Search

Personalized medicine (PM) is becoming increasingly important in contemporary clinical and research scenarios. In the context of PM, pharmacogenomics and pharmacogenetics are aimed at the genetic personalization of drug response. Extrinsic and intrinsic factors may explain interindividual variability in drug response. Among such factors, age seems to specifically intervene to modulate drug response since normal developmental changes may influence the exposure-response relation. Consequently, the potential benefit of pharmacogenomics (PGx) in the paediatric population is considerable. However, many challenges still exist in incorporating PGx into clinical practice. In fact, drug prescribing in the paediatric population is often based on extrapolation from clinical trials conducted on adults as there is often a lack of paediatric data. Children are not just 'small adults', as they have their own pharmacological characteristics in terms of drug metabolism and efficacy, adverse drug reactions and toxicity. Although children might potentially benefit from such research, many ethical concerns arise at the intersection of the spheres of drug development and genetic testing. Children require particular attention because of their vulnerability both in research and the clinical applications of PGx; furthermore, children range from preterm newborns and neonates to infants and toddlers and to adolescents, thus forming a further heterogeneous target group. In this paper, we focus on some ethically relevant concerns (i.e., informed consent, stigmatization, ancillary information) that might arise as a result of the possible application of PGx tests in both paediatric practice and research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Cross-border reproductive care (CBRC) is a multifaceted phenomenon. It may involve both the movement of patients to undertake assisted reproductive treatment through technologies otherwise denied and the movement of assisted reproduction professionals, egg and sperm donors and surrogates, as well as the importing and exporting of gametes. The reasons for CBRC vary between countries. In this global landscape, the search for donor oocytes is one of the main reasons for patients seeking cross-border reproductive care. The egg market has led to ethical and political concerns about the means of procuring donor oocytes, the possibility of exploiting economically underprivileged women mainly in poor countries, and the issue of the responsibility and accountability of medical doctors and fertility clinics. Ethical concerns relating to international egg donation are discussed with special focus on the issues of compensation/ reimbursement, the health and welfare of women donating eggs, informed consent to donation, the possible conflict of interest for physicians involved in egg donation programmes, and equity in the distribution of economic resources from CBRC. Finally, the need for global solutions to this global issue is underlined.

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.

The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long - term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies.

Cardiac muscle necrosis is associated with inflammatory cascade that clears the infarct from dead cells and matrix debris, and then replaces the damaged tissue with scar, through three overlapping phases: the inflammatory phase, the proliferative phase and the maturation phase. Western blotting, laser confocal microscopy, Raman microscopy are valuable tools for studying the inflammatory response following myocardial infarction both humoral and cellular phase, allowing the identification and semiquantitative analysis of proteins produced during the inflammatory cascade activation and the topographical distribution and expression of proteins and cells involved in myocardial inflammation. Confocal laser scanning microscopy (CLSM) is a relatively new technique for microscopic imaging, that allows greater resolution, optical sectioning of the sample and three-dimensional reconstruction of the same sample. Western blotting used to detect the presence of a specific protein with antibody-antigen interaction in the midst of a complex protein mixture extracted from cells, produced semi-quantitative data quite easy to interpret. Confocal Raman microscopy combines the three-dimensional optical resolution of confocal microscopy and the sensitivity to molecular vibrations, which characterizes Raman spectroscopy. The combined use of western blotting and confocal microscope allows detecting the presence of proteins in the sample and trying to observe the exact location within the tissue, or the topographical distribution of the same. Once demonstrated the presence of proteins (cytokines, chemokines, etc.) is important to know the topographical distribution, obtaining in this way additional information regarding the extension of the inflammatory process in function of the time stayed from the time of myocardial infarction. These methods may be useful to study and define the expression of a wide range of inflammatory mediators at several different timepoints providing a more detailed analysis of the time course of the infarct.

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-α (Tumor Necrosis Factor α), IL-1β (Interleukin- 1β) 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 injury.

Although a decline in the all-cause and cardiac mortality rates following myocardial infarction (MI) during the past 3 decades has been reported, MI is a major cause of death and disability worldwide. From a pathological point of view MI consists in a particular myocardial cell death due to prolonged ischemia. After the onset of myocardial ischemia, cell death is not immediate, but takes a finite period of time to develop. Once complete myocytes' necrosis has occurred, a process leading to a healed infarction takes place. In fact, MI is a dynamic process that begins with the transition from reversible to irreversible ischemic injury and culminates in the replacement of dead myocardium by a fibrous scar. The pathobiological mechanisms underlying this process are very complex, involving an inflammatory response by several pathways, and pose a major challenge to ability to improve our knowledge. An improved understanding of the pathobiology of cardiac repair after MI and further studies of its underlying mechanisms provide avenues for the development of future strategies directed toward the identification of novel therapies. The chronologic dating of MI is of great importance both to clinical and forensic investigation, that is, the ability to create a theoretical timeline upon which either clinicians or forensic pathologists may increase their ability to estimate the time of MI. Aging of MI has very important practical implications in clinical practice since, based on the chronological dating of MI, attractive alternatives to solve therapeutic strategies in the various phases of MI are developing.

Amniotic fluid embolism (AFE) is a rare, catastrophic syndrome that presents during labor and delivery or immediately postpartum. Efforts to develop a clinical diagnostic test are ongoing; however the diagnosis still relies on rapid bedside evaluation and depends on the exclusion of other diseases. Classically, the diagnosis was made at autopsy, with the demonstration of squamous cells or debris in the maternal pulmonary vasculature. Clinico-pathological correlations have strengthened the evidence for a role of the immune system in the pathogenesis of AFE and have lead to the development of new laboratory tests, such as the serum tryptase and complement measurements, which should provide scientific support for the presumed immunological mechanism of AFE. Recently, studies on the effects of amniotic fluid (AF) on platelet - neutrophil aggregation and neutrophil/platelet activation have opened new insight in the comprehension of the mechanisms underlying AFE, suggesting that a severe inflammatory response might have a paramount causative role, so opening new diagnostic and therapeutic perspectives. Considering the complex interplay between the different mechanisms involved in the pathogenesis of AFE, the diagnosis still arises from a complex diagnostic puzzle in which clinical, macroscopic, laboratory, histological and immunohistochemical data converge toward AFE.

Cocaine is a widely abused drug responsible for the majority of deaths ascribed to drug overdose. Many mechanisms have been proposed in order to explain the various cocaine associated cardiovascular complications. Conventionally, cocaine cardiotoxicity has been thought to be mediated indirectly through its sympathomimetic effect, i.e., by inhibiting the reuptake and thus increasing the levels of neuronal catecholamines at work on adrenoceptors. Increased oxidative stress, reactive oxygen species, and cocaine-induced apoptosis in the heart muscle have suggested a new way to understand the cardiotoxic effects of cocaine. More recent studies have led the attention to the interaction of cocaine and some metabolites with cardiac sodium, calcium and potassium channels. The current paper is aimed to investigate the molecular mechanisms of cocaine cardiotoxicity which have a specific clinical and forensic interest. From a clinical point of view the full knowledge of the exact mechanisms by which cocaine exerts cardio - vascular damage is essential to identify potential therapeutic targets and improve novel strategies for cocaine related cardiovascular diseases. From a forensic point of view, it is to be underlined that cocaine use is often associated to sudden death in young, otherwise healthy individuals. While such events are widely reported, the relationship between cardiac morphological alterations and molecular/cellular mechanisms is still controversial. In conclusion, the study of cocaine cardiovascular toxicity needs a strict collaboration between clinicians and pathologists which may be very effective in further dissecting the mechanisms underlying cocaine cardiotoxicity and understanding the cardiac cocaine connection.

Drug use is seen more as an individualistic behaviour and is therefore not readily conceived of from a population perspective. There is general recognition of several phases and degrees of drug abuse, from initiation and early-use patterns to long-term chronic use. Cocaine and its derivative "crack" cocaine provide an example of both the globalization of substance use and the cyclical nature of drug epidemics. Cocaine is a powerful CNS (Central Nervous System) stimulant but exerts its action in a several types of adverse health effects, including acute toxic effects (i.e. overdose, accidental injury and violence), dependence, cardiovascular disease, cirrhosis, bloodborne bacterial and viral infections, and mental disorders. Of interest, many people who use Cocaine will use also other drugs; therefore, ascribing adverse health effect to a certain drug might be difficult. Any mucous membrane can act as a port of entry for cocaine and the systemic effect is greatly influenced by the route and speed of administration. The effects of Cocaine mainly depend on the user's addiction, the dose received and the mode of assumption. Laws restricting the availability of cocaine saw a decrease in consumption in these countries until the 1960s. The number of cocaine users worldwide ranged from 14 million to 21 million (0.3-0.5% of the population aged 15-64 years). The largest market was North America, then western and central Europe and South America.

Cocaine-induced cardiovascular disorders such as hypertension, thrombosis, myocardial dysfunction, cardiac dysrhythmias and endocarditis have received widespread attention in the context of cocaine abuse. The number of sudden deaths from cardiac causes, including myocardial infarction, ventricular tachyarrhythmia or aortic dissection, is also increasing. This manuscript will highlight the recent employment of study about cocaine cardiotoxicity and oxidative stress. Evidence has revealed that cardiac oxidative stress is a prominent early event of cocaine administration, which severely compromises the cardiac antioxidant cellular system and causes cardiac antioxidant cellular system injuries. Oxidative damage such as peroxidation of membrane phospholipids and depletion of nonenzymatic antioxidants such as glutathione have been found in the myocardium of chronic cocaine-treated animals and in patients. The data indicate that cocaine administration compromised the heart's antioxidant defense system. About the mechanisms involved in the cellular damage, the evidence that cocaine causes apoptosis in the heart comes from in vivo study. In animals model after short-term and long term-cocaine administration, the investigators demonstrates the role of Reactive Oxygen Species as a trigger of cardiac injury induced by cocaine. Cocaine also increased infiltration of inflammatory cells in the heart, and apoptotic cells were predominantly found near inflammatory cells. The role of oxidative stress in cocaine-induced apoptosis in the heart is wide studied and documented.

Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse.

The anabolic-androgenic steroids (AAS) are all synthetic derivates of testosterone and are commonly used as sport performance enhancers in athletes. The heart is one of the organs most frequently affected by administration of anabolic steroids. A direct myocardial injury caused by AAS is supposed to determine marked hypertrophy in myocardial cells, extensive regional fibrosis and necrosis. A number of excellent studies, using animal models, were performed to evaluate the cardiac effects of AAS. It is known that exogenous administration induced cardiac hypertrophy in vitro and in vivo, and when combined with exercise, anabolic steroid use has been shown to change exercise-induced physiological cardiac hypertrophy to pathophysiological cardiac hypertrophy. However the molecular mechanisms are still poorly understood. It's described that sudden cardiac death, myocardial infarct; ventricular remodelling and cardiomyopathy do to AAS is related to apoptosis and oxidative stress when associated with exercise. Mechanical stimuli and circulating humoral factors (TNF-α, HSP-70, IL-1β) released by the heart and peripheral organs are responsible. Testosterone and derivates can work through genomic (activation of specific androgen receptor, interaction with coactivators and co-repressors transcription factors, gene regulation) and non-genomic mechanism (membrane-receptor-second messenger cascades). Chronic AAS abuse results in different patterns of pathologic alterations, which depend on type, dose, frequency, and mode of use. The difficulty in interpreting experimental data on animals (mice and rats) lies in the diversity of experiments (the diversity of substances, which show different properties, different mice / rats by sex and age, duration of treatment with AAS, dosages used, type, scope and exercise duration).

In the athletes the wide use of Anabolic Androgenic Steroids (AAS) cause series damage in various organs, in particular, analyzing the liver, elevation on the levels of liver enzymes, cholestatic jaundice, liver tumors, both benign and malignant, and peliosis hepatis are described. A prolonged AAS administration provokes an increase in the activities of liver lysosomal hydrolases and a decrease in some components of the microsomal drug-metabolizing system and in the activity of the mitochondrial respiratory chain complexes without modifying classical serum indicators of hepatic function. Liver is a key organ actively involved in numerous metabolic and detoxifying functions. As a consequence, it is continuously exposed to high levels of endogenous and exogenous oxidants that are by-products of many biochemical pathways and, in fact, it has been demonstrated that intracellular oxidant production is more active in liver than in tissues, like the increase of inflammatory cytokines, apoptosis and the inhibitors of apoptosis NF- κB and Heat Shock Proteins.

Anabolic - androgenic steroids (AAS) were originally developed to promote growth of skeletal muscle. AAS abuse is commonly associated with bodybuilders, weightlifters, and other athletes. The issue of AAS toxicity is not yet completely understood since the adverse effects outline a varied scenario with side effects reported affecting many organs and systems in humans. The true incidence of AAS related medical problems is not known, due to several drawbacks in human studies. The entity of side effects depends on the sex, the dose, the duration of treatment, whether they are taken during exercise training or under sedentary conditions, and the susceptibility of the individuals themselves to androgen exposure partly depending on genetic factors. Both the acute and the chronic effects can lead to toxicity, but generally the serious and even fatal effects depend on the time and the duration of AAS administration. A limitation of human studies is represented by the fact that information about the intake of steroids are, generally, self reported and it is hardly possible to assess the exact dosage. AAS are often used in combination with other dugs or substances, so it is difficult to separate their toxic effects from those caused by the other drugs abused. Hence experimental studies conducted on animal models are mandatory to investigate the mechanisms underlying to AAS toxicity and the organ alterations due to these substances. Finally, clinicians should be aware of the complex and varied pattern of toxicity so as to be able to perform correct diagnoses and treatments.

Few animal model studies have been conducted in order to evaluate the impact of androgenic anabolic steroids (AAS) supraphysiological doses on the cardiovascular system and myocardial injury. Twenty-five male CD1 mice (8-10 weeks old; 35g initial body weight) were randomized into three AAS treated groups and two control groups. The AAS mice received intramuscular Nandrolone Decanoate (DECA-DURABOLIN), vehicled in arachidis oil, for 42 days, twice per week, with different dosages, studying plasma lipid analysis, cardiac histopathological features, cardiac β (1) adrenergic receptor expression, and the effects of the myocardial expression of inflammatory mediators (IL-1β, TNF-α) on the induction of cardiomyocytes apoptosis (HSP 70, TUNEL), using proteomic and immunohistochemical analysis. The mice had free movements in their animal rooms (two groups) or exercised by running on a motor-driven treadmill the others three groups. Recurring high dose AAS administration and physical training in mice produce significant increase in body weight and for total cholesterol. A moderate increase of the heart weight, cardiac hypertrophy and wide colliquative myocytolysis, were observed in high dose AAS administration and physical training group. The expression of HSP70 and inflammatory cytokine IL-1β, increased in the three AAS-treated groups. TNF- α showed a more extensive expression in the AAS-high dose group. A significant apoptotic process randomly sparse in the myocardium was described. Our data support the hypothesis that the combined effects of vigorous training, anabolic steroid abuse and stimulation of the sympathetic nervous system, may predispose to myocardial injury.

Studies conducted in humans or in animals explored the presence, nature and potential causes of 3,4-methylenedioxymethamphetamine (MDMA) toxicity. According to literature, there are four principal types of such serious toxicity: hepatic, cardiovascular, cerebral and hyperpyrexic. The molecular mechanisms involved in the genesis of these toxic effects are not yet fully clarified, but the oxidative stress, excitotoxicity, and mitochondrial dysfunction appear to be causal events that converge to mediate MDMA-induced toxicity. Studies conducted on animals demonstrated that the acute administration of MDMA elicits cardiovascular responses that are similar to those elicited by d-amphetamine, and that these responses appear to involve catecholaminergic and non-catecholaminergic-dependent mechanisms. Although there is undeniable evidence of MDMA-induced cardiac toxicity, the mechanism responsible remains to be clarified. While many reports both in humans and in animals have demonstrated MDMA-induced liver damage, the underlying mechanism accounting for hepatic toxicity is poorly understood. Various mechanisms may contribute to MDMA-induced liver toxicity, including the metabolism of MDMA, the increased efflux of neurotransmitters, the oxidation of biogenic amines, and hyperthermia. The molecular mechanisms involved in the genesis of these toxic effects are not yet fully clarified, but the oxidative stress, excitotoxicity, and mitochondrial dysfunction appear to be causal events that converge to mediate MDMA-induced neurotoxicity, as measured by loss of various markers of dopaminergic and serotonergic terminals. The evidence is overwhelming that MDMA produces acute and long-lasting toxic anatomic effects in animals and humans. Anatomical and functional MDMA consequences must be better understood.