Novel perspectives in redox biology and pathophysiology of failing myocytes: modulation of the intramyocardial redox milieu for therapeutic interventions - A review article from the Working Group of Cardiac Cell Biology, Italian Society of Cardiology

The prevalence of heart failure (HF) is still increasing worldwide, with enormous human, social, and economic costs, in spite of huge efforts in understanding pathogeneticmechanisms and in developing effective therapies that have transformed this syndrome into a chronic disease. Myocardial redox imbalance is a hallmark of this syndrome, since excessive reactive oxygen and nitrogen species can behave as signaling molecules in the pathogenesis of hypertrophy and heart failure, leading to dysregulation of cellular calcium handling, of the contractile machinery, of myocardial energetics and metabolism, and of extracellular matrix deposition. Recently, following new interesting advances in understanding myocardial ROS and RNS signaling pathways, new promising therapeutical approaches with antioxidant properties are being developed, keeping in mind that scavenging ROS and RNS tout court is detrimental as well, since these molecules also play a role in physiological myocardial homeostasis

Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy

It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of myocyte hypertrophy and hyperplasia. Intense new myocyte formation results from the differentiation of stem-like cells committed to the myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and myocyte precursors, as well as very primitive myocytes that turn into terminally differentiated myocytes, provides a link between cardiac stem cells and myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the myocyte lineage in response to increased workload. Their presence is consistent with the notion that myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling myocytes

Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy.

BACKGROUND: Diabetes mellitus (DM) has multifactorial detrimental effects on myocardial tissue. Recently, carbonic anhydrases (CAs) have been shown to play a major role in diabetic microangiopathy but their role in the diabetic cardiomyopathy is still unknown. METHODS AND RESULTS: We obtained left ventricular samples from patients with DM type 2 (DM-T2) and nondiabetic (NDM) patients with postinfarct heart failure who were undergoing surgical coronary revascularization. Myocardial levels of CA-I and CA-II were 6- and 11-fold higher, respectively, in DM-T2 versus NDM patients. Elevated CA-I expression was mainly localized in the cardiac interstitium and endothelial cells. CA-I induced by high glucose levels hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro. Accordingly, capillary density was significantly lower in the DM-T2 myocardial samples (mean±SE=2152±146 versus 4545±211/mm(2)). On the other hand, CA-II was mainly upregulated in cardiomyocytes. The latter was associated with sodium-hydrogen exchanger-1 hyperphosphorylation, exaggerated myocyte hypertrophy (cross-sectional area 565±34 versus 412±27 μm(2)), and apoptotic death (830±54 versus 470±34 per 10(6) myocytes) in DM-T2 versus NDM patients. CA-II is activated by high glucose levels and directly induces cardiomyocyte hypertrophy and death in vitro, which are prevented by sodium-hydrogen exchanger-1 inhibition. CA-II was shown to be a direct target for repression by microRNA-23b, which was downregulated in myocardial samples from DM-T2 patients. MicroRNA-23b is regulated by p38 mitogen-activated protein kinase, and it modulates high-glucose CA-II-dependent effects on cardiomyocyte survival in vitro. CONCLUSIONS: Myocardial CA activation is significantly elevated in human diabetic ischemic cardiomyopathy. These data may open new avenues for targeted treatment of diabetic heart failure

Serum anti‐müllerian hormone levels and risk of premature ovarian insufficiency in female childhood cancer survivors: Systematic review and network meta‐analysis

Background: Female childhood cancer survivors (CCS) might have impaired ovarian reserves, especially after alkylating agents or radiotherapy. The purpose of this systematic review and network meta‐analysis is to evaluate the role of serum anti‐Müllerian hormone (AMH) for ovarian reserve screening and the risk of premature ovarian insufficiency (POI) according to the subtype of childhood cancer. (2) Methods: PRISMA‐NMA guidelines were followed. We carried out a network meta‐analysis based on a random effects model for mixed multiple treatment comparisons to rank childhood cancers effects on fertility by surface under the cumulative ranking curve (SUCRA). Studies were selected only if they had an age‐matched control group. Quality assessment was performed using Newcastle–Ottawa Scale. The co‐primary outcomes were mean AMH levels and the incidence of POI. (3) Results: A total of 8 studies (1303 participants) were included. Women treated for a neuroblastoma during infancy were more likely to be ranked first for impaired AMH levels (SUCRA = 65.4%), followed by mixed CCS (SUCRA = 29.6%). The greatest rates of POI were found in neuroblastoma survivors (SUCRA = 42.5%), followed by acute lymphoid leukemia (SUCRA = 26.3%) or any other neoplasia (SUCR A= 20.5%). (4) Conclusions: AMH represents a trustworthy approach for ovarian reserve screening. Direct and indirect comparisons found no differences in mean AMH levels and POI risk between subtypes of CCS and healthy controls. SUCRA analysis showed that female neuroblastoma survivors were more at risk for reduced serum AMH levels and increased risk of POI

Stent frame movement following endovascular aneurysm sealing in the abdominal aorta

Purpose: We investigated the incidence and extent of stent migration after endovascular sealing of abdominal aortic aneurysms (EVAS), its relationship with adherence to the instructions for use of the Nellix endograft and its association with aneurysm growth. Methods: In this retrospective single centre study, the clinical data and follow-up CT images of patients undergoing infra-renal EVAS with a minimum follow-up of 1 year were reviewed. The first postoperative CT scan at one month and the subsequent scans were used to measure the distances between the proximal end of the stent and reference visceral vessels using a previously validated technique. Device migration was based on the Society of Vascular Surgery definition of >10mm downward movement of either Nellix stent in the proximal landing zone; furthermore, we defined proximal displacement a downward movement of ≥4mm. Patients were categorised according to adherence to the old (2013) or new (2016) Nellix IFU. Aneurysm diameter was measured for each scan and a change of ≥5mm was deemed indicative of aneurysm growth. Results: Seventy-five patients were eligible for inclusion in our study. Over a 4-year period, migration ≥4mm occurred in 42 (56%) patients and migration of ≥10mm in 16 (21%), with similar incidence in right and left stents. Migration ≥4mm was significantly more frequent among patients whose anatomy did not conform to any IFU (p=0.025). Presence of aneurysm growth ≥5mm was observed in 14 patients (19%) and was significantly associated with proximal displacement ≥4mm (p=0.03). Conclusion: Infra-renal EVAS may be complicated by proximal displacement and migration, particularly when performed outside IFU. The definition of migration used for EVAR is inappropriate for EVAS; a new consensus on definition and measurement technique is necessary

Human resource management, Lean processes and outcomes for employees: towards a research agenda

Lean management or lean thinking is a process improvement technique that along with Six Sigma is used in an increasing range of workplaces. This special issue focuses on the use of Lean in developed countries. This increased usage reflects a growing propensity for managers to launch initiatives to upgrade the efficiency and productivity of the enterprises that they manage, usually in an attempt to enhance the cost- effectiveness of operations. This special issue of the IJHRM includes eight articles in addition to this one on various aspects of the connections between lean management, human resource management (HRM) and outcomes for employees. The present article reviews the context for the increasing popularity of lean ideas among managers. Drawing on research in a range of countries, the articles in the special issue provide interesting insights into the relationships between process improvement innovations and HRM, as well as raise further important questions for research, which enable us to suggest an agenda for future research. This includes asking: what are the differences in the ways that Lean is implemented, for example the differences that may reflect industry, regional and national variables

Regulating working families in the European Union: a history of disjointed strategies

Families in market economies worldwide have long been confronted with the demands of participating in paid work and providing care for their dependent members. The social, economic and political contexts within which families do so differ from country to country but an increasing number of governments are being asked to engage, or better engage, with this important area of public policy. What seems like a relatively simple goal – to enable families to better balance care-giving and paid employment – has raised several difficulties and dilemmas for policy makers which have been approached in different ways. This paper aims to identify and critique the nature and development of the means by which legal engagement with work-family reconciliation has, historically, been framed in the European Union. In doing so, and with reference to specific cohorts of workers, we demonstrate how disjointed the strategies are in relation to working carers and argue that the EU is unlikely to provide the legal framework necessary to bring about effective change in this fundamentally important area of social policy

Potential therapeutic effects of natural heme oxygenase-1 inducers in cardiovascular diseases.

Significance: Many physiological effects of natural antioxidants, their extracts or their major active components, have been reported in recent decades. Most of these compounds are characterized by a phenolic structure, similar to that of α-tocopherol, and present antioxidant properties that have been demonstrated both in vitro and in vivo. Polyphenols may increase the capacity of endogenous antioxidant defenses and modulate the cellular redox state. Such effects may have wide-ranging consequences for cellular growth and differentiation. Critical Issues: The majority of in vitro and in vivo studies conducted so far have attributed the protective effect of bioactive polyphenols to their chemical reactivity toward free radicals and their capacity to prevent the oxidation of important intracellular components. One possible protective molecular mechanism of polyphenols is nuclear factor erythroid 2-related factor (Nrf2) activation, which in turn regulates a number of detoxification enzymes. Recent Advances: Among the latter, the heme oxygenase-1 (HO-1) pathway is likely to contribute to the established and powerful antioxidant/anti-inflammatory properties of polyphenols. In this context, it is interesting to note that induction of HO-1 expression by means of natural compounds contributes to prevention of cardiovascular diseases in various experimental models. Future Directions: The focus of this review is on the role of natural HO-1 inducers as a potential therapeutic strategy to protect the cardiovascular system against various stressors in several pathological conditions

Hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer recurrence: systematic review and meta-analysis.

Background: Ovarian cancer is the first cause of death among gynecological malignancies with a high incidence of recurrence. Different treatment options are suitable to prolong the survival rate of these patients. Over the last years, one of the most intriguing methods, adopted in different oncologic centers worldwide, is the hyperthermic intraperitoneal chemotherapy (HIPEC). Methods: A meta-analysis was performed to value the role of HIPEC for ovarian cancer recurrence. Search strategy was conducted with a combination of the following keywords: "ovarian recurrence, ovarian cancer recurrence, peritoneal cancer recurrence, ovarian recurrence AND HIPEC, secondary cytoreduction HIPEC". Seven studies were selected for analysis. Results: In women with recurrent ovarian cancer (ROC), the use of HIPEC in addition to cytoreductive surgery and chemotherapy significantly improved 1-year overall survival (OS) when compared to protocols without HIPEC (OR 2.42; 95% CI, 1.06-5.56; P=0.04; I2=4%). The improvement in OS was maintained significant also after 2, 3 and 5 years respectively (OR 3.33; 95% CI, 1.81-6.10; P<0.01; I2=0%), (OR 4.22; 95% CI, 2.07-8.60; P<0.01; I2=52%), (OR 5.17; 95% CI, 1.40-19.09; P=0.01; I2=82%). Conclusions: HIPEC seems to have an effective role to prolong survival in patients affected by ROC

Brexit and the work-family conflict:a Scottish perspective

This paper examines the Scottish Government’s desire to maintain ties with EU law post-Brexit in the context of employment and equality law, particularly those laws which impact on work-family conflict. The paper critically examines whether there is, or could be, a distinctly Scottish perspective in the context of work-family rights post-Brexit. The paper frames the analysis by considering the potentially gendered implications of Brexit in this context. In doing so, it examines this issue from the perspective of traditional heterosexual dual-partnered working family models. It is argued that rights for working fathers will be most vulnerable post-Brexit, with related consequences for working mothers. Consequently, the implications of Brexit in this context are primarily viewed through the lens of working fathers. The paper then critically examines the Scottish Government’s position on EU employment and equality law in the post-Brexit context