ISSN (Print): 1389-2010
ISSN (Online): 1873-4316
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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316
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Davide Prosperi Department of Biotechnology and Bioscience University of Milan Bicocca Milano Italy
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Special Issue Submission
"Current Pharmaceutical Biotechnology presents the latest developments in the area of biotechnology. This is strongly recommended."
PREECLAMPSIA - AETIOPATHOGENESIS AND CLINICAL MANAGEMENT
Guest Editor(s): Marzena Laskowska
Tentative Publication Date: March, 2018
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DIAGNOSTIC AND PROGNOSTIC INSIGHTS OF BIOMARKERS IN CARDIOVASCULAR DISEASES
Guest Editor(s): Michael Behnes, Ibrahim Akin
It was a great experience for me working with Bentham Science Publishers because of the following reasons:
-High quality services
-Great and kind cooperation and collaboration
Dr. Helmy Selman(The CIVF Center Doha Center Clinic Hospital Doha, Qatar)
Has contributed: Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature
6 Abstract Ahead of Print are available electronically
26 Articles Ahead of Print are available electronically
An established and validated HcAI definition to guide both daily clinical practice and infection surveillance is needed.
HcAIs are defined as infections that occur during hospitalization or in a place of care and assistance, neither present clinically,
nor in incubation, at the time of admission or including those which occur after discharge, despite being causally traceable by
incubation time, etiologic agent and modality of transmission to the same hospitalization.
In recent years, the number of HcAIs has increased; as a result of the increase in the age of the population, the greater number
of examinations and invasive procedures are being carried out during hospitalization and, finally, the increasingly frequent
development of phenomena of antibiotic -resistance.
The incidence of a HcAI depends strongly on the type of hospital, the patient population studied, the definition of HcAI
adopted and the detection systems used. It is therefore a phenomenon of broad relevance not only clinical, but also economic
and social if only the costs, associated with the HcAI that the literature documents and reports as extremely high, are taken into
account. For example, in the European Union, additional health costs and loss of productivity of at least 1.5 billion euros are
estimated each year, due to infections caused by antimicrobial resistant bacteria.
Moreover, a HcAI needs agreed-upon and uniform nomenclature to avoid potentially confusing terminology, such as
“community onset,” “community associated,” “outpatient infections,” “infections among nonhospitalized patients,” “nonnosocomial,”
and “infections in the first 48 hours of hospitalization” .
The Study on the Efficacy of Nosocomial Infection Control (SENIC), conducted on some USA hospitals between 1975 and
1976, is the only study that has estimated the rate of hospital infections at the national level. In this study, the rate of infected
patient amounted to 5.2% while the rate of infections was observed to be 6.6%. Thereafter many prevalence studies have been
conducted in the USA and in Europe so as to estimate the impact of HcAI. In 2002 in the USA, the HAI rate was set at 4.5%,
which means that every day, 9.3 out of 1000 patients are at risk for HcAI which results in 1.7 million infected patients. The
European Center for Disease Prevention and Control (ECDC) has estimated that around 4.544.100 HcAI episodes occur in
Europe, with an estimated prevalence of 7.6% between 1995 and 2010, i.e. around 37.000 deaths in a year. It was estimated that
more than 220.000 HcAI episodes occur in Canada every year which lead to 8.500-12.000 deaths every year.
In the USA, there are many institutions and societies that act at the national level to control the HAI, to name but a few:
CMS (Center for Medicare and Medicaid Services), CDC (Center for Disease Control), OSHA (Occupational Safety and Health
Administrations), QIO (Quality Improvement Organization), etc.
The CMS is an institution that deals with the governmental healthcare system and that, in recent years, started coordinating
the HAI control.
In 2007, it developed a program to improve the quality of assistance: the Plan to Implement a Medicare Hospital Value-
Based Purchasing Program. This project involves the use of incentives for the high-performance actions in several domains
such as patient safety, the treatment process, the outcomes, the patient experience, and the efficacy of coordinated treatments.
Despite this, from the CMS 2008 inspections conducted on about 70% of the hospitals to evaluate the acknowledgement of the
new guidelines, it came out that the HcAI were within the first 12 principal deficiencies. In 2008, the CMS in cooperation with
the CDC has developed a new payment of benefits plan. Some indicators (the PoA indicators) have been identified so as to
evaluate if a certain primary or secondary diagnosis was made at the time of admission.
The activity of all these institutions implemented the construction of the 2009 Action Plan. This project represents a real
attack, at all levels, to the HcAI and all the main organizations in the field of health took part in its preparation. The activity of
the Action Plan was articulated in 5 working groups and had seven main goals to achieve in five years, each goal had its indicator.
This special issue has the primary aim of evaluating the risks of acquiring a HcAI. As its secondary objectives, the special
issue aims at evaluating if the introduction of the preventive actions, therapies and new measures of clinical risk management in
the HcAI control has efficacy in reducing the HcAI prevalence.
The papers collected in this special issue aim at identifying the epidemiology of HcAI, the main related risk factors and the
possible use of antibiotic-therapies or the ongoing related-measures to prevent and/or to treat the related adverse events.
Over the years, inappropriate use and abuse of antibiotic drugs around the world have led to the selection of multi-resistant
pathogenic microorganisms making infections a major health problem due to relative increases in costs, prolongation of hospitalizations,
as well as morbidity and mortality risk. This is one of the themes dealt in the paper by Orsi et al.; they present a
retrospective matched cohort study conducted through the analysis of hospital admissions at Sant’Andrea Teaching Hospital in
Rome from April to December 2015. The healthcare facility has 450 beds, 13,729 annual admissions, 6,264 Day Hospital hospitalizations
and 1,076,469 outpatient accesses, showing an annual HAI prevalence of 6.34%. The present study demonstrates
once again that HAIs caused by multidrug-resistant organisms are associated with higher mortality, longer hospital stays, and
increased costs. Economic assessment may provide valuable information for implementing health policies and prevention of
healthcare-associated infections due to alert organisms .
CRBSIs are defined as a bloodstream infection originated from an intravenous catheter. Intravascular device use is frequently
associated with local and systemic infectious complications, such as insertion site infection, septic thrombophlebitis,
endocarditis, bacteriemia, sepsis, metastatic infections (pulmonary abscess, cerebral abscess, pancreatic abscess, osteomyelitis,
arthritis, endophthalmitis) and intravascular catheter-related bloodstream infections (CRBSIs). Caroleo et al. analyzed this important
topic describing four cases of O. anthropi CRSBIs occurred almost simultaneously in Oncology Unit, the goal of this
paper is to establish the role of the root cause analysis and clinical risk management in adverse events’ prevention and in
healthcare quality implementation. The experience presented by these authors demonstrated that clinical audit and root cause
analysis process, by determining the infection source, led to adopt prevention measures: a) in order to avoid the catheters contamination,
a single-dose of flush sterilization solution has been used; b) both hand hygiene accuracy and information regarding
guidelines-based CRBSIs prevention and surveillance strategies among healthcare workers have been implemented .
The Bambino Gesù Hospital’s (OPBG) experience about the improvement of HcAI control could lead to a reduction in expenditure
related to prolonged hospitalization, outcomes and compensation for claims. In fact, according to several international
studies, health-care associated infections have a notable impact both in social and economic terms. The aim of the study carried
out in a pediatric hospital was to evaluate the effectiveness of the introduction of the mortality review committee on the improvement
of the assistance provided at the OPBG in the period examined, especially related to preventable deaths that follow
HAIs. Since 2010, as shown in the present study and in other works that evaluated HAI prevalence, in the OPBG, there was a
very low rate of mortality due to infections associated with health-care. In fact, possible areas of intervention were identified
that could potentially lead to an improvement in the quality of care provided. These improvements involved the prevention and
management of healthcare-related infections .
Quality of care and related analysis of litigation of a high-income hospital such as the Umberto I general hospital in Rome is
the aim of the paper by La Russa et al. . The Umberto I general hospital counts on 1,200 beds for a total of 38,000 annual
hospitalizations, 27,000 Day Hospital admissions and 2,303,046 outpatient accesses. In particular, the authors carried out a
study on HAI claims with the aim of outlining a methodological approach to the litigation management and characterizing the
economic impact of infections on health facilities resources. The proposed approach is based on an integrated evaluation of
HAI claims by determining the risk of loss and technical estimates. The first task was to create a scoring system based on objective
parameters evaluable from the medico-legal point of view, the Advanced Loss Eventuality Assessment (ALEA). For the
determination of the technical estimates, it instead adopted a systematic procedure based on common evaluation systems of
personal impairment in order to quantify the claim reserves on current liabilities for claims reported but not yet settled .
Prevention and surveillance programs showed to be helpful tools for infections control, having allowed to increase patients’
safety and healthcare system quality. Quality of medical care is defined as the capacity of the healthcare system to achieve several
medical and non-medical goals. In this regard, several studies suggested a key role of quality medical records in determining
medical care process, risk management and preventing liability. The problem of the HcAI has been largely debated in the
last years. Albano et al., presented a number of cases in which surgical site infections (SSIs) were analyzed. SSIs are frequent
complications that occur in 2-5% of patients who undergo surgery. More than 60% of SSIs have been estimated to be preventable
by using evidence-based guidelines. Guidelines-based medical records filling was demonstrated to reduce HAIs-related
litigation, improve patient medical care appraisal, therefore HS quality. The most frequent type of infections, SSIs and isolate
meticillin-resistant Staphylococcus Aureus (MRSA), are more likely to be seen as preventable, and, in a judicial trial, medical
records are the only elements able to demonstrate standard care adhesion for infection control .
Di Paolo et al. discussed the forensic perspectives in approaching HcAIs, ranging from legal responsibilities of the
healthcare professional and the duty of care they have incumbent upon them in ensuring prevention of HcAIs, to the role of
forensic pathologists in assessing the cause of death in cases of HcAIs fatalities and, finally, ethical issues such as the emerging
role of patients and families’empowerment and autonomy in prevention and control of HcAIs. Authors concluded that HcAI are
a major problem for patient safety in every health-care facility and system around the world and their control and prevention
represent a challenging priority for health care institutions and workers committed to making health care safer. The burden of
HcAI implies longer hospital stay, increased morbidities, additional financial burden, high costs for patients and their families,
and excess deaths. Clinicians are at the forefront in the war against HcAIs, however, also forensic pathologists have a remarkable
Finally, Albolino et al. presented the Italian law that establishes that health professionals should comply, as far as possible
and within the bounds of each specific case, with the recommendations included in the guidelines drafted by public and private
healthcare organizations and institutions, as well as scientific societies and technical-scientific associations registered on the list compiled and regulated by Ministerial decree and updated every two years. In the absence of recommendations, healthcare professionals
should follow good clinical practice.
According to the 2011 definition provided by the Institute of Medicine (IOM), clinical guidelines are “Statements that include
recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment
of the benefits and harms of alternative care options”. The definition of good clinical practice (GCP) is more complicated.
In Italy, a Ministerial Decree refers to “an international ethical and scientific quality standard for designing, recording and reporting
trials that involve the participation of human subjects”. The European Union Network for Patient and Quality of Care is
drawing up a project to define and implement patient safety procedures, in conjunction with the Italian National Agency for
Regional Health Services (AGENAS) as associated partner and National Contact Point. Patient safety practices have been defined
as “those that reduce the risk of adverse events related to exposure to medical care across a range of diagnoses or conditions”.
Patient safety practices are transversal to clinical pathologies, the literature indicates the list of the ones strongly recommended
as evidence-based, thus these are clearly indicated to be applied in the framework of the new Italian law. In conclusion,
the law delineates a global patient care system, pointing to the opportunities for engagement and partnering of the healthcare
system with health institutions, professional health associations, health training institutions, health-associated civil society
groups, and citizens .
In this special issue, researchers discussed clinical, pharmacological, economic and juridical aspects of relevance for advancing
in these particular topics. HcAIs represent a major public health problem, widespread in patients of all ages. Of every
hundred hospitalized patients, seven in developed and ten in developing countries can acquire one of the HAIs Studies dedicated
to advanced techniques will provide systematic reviews of new horizons opened in HcAIs, to understand and explain
clinical events of social-economic relevance.
The Mental Health is stressed in the definition of Health given by World
Health Organization´s (WHO): "Health is a state of complete physical, mental
and social well-being and not merely the absence of disease or infirmity" .
According to WHO, there are more than 450 million people worldwide suffering
from different mental disorders including schizophrenia, depression, intellectual
disabilities and drug abuse disorders . Although they have a vast
range of symptoms, combination of abnormal thoughts, emotions, behavior
and relationships with others is generally observed. Around 20% of the world's
children and adolescents have mental disorders or problems and more than 350
million people across the world, of all ages and from all communities, suffer from depression .
Regarding dementia, is a syndrome in which there is a deterioration of cognitive function beyond the expected from normal
ageing, it affects around 47 million people worldwide, with nearly 60% living in low- and middle-income countries. Dementia
is caused by a variety of diseases and injuries, such as Alzheimer's disease or stroke (WHO, 2018).
Most of mental disorders can be successfully treated by conventional therapies but the discrimination and stigma of patients
with psychiatric disorders perpetuates and demands for more attention from all the mental health professionals in order to
change attitudes and enhance the efficiency of services and therapies.
It is consensual that an equilibrated diet is a key factor for the healthy status of an individual, not only physically but also in
what concerns to mental health.
Several studies have been dedicated to the relationship between diet and mental disorders [4-10] Jacka et al., 2011; Allen
et al., 2014; Tampubolan and Hanandite, 2014; Morris, 2016; Jebena et al., 2016). In a study carried out by Jacka et al. ,
people with better quality diets were less likely to be depressed, whereas a higher intake of processed and unhealthy foods was
associated with increased anxiety. Moreover, it has also been observed strong evidence for preventive effects on dementia of
vitamin E, B vitamins, and n-3 fatty acids and deleterious effects of saturated fat in this syndrome .
This thematic issue is focused in the existing body of evidence which supports that food or particular food components can
enhance mental health or protect from psychiatric disorders. In this line, this thematic issue is composed of important contributions
on this topic. Due to the interest and diversity of the received papers, we have separated in two parts (PART 1 and PART
2), wherein each one will describe the diverse scope between the food and the human health
Thus, the first paper of this thematic issue entitled “Food Components with Potential to be Used in the Therapeutic Approach
of Mental Diseases”. This review compiles the main evidences from scientific studies on the most promising food components,
as part of diet or dietary supplements, that constitute a valid alternative or a complement of the traditional drug treatments.
These food components include vitamins, fatty acids, bioactive peptides, probiotics, carotenoids, polyphenols, saponins
and creatine. Results of in vitro and in vivo animal studies, of randomized and placebo control trials, and systematic reviews
have been addressed. The most recent advances were discussed, namely regarding mechanisms of action of the compounds
responsible for their biological activities (e.g. anti-oxidative properties, neuronal protection and anti-inflammatory). Authors
concluded that is required more research to prove the therapeutic potential of the food components based on scientific evidence
and intervention studies to demonstrate the improvement of neuronal and cognitive impairments.
The second review of the thematic issue entitles “Food with Influence in the Sexual and Reproductive Health”. This paper
focuses in two prevalent conditions in general population, infertility and sexual dysfunction. These conditions have multifactorial
etiology and affect both men and women. Data on the factors that most influence both female and male sexual and reproductive
function were discussed. These factors include general nutritional status, specific foods (e.g. dairy food), nutrients and
other food components and dietary supplements.
It was concluded that the food insufficiency was associated with increased sexual risk behaviours more relevant in women,
while in men, obesity showed a negative influence in male fertility. Moreover, the consumption of trans-fatty acids, high glycemic
index food, high carbohydrate diet and high animal protein intake was associated with low fertility while consumption of
vegetable proteins, antioxidants, omega-3 and omega-6 fatty acids and low glycemic index food was associated with improvement
of fertility. According to the authors further studies are required to clarify the association between food/food components
and sexual and reproductive Health, to be able to improve the treatment of patients with sexual and/or reproductive dysfunctions.
The third review (“Does diet affect the symptoms of ADHD?”) of this thematic issue is dedicated to one common psychiatric
diagnosis in childhood and adolescence, Attention Deficit Hyperactivity Disorder (ADHD). Although the conventional treatment
is psychopharmacological, it originates several undesirable side effects. Therefore, the aim of this review paper is to compile
information on dietary patterns of individuals with ADHD diagnosis, current treatments recommended in individuals with
this diagnosis and dietary factors possibly implicated in the etiology and treatment of this disorder.
Authors reported that there is still lack of evidence on the role of omega-3 PUFAs and vitamin supplementation in the effective
therapeutic approach of this disorder. In this line, data on elimination diets were unclear as to the benefits provided to individuals
with ADHD. One of the results indicated that children with ADHD are less likely to engage in healthy lifestyle behaviors
than non-ADHD children. Authors mentioned that the effects of unhealthy diet patterns in ADHD individuals are not yet
fully understood, however children with ADHD may benefit from a healthy lifestyle.
Finally, in the fourth review paper (“Dietary Patterns: A New Therapeutic Approach for Depression?”), the relationship
between the most common mental disorder, depression, and dietary patterns is addressed. Studies published between 2010 and
2018 and focusing on the impact of dietary patterns in depression and depressive symptoms were discussed. The goal is to
evaluate if there is enough evidence on the dietary cost-effective intervention in depression. This is a subject of high importance
due to the large-scale impact of this mental disorder. The paper concluded that, although etiological pathways are unknown,
there is a well-established association between dietary patterns and depression. In fact, it was reported that healthier dietary
patterns, can play a significant role in the prevention and adjunctive therapy of depression and depressive symptoms.
The consumption of fruits, vegetables, lean meats, nuts and whole grains, and with low intake of processed and sugary
foods was inversely associated with depression and depressive symptoms. Although it is difficult to infer causality because
most of the studies were of cross-sectional design, a randomized controlled trial presented similar results.
Authors highlight the need of large scale randomized clinical trials to confirm the association between lower risk of depression
and depressive symptoms and high-quality dietary patterns.
In the second last decade of the last century circulating extracellular RNA (exRNA)-
proteolipid complexes have been identified in cancer patients. It has been hypothesized that
they mediate host-tumor interactions and specific exRNAs have been shown to be useful
tumor markers. Meanwhile, extracellular nucleic acids were demonstrated to trigger
inflammation and accordingly to promote inflammatory diseases such as cancer, rheumatoid
arthritis, and atherosclerosis. Moreover, exRNA has been identified as “natural foreign
surface” initiating blood coagulation and hence thrombus formation, and to trigger edema
formation. Neutrophil extracellular traps (NETs), which were initially thought to have
beneficial functions by trapping bacteria and limit their dissemination, are now known to
trigger pathological situations. In a model of experimental heart transplantation promoting
exRNA degradation has not been only demonstrated to be safe but to counteract graft
rejection. Accordingly, extracellular nucleic acids present promising new drug targets for
treatment of a multitude of burdening diseases. The purpose of this issue is to summarize the
functions of extracellular nucleic acids in chronic and acute diseases disclosing them as
specific drug targets. Moreover, the nature of pharmaceutical drugs required for treating acute
diseases on the one hand, and more chronic diseases on the other hand will be outlined.
Food Science is a modern, multidimensional, rapidly developing scientific field which is continuously and drastically promoting
significant and innovative scientific advances that strongly reinforce human public health and quality of life. In the last
few decades, there is plenty of substantial evidence that several bioactive food components may exert beneficial effects against
diverse chronic diseases by preventive and/or therapeutic mechanisms of action [1-3]. Notably, it should be noted that more
than 60% of the currently available drugs in medicine have been directly or indirectly derived by naturally occurring sources
such as foods, plants and herbs [1-3]. In this aspect, Food Science cooperatively utilizes modern methodological techniques and
cutting edge technologies based on diverse basic sciences such as molecular biology, biotechnology, biochemistry, physiology
and epidemiology. In view of the above considerations, the purpose of this special issue is to highlight recent advances in the
multidimensional field of Food Science that collectively promote human public health and quality of life.
Medicinal Chemistry and Drug Design scientific domains have been currently focused on drug-like compounds of natural
origin, e.g. naturally-derived molecules from foods, plants and herbs that are used as lead compounds for discovering novel,
more effective drug candidates with less adverse effects in order to be introduced in the clinical practice. In this aspect, at the
first part of this special issue, Pontiki et al. present in depth, from a medicinal chemistry and pharmacological point of view, the
multiple biological activities of cinnamate hybrids analogues, such as anti-Alzheimer, anticancer, cardioprotective, antiviral and
antimalarial activities . In a second review article, Mantzorou and Giaginis critically analyze, at a clinical level, the currently
existing clinical trials that have evaluated the efficacy of supplementing cranberry products against urinary tract infections in
different human subpopulations . The authors conclude that cranberry supplementation can safely be suggested as complementary
therapy in women with recurrent urinary tract infections, whereas no conclusive and precise results have currently
been obtained concerning other human subpopulations, especially in human populations at increased risk for contracting urinary
tract infections .
Medical and Molecular Biology scientific domains have also been focused on natural-derived drugs that are currently used
in the clinical practice, as well as natural-derived drug-like compounds, evaluating their biological activity against several
chronic diseases. In this aspect, Kontos et al. assessed the molecular effects of treatment of human colorectal cancer cells with
doxorubicin, a 14-OH derivative of the natural product daunorubicin, and common chemotherapeutic drugs . They found
significant alterations in the expression levels of BCL2 family genes favoring apoptosis and/or particular proapoptotic transcripts
. In another study, Mavrogiannis et al. investigated the effects of vinca alkaloids (vincristine, vinblastine, and vinorelbine)
on miRNA expression of breast cancer cells . This study supports substantial evidence for the possible involvement
of miR-222-3p in breast cancer cell apoptosis, triggered by vincristine, vinblastine, and vinorelbine . Moreover,
Kalantzis et al. evaluated the effect of chemotherapeutic agents, Docetaxel and Mitoxantrone, on the expression of human LDopa
decarboxylase in human prostate and breast cancer cell lines . L-Dopa decarboxylase has been implicated in the pathophysiological
mechanisms of several human cancers. Interestingly, Docetaxel is a semi-synthetic analogue of Paclitaxel, an
extract from the bark of the rare Pacific yew tree Taxus brevifolia, and Mitoxantrone is an anthraquinone derivative bearing
polyamine side chains that can be considered as a partial analog of anthracyclines which are extracted from Streptomyces bacterium.
This study supports substantial evidence for the possible involvement of L-Dopa decarboxylase expression in Docetaxel
and Mitoxantrone induced cytotoxicity and apoptosis . In conclusion, all the above studies cooperatively reinforce the multidimensional
advancements of Food Science that significantly promote human public health and quality of life.
Preeclampsia, a unique human pregnancy disorder, is a major cause of maternal and fetal mortality and
morbidity worldwide. It remains amongst the biggest challenges in obstetrics, but its precise
aetiopathogenesis is still unclear.
Although the main symptom is hypertension, preeclamptic woman manifests the change in many
organs. PE is characterized by an increased vascular resistance, increased activation of the coagulation
system, and reduction of intravascular volume, injury of vascular endothelium, leading to a reduced
perfusion of all maternal organs, including the uterus, kidney, brain and placenta. Severe cases may
include eclamptic seizures, placental abruption, premature labour, intracranial haemorrhage, DIC,
HELLP syndrome, renal and hepatic failure. Severe preeclampsia is always a life threatening human
pregnancy complication. Preeclampsia affects not only the mother but also fetus. IUGR affects
approximately 13 to 60% of infants born from preeclamptic pregnancies.
Currently, no definitive treatment or effective prophylaxis for preeclampsia are available. Delivery still
remains the only curative treatment in cases of severe preeclampsia, but is not always advantageous for
the fetus. The decision is always very difficult because preterm birth may result in many health
consequences for the child.
The aim of this special issue is exploration of aetiopathogenesis of preeclampsia as well as best practices
update and current clinical management of severe preeclampsia, eclampsia and HELLP syndrome.
The understanding the etiological determinants of preeclampsia may lead to new therapeutic
approaches and is essential for effective therapies and lowering maternal and fetal mortality and
morbidity related to these serious pregnancy complications.
Along with the increasing prevalence of cardiovascular and immunological disorders, in a continuously-
ageing population, our understanding of the precise mechanisms that regulate cellular complex
biochemical environments is increasing. Cellular networks, pathways and biochemical codes are being
deciphered, shedding lights on novel therapeutic routes. In this context, inflammation and dysregulated
immune system represent a true cellular model that links the pathophysiology of cardiovascular disease
and the fine tuning of all the mechanisms that orchestrate the cellular systems. This Special Issue is
composed of important contributions on the topic.
The first manuscript addresses an important immunological disease, such as Common variable immunodeficiency
(CVID), the most frequent symptomatic antibody deficiency in adults, in which the
humoral immune impairment exposes patients to a wide spectrum of clinical manifestation, including recurrent infections. Interestingly,
patients with CVID can present with inflammatory, autoimmune disease, hematologic disease and cancers. Varricchi
and collaborators  present interesting results from 58 patients diagnosed with CVID and treated with regular immunoglobulin
replacement therapy who underwent gastrointestinal endoscopic examination for the evaluation of gastroduodenal
manifestations of their CVID. Histopathologic findings revealed a high prevalence of chronic inflammatory gastrointestinal
disorders (chronic gastritis, chronic duodenitis, increasing intraepitelial lymphocytes, and the absence of plasma cells) that are
not responsive to the immunoglobulin replacement therapy. This observation points out that in CVID patients there is a more
complex immune dysregulation rather than a true humoral immunity deficiency. Indeed, these patients could represent a real in
vivo model to deeply study immune system activation, autoimmunity and inflammation. In this context, in the second article, dr
Pecoraro and colleagues  explored the ability of a simple screening test, the Calculated Gobulin (CG), to be effective in the
early detection of antibody deficiency, in order to reduce diagnostic delays as well as the healthcare costs of specific immunoglobulin
dosage. The CG derives from the difference between total protein and albumin, and a ROC curve analysis-derived cutoff
of 19 g/l was able to detected patients with IgG lower than 600 mg/dl with a sensitivity of 70% and a specificity of 75%.
Inflammation plays a major role also in the manuscript authored by Pasqua and coworkers , that addresses mechanisms
of hypertension, the most prevalent cardiovascular disorder. Here, the authors describe in details the role of NLRP (nucleotide
binding oligomerization domain Leucine-rich repeat) in the pathophysiology of arterial hypertension. NLRPs are members of
pattern recognition receptors (PRR) that have the ability to activate immune cells detecting PAMPs (pattern associated molecular
patterns) and DAMPs (damage associated molecular patterns). In the context of the danger-model of hypertension, priming
hypertensive stimuli could promote the activation of the NLRP3-inflammosome that maintains a low-grade of sterile inflammation
in a vicious circle that sustains hypertension itself, thus leading to organ damages.
Despite the role of Chemokines in inflammation has been extensively underscored, Sara Paccosi and Astrid Parenti  dissect
the role of chemokine pathways in modulating vascular growth mechanisms. In particular, the family of CC-Chemokines
directly interacts with vascular cells, endothelial cells, vascular smooth muscular cells (VSMC), fibroblasts, platelets, erythrocytes,
and glomerular renal cells in a leukocyte independent-way, being involved in compensatory vascular remodeling such as
angiogenesis, atherosclerosis, arteriogenesis. For example, the CCL-2/CCR2 axis plays an important role in restenosis and
plaque formation, with a direct effect on VSMC proliferation. The authors focused on Atypical Chemokine Receptors Families
(ACKRs), chemokine receptors that were found to have an important scavenger function in regulating chemokine trafficking,
and could be considered an interesting potential therapeutic target.
Finally, two complementary and extensive reviews point out the crucial role of the endothelial progenitor cells (EPCs), a
subunit of mononuclear cells (MNCs), in the angiogenesis and remodeling processes, with a special focus as potential therapeutic
targets. Guerra and collaborators  investigate the precise role of the circulating EPCs in the remodeling mechanism involved
in pulmonary vascular diseases. Pulmonary arterial hypertension (PAH) is characterized by circulating progenitor recruitment,
enhanced angiogenesis and endothelial cell dysfunction that lead to increasing vascular resistances. Manipulating the
VEGF (vascular endotelial grow factor) signaling pathway to stimulate endothelial vascular growth seems to be a promising venate the angiogenic activity. The exhaustive review of Moccia and coworkers  illustrates how the Ca2+ toolkit, the “signalosome”
that regulates the intracellular Ca2+ concentration, drives proliferation, tube formation and neovessel formation, in
the ECFCs cells, a subset of EPCs that possesses high intrinsic clonal potential. All the signaling components (channels, transporters,
pumps and receptors) of the Ca2+toolkit can be tuned and genetically manipulated to improve the vascular regenerative
potential. This systematic review offers a complete survey of the signaling cascade that from VEGF and Stromal cell-derived
factor-1a (SDF-1a) leads to oscillation of intracellular Ca2+ concentrations in peripheral blood and umbilical cord blood-derived
ECFCs, triggering store operated Ca2+entry (SOCE). Arachidonic-acid and nicotine acid adenine dinucleotide phosphate
(NAAP) could stimulate Ca2+ release from the endolysosomal compartment and activate ECFC proliferation, supported by TRP
In conclusion, all the manuscripts of this Special Issue offer different views of the complex mechanisms that regulate inflammation
and cardiovascular diseases, from basic science to clinical works, focusing on the special approach that regenerative
medicine and genetic manipulation have opened. These observations should open new routes in the knowledge of different
conditions and new promising therapeutic targets.
The mechanism of RNA interference (RNAi) mediated by small non-coding RNAs (ncRNAs) was
discovered only two decades ago, and research into this field has already achieved therapeutical results
by the development of a small interfering RNA (siRNA)-based drug for the treatment of the Hereditary
Transthyretin Amyloidosis, an autosomal dominant disease . Moreover, microRNAs (miRNAs)
known to trigger the RNAi pathway in human cells have also shown to be useful biomarkers for disease
diagnosis and therapy response [2-4]. Nowadays, ncRNAs are recognized to be important
transcriptional modulators not only capable of suppressing but also of promoting gene expression. This
mechanism, referred to as RNA-mediated gene activation (RNAa), is triggered by small activating
RNA (saRNA) molecules that bind to complementary gene sequences and activate transcription [5-9].
Recent research into RNAa has started to unravel the underlying basis linked to saRNA-based activation
phenomena and enabled the design of saRNAs with ability to regulate the expression of target genes in different cells types
[10-13], even being in the process of developing a RNAa therapy against hepatocellular carcinoma [14,15]. Similarly to siRNAs,
short activating RNAs might be used as therapeutic agents for treatment of different diseases, associated in this last case
with the occurrence of loss of function mutations and/or haploinsufficiencies [8,16]. In the near future, it is expected that versatile
delivery systems consisting of siRNA/saRNA-based drugs enable the setup of personalized therapeutic treatments and targeted
molecular therapies, thereby opening exciting new possibilities in clinical medicine and pharmaceutical biotechnology.
In this thematic issue, Drs. Yoon and Rossi  provided a comprehensive overview about the RNAa mechanism, methodologies/
insights for the design and delivery of saRNAs, intracellular functioning and chemical modifications to increase the
oligonucleotide's resistance to nuclease degradation. This work is an analytical overview that focuses on the potential that
RNAa have for the development of therapeutic strategies. Moreover, canonical and non-canonical mechanisms involving
saRNA-mediated gene activation phenomena are also illustrated here.
In the next article, Setten et al.  described the progress of MTL-CEBPA (MiNA Therapeutics, UK), the first saRNAtargeting
drug currently tested in clinical trials (Phase I). Remarkably, this oligonucleotide can be used to induce targeted expression
of the CCAAT/enhancer-binding protein alpha (CEBPα) gene, a known tumor suppressor capable of modulating transcriptional
activity in hepatic cells . In this work, the authors considered the reasons for which MTL-CEBPA represents a
promising saRNA drug against hepatocellular carcinoma, thereby opening the door to the development of new therapeutic
agents in the treatment of patients with cancer and other diseases.
Finally, Drs. Li and Hu  reviewed the state of the research in the RNAa field and underlie the potential of saRNAs to act
as gene modulators, with special emphasis on their use in the treatment of kidney diseases. In this article, the authors associated
short ncRNA-mediated gene regulation pathways (i.e., RNAi and RNAa), and discussed how research into RNAi might be useful
for understanding the molecular mechanisms underlying the endogenous RNAa phenomena.
We here introduce the second part of a thematic issue devoted to the analytical advances in clinical and forensic toxicology,
with a particular focus on the determination of new psychoactive substances and eventual metabolites in conventional and nonconventional
biological matrices .
This second part opens with a review which explores the close connections between clinical and forensic toxicology in
overlapping areas of interest, such as prenatal exposure to drugs or fetal alcohol syndrome, doping control, sudden cardiac
death, determination of brain death, sudden infant death syndrome, Munchausen syndrome by proxy, drug-facilitated crimes
and intoxications by new psychoactive substances. Some of these topics are initially treated in hospital emergency departments,
involving clinical laboratories and sometimes lately derived to forensic laboratories. Conversely, cases with initial medicallegal
implications and fatalities are directly handled by forensic toxicology, but may trigger further studies in the clinical setting.
Thus, increasing relationships are improving the growth, reliability and robustness of both kind of laboratories, respecting
in both cases most recent updated and standard practices for the development and validation of the analytical methods [2-4].
The first example of the bridges between clinical and forensic toxicology laboratories is given by the case report described
by Jarque et al. concerning a case report of prenatal methamphetamine exposure with toxicological analytical confirmation in
maternal and biological matrices. The toxicological findings prompted the removal of guardianship to the parents and authorized
a temporary foster care. In addition, authors reviewed the updated literature regarding this new outbreak of methamphetamine
abuse with several consequences in young male and male adults .
Not only a case report was presented concerning prenatal exposure to a psychotropic drug, but also an epidemiological
study on gestational consumption and consequent prenatal exposure to drugs of abuse and psychoactive prescription drugs in
513 mother-newborn dyads from Sant Joan de Déu Barcelona Hospital analysing maternal hair and neonatal meconium by
validated chromatographic mass spectrometric methodologies.
An amount of 1.2% gestational drugs of abuse consumption was objectively assessed in maternal hair and 0.4% prenatal
exposure measured in meconium while gestational consumption of psychoactive prescription drugs was 1.7% as measured maternal
hair and prenatal exposure 1.2% in meconium .
Another interesting issue in clinical and forensic toxicology is that of ethyl glucuronide in hair (hEtG) used as a biomarker
in the diagnosis of chronic excessive alcohol consumption. Since some cosmetic treatments may influence the hEtG concentration
leading to false positive results, the effect of alcohol-based perfumes was studied in four different subjects. The liquid
chromatographic mass spectrometric analysis showed in all the cases that prolonged exposition of hair to alcohol-based perfumes
may increase hEtG levels, resulting in false positive results .
Analytical advances were also reported in a remarkable study concerning a striking problem in doping control: the detection
of autologous blood transfusion. The article of Donati et al. reported the results of an investigation aimed to pre-select potential
biomarkers of blood aging and storage that can be measured to identify the presence in the sample of re-infused blood. The parameters
more strongly affected by the ex vivo storage of whole blood resulted to be erythrocytes size and density, annexin V
and microparticles, appearing as a very encouraging suggestion towards the development of a direct method for detecting
autologous blood transfusion in sport doping .
With respect to the determination of new psychoactive substances and eventual metabolites in conventional and nonconventional
biological matrices, an essential contribution has been that of Guillou et al. from the Joint Research Centre of
European Commission in charge of providing its scientific support to the EU Customs laboratories and more in general to the
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) to facilitate the rapid identification and characterisation
of new psychoactive substances in suspected seized samples.
In the presented report the research group described and discussed the implementation of the workflow mechanism, regarding
the harmonisation of procedures to facilitate the monitoring, communication and management of analytical data obtained by
extensive analysis of unknown seized material with some recent real examples. The rapid dissemination of the obtained information
is at the moment an essential tool for control authorities to facilitate the protection against the health risks posed by potential
harmful psychotropic substances .
On the same line of the previous report has been that of the analytical approaches reviewed by Gerace et al. to disclose the
presence of new synthetic opioids in fatal intoxications . Due to the high potency and the low doses required to produce
desired effects, the risk of overdose for these compounds including severe health implications, is quite high. For this reason, the
detection of these compounds in biological samples is crucial in order to get a better understanding of their concentration and
distribution in body fluids.
A specific example of analytical approach to detect a new synthetic opioid as a cause of an intoxication is that of Vogliardi
et al. using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in a case involving U-47700, a synthetic hair and a white powder found at consumer home were analysed by LC-HRMS, which allowed to reveal the presence of
U-47700 and its phase I and phase II metabolites in blood, urine and pubic hair and also cocaine, benzoylecgonine, norcocaine,
mephedrone, ketamine, norketamine, 3,4-methylenedioxymethamphetamine, tetrahydrocannabinol and cannabinol only in pubic
hair . Conclusion. The toxicological findings confirmed the use of U-47700 in the intoxicated patient and also revealed a
history of a poly-drug use. The use of LC-HRMS allowed the easy identification of the NPS and its metabolites in fluids and
The thematic issue closes with a noteworthy investigation on the metabolites of synthetic cannabinoids most recently used
and encountered in clinical/forensic caseworks . This is the last of a series of studies leadered by Prof Auwarter [13-15],
which provided useful information on what to look for in biological fluids of suspected intoxications by risky synthetic cannabinoids
and analytical methods to better recognize the causing substances.
We wish to thank all the authors who have contributed with valuable manuscripts to this Thematic Issue, the Reviewers who
carried out an excellent job in guarantying the highest standard of quality for each manuscript, the Editorial Manager (Ms. Sumaiya
Azhar) of the Journal for the continuous support and expertise and finally a special thanks to Prof. Davide Prosperi, Editor
in Chief of Current Pharmaceutical Biotechnology, who allowed us to guest edit this thematic issue.
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