Synthetic androgen and new psycho-active compounds (smart drugs) abuse and dependance. Neuropathological and toxicological findings, with an approach designed for the future

Self-administration of high doses of synthetic androgen (SA) is widespread among young people, to enhance physical aspect and gain muscle mass. The mechanisms of SA toxicity are not yet completely understood while the adverse effects of SA are known to be complex and likely to arise from effects on several organ systems in humans. Moreover, the negative health consequences of SA have many variable as the sex, dose and the duration of administration and many of the side effects may be reversible. The genomic action of Androgenic Receptors is modulated by a large variety of coregulators, which are proteins that target gene expression by enhancing (coactivator) or restraining (corepressor) transcription. SA may also have direct rewarding or hedonic properties, mediated not so much by their genomic effects (although these may well contribute) but more directly by the effects of SA and their metabolites on plasma membranes. As for other steroids, non-genomic androgen effects typically involve the fast induction of conventional second messenger signal transduction cascades, including increases in cytosolic calcium and activation of protein kinase A, protein kinase C, and MAPK (mitogen- activated protein kinase), leading to diverse cellular effects including smooth muscle relaxation, neuromuscular and junctional signal transmission and neuronal plasticity. Most nongenomic effects involve a membrane receptor, and putative binding sites are described for androgens. The use of AAS among young people has been associated with abuse of additional substances in several cross-sectional survey studies. More often new psychoactive substances that comprise of natural vegetable and synthetic compounds containing both active ingredients such as caffeine, taurine, ephedrine - essentially stimulating substances - and hallucinogenic substances are frequently used in association with SA especially in non athletes frequenting fitness or sport centers. Recently, all over the world the availability of new products sold as “Legal Highs” or “Herbal Highs” (psychoactive compounds not included in the list of Controlled Substances) has been described. This new heterogeneous class of products is also named “Smart Drugs” (SD) and includes several types of preparations such as teas, herbal mixtures, incenses, ambient scents, energetic drinks and food additives. Because of the lack of legal regulations to their marketing, SDs are easily available in common shops such as herbalist shops, in the so- called “Smart Shops” or through e-commerce. It is widely reported that the use of SDs is associated with dissociate mental states and mild psychedelic sensations. Moreover, SDs may induce amphetamine-like effects on both fatigueand mood as well as performance enhancement

An immunohistochemical study of the diagnostic value of TREM-1 as marker for fatal sepsis cases

Triggering receptor expressed on myeloid cells-1 (TREM-1) is produced and up-regulated by exposure of myeloid cells to lipopolysaccharides or other components of either bacterial or fungal origin, which causes it to be strongly expressed on phagocytes that accumulate in inflamed areas. Because TREM-1 participates in septic shock and in amplifying the inflammatory response to bacterial and fungal infections, we believe it could be an immunohistochemical marker for postmortem diagnosis of sepsis. We tested the anti-TREM-1 antibody in 28 cases of death by septic shock and divided them into two groups. The diagnosis was made according to the criteria of the Surviving Sepsis Campaign. In all cases, blood cultures were positive. The first group was comprised subjects that presented high ante-mortem serum procalcitonin and the soluble form of TREM-1 (s-TREM-1) values. The second group comprised subjects in which s-TREM-1 was not measured ante-mortem. We used samples of brain, heart, lung, liver and kidney for each case to test the anti-TREM-1 antibody. A semiquantitative evaluation of the immunohistochemical findings was made. In lung samples, we found immunostaining in the cells of the monocyte line in 24 of 28 cases, which suggests that TREM-1 is produced principally by cells of the monocyte line. In liver tissue, we found low TREM-staining in the hepatocyte cytoplasm, duct epithelium, the portal-biliary space and blood vessel. In kidney tissue samples, we found the TREM-1 antibody immunostaining in glomeruli and renal tubules. We also found TREM-1 staining in the lumen of blood vessels. Immunohistochemical staining using the anti-TREM-1 antibody can be useful for postmortem diagnosis of sepsis

Commentary on Raphael's The Transfiguration

Historical sources about Raphael’s death provide different hypotheses about its cause. Continuous fever is the only symptom described. Raphael’s lucidity in managing his last affairs exclude syphilis, made widespread by the French army. The same applies to malaria, which was endemic in Rome. Not even the reference to bloodletting helps us,1 as it was a longstanding therapy to reduce fever. The most prudent hypothesis is an infectious diseas

Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction

Oxidative stress in heart failure or during ischemia/reperfusion occurs as a result of the excessive generation or accumulation of free radicals or their oxidation products. Free radicals formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks. Oxidative stress is a condition in which oxidant metabolites exert toxic effects because of their increased production or an altered cellular mechanism of protection. In the early phase of acute heart ischemia cytokines have the feature to be functional pleiotropy and redundancy, moreover, several cytokines exert similar and overlapping actions on the same cell type and one cytokine shows a wide range of biological effects on various cell types. Activation of cytokine cascades in the infarcted myocardium was established in numerous studies. In experimental models of myocardial infarction, induction and release of the pro-inflammatory cytokines like TNF-&alpha (Tumor Necrosis Factor &alpha), IL-1&beta (Interleukin- 1&beta) and IL-6 (Interleukin-6) and chemokines are steadily described. The current review examines the role of oxidative stress and pro-inflammatory cytokines response following acute myocardial infarction and explores the inflammatory mechanisms of cardiac injur

Cardiovascular Involvement in Sepsis.

This special issue wants to contribute to a better understanding of cardiac involvement in sepsis. Sepsis is a complex syndrome that has recently been defined as “life-threatening organ dysfunction due to a dysregulated host response to infection”. It should be considered a major public health problem since it affects millions of people worldwide each year, and it accounts for most deaths in critically ill patients. The presence of myocardial dysfunction in sepsis is associated with higher mortality. A great attention has been dedicated to improving our knowledge and understanding of the intricate mechanisms underlying sepsis. However, data from the literature suggest the need to implement strategies to reliably measure sepsis morbidity and mortality. In fact, methods based on analyses of insurance claim data using sepsis-specific codes or separate codes for infection and organ dysfunction are unreliable in informing or measuring the effects of policy changes, and the postmortem diagnosis of sepsis is often elusive since postmortem investigations lack certain pathognomonic macroscopic and histopathological findings. From a morphological and diagnostic point of view, the term “septic disease” has been created to describe the cardiac involvement in the syndrome. However, this definition, rather than describing a morphological finding, was instead referred to the clinical setting. Although in recent years the concept of septic cardiomyopathy has evolved and it involves pathological alterations of myocardial cells in response to the multiplicity of acting mechanism of damage, the importance of structural changes during sepsis is often overlooked. In patients with sepsis, death is usually the result of a progressive multiorgan dysfunction, overlooking the primary infection through the hyperinflammation. The cardiac involvement as fundamental part of septic multiorgan dysfunction syndrome has been discussed for a long time

Response to the letter by Meng-jun Zhan et al. regarding the paper \u201cA technical report from the Italian SARS-CoV-2 outbreak. Postmortem sampling and autopsy investigation in cases of suspected or probable COVID-19\u201d

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A theoretical timeline for myocardial infarction: immunohistochemical evaluation and western blot quantification for Interleukin-15 and Monocyte chemotactic protein-1 as very early markers

Background: Experimental and human studies have demonstrated that innate immune mechanisms and consequent inflammatory reaction play a critical role in cardiac response to ischemic injury. Thus, the detection of immuno-inflammatory and cellular phenomena accompanying cardiac alterations during the early inflammatory phase of myocardial infarction (MI) may be an excellent diagnostic tool. Current knowledge of the chronology of the responses of myocardial tissue following the occurrence of ischemic insult, as well as the existence of numerous studies aiming to identify reliable markers in dating MI, induced us to investigate the myocardial specimens of MI fatal cases in order to better define the age of MI. Methods: We performed an immunohistochemical study and a Western blot analysis to evaluate detectable morphological changes in myocardial specimens of fatal MI cases and to quantify the effects of cardiac expression of inflammatory mediators (CD15, IL-1 β, IL-6, TNF-α, IL-15, IL-8, MCP-1, ICAM-1, CD18, tryptase) and structural and functional cardiac proteins. Results: We observed a biphasic course of MCP-1: it was strongly expressed in the very early phase (0-4 hrs), to diminish in the early period (after 6-8 hrs). Again, our choice of IL-15 is explained by the synergism with neutrophilic granulocytes (CD15) and our study shows the potential for striking cytokine synergy in promoting fast, local neutrophil response in damaged tissues. A progressively stronger immunoreaction for the CD15 antibody was visible in the areas where the margination of circulating inflammatory cells was detectable, up to very strong expression in the oldest ones (>12 hours). Further, the induction of CD15, IL-15, MCP-1 expression levels was quantified by Western blot analysis. The resultswereasfollows:IL-15/β-actin 0.80, CD15/ β-actin 0.30, and MCP-1/β-actin 0.60, matching perfectly with the results of immunohistochemistry. Control hearts from traumatic death cases did not show any immunoreactivity to the pro-inflammatory markers, neither were there any reactions in Western blot analysis. Conclusions: Essential markers (i.e. IL-15, MCP-1) are suitable indicators of myocardial response to ischemic insult involving very early phase reaction (inflammatory response and cytokine release). In the very near future, proteomics may help clinicians and pathologists to better understand mechanisms relating to cardiac repair and remodeling and provide targets for future therapies

Post-mortem diagnosis of intravascular large B-cell lymphoma

Intravascular large B-cell lymphoma (IVLBCL) is a rare (<1%), typically aggressive extranodal variant of mature non-Hodgkin B-cell lymphoma. IVLBCL is characterized by malignant lymphoid cells lodged within blood vessels, particularly capillary channels. Herein, we present a case of a 50-year-old man with a history of myeloradiculitis (∼1 year) and paraparesis requiring hospitalization. During the course of his hospital stay, computed tomography (CT), magnetic resonance imaging, CT-positron emission tomography, and biopsy failed to establish a diagnosis. The patient died 2 months later from bilateral pneumonia. Postmortem examination was undertaken to determine the cause of death. Histologic sections of the patient’s brain, heart, lung, and liver showed aggregates of highly atypical cells bearing enlarged, pleomorphic, and hyperchromatic nuclei. Strong intravascular positivity for CD45 and CD20 markers indicated the cells were of B-cell origin, supporting a diagnosis of IVLBCL

Autopsy findings in COVID-19-related deaths. A literature review

Although many clinical reports have been published, little is known about the pathological post-mortem findings from people who have died of the novel coronavirus disease. The need for postmortem information is urgent to improve patient management of mild and severe illness, and treatment strategies. The present systematic review was carried out according to the Preferred Reporting Items for Systematic Review (PRISMA) standards. A systematic literature search and a critical review of the collected studies were conducted. An electronic search of PubMed, Science Direct Scopus, Google Scholar, and Excerpta Medica Database (EMBASE) from database inception to June 2020 was performed. We found 28 scientific papers; the total amount of cases is 341. The major histological feature in the lung is diffuse alveolar damage with hyaline membrane formation, alongside microthrombi in small pulmonary vessels. It appears that there is a high incidence of deep vein thrombosis and pulmonary embolism among COVID-19 decedents, suggesting endothelial involvement, but more studies are needed. A uniform COVID-19 post-mortem diagnostic protocol has not yet been developed. In a time in which international collaboration is essential, standardized diagnostic criteria are fundamental requirements

Comparing extrapolations of the coronal magnetic field structure at 2.5 solar radii with multi-viewpoint coronagraphic observations

The magnetic field shapes the structure of the solar corona but we still know little about the interrelationships between the coronal magnetic field configurations and the resulting quasi-stationary structures observed in coronagraphic images (as streamers, plumes, coronal holes). One way to obtain information on the large-scale structure of the coronal magnetic field is to extrapolate it from photospheric data and compare the results with coronagraphic images. Our aim is to verify if this comparison can be a fast method to check systematically the reliability of the many methods available to reconstruct the coronal magnetic field. Coronal fields are usually extrapolated from photospheric measurements typically in a region close to the central meridian on the solar disk and then compared with coronagraphic images at the limbs, acquired at least 7 days before or after to account for solar rotation, implicitly assuming that no significant changes occurred in the corona during that period. In this work, we combine images from three coronagraphs (SOHO/LASCO-C2 and the two STEREO/SECCHI-COR1) observing the Sun from different viewing angles to build Carrington maps covering the entire corona to reduce the effect of temporal evolution to ~ 5 days. We then compare the position of the observed streamers in these Carrington maps with that of the neutral lines obtained from four different magnetic field extrapolations, to evaluate the performances of the latter in the solar corona. Our results show that the location of coronal streamers can provide important indications to discriminate between different magnetic field extrapolations.Comment: Accepted by A&A the 20th of May, 201