Epigenetic Signatures in Arterial Hypertension: Focus on the Microvasculature

Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (endothelial cells, vascular smooth muscle cells and perivascular adipose tissue) as well as the involvement of mechanical/hemodynamic factors, namely, shear stress

Different patterns of H2S/NO activity and cross-talk in the control of the coronary vascular bed under normotensive or hypertensive conditions

Hydrogen sulfide (H2S) and nitric oxide (NO) play pivotal roles in the cardiovascular system. Conflicting results have been reported about their cross-talk. This study investigated their interplays in coronary bed of normotensive (NTRs) and spontaneously hypertensive rats (SHRs). The effects of H2S- (NaHS) and NO-donors (sodium nitroprusside, SNP) on coronary flow (CF) were measured in Langendorff-perfused hearts of NTRs and SHRs, in the absence or in the presence of propargylglycine (PAG, inhibitor of H2S biosynthesis), L-NAME (inhibitor of NO biosynthesis), ODQ (inhibitor of guanylate cyclase), L-Cysteine (substrate for H2S biosynthesis) or L-Arginine (substrate for NO biosynthesis). In NTRs, NaHS and SNP increased CF; their effects were particularly evident in Angiotensin II (AngII)-contracted coronary arteries. The dilatory effects of NaHS were abolished by L-NAME and ODQ; conversely, PAG abolished the effects of SNP. In SHRs, high levels of myocardial ROS production were observed. NaHS and SNP did not reduce the oxidative stress, but produced clear increases of the basal CF. In contrast, in AngII-contracted coronary arteries of SHRs, significant hyporeactivity to NaHS and SNP was observed. In SHRs, the vasodilatory effects of NaHS were only modestly affected by L-NAME and ODQ; PAG poorly influenced the effects of SNP. Then, in NTRs, the vascular actions of H2S required NO and vice versa. By contrast, in SHRs, the H2S-induced actions scarcely depend on NO release; as well, the NO effects are largely H2S-independent. These results represent the first step for understanding pathophysiological mechanisms of NO/H2S interplays under both normotensive and hypertensive conditions

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

La vittimologia dell’anziano

Elder abuse has received increasing attention over the past decade as a pervasive and growing problem with serious consequences for the ealth and wellbeing of old people. Abuse against elderly persons is extremely frequent, althought very often is not declared and it’s difficult to get information to define the real dimension of the phenomenon. Factors contributing to misdiagnosis and underreporting included denial by both the victim and the perpetrator, clinicians’ reluctance to report victims, disbelief by medical providers and clinicians’ lack of awarness of warning signs. Elder abuse could be defined as a single or repeated act or lack of appropriate action wich causes harm or distress to an older person. There are five main types of abuse following described: physical, psychological or emotional, sexual, neglect, self-neglect, financial or material, medical, abandonment and violation of rights. Often abuse takes place in unexpected scenarios and is perpetrated by those who might be expected to care and have particularly attention and emphaty to elderly persons: the victim, usually socially isolated, lives in close proximity to or with the perpetrator, has got a personal relationship with the perpetrator and is often dependent on him. Understanding the typical victim, perpetrator and scenario is crucial to detecting and preventing elder abuse. Research shows that there are a number of risk factors, correlated to the victim, the perpetrator or the relationship between them, which include social isolation, a poor quality relationship between the abuser and the abused, a pattern of family violence, dependence feelings (physical, emotional or financial one), victim or caregiver psychopathology (Axis I major mental mental disorders, personality disorders and drug/alcohol related problems). This article reviews the terminology, epidemiology, clinical signs and risk factors associated with elder abuse in the community and in istitutional settings, in order to permit early identification of abuse or maltreatment and to provide strategies of adequate intervention for elder abuse.Il problema dell’abuso sugli anziani è comparso solo da pochi anni nel dibattito della vittimologia. La violenza contro le persone anziane è un problema in crescita proporzionale all’incremento della popolazione mondiale di anziani ed al conseguente aumento delle malattie croniche che creano disabilità. Nonostante sia un fenomeno estremamente frequente e gravato da elevati costi umani e finanziari, spesso non è denunciato. Fattori che contribuiscono alla mancata denuncia e alla sottostima del fenomeno includono negazione da parte della vittima e dell’abusatore e riluttanza da parte degli operatori nel denunciare l’abuso associata ad una incompleta consapevolezza dei segni d’allarme. Le due categorie più comuni di abuso sulla persona anziana sono quello domestico (maltrattamento della persona anziana nella sua abitazione o in quella del caregiver) ed istituzionale (maltrattamento degli anziani che vivono in case di riposo o residenze assistenziali). L’abuso può esprimersi sotto varie forme: abuso fisico, abuso sessuale, violenza per omissione (trascuratezza intenzionale o meno), violenza medica, autolesionismo, abuso psicologico o emotivo, abuso finanziario, violenza civica ed abbandono. L’abuso è un’entità multifattoriale: la comprensione delle caratteristiche tipiche della vittima, dell’abusatore, della relazione tra i due e dello scenario in cui si compie l’abuso sono cruciali per svelare e prevenire i maltrattamenti nell’anziano. Il seguente scritto si propone di descrivere la terminologia, l’epidemiologia, i segni clinici ed i fattori di rischio associati all’abuso, sia a domicilio che in ambiente residenziale, al fine di delineare strategie per una precoce identificazione del fenomeno ed un adeguato intervento in caso di abuso sull’anziano

Italian university students' self-perceived health and satisfaction of life

INTRODUCTION: Health is defined as a state of complete physical, social and mental wellbeing, therefore, it should not be considered as simply the absence of disease. In this light, the assessment of self-perceived health and life satisfaction plays an important role as it allows addressing the subjective perception of physical health, as well as mental health and social functioning. MATERIAL AND METHODS: This study analyzed data from 8516 university students enrolled in the "Sportello Salute Giovani" project ("Youth Health Information Desk"). In particular, it addressed self-perceived health and life satisfaction, reported somatic and psychological symptoms and ability to cope with daily problems of university students from 18 to 30 years old. RESULTS: Overall, 77.1% of students declared to have a good or very good health and the mean score of life satisfaction was 7.46. In respect to somatic and psychological symptoms, 25.8% of students reported to suffer almost daily of at least one among headache, stomach pain, back pain, tiredness, nervousness, dizziness and troubles falling asleep. Results varied on the basis of sex, with women showing lower self-perceived health compared to men and reporting more symptoms. Furthermore, self-perceived health was shown better in younger students and in those belonging to higher socio-economic level. DISCUSSION: The survey showed that concern exists with respect to university students' self-perceived health, which is different from that arising from other evidence. Female students had a significant lower self-perceived health and reported somatic and psychological symptoms more commonly than men. On the other hand, results about life satisfaction seem to be aligned with the literature. CONCLUSION: One of the most important implications of the study is the need to address self-perceived health and reported symptoms in university students in order to monitor them and initiate interventions aimed at improving well-being and controlling inequalities

Effect of Genetic Factors, Age and Sex on Levels of Circulating Extracellular Vesicles and Platelets

Extracellular vesicles (EVs) mediate cell interactions in biological processes, such as receptor activation or molecule transfer. Estimates of variation by age and sex have been limited by small sample size, and no report has assessed the contribution of genetic factors to levels of EVs. Here, we evaluated blood levels of 25 EV and 3 platelet traits in 974 individuals (933 genotyped) and reported the first genome-wide association study (GWAS) on levels of these traits. EV levels all decreased with age, whereas the trend for their surface markers was more heterogeneous. Platelets and CD31dim platelet EVs significantly increased in females compared to males, although CD31 expression on both platelets and platelet EVs decreased in females. Levels of the other EV subsets were similar between sexes. GWAS revealed three statistically significant genetic signals associated with EV levels in the F10 and GBP1 genes and in the intergenic region between LRIG1 and KBTBD8. These add to a signal in the 3′UTR of RHOF associated with CD31 expression on platelets that was previously found to be associated with other platelet traits. These findings suggest that EV formation is not a simple, constant adjunct of metabolism but is under both age-related and genetic control that can be independent of the regulation of the levels of the cells from which the EVs derive

Epigenetic Signatures in Arterial Hypertension: Focus on the Microvasculature

Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (endothelial cells, vascular smooth muscle cells and perivascular adipose tissue) as well as the involvement of mechanical/hemodynamic factors, namely, shear stress

Role of perturbation of methionine metabolism and global dna methylation in the generation of genomic instability in transgenic mouse models of liver cancer

Background and Aims: Genomic instability (GI) is involved in rodent and human hepatocellular carcinoma (HCC) pathogenesis. DNA hypomethylation may drive malignant transformation by generating GI, but whether DNA hypomethylation is a prerequisite for HCC development remains unclear. We investigated the correlation between GI and DNA methylation, and influence of methionine metabolism deregulation on these parameters in c-Myc and c-Myc/Tgf-a transgenic mouse models of HCC. Methods: S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver content was assessed by HPLC, activity of methionine adenosyltransferases by enzymatic assay, levels of methionine metabolism regulators by RT-PCR, GI by RAPD, and global DNA methylation by [3 H]dCTP incorporation into DNA. Results: SAMiSAH ratio and liver-specific methionine adenosyltransferase levels progressively decreased in dysplastic and neoplastic liver of c-Myc transgenic mice, leading to global DNA hypomethylation and GI, but not in c-Myc/Tgf-cc lesions, where highest GI correlated with proliferative activity. Upregulation of genes involved in polyamine synthesis, methionine salvage, and downregulation of polyamine negative regulator OAZl, was highest in c-MyciTgf-a HCCs, indicating SAM requirement for polyamine-induced growth in aggressive c-MyciTgf-a HCCs. Conclusions: Our results indicate that aggressive HCC may develop in the absence of DNA hypomethylation. Genome-wide hypomethylation may favor development of slow growing HCC with relatively low GI and polyamine synthesis

Tomentosin a Sesquiterpene Lactone Induces Antiproliferative and Proapoptotic Effects in Human Burkitt Lymphoma by Deregulation of Anti- and Pro-Apoptotic Genes

(1) Tomentosin is the most representative sesquiterpene lactone extracted by I. viscosa. Recently, it has gained particular attention in therapeutic oncologic fields due to its anti-tumor properties. (2) In this study, the potential anticancer features of tomentosin were evaluated on human Burkitt’s lymphoma (BL) cell line, treated with increasing tomentosin concentration for cytotoxicity screening. (3) Our data showed that both cell cycle arrest and cell apoptosis induction are responsible of the antiproliferative effects of tomentosin and may end in the inhibition of BL cell viability. Moreover, a microarray gene expression profile was performed to assess differentially expressed genes contributing to tomentosin activity. Seventy-five genes deregulated by tomentosin have been identified. Downregulated genes are enriched in immune-system pathways, and PI3K/AKT and JAK/STAT pathways which favor proliferation and growth processes. Importantly, different deregulated genes identified in tomentosin-treated BL cells are prevalent in molecular pathways known to lead to cellular death, specifically by apoptosis. Tomentosin-treatment in BL cells induces the downregulation of antiapoptotic genes such as BCL2A1 and CDKN1A and upregulation of the proapoptotic PMAIP1 gene. (4) Overall, our results suggest that tomentosin could be taken into consideration as a potential natural product with limited toxicity and relevant anti-tumoral activity in the therapeutic options available to BL patients

Somatosensory Evoked Potentials of Inferior Alveolar Nerve: confirmation of a possible non-invasive neurophysiological approach

INTRODUCTION: The use of inferior alveolar nerve (IAN) somatosensory evoked potentials (SEPs) may represent a non-invasive method to evaluate the sensory nerve function in the maxillofacial region. The aim of this work is to confirm the feasibility of a technique, previously reported in the literature, and the data previously obtained. MATERIALS AND METHODS: SEPs were obtained following electrical stimulation (square wave pulses 0.2 millisecond [ms] in duration, 4 to 6.5 mA, 0.7/second repetition rate, 200 averages) of the gum at the mental foramen level, in the IAN region, via a new designed type of intraoral surface electrodes and recorded from the contralateral central scalp sites. RESULTS: We recognized waveforms of sufficient quality and consistently recorded a "W"-shaped response. Peak latencies of waves were at 14, 20, 27, 34 and 43 ms respectively. One side of the lower lip can be compared with the contralateral side. CONCLUSIONS: IAN SEPs, obtained with the present technique, may represent an objective, non-invasive, and reliable way of testing sensory nerve function in the maxillofacial region