of view, prolonged AAS consumption seemed to be related to lower connectivity between amygdala and frontal, striatal, limbic, hippocampal and visual cortical areas. On the other hand, AAS use seems to negatively condition the positive effects of the sport exercise, reducing its important anti-apoptotic and pro-proliferative functions on the hippocampus, implicated in anxiolytic control. Conclusion: This review clarifies the major aspects of the side effects related to AAS use/abuse highlighting the complex mechanisms on neuropsychiatric and cognitive pathological alterations and also the emotional and behavioral dysfunctions.

Immunodeficiency as a side effect of anabolic androgenic steroid abuse: a case of necrotizing myofasciitis.

Even if there are well-known consequences of anabolic androgenic steroid (AAS) abuse, their full pathway of action is still being investigated. In this context, the presented case report aims to discuss and provide evidence of unusual adverse effects linked to immunodeficiency in an AAS abuser. In fact, this kind of chronic complication, even if not usually considered, may lead sudden death. In this case a 31-year-old aesthetic weightlifter, who presented to the emergency department due to an accidental fall that resulted in left thigh trauma. This subsequently developed into left thigh necrotizing myofasciitis in the following few days. Although surgery and hyperbaric therapy were carried out, the man died. An autopsy with complete biological sampling for toxicological studies was performed. This case highlights the close relationship between AAS abuse and immunodeficiency and highlights it's importance for further studies. However, it should be considered that of all the dangerous effects produced by AAS use, necrotizing fasciitis is not such an unusual consequence.

Occupational exposure to fluoro-edenite and prevalence of anti-nuclear autoantibodies.

An environmental contamination due to an asbestiform mineral fiber, fluoro-edenite (FE), caused a significantly increased mortality rate for malignant mesothelioma in Biancavilla, Italy. Exposure to fluoro-edenite has been associated with inflammatory processes as an early response to inhaled fibers. The aim was to explore prevalence of anti-nuclear autoantibodies (ANA) in a group of construction workers residing and working in the contaminated area. Prevalences for samples positive to ANA were 60% (n = 9) and 13% (n = 2), for exposed and nonexposed, respectively (p-value <0.05), the odds ratio was 9.75 (95% CI: 1.59-59.69). The significance of elevated ANAs in subjects exposed to fibers is unknown; additional studies may provide a better opportunity to establish a correlation between autoimmunity and environmental exposure.

Nandrolone decanoate interferes with testosterone biosynthesis altering blood-testis barrier components.

The aim of this study was to investigate whether nandrolone decanoate (ND) use affects testosterone production and testicular morphology in a model of trained and sedentary mice. A group of mice underwent endurance training while another set led a sedentary lifestyle and were freely mobile within cages. All experimental groups were treated with either ND or peanut oil at different doses for 6 weeks. Testosterone serum levels were measured via liquid chromatography-mass spectrometry. Western blot analysis and quantitative real-time PCR were utilized to determine gene and protein expression levels of the primary enzymes implicated in testosterone biosynthesis and gene expression levels of the blood-testis barrier (BTB) components. Immunohistochemistry and immunofluorescence were conducted for testicular morphological evaluation. The study demonstrated that moderate to high doses of ND induced a diminished serum testosterone level and altered the expression level of the key steroidogenic enzymes involved in testosterone biosynthesis. At the morphological level, ND induced degradation of the BTB by targeting the tight junction protein-1 (TJP1). ND stimulation deregulated metalloproteinase-9, metalloproteinase-2 (MMP-2) and the tissue inhibitor of MMP-2. Moreover, ND administration resulted in a mislocalization of mucin-1. In conclusion, ND abuse induces a decline in testosterone production that is unable to regulate the internalization and redistribution of TJP1 and may induce the deregulation of other BTB constituents via the inhibition of MMP-2. ND may well be considered as both a potential inducer of male infertility and a potential risk factor to a low endogenous bioavailable testosterone.

Effects of Conjugated Linoleic Acid Associated With Endurance Exercise on Muscle Fibres and Peroxisome Proliferator-Activated Receptor γ Coactivator 1 α Isoforms.

Conjugated linoleic acid (CLA) has been reported to improve muscle hypertrophy, steroidogenesis, physical activity, and endurance capacity in mice, although the molecular mechanisms of its actions are not completely understood. The aim of the present study was to identify whether CLA alters the expression of any of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) isoforms, and to evaluate the possible existence of fibre-type-specific hypertrophy in the gastrocnemius and plantaris muscles. Mice were randomly assigned to one of four groups: placebo sedentary, CLA sedentary, placebo trained, or CLA trained. The CLA groups were gavaged with 35 µl per day of Tonalin® FFA 80 food supplement containing CLA throughout the 6-week experimental period, whereas the placebo groups were gavaged with 35 µl sunflower oil each day. Each administered dose of CLA corresponded to approximately 0.7 g/kg or 0.5%, of the dietary daily intake. Trained groups ran 5 days per week on a Rota-Rod for 6 weeks at increasing speeds and durations. Mice were sacrificed by cervical dislocation and hind limb posterior muscle groups were dissected and used for histological and molecular analyses. Endurance training stimulated mitochondrial biogenesis by PGC1α isoforms (tot, α1, α2, and α3) but CLA supplementation did not stimulate PGC1α isoforms or mitochondrial biogenesis in trained or sedentary mice. In the plantaris muscle, CLA supplementation induced a fibre-type-specific hypertrophy of type IIx muscle fibres, which was associated with increased capillary density and was different from the fibre-type-specific hypertrophy induced by endurance exercise (of types I and IIb muscle fibres). J. Cell. Physiol. 232: 1086-1094, 2017. © 2016 Wiley Periodicals, Inc.

Ischemia/Reperfusion Injury following Acute Myocardial Infarction: A Critical Issue for Clinicians and Forensic Pathologists.

Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality. Reperfusion strategies are the current standard therapy for AMI. However, they may result in paradoxical cardiomyocyte dysfunction, known as ischemic reperfusion injury (IRI). Different forms of IRI are recognized, of which only the first two are reversible: reperfusion-induced arrhythmias, myocardial stunning, microvascular obstruction, and lethal myocardial reperfusion injury. Sudden death is the most common pattern for ischemia-induced lethal ventricular arrhythmias during AMI. The exact mechanisms of IRI are not fully known. Molecular, cellular, and tissue alterations such as cell death, inflammation, neurohumoral activation, and oxidative stress are considered to be of paramount importance in IRI. However, comprehension of the exact pathophysiological mechanisms remains a challenge for clinicians. Furthermore, myocardial IRI is a critical issue also for forensic pathologists since sudden death may occur despite timely reperfusion following AMI, that is one of the most frequently litigated areas of cardiology practice. In this paper we explore the literature regarding the pathophysiology of myocardial IRI, focusing on the possible role of the calpain system, oxidative-nitrosative stress, and matrix metalloproteinases and aiming to foster knowledge of IRI pathophysiology also in terms of medicolegal understanding of sudden deaths following AMI.

Lipid peroxidation and apoptotic response in rat brain areas induced by long-term administration of nandrolone: the mutual crosstalk between ROS and NF-kB.

The aim of this study was to evaluate the played by oxidative stress in the apoptotic response in different brain areas of rats chronically treated with supra-physiological doses of nandrolone decanoate (ND). Immunohistochemical study and Western blot analysis were performed to evaluate cells' apoptosis and to measure the effects of expression of specific mediators, such as NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), Bcl-2 (B-cell lymphoma 2), SMAC/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low PI) and VMAT2 (vesicular monoamine transporter 2) on apoptosis. The results of the present study indicate that a long-term administration of ND promotes oxidative injury in rat brain specific areas. A link between oxidative stress and NF-κB signalling pathways is supported by our results. In addition to high levels of oxidative stress, we consistently observed a strong immunopositivity to NF-κB. It has been argued that one of the pathways leading to the activation of NF-κB could be under reactive oxygen species (ROS)-mediated control. In fact, growing evidence suggests that although in limited doses, endogenous ROS may play an activating role in NF-κB signalling, while above a certain threshold, they may negatively impact upon this signalling. However, a mutual crosstalk between ROS and NF-κB exists and recent studies have shown that ROS activity is subject to negative feedback regulation by NF-κB, and that this negative regulation of ROS is the means through which NF-κB counters programmed cells.

Effects of Nandrolone Stimulation on Testosterone Biosynthesis in Leydig Cells.

Anabolic androgenic steroids (AAS) are among the drugs most used by athletes for improving physical performance, as well as for aesthetic purposes. A number of papers have showed the side effects of AAS in different organs and tissues. For example, AAS are known to suppress gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone. This study investigates the effects of nandrolone on testosterone biosynthesis in Leydig cells using various methods, including mass spectrometry, western blotting, confocal microscopy and quantitative real-time PCR. The results obtained show that testosterone levels increase at a 3.9 µM concentration of nandrolone and return to the basal level a 15.6 µM dose of nandrolone. Nandrolone-induced testosterone increment was associated with upregulation of the steroidogenic acute regulatory protein (StAR) and downregulation of 17a-hydroxylase/17, 20 lyase (CYP17A1). Instead, a 15.6 µM dose of nandrolone induced a down-regulation of CYP17A1. Further in vivo studies based on these data are needed to better understand the relationship between disturbed testosterone homeostasis and reproductive system impairment in male subjects.

High risk of pleural plaques and parenchymal abnormalities in women living in Biancavilla (Italy).

Fluoro-edenite is a natural mineral species first isolated in Biancavilla, Sicily, used for construction of houses and roads, with health effects allegedly the same as those of asbestos. The aim of the current study was to evaluate the risks of pleural plaques and parenchymal abnormalities in women living in Biancavilla through a retrospective cross-sectional study. The evaluation pointed out a relative risk of pleural plaques of 39.67 (95% CI: 11.33-138.82) and 27.67 (95% CI: 5.43-141.00) for parenchymal abnormalities as well. These findings have prompted urge to extend the screening on the possible abnormalities of the respiratory tract to all Biancavilla's population, particularly in those aged more than 30 years.

Early effects of fluoro-edenite: correlation between IL-18 serum levels and pleural and parenchymal abnormalities.

Fluoro-edenite (FE) is a natural mineral asbestos-like fibrous species first isolated in Biancavilla, Sicily. In order to clarify potential involvement of IL-18 in the pathogenesis of FE-induced chest abnormalities, we analyzed IL-18 serum levels in FE-exposed workers (FEEW) and correlated them with pleural and parenchymal abnormalities. A total of 21 FEEWs, residing in Biancavilla for >30 years, with a working seniority of 17 ± 6.1 years were examined. High-resolution computed tomography scans revealed low grade of fibrosis in 8 (38%) FEEWs, and pleural plaques (PPs) in 13 (62%) FEEWs. The mean IL-18 level was 203.13 ± 90.43 pg/ml. Pearson correlation showed a significant association (p < 0.0001) between IL-18 and PPs and parenchymal abnormality scores. Data suggest a potential role of IL-18 in the pathogenesis of these diseases.

Natural carcinogenic fiber and pleural plaques assessment in a general population: A cross-sectional study.

Natural carcinogenic fibers are asbestos and asbestiform fibers present as a natural component of soils or rocks. These fibers are released into the environment resulting in exposure of the general population. Environmental contamination by fibers are those cases occurred in: rural regions of Turkey, in Mediterranean countries and in other sites of the world, including northern Europe, USA and China. Fluoro-edenite(FE) is a natural mineral species first isolated in Biancavilla, Sicily. The fibers are similar in size and morphology to some amphibolic asbestos fibers, whose inhalation can cause chronic inflammation and cancer. The aim of the current study is to assess the presence and features of pleural plaques (PPs) in Biancavilla's general population exposed to FE through a retrospective cross-sectional study. All High-Resolution Computed Tomography (HRCT) chest scans carried out between June 2009 and June 2015 in Biancavilla municipality hospital site (exposed subjects) were reviewed. The exposed groups were 1:1 subjects, matched according to age and sex distributions, with unexposed subjects (n.1.240) randomly selected among HRCT chest scans carried out in a Hospital 30km away from Biancavilla. Subjects from Biancavilla with PPs were significantly more numerous than the control group ones (218 vs 38). Average age of either group was >60 years; the age of exposed subjects was significantly (p=0.0312) lesser than the unexposed group. In exposed subjects, in most PPs thickness ranged between 2 and 4.9cm(38%, n=83); while in unexposed ones PPs thickness was less than 2cm (55%, n=21). As to the size of PPs in exposed subjects, in most cases it ranged between 1cm and 24% of chest wall (53%, n=116); while in unexposed ones the size of PPs was lesser than 1cm (23%, n=58). Among exposed subjects, 36 cases (17%) PPs were detected with calcification, whereas in unexposed ones only three (8%) presented calcification. 137 lung parenchymal abnormalities were observed in exposed group; whereas, 12 lung parenchymal involvement were registered in unexposed subjects. The RR for PPs is 6,74 CI 95% (4,47-9,58) p<0,0001 in the exposed population. These findings, suggested the urge to extend the screening on the possible involvement of the respiratory tract to all Biancavilla's population, particularly in those aged more than 30. Besides, it seems essential to start indoor monitoring Biancavilla's municipality.

Sheep lymph-nodes as a biological indicator of environmental exposure to fluoro-edenite.

A significantly increased incidence of pleural mesothelioma in Biancavilla (Sicily, Italy) has been attributed to exposure to fluoro-edenite (FE), a fibrous amphibole extracted from a local stone quarry. The lymph-nodes draining the pulmonary lobes of sheep grazing around the town were examined, to gain insights into fibre diffusion. The pasture areas of six sheep flocks lying about 3km from Biancavilla were located using the global positioning system. The cranial tracheobronchial and one middle mediastinal lymph-node as well as four lung tissue samples were collected from 10 animals from each flock and from 10 control sheep for light and scanning electron microscopy (SEM) examination. The lymph-nodes from exposed sheep were enlarged and exhibited signs of anthracosis. Histologically, especially at the paracortical level, they showed lymph-follicle hyperplasia with large reactive cores and several macrophages (coniophages) containing grey-brownish particulate interspersed with elements with a fibril structure, forming aggregates of varying dimensions (coniophage nodules). Similar findings were detected in some peribronchiolar areas of the lung parenchyma. SEM examination showed that FE fibres measured 8-41µm in length and 0.4-1.39µm in diameter in both lymph-nodes and lung tissue. Monitoring of FE fibres in sheep lymph-nodes using appropriate techniques can help set up environmental pollution surveillance.

Italian law on medically assisted reproduction: do women's autonomy and health matter?

BACKGROUND: In Italy in 2004, a very restrictive law was passed on medically assisted reproduction (MAR) (Law 40/2004) that placed Italy at the most conservative end of the European spectrum. The law was widely criticized and many couples seeking MAR brought their cases before the Italian Civil Courts with regard to pre-implantation genetic diagnosis (PGD), donor insemination and the issue of consent. Ten years on, having suffered the blows of the Italian Constitutional Court, little remains of law 40/2004. DISCUSSION: In 2009, the Constitutional Court declared the maximum limit of the number of embryos to be produced and transferred for each cycle (i.e. three), as stated in the original version of the law, to be constitutionally illegitimate. In 2014, the same Court declared as unconstitutional the ban on donor insemination, thus opening the way to heterologous assisted reproduction. Heterologous MAR is therefore perfectly legitimate in Italy. Finally, in 2015 a further ruling by the Constitutional Court granted the right to access MAR to couples who are fertile but carriers of genetic diseases. However, there is still much room for criticism. Many couples and groups are still, in fact, excluded from MAR. Same-sex couples, single women and those of advanced reproductive age are, at the present time, discriminated against in that Italian law denies these subjects access to MAR. The history of Law 40/2004 has been a particularly troubled one. Numerous rulings have, over the years, dismantled much of a law constructed in violation of the rights and autonomy of women and couples. However, a number of troubling issues still exist from what is left of the law and the debate is still open at national and transnational level regarding some of the contradictions and gaps in the law highlighted in this article. Only by abolishing the final prohibitions and adopting more liberal views on these controversial yet crucial issues will Law 40/2004 become what it should have been from the start, i.e. a law which outlines the 'rules of use' of MAR and not, as it has been until now, a law of bans which sets limits to the freedom to reproduce.

Neurotoxicity by synthetic androgen steroids: oxidative stress, apoptosis, and neuropathology: A review.

Anabolic-androgenic steroids (AAS) are synthetic substances derived from testosterone that are largely employed due to their trophic effect on muscle tissue of athletes at all levels. Since a great number of organs and systems are a target of AAS, their adverse effects are primarily on the following systems: reproductive, hepatic, musculoskeletal, endocrine, renal, immunological, infectious, cardiovascular, cerebrovascular, and hematological. Neuropsychiatric and behavioral effects as a result of AAS abuse are well known and described in the literature. Mounting evidence exists suggesting that in addition to psychiatric and behavioral effects, non-medical use of AAS carries neurodegenerative potential. Although, the nature of this association remains largely unexplored, recent animal studies have shown the recurrence of this AAS effect, ranging from neurotrophin unbalance to increased neuronal susceptibility to apoptotic stimuli. Experimental and animal studies strongly suggest that apoptotic mechanisms are at least in part involved in AAS-induced neurotoxicity. Furthermore, a great body of evidence is emerging suggesting that increased susceptibility to cellular oxidative stress could play a pivotal role in the pathogenesis of many neurodegenerative disorders and cognitive impairment. As in other drug-evoked encephalopathies, the key mechanisms involved in AAS - induced neuropathology could represent a target for future neuroprotective strategies. Progress in the understanding of these mechanisms will provide important insights into the complex pathophysiology of AAS-induced neurodegeneration, and will pave the way for forthcoming studies. Supplementary to abandoning the drug abuse that represents the first step in reducing the possibility of irreversible brain damage in AAS abusers, neuroprotective strategies have to be developed and implemented in future.

Anabolic-androgenic steroid use and psychopathology in athletes. A systematic review.

The use of anabolic-androgenic steroids (AASs) by professional and recreational athletes is increasing worldwide. The underlying motivations are mainly performance enhancement and body image improvement. AAS abuse and dependence, which are specifically classified and coded by the DSM-5, are not uncommon. AAS-using athletes are frequently present with psychiatric symptoms and disorders, mainly somatoform and eating, but also mood, and schizophrenia-related disorders. Some psychiatric disorders are typical of athletes, like muscle dysmorphia. This raises the issue of whether AAS use causes these disorders in athletes, by determining neuroadaptive changes in the reward neural circuit or by exacerbating stress vulnerability, or rather these are athletes with premorbid abnormal personalities or a history of psychiatric disorders who are attracted to AAS use, prompted by the desire to improve their appearance and control their weights. This may predispose to eating disorders, but AASs also show mood destabilizing effects, with longterm use inducing depression and short-term hypomania; withdrawal/discontinuation may be accompanied by depression. The effects of AASs on anxiety behavior are unclear and studies are inconsistent. AASs are also linked to psychotic behavior. The psychological characteristics that could prompt athletes to use AASs have not been elucidated.