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Background: Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes., Methods: Urinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery, n = 74 and validation set, n = 177) and healthy controls (n = 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A-1B) and fast progressors (1C-1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression., Results: Baseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r = - 0.6, p < 0.001), estimated glomerular filtration rate (r = 0.69 p < 0.001), discriminated between Mayo Clinic Imaging Classes (p < 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r = - 0.51, p < 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p = 6.51E-16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p = 0.006, r = 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 ± 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: - 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) and Pkd1 knock-out mouse kidney (Egf: - 14.8-fold, fdr = 2.37E-20, Mcp1: 2.8-fold, fdr = 6.82E-15)., Conclusion: The ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease., (© 2022. The Author(s).)

Healthy life expectancy (HLE) is an indicator that measures the number of years individuals at a given age are expected to live free of disease or disability. HLE forecasting is essential for planning the provision of health care to elderly populations and appropriately pricing Long Term Care insurance products. In this paper, we propose a methodology that simultaneously forecasts HLE for groups of countries and allows for investigating similarities in their HLE patterns. We firstly apply a functional data clustering to the multivariate time series of HLE at birth of different countries for the years 1990-2019 provided by the Global Burden of Disease Study. Three clusters are identified for both genders. Then, we carry out the HLE simultaneous forecasting of the populations within each cluster by a multivariate random walk with drift. Numerical results and the statistical significance of the parameters of the identified multivariate processes are shown. Demographic evidences on the different evolution of HLE between countries are commented., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Life expectancy at birth has attracted interest in various fields, as a health indicator that measures the quality of life. Its appeal relies on the ability to enclose and summarize all the factors affecting longevity. However, more granular information, provided by social indicators such as cause-of-death mortality rates, plays a crucial role in defining appropriate policies for governments to achieve well-being and sustainability goals. Unfortunately, their availability is not always guaranteed. Exploiting the relationship between life expectancy at birth and cause-of-death mortality rates, in this paper we propose an indirect model to produce estimates of death rates due to specific causes using the summary indicator of life expectancy at birth, thus the general levels of the observed mortality. By leveraging on a constrained optimization procedure, we ensure a robust framework where the cause-specific mortality rates are coherent to the aggregate mortality. The main advantage is that indirect estimations allow us to overcome the data availability problem: very often the cause-specific mortality data are incomplete, whereas data on the aggregate mortality are not. Using data from the Human Cause-of-Death Database, we show a numerical application of our model to two different countries, Russia and Spain, which have experienced a different evolution of life expectancy and different leading causes of death. In Spain, we detected the impact of several public health policies on the lowered levels of cancer deaths and related life expectancy increases. As regards the Russia, our results catch the effects of the anti-alcohol campaign of 1985-1988 on longevity changes., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

Introduction: Recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KTx) develops in 40% of patients, leading to graft loss in half of cases. Extracorporeal apheretic treatments, combined with immunosuppressive drugs, seem to be the most promising therapies, but at now limited reports are available, mainly in pediatric patients., Objective: We aimed to assess the efficacy of immunoadsorption (IA) to treat recurrent FSGS in pediatric patients., Methods: We report a case series of 4 pediatric patients (aged 4-12 years) followed at our institution for early recurrent FSGS after KTx. FSGS recurrence was treated with early and intensive apheretic treatments IA., Results: After IA initiation, a partial remission (PR) of proteinuria at 24-month follow-up was achieved only in 1 patient. The others showed a mild reduction of nephrotic proteinuria, without PR, but gained a significant improvement in clinical signs of nephrotic syndrome (reduction of edema, increased serum albumin, and total protein levels). After a median follow-up of 38 (22-48) months, renal function was almost stable over time in all patients, except one who returned to hemodialysis after 22 months. No severe IA-related complications occurred., Conclusions: According to our clinical experience, IA revealed as a safe and effective therapy to treat patients with recurrent FSGS after KTx and it could maintain stable renal function in 75% of patients., (© 2022 S. Karger AG, Basel.)

Background: The Neurological involvement is the most common extra-renal complication of Shiga toxin-producing E. coli-hemolytic uremic syndrome (HUS) or typical HUS. On brain magnetic resonance examination, main neurological signs encompass acute lesions of the basal ganglia and the white matter, which could usually regress after Eculizumab infusion. In contrast, peripheral nervous system (PNS) manifestations in typical HUS are very rare and, when occurring, they require a careful management of neurological sequelae and an intensive multidisciplinary neuro-rehabilitation program., Case Presentation: Here, we present two pediatric cases of severe and complicated typical HUS with PNS manifestations who required therapeutic treatment and an intensive multidisciplinary neuro-rehabilitation program. In both cases, PNS manifestations were followed by the recovery from typical HUS-related severe central neurological damage and manifested mainly with marked bilateral motor deficit and hyporeflexia/areflexia in the lower limbs. The peripheral polyneuropathy was treated with immunosuppressive therapy (methylprednisolone boluses, i.v. immunoglobulins, plasma exchange), followed by a prolonged intensive neuro-rehabilitation program. After 8 months of rehabilitation, both patients gained complete functional recovery., Conclusions: PNS manifestations during typical HUS are a rare event and potentially leading to severe disability. A timely clinical assessment is mandatory to set up a prompt therapeutic and rehabilitation program and to obtain a complete clinical and functional recovery., (© 2021. The Author(s).)

Background: The correlation between the severity of hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS) and involvement of the complement system has been examined in a small number of studies, with conflicting results. In the present study, we investigated whether serum C3 levels on admission are associated with neurologic involvement. Methods: To this purpose, 68 consecutive STEC-HUS patients were recruited and main clinical and laboratory variables ad hospital admission were compared between those with or without neurologic involvement. Results: STEC-HUS patients who developed neurologic involvement (NI) showed significant higher leukocyte count, C-reactive protein and hemoglobin, and lower sodium levels as compared with those without. Interestingly, baseline serum levels of C3 were significantly lower in patients with NI as compared with those without ( p < 0.001). Moreover, when stratified according to need of Eculizumab rescue therapy due to severe NI, patients treated with this drug showed baseline C3 serum levels significantly lower than those who were not ( p < 0.001). Low C3 was independent risk factor for NI in our patients' population when entered as covariate in a multivariate logistic regression analysis including other major variables previously proposed as possible predictors of poor prognosis in STEC-HUS (for instance, leukocyte count, c-reactive protein, sodium levels) (HR 6.401, 95%CI 1.617-25.334, p = 0.008 for C3). To underline the role of complement in the worsening of STEC-HUS patients' clinical conditions and outcomes, all patients were divided into two groups according to the baseline lower vs. normal serum levels of C3 and the main data on care needs were assessed. Interestingly more patients with lower C3 serum levels required renal replacement therapy ( p = 0.024), anti-hypertensive therapy ( p = 0.011), Intensive Care Unit admission ( p = 0.009), and longer hospitalization ( p = 0.003), thus displaying significantly more severe disease features as compared with those with normal C3 serum levels. Conclusions: Our data suggests that children with STEC-HUS with decreased C3 concentrations at admission are more likely to develop neurologic involvement and are at increased risk of having severe clinical complications., (Copyright © 2020 Netti, Santangelo, Paulucci, Piscopo, Torres, Carbone, Giordano, Spadaccino, Castellano, Stallone, Gesualdo, Chironna, Ranieri and Giordano.)

Introduction: Von Hippel-Lindau (VHL) disease is a dominantly inherited condition associated with tumors in multiple organs, whose treatment requires heightened multidisciplinary teamwork. Therefore, a document summarizing all the pertinent knowledge is needed to enhance coordination of care., Evidence Acquisition: A systematic review of the literature from the Medline, Embase and Cochrane Central databases was performed. From 1970 to 2017, all articles meeting specific inclusion criteria were included by at least one specialist physician for each field., Evidence Synthesis: We included 95 articles, mostly dealing with genetics or management of VHL associated tumors in one organ system. There were no papers discussing the manifestations of VHL altogether, which was the aim of our paper., Conclusions: VHL requires a multidisciplinary management to provide the highest quality of care. Coordination and communication between patients and caregivers is enhanced when knowledge is shared. Gathering together specialists in different domains around the production and reading of a comprehensive document such as the one hereby may contribute to this purpose.

Directed Energy Deposition (DED) is one of the most promising additive manufacturing technologies for the production of large metal components and because of the possibility it offers of adding material to an existing part. Nevertheless, DED is considered premature for industrial production, because the identification of the process parameters may be a very complex task. An original hybrid analytic-numerical model, related to the physics of laser powder DED, is presented in this work in order to evaluate easily and quickly the effects of different sets of process parameters on track deposition outcomes. In the proposed model, the volume of the deposited material is modeled as a function of process parameters using a synergistic interaction between regression-based analytic models and a novel element activation strategy. The model is implemented in a Finite Element (FE) software, and the forecasting capability is assessed by comparing the numerical results with experimental data from the literature. The predicted results show a reasonable correlation with the experimental dimensions of the melt pool and demonstrate that the proposed model may be used for prediction purposes, if a specific set of process parameters that guarantees adequate adhesion of the deposited track to the substrate is introduced.

Endocrine disrupters are strictly associated to cancer and several cardiovascular risk factors. Bisphenol A (BPA) is an endocrine disrupter commonly used in the manufacturing of plastics based on polycarbonate, polyvinyl chloride and resins. Our study aims to investigate whether BPA may cause pro-oxidative and pro-inflammatory effects on cardiomyoblasts, thus exacerbating the Doxorubicin (DOXO)-induced cardiotoxicity phenomena. We tested the metabolic effects of BPA at low doses analyzing its affections on the intracellular calcium uptake, oxidative stress, lipid peroxidation and production of nitric oxide and interleukins. Co-incubation of BPA and DOXO significantly reduced the cardiomyoblast viability, compared to only DOXO exposure cells. The mechanisms underlying these effects are based on the stimulation of the intracellular calcium accumulation and lipid peroxidation. Notably, BPA increase the production of pro-inflammatory interleukins involved in cardiovascular diseases as well as in DOXO-Induced cardiotoxicity phenomena. This study provides a rationale for translational studies in the field of cardio-oncology., (Copyright © 2019. Published by Elsevier B.V.)

Doxorubicin is a highly active antineoplastic agent, but its clinical use is limited because of its cardiotoxicity. Although nutraceuticals endowed with anti-inflammatory properties exert cardioprotective activity, their bioavailability and stability are inconsistent. In an attempt to address this issue, we evaluated whether bioavailable nanoemulsions loaded with nutraceuticals (curcumin and fresh and dry tomato extracts rich in lycopene) protect cardiomyoblasts (H9C2 cells) from doxorubicin-induced toxicity. Nanoemulsions were produced with a high-pressure homogenizer. H9C2 cells were incubated with nanoemulsions loaded with different nutraceuticals alone or in combination with doxorubicin. Cell viability was evaluated with a modified MTT method. The levels of the lipid peroxidation products malondialdehyde (MDA) and 4-hydroxy-2-butanone (4-HNA), and of the cardiotoxic-related interleukins IL-6, IL-8, IL-1β and IL-10, tumor necrosis factor-alpha (TNF-α), and nitric oxide were analyzed in cardiomyoblasts. The hydrodynamic size of nanoemulsions was around 100 nm. Cell viability enhancement was 35⁻40% higher in cardiomyoblasts treated with nanoemulsion + doxorubicin than in cardiomyoblasts treated with doxorubicin alone. Nanoemulsions also protected against oxidative stress as witnessed by a reduction of MDA and 4-HNA. Notably, nanoemulsions inhibited the release of IL-6, IL-8, IL-1β, TNF-α and nitric oxide by around 35⁻40% and increased IL-10 production by 25⁻27% versus cells not treated with emulsions. Of the nutraceuticals evaluated, lycopene-rich nanoemulsions had the best cardioprotective profile. In conclusion, nanoemulsions loaded with the nutraceuticals described herein protect against cardiotoxicity, by reducing inflammation and lipid oxidative stress. These results set the stage for studies in preclinical models.

The Autosomal Dominant Polycystic Kidney Disease(ADPKD) is the most frequent renal genetic condition and involves 7 to 10% of subjects undergoing renal replacement therapy. It is estimated that between 24,000 and 34,000 subjects in Italy are affected by this condition. For an illness that has long been neglected due to a lack of treatment options, an attractive treatment possibility is now available: tolvaptan has shown clinical efficacy regarding disease progression in two clinical trials (ADPKD patients with mild renal failure and ADPKD patients with advanced renal failure). The possible liver toxicity expressed in about 4% of the subjects exposed to the drug and an important aquaretic effect suggest prudence and attention in the use of this new molecule. Based on these critical points, some clinicians with direct experience in the use of the drug have briefly collected in the pages to follow the main clinical recommendations for the treatment of ADPKD patints. The recommendations concern the general approach to the patient affected by ADPKD but with particular attention to the aspects related to the new treatment. The delicate task of introducing the opportunities and limitations of the offered therapy to the patient will be deepened. Finally, the document wants to suggest how best to organize a clinic dedicated to this condition., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab. Trastuzumab cardiotoxicity was accompanied by elevations in natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated with co-treatment with ranolazine. Trastuzumab also increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Interestingly, Neonatal Rat Ventricular Myocytes (NRVMs), labeled with MitoTracker Red and treated with trastuzumab, showed only a small increase in ROS compared to baseline conditions. We then stressed trastuzumab-treated cells with the beta-agonist isoproterenol to increase workload, and we observed a significant increase of probe fluorescence, compared with cells treated with isoproterenol alone, reflecting induction of oxidative stress. These effects were blunted by ranolazine, supporting a role for I Na inhibition in the regulation of redox balance also in trastuzumab cardiotoxicity.

The side effects of anticancer drugs still play a critical role in survival and quality of life. Although the recent progresses of cancer therapies have significantly improved the prognosis of oncologic patients, side effects of antineoplastic treatments are still responsible for the increased mortality of cancer survivors. Cardiovascular toxicity is the most dangerous adverse effect induced by anticancer therapies. A survey conducted by the National Health and Nutrition Examination, showed that 1807 cancer survivors followed up for seven years: 51% died of cancer and 33% of heart disease (Vejpongsa and Yeh, 2014). Moreover, the risk of cardiotoxicity persists even with the targeted therapy, the newer type of cancer treatment, due to the presence of on-target and off-target effects related to this new class of drugs. The potential cardiovascular toxicity of anticancer agents includes: QT prolongation, arrhythmias, myocardial ischemia, stroke, hypertension (HTN), thromboembolism, left ventricular dysfunction and heart failure (HF). Compared to other cardiovascular disorders, the interest in QT prolongation and its complications is fairly recent. However, oncologists have to deal with it and to evaluate the risk-benefit ratio before starting the treatment or during the same. Electrolyte abnormalities, low levels of serum potassium and several drugs may favour the acquired QT prolongation. Treatment of marked QT prolongation includes cardiac monitoring, caution in the use or suspension of cancer drugs and correction of electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia). Syndrome of QT prolongation can be associated with potentially fatal cardiac arrhythmias and its treatment consists of intravenous administration of magnesium sulphate and the use of electrical cardioversion., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Several cross-sectional and prospective studies highlight the existence of an association between bone fractures and abdominal aortic calcifications, especially if particularly severe and independent from confounders such as aging, smoking habits and diabetes. This phenomenon affects not only the general population but also patients with chronic kidney disease in which cortical bone lesions are prevalent. Moreover, bone fractures and aortic calcifications have been proved to be linked to increased cardiovascular morbidity and mortality, both in the general populations and in patients with chronic kidney disease, who notoriously show elevated cardiovascular risks. Therefore, diagnostic investigations about bone fractures and abdominal aortic calcifications, particularly in patients with chronic kidney disease, may represent a useful tool for identification of patients with a higher cardiovascular risk in order to optimize therapies for bone metabolism disorders., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Objective: Considering that global left ventricular systolic radial strain is a sensitive technique for the early detection of left ventricular dysfunction due to antineoplastics and the analysis of segmental myocardial contractility, we evaluated this technique for early detection of trastuzumab-related cardiotoxicity by comparing it with cardiac structural damage., Methods: Groups of six mice were injected with trastuzumab or doxorubicin, used either as single agents or in combination. Cardiac function was evaluated by transthoracic echocardiography measurements before and after treatment for 2 or 7 days, by using a Vevo 2100 high-resolution imaging system. After echocardiography, mice were euthanized, and hearts were processed for histological evaluations, such as cardiac fibrosis, apoptosis, capillary density, and inflammatory response., Results: Trastuzumab-related cardiotoxicity was detected early by 2D strain imaging. Radial strain was reduced after 2 days in mice treated with trastuzumab alone (21.2%±8.0% vs 40.5%±4.8% sham; P <0.01). Similarly, trastuzumab was found to induce apoptosis, capillary density reduction, and inflammatory response in cardiac tissue after 2 days of treatment, in a fashion similar to doxorubicin. On the contrary, fractional shortening reduction and cardiac fibrosis were observed only after 7 days of trastuzumab treatment, in contrast to doxorubicin treatment which induced early fibrosis and fractional shortening reduction., Conclusion: The reduction of left ventricular systolic strain after 2 days of trastuzumab treatment may indicate early myocardial functional damage before the reduction in left ventricular ejection fraction and this early dysfunction is well correlated with structural myocardial damage, such as apoptosis and inflammatory response. Fractional shortening reduction after 7 days of trastuzumab treatment is related to fibrosis in cardiac tissue., Competing Interests: The authors report no conflicts of interest in this work.

Replacement therapy implemented by renal transplantation is preferable to dialysis treatment and also in uremic population with ADPKD. In preparation for the transplant nephrectomy is a procedure associated with morbidity and mortality in patient with ADPKD, it should be performed on the basis of stringent clinical indications. When the kidney transplant is not possible, peritoneal dialysis in appropriate patients is not contraindicated with comparable results to the extracorporeal dialytic treatment. The therapeutic targets in substitution treatment with respect to pressure levels, lipids, hemoglobin, anticoagulation regime are comparable to the non ADPKD uremic population.

ADPKD is a systemic disorder, associated with numerous extrarenal manifestations, including polycystic liver disease (PCLD) and other gastrointestinal manifestations, as well as pancreatic cysts, diverticular disease, inguinal and ventral hernias which play a significant role in disease burden, particularly in the advanced stage of ADPKD. In most cases the natural history of ADPKD goes through a long period of stability followed by a progressive decline in renal function. The coexistence of hypertension, cyst infections and nephrolithiasis can influence and accelerate the progression of kidney failure. The early diagnosis and prevention of these conditions are of foundamental importance. Nephrologists should know how to recognize and handle other clinical manifestations related to ADPKD like haematuria, renal cell carcinoma and intracranial aneurysms (ICA).

Inadequate health literacy, namely the problematic individual's ability to navigate the health care system, has been depicted as a silent epidemic affecting a large part of the world population. Inadequate health literacy has been variously found to be a predictor of patient disengagement, inappropriateness of care, increased health care costs, and higher mortality rates. However, to date the evidence on the prevalence of limited health literacy is heterogeneous; moreover, studies dealing with this topic show a pronounced geographical concentration. To contribute in filling these gaps, this paper investigates health literacy skills in Italy. Drawing on the European Health Literacy Survey (HLS-EU), a tool to measure self-perceived levels of health literacy was administered to a representative sample of Italian citizens. A stepwise regression analysis allowed to shed light on the determinants and consequences of limited health literacy. Findings suggested that inadequate health literacy is a prevailing problem in Italy, even though it has been overlooked by both policy makers and health care practitioners. Financial deprivation was found to be a significant predictor of inadequate health literacy. Low health literate patients reported higher hospitalization rates and greater use of health services. As compared with the European Countries, Italy showed some peculiarities in terms of health literacy levels and socio-demographic determinants of health literacy, which provide with intriguing insights for policy making., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The improvement in cancer therapy and the increasing number of long term survivors unearth the issue of cardiovascular side effects of anticancer treatments. As a paradox in cancer survivors, delayed cardiotoxicity has emerged as a significant problem. Two categories of cardiotoxic side effects of antineoplastic drugs have been previously proposed: Type I cardiotoxicity, defined as permanent cardiotoxicity, is usually caused by anthracyclines; Type II cardiotoxicity, considered as reversible cardiotoxicity, has been mainly related to monoclonal antibodies. The cardiotoxicity of antibodies has been associated to trastuzumab, a humanized anti-ErbB2 monoclonal antibody currently in clinical use for the therapy of breast carcinomas, which induces cardiac dysfunction when used in monotherapy, or in combination with anthracyclines. Furthermore, recent retrospective studies have shown an increased incidence of heart failure and/or cardiomyopathy in patients treated with trastuzumab, that can persist many years after the conclusion of the therapy, thus suggesting that the side toxic effects are not always reversible as it was initially proposed. On the other hand, early detection and prompt therapy of anthracycline associated cardiotoxicity can lead to substantial recovery of cardiac function. On the basis of these observations, we propose to find a new different classification for cardiotoxic side effects of drugs used in cancer therapy.

The progress in cancer therapy and the increase in number of long-term survivors reveal the issue of cardiovascular side-effects of anticancer drugs. Cardiotoxicity has become a significant problem, and the risks of adverse cardiac events induced by systemic drugs need to be seriously considered. Potential cardiovascular toxicities linked to anticancer agents include arrhythmias, myocardial ischemia and infarction, hypertension, thromboembolism, left ventricular dysfunction, and heart failure. It has been shown that several anticancer drugs seriously affect the cardiovascular system, such as ErbB2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, multitargeted kinase inhibitors, Abelson murine leukemia viral oncogene homolog inhibitors, and others. Each of these agents has a different mechanism through which it affects the cardiovascular system. ErbB2 inhibitors block the ErbB4/ErbB2 heterodimerization pathway triggered by Neuregulin-1, which is essential for cardiomyocyte survival. VEGF signaling is crucial for vascular growth, but it also has a major impact on myocardial function, and the VEGF pathway is also essential for maintenance of cardiovascular homeostasis. Drugs that inhibit the VEGF signaling pathway lead to a net reduction in capillary density and loss of contractile function. Here, we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of ErbB2 inhibitors and antiangiogenic drugs. Moreover, we highlight the role of cardioncology in recognizing these toxicities, developing strategies to prevent or minimize cardiovascular toxicity, and reducing long-term cardiotoxic effects.

The progress in cancer therapy and the increase in number of long-term survivors reveal the issue of cardiovascular side-effects of anticancer drugs. Cardiotoxicity has become a significant problem, and the risks of adverse cardiac events induced by systemic drugs need to be seriously considered. Potential cardiovascular toxicities linked to anticancer agents include arrhythmias, myocardial ischemia and infarction, hypertension, thromboembolism, left ventricular dysfunction, and heart failure. It has been shown that several anticancer drugs seriously affect the cardiovascular system, such as ErbB2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, multitargeted kinase inhibitors, Abelson murine leukemia viral oncogene homolog inhibitors, and others. Each of these agents has a different mechanism through which it affects the cardiovascular system. ErbB2 inhibitors block the ErbB4/ErbB2 heterodimerization pathway triggered by Neuregulin-1, which is essential for cardiomyocyte survival. VEGF signaling is crucial for vascular growth, but it also has a major impact on myocardial function, and the VEGF pathway is also essential for maintenance of cardiovascular homeostasis. Drugs that inhibit the VEGF signaling pathway lead to a net reduction in capillary density and loss of contractile function. Here, we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of ErbB2 inhibitors and antiangiogenic drugs. Moreover, we highlight the role of cardioncology in recognizing these toxicities, developing strategies to prevent or minimize cardiovascular toxicity, and reducing long-term cardiotoxic effects.

The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.

The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.

Ahead of Print article withdrawn by publisher., (©AlphaMed Press.)

We investigated the usefulness of a new examiner-independent method based on the duration of vibration sensation following the placement of the Rydel-Seiffer tuning fork over the dorsum of the interphalangeal hallux joint. This method demonstrated the same diagnostic efficacy as the Rydel-Seiffer method coupled with greater ease of use., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

To investigate if protracted living in degraded environments of the Caserta and Naples provinces (Campania Region, Italy) had an impact on exposure of local people, highly toxic persistent contaminants were measured in blood, blood serum, and human milk of a large number of healthy donors. Sampling was carried out from 2008 to 2009. Blood was collected from over 850 20-64-year old donors; by pooling, 84 blood and 84 serum samples were obtained. Milk was donated by 52 mothers: specimens were pooled into six samples. Polychlorodibenzodioxins (PCDDs), polychlorodibenzofurans (PCDFs), and polychlorobiphenyls (PCBs, dioxin-like (DL) and non-dioxin-like (Σ6PCBs)), arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) were measured in serum (organic biomarkers) and blood (metals); these chemicals and polybromobiphenyl ethers (Σ9PBDEs) were analyzed in milk. PCDD+PCDF, DL-PCB, TEQTOT, and Σ6PCB concentration ranges (medians) in serum were 6.26-23.1 (12.4), 3.42-31.7 (11.5), 10.0-52.8 (23.9) pgTEQ97/g fat, and 55.5-647 (219) ng/g fat, respectively, while in milk concentration ranges were 5.99-8.77, 4.02-6.15, 10.0-14.2 pgTEQ97/g fat, and 48.7-74.2 ng/g fat. Likewise, As, Cd, Hg, and Pb findings in blood spanned 2.34-13.4 (5.83), 0.180-0.930 (0.475), 1.09-7.60 (2.60), 10.2-55.9 (28.8) μg/L, respectively; only Pb could be measured in milk (2.78-5.99 μg/L). Σ9PBDE levels in milk samples were 0.965-6.05 ng/g fat. Biomarkers' concentrations were found to be compatible with their current values in European countries and in Italy, and consistent with an exposure primarily determined by consumption of commercial food from the large distribution system. Based on relatively higher biomarker values within the hematic biomonitoring database, the following municipalities were flagged as possibly deserving attention for health-oriented interventions: Brusciano and Caivano (As), Giugliano (Hg), Pianura (PCDDs+PCDFs), and Qualiano-Villaricca (As, Hg). The analysis of samples' qualitative variability indicated that biomarker composition was sensitive at municipality level, a feature that can potentially drive interventions for future local risk assessment and/or management measures., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aims: Doxorubicin is widely used against cancer; however, it can produce heart failure (HF). Among other hallmarks, oxidative stress is a major contributor to HF pathophysiology. The late INa inhibitor ranolazine has proven effective in treating experimental HF. Since elevated [Na+]i is present in failing myocytes, and has been recently linked with reactive oxygen species (ROS) production, our aim was to assess whether ranolazine prevents doxorubicin-induced cardiotoxicity, and whether blunted oxidative stress is a mechanism accounting for such protection., Methods and Result: In C57BL6 mice, doxorubicin treatment for 7 days produced LV dilation and decreased echo-measured fractional shortening (FS). Ranolazine (305 mg/kg/day) prevented LV dilation and dysfunction when co-administered with doxorubicin. Doxorubicin-induced cardiotoxicity was accompanied instead by elevations in atrial natriuretic peptide (ANP), BNP, connective tissue growth factor (CTGF), and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated on co-treatment with ranolazine. Alterations in extracellular matrix remodelling were confirmed by an increase in interstitial collagen, which did not rise in ranolazine-co-treated hearts. Levels of poly(ADP-ribose) polymerase (PARP) and pro-caspase-3 measured by western blotting were lowered with doxorubicin, with increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Furthermore, in HL-1 cardiomyocytes transfected with HyPer to monitor H2O2 emission, besides reducing the extent of cell death, ranolazine prevented the occurrence of oxidative stress caused by doxorubicin. Interestingly, similar protective results were obtained with the Na+/Ca2+ exchanger (NCX) inhibitor KB-R7943., Conclusions: Ranolazine protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by a reduction in oxidative stress, suggesting that INa modulates cardiac redox balance, resulting in functional and morphological derangements., (© 2014 The Authors. European Journal of Heart Failure © 2013 European Society of Cardiology.)

This report describes two cases of Acremonium sp. endophthalmitis, occurring in two patients who underwent cataract surgery on the same day in the same operating room of our hospital ophthalmology clinic. Diagnosis of fungal endophthalmitis was established by the repeated isolation of the same fungal agent from vitreous washing, acqueous fluid and intraocular lens samples and by its identification on the basis of morphological and molecular features. The cases reported in this study emphasize the need for clinical microbiology laboratories to be prepared to face the diagnosis of uncommon infectious diseases such as exogenous fungal endophthalmitis by Acremonium, and to enhance the awareness of surgeons and clinicians of this occurrence.

Left ventricular dysfunction from anticancer drugs has emerged as a relevant problem in the clinical and scientific communities. Anthracycline toxicity has always been the most relevant, but with the increasing use of biological targeted therapies in treatment protocols, with an increasing number of cancer survivors, new toxicities have been increasing in more recent years. Cardiomyopathy after ErbB2 inhibitors has been intensively studied. Another important class of biological anticancer drugs are vascular endothelial growth factor (VEGF) inhibitors. VEGF signalling is crucial for vascular growth, but it also has a major impact on myocardial function. Also, it is important to note that such angiogenesis inhibitors are multitargeted in most cases, and can produce a broad spectrum of cardiovascular side effects. Here we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of antiangiogenic drugs, and particular attention is drawn to LV dysfunction, discussing the assessment and management on the basis of the most recent cardio-oncological findings and heart failure guidelines.

In microcirculation disorders, the therapeutic apheresis seems to have two different effects. The first, achieved after only a few sessions, is acute, consisting of drastic reduction of blood viscosity and obtained with the use of low-density lipoprotein (LDL) apheresis, rheopheresis, or fibrinogen apheresis. The second effect is long term, or chronic, and needs to be evaluated after a long course of treatment. The mechanisms underlying the chronic effect are still objects of debate and take into account the pleiotropic effects of apheresis. However, it is likely that the acute effect of apheresis mainly influences the functional components of the vascular damage, and so the derived rheological benefit might last only for a short period. The chronic effect, on the contrary, by acting on the morphological alterations of the vascular walls, requires the apheresis treatment to be prolonged for a longer period or even cycles of treatment to be programmed.

The antibody trastuzumab, targeted to inhibit the signalling of ErbB2, a tyrosine kinase receptor overexpressed in 20-30% of breast cancers, improves the prognosis in women affected by this tumour, but produces cardiotoxicity, since ErbB2 is also involved in myocardial homeostasis. In this review, we discuss the pathophysiology of trastuzumab cardiomyopathy and the complex interplay between ErbB2 inhibition and anthracyclines, and we focus on the actual challenges of detecting, monitoring, and managing trastuzumab cardiotoxicity: the research of new, sensitive markers of early trastuzumab toxicity, before the ejection fraction is reduced, is an active field of research.

An alteration of Th1/Th2 homeostasis may lead to diseases in humans. In this study, we investigated whether an impaired IL-12R signaling occurred in children with elevated serum IgE levels divided on the basis of the IgE levels (group A: >2000kU/l; group B: <2000kU/l). We evaluated the integrity of the IL-12R signaling through the analysis of phosphorylation/activation of STAT4, and mRNA expression and membrane assembly of the receptor chains. At a functional level, a proliferative defect of lymphocytes from group A patients was observed. In these patients, an abnormal IL-12R signaling was documented, and this finding was associated with abnormal expression of the IL-12Rbeta2 chain. Our data indicate that in patients with very high IgE levels the generation of Th1 response is impaired, and that this abnormality associates with abnormal IL-12R signaling., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Aim: The aim of this retrospective clinical and radiographic study was to provide follow-up data on the surgical success and patient outcome of polyetheretherketone (PEEK) cage-assisted anterior cervical discectomy and fusion (ACDF) at four levels. The literature on four-level ACDF is scanty, and the reported series are not enterely comparable because of differences in patient characteristics, types of spinal arthrodesis, and methods for quantitating outcome., Methods: During the period between January 2003 and January 2005 10 patients (3 males and 7 females, with a mean age of 54.9 years) suffering from cervical myeloradiculopathy due to compressive spondylosys from C3-C4 to C6-C7 underwent PEEK cage-assisted ACDF at four levels., Results: No intra- or postoperative complications were noted. The follow-up period ranged from 12 to 24 months (mean 15.8 months). The NCSS score was 9.2+/-1.48 preoperatively and 12.7+/-0.67 at follow-up examination (P<0.05). Preoperatively, the curvature, range of motion (ROM), and height of the foramina of the cervical spine were 16.9+/-5.84 degrees , 27.6+/-3.5 degrees , and 8.1+/-2.33 mm respectively, whereas at follow-up evaluation they were 19.5+/-7.03 degrees (P>0.05), 22.2+/-3.43 degrees (P<0.05), and 10.6+/-1.71 mm (P<0.05) respectively. None of the patients showed pre- or postoperative cervical instability. The fusion rate was 97.5%., Conclusion: PEEK cage-assisted ACDF at four levels is an effective procedure for the treatment of patients with spondylotic compression of the spinal cord and/or nerve roots from C3-C4 to C6-C7.

A peculiar type of meningioma with conspicious plasma-cell components is described. In accordance with the World Health Organization's Histological Typing of Tumours of the Central Nervous System, this rare clinical entity is recently designed as lymphoplasmacyte rich (LPR) meningioma. This type of meningioma is usually accompanied by prominent peripheral blood abnormalities, anemia and/or policlonal gammophaty, that disappear after surgical removal of the tumor. Actually, the origin (neoplastic or inflammatory) of this tumor is unclear; its biological behavior and clinical course are anomalous so it is considered closer to intracranial inflammatory masses rather than typical meningioma. In this paper, a new case of intracranial LPR meningioma occurring in a woman, is reported and a review the literature is made.

Gross intracranial hemorrhage associated with brain tumor has been reported to range from 3.6-10%. Brain metastases and malignant glioma are the most frequent underlying pathologies. Intracranial hemorrhage related to meningioma is a rare condition. Subarachnoid hemorrhage, acute subdural hematoma, intratumoral and intraparenchymal hematomas are the most common forms of bleeding associated with meningioma. By contrast, chronic subdural hematoma (cSDH) and intraventricular hemorrhage are seen less frequently. The authors report a very rare case of left fronto-parietal convexity meningioma associated with bilateral cSDH in a patient with history of recent minor head trauma and review the literature on hemorrhage associated with meningiomas.

In order to have knowledge on the histopathologic characteristics of the HCV infections in our geographical area and its relation with some epidemiologic variables, a series of 54 biopsies of Anti HCV (R) patients was analyzed. The histologic lesions found in this study correspond mostly to patients with relatively early infections, on the contrary to other studies of the some kind. The most frequent histopathologic diagnosis were chronic hepatitis 38/54 (70.4%), steatosis 4/54 (7.4%) and 12/54 (22.2%) with no changes. The presence of lymphoid follicles in the portal tracts was the most frequent histological change in this series (66.7%), followed by the alteration in bile ducts (53.7%); they occurred in a significantly higher proportion in the biopsies which had a diagnosis of chronic hepatitis (p = 0.02) (p = 0.000002). The presence of steatosis and acidophilic bodies in the acinus were found in nearly one third of the biopsies. This findings suggest that the hepatic damage in the anti HCV reactive patients might take place through immunologic mechanisms and cytopathic direct action. It was not found that histologic changes produced by HCV might differ according to epidemiologic variables (post-transfusional, drug abuse i.v. and sporadic).