Istituto Di Ricovero E Cura A Carattere Scientifico Research Articles

Study on frequency and risk factors for secondary infections among COVID-19 individuals

Secondary Infections (SIs) refer to infections that occur in addition to the initial Corona Virus Disease 2019 (COVID-19) infection. These SI can be caused by bacteria, fungi, or other viruses and they can complicate the clinical course of the disease, leading to worse outcomes. The purpose of the study is to describe the incidence as well as danger factors for SIs in people with COVID-19 diagnoses. This statement describes the methodology used in an ensemble study of COVID-19 individuals who were hospitalized at Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), from February to April 2020, San Raffaele Hospital. In the study's 731 individuals, 68 had SIs, which resulted in an overall 28-day cumulative frequency and risk factors. Infections with gram-positive bacteria, particularly coagulase-negative staphylococcus have been accountable for most bloodstream infections (BSIs), but gram-negative pathogens, such Acinetobacter baumannii and Escherichia coli, were less frequent. Eleven people were identified in the investigation as possibly suffering from significant aspergillosis. Following the very first 48 hours following residential therapy, the individual was brought to the Intensive-Care Unit (ICU) due to an insufficient initial lymphocytes level. The finding that early need for ICU has been connected to a higher chance of developing infections in the future highlights the importance of prompt and appropriate treatment for individuals with serious COVID-19.

Denosumab for giant cell tumors of bone from 2010 to 2022: a bibliometric analysis.

Giant cell tumors of the bone (GCTB) are considered moderately malignant bone tumors. Denosumab, as a neoadjuvant therapy, provides new possibilities for treating GCTB. However, even after multiple studies and long-term clinical trials, there are limitations in the treatment process. Research data and Medical Subject Headings terms related to denosumab and GCTB were collected from January 2010 to October 2022 using the Web of Science and MeSH ( https://meshb.nlm.nih.gov ) browsers. These data were imported into CiteSpace and VOSviewer softwares for bibliometric analysis. Overall, 445 publications on denosumab and GCTB were identified. Over the last 12years, the growth rate of the total number of publications has remained relatively stable. The USA published the highest number of articles (83) and had the highest centrality (0.42). Amgen Inc. and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) First Ortoped Rizzoli were identified as the most influential institutions. Many authors have made outstanding contributions to this field. Lancet Oncology had the highest journal impact factor (54.433). Local recurrence and drug dosage are current research hotspots, and future development trends will mainly focus on prognostic markers of GCTB and the development of new therapies. Further research is required to analyze denosumab's safety and efficacy and understand its local recurrence of GCTB, to identify the optimal dose. Future progress in this field will likely focus on exploring new diagnostic and recurrence markers to monitor disease progression and examine new therapeutic targets and treatment strategies.

Determinants of epigenetic resistance to HDAC inhibitors in dystrophic fibro-adipogenic progenitors.

Pharmacological treatment of Duchenne muscular dystrophy (DMD) with histone deacetylase inhibitors (HDACi) is currently being tested in clinical trials; however, pre‐clinical studies indicated that the beneficial effects of HDACi are restricted to early stages of disease. We show that FAPs from late‐stage mdx mice exhibit aberrant HDAC activity and genome‐wide alterations of histone acetylation that are not fully reversed by HDACi. In particular, combinatorial H3K27 and/or H3K9/14 hypo‐acetylation at promoters of genes required for cell cycle activation and progression, as well as glycolysis, are associated with their downregulation in late‐stage mdx FAPs. These alterations could not be reversed by HDACi, due to a general resistance to HDACi‐induced H3K9/14 hyperacetylation. Conversely, H3K9/14 hyper‐acetylation at promoters of Senescence Associated Secretory Phenotype (SASP) genes is associated with their upregulation in late‐stage mdx FAPs; however, HDACi could reduce promoter acetylation and blunt SASP gene activation. These data reveal that during DMD progression FAPs develop disease‐associated features reminiscent of cellular senescence, through epigenetically distinct and pharmacologically dissociable events. They also indicate that HDACi might retain anti‐fibrotic effects at late stages of DMD.

Psychological Support in a COVID-19 Hospital: A Community Case Study.

Burnout is a well-documented entity in Care Workers population, affecting up to 50% of physicians, just as it is equally well established that managing an infectious disease outbreaks, such as confirmed in the COVID-19 pandemic, increases Post-Traumatic Stress Disorder (PTSD) and the psychological burden. Mental health support, in the form of formal or remote sessions, has been shown to be helpful to health care staff, despite the organizational difficulties in an emergency. During the first emergence of COVID-19 in Italy, the Scientific Institute for Research, Hospitalization and Health Care Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo Foundation (Pavia, Lombardy), the Italian hospital that treated “patient 1,” has activated an agreement with the Soleterre Foundation, an international Non-Governmental Organization (NGO) that manages health emergency projects, to provide psychological support. A task force of psychologists was created with the aim of designing and administering a Therapeutic Mental Health Assessment for COVID-19 Care Workers (TMHA COVID-19 CWs) to evaluate and support health care workers’ mental health. The assessment battery was developed to evaluate symptoms and behaviors associated with trauma and the corresponding maladaptive behaviors (the National Stressful Events Survey for PTSD-Short Scale “NSESSS” and the Diagnostic and Statistical Manual of Mental Disorders “DSM-5” Self-Rated Level 1 transversal Symptom Measure—Adult). Once the TMHA COVID-19 CWs had been developed, the team of psychologists regularly visited healthcare staff in the ward to administer it. One hundred seven care workers (44 males, mean age 40 ± 15) across Intensive Care Units (ICUs), the emergency room and medical ward were administered the TMHA COVID-19 CWs. PTSD symptoms were reported as severe by 13% of the population. Depressive symptoms as severe for 7% and Anxiety symptoms as severe for 14%. Severe psychotic symptoms were experienced by 2% and severe suicidal thoughts by 1% of the population. The possibility of acting upon the results of the TMHA COVID-19 CWs allowed an early intervention through individual session beyond the cut-off level (moderate and severe symptoms) for PTSD in NSESSS. In fact, 280 individual support sessions were offered. Therefore, we considered our project a protective and support factor for healthcare workers’ mental well-being and we recommend implementing a mental health screening program in ward involved in COVID-19 patients’ care.

713 Culprit plaque morphology and healing capacity in patients with and without preinfarction angina: an optical coherence tomography imaging study

Abstract Aims The relationship between culprit plaque morphology, healed culprit plaques prevalence and clinical presentation of acute myocardial infarction (AMI) remains largely unexplored. We hypothesized that angina preceding the occurrence of AMI (pre-infarction angina, PIA) may reflect a distinct morphologic phenotype of culprit plaques and potentially different healing capacity. Methods and results We conducted a retrospective observational study in patients with AMI who underwent intracoronary optical coherence tomography (OCT) imaging of the culprit lesion before PCI at the Fondazione Policlinico A. Gemelli–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome. Based on the clinical history, patients were classified into two groups: (i) PIA group, defined as either intermittent chest pain within 6 h preceding the final episode of chest pain, or unstable angina (or both) in the week preceding AMI or (ii) no-PIA group, defined as a single episode of chest pain without prodromal symptoms in the preceding week. Culprit plaques were classified as plaque rupture (PR) or intact fibrous cap (IFC), and presence of layered appearance (healed plaque, HP) was assessed. Thrombus burden (TB) was estimated, and prevalence of diffuse calcification, neovascularization, and OCT-defined macrophage accumulation were evaluated. A total of 102 patients with AMI were included (50 PIA, 52 no-PIA). Patients with PIA showed a higher prevalence of IFC than PR (58% vs. 42%, P = 0.030). PR in patients with PIA were more frequently associated with macrophage accumulation (71.4% vs. 28.6% P = 0.001), and TB tended to be lower [22.0 (15.8–30.3) vs. 38.5 (12.8–67.5), P = 0.145]. Diffuse calcifications were significantly less frequent in patients with PIA (22.0% vs. 40.4%, P = 0.045), while neovascularization tended to be more frequent (58.0% vs. 42.3%, P = 0.113). HPs prevalence was significantly higher in the PIA than in the no-PIA group (66.0% vs. 25.0%, P < 0.001). Conclusions Patients with PIA have a distinct culprit plaque phenotype, more frequently characterized by IFC and a relatively lower TB, with a significantly higher prevalence of plaque healing.

The Monitoring of Psychosocial Factors During Hospitalization Before and After Cardiac Surgery Until Discharge From Cardiac Rehabilitation: A Research Protocol.

Introduction: There is considerable evidence that psychosocial factors contribute to the etiology and prognosis of cardiac illness. Currently, in Italy, psychologists are only obligatory in the cardiac rehabilitation setting, although there are indications that patients could be experiencing distress also during other moments of hospitalization, such as on admission for cardiac surgery. Objective and Methods: The objective of this protocol is to gain more information about cardiac patients, specifically during the various moments of hospitalization for cardiac surgery, by collecting data at admission before cardiac surgery (t0), at admission to cardiac rehabilitation (t1), and at discharge (t2) at the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato hospital. A psychosocial questionnaire was constructed after consulting the relevant national and international guidelines. Patients admitted for cardiac surgery and attending a rehabilitation program will be evaluated by acquiring data about their civil status, religiosity, education and work capacity, social condition (including the presence and quality of intimate relationships and support received), previous psychological and psychiatric histories, psychological status, lifestyle (including questions on nutrition, smoking, alcohol, and substance abuse), adherence to therapy, quality of life (QoL), health perception, anxiety, and depression at t0. Health perception, anxiety, and depression are also measured at t1 and t2. Discussion and Conclusion: This study is an attempt to identify the recommended psychosocial variables which need to be monitored during cardiac patients’ hospitalization for cardiac surgery, through to the completion of cardiac rehabilitation. After implementing this study at the IRCCS Policlinico San Donato, attempts will be made to create studies on a national and international level to generate more evidence regarding these variables, in order to create tailor-made interventions for these patients during these specific and delicate moments.

Characterization of Sarcopenia in an IBD Population Attending an Italian Gastroenterology Tertiary Center

(1) Background: There is growing interest in the assessment of muscular mass in inflammatory bowel disease (IBD) as sarcopenia is associated with important outcomes. The aim of the study was to evaluate the percentage of sarcopenia in IBD patients, characterizing methods for assessment and clinical symptoms associated to it. (2) Methods: Consecutive IBD patients accessing the Fondazione Policlinico Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) were enrolled. Healthy patients, elderly or elderly sarcopenic patients, were enrolled as controls. Skeletal muscle mass was evaluated by Dual Energy X-ray Absorptiometry (DEXA) or Bio-Impedensometric Analysis (BIA). Asthenia degree was assessed by subjective visual analogue scales (VAS). Quality of life was measured by the EQ-5D questionnaire. (3) Results: Patients with IBD showed a significant reduction in skeletal muscle mass than healthy controls with lower DEXA and BIA parameters. Moreover, IBD patients presented a lower perception of muscle strength with a higher incidence of asthenia and reduction in quality of life when compared with healthy controls. A significant association between loss in skeletal muscle mass and high asthenia degree was found, configuring a condition of sarcopenia in about one third of patients with IBD. (4) Conclusions: Sarcopenia is common in IBD patients and it is associated with fatigue perception as well as a reduction in quality of life. Therefore, routine assessment of nutritional status and body composition should be a cornerstone in clinical practice, bringing gastroenterologists and nutritionists closer together for a compact, defined picture.

How to Develop IoT Cloud e-Health Systems Based on FIWARE: A Lesson Learnt

Nowadays, the penetration of sensors and actuators in different application fields is revolutionizing all aspects of our daily life. One of the major sectors that is taking advantage of such cutting-edge cheap smart devices is healthcare. In this context, Remote Patient Monitoring (RPM) at home represents a tempting opportunity for hospitals to reduce clinical costs and to improve the quality of life of both patients and their families. It allows patients to be monitored remotely by means networks of Internet of Things (IoT) medical devices equipped with sensors and actuators that collect healthcare data from patients and send them to a Cloud-based Hospital Information System (HIS) for processing. Up to now, many different proprietary software systems have been developed as stand-along expensive solutions, presenting interoperability, extensibility, and scalability issues. In recent years, the European Commission (EC) has promoted the wide adoption of FIWARE technology, launching 16 Industrial Accelerators focusing on different application fields. One of these, i.e., FICHe, is specialized in healthcare, providing the guidelines on how to develop eHealth systems. This paper focuses on how to compose new cutting-edge IoT and Cloud-based Cyber Physical Health Sytem (CPHS) services and applications interconnected with remote medical sensors and actuators using FIWARE technology in the context envisioned by FICHe. In particular, we discuss the design and development of an RPM system implemented through the collaboration between the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Bonino Pulejo” (i.e., a clinical and research healthcare centre specialized in the treatment of neuro lesions), University of Messina, IBM Research, Telefónica, and the University of the Western Cape in South Africa. The description of our best practice provides a model and guidelines for the development of lightweight and low cost RPM services for rural and isolated areas, with the expectation of expanding healthcare to the developing world and in general allows us to outline how to deal with the real adoption of the FIWARE technology in an e-health project.

Sleep Disturbance in Mild Cognitive Impairment and Association With Cognitive Functioning. A Case-Control Study.

Objectives: The aims of the current study are to (1) report the frequency of specific sleep disturbance symptoms in Mild Cognitive Impairment (MCI) and cognitive healthy older persons; (2) examine whether overall poor sleep and specific sleep disturbance symptoms are more common in persons with MCI compared to cognitive healthy older controls and; (3) examine the association between sleep disturbances and performance in general and specific cognitive domains in persons with MCI and separately in cognitive healthy older persons.Methods: Data were collected at the Fondazione Ospedale San Camillo Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Venice, Italy as part of the European VPH-DARE@IT project. We included 69 persons with MCI (mean age 75.7; SD = 7.7) and 72 sex-matched cognitively healthy controls (mean age 71.8; SD = 7.0). Participants underwent extensive neuropsychological assessment and evaluation of subjective sleep performance with the Sleep Continuity in Alzheimer’s Disease Scale(SCADS).Results: A fifth of MCI patients (21.7%, n = 15) had poor sleep compared to 15.3% (n = 11) of cognitively healthy controls. MCI patients had a 3.2 higher odds of having poor sleep compared to cognitively healthy controls after adjustment for age, education, sex, and general cognitive functioning (Odds Ratio (OR) = 3.2; 95% Confidence Interval (CI) = 1.1–9.2). Persons who reported waking up twice or more during the night had higher odds of being MCI compared to those who never wake or wake only once (OR = 2.6; 95% CI = 1.1–6.1). In MCI patients, poor sleep was associated with better general cognitive functioning and short-term working memory, whereas in cognitive healthy older persons poor sleep was associated with impairment in episodic memory performance and executive functioning.Discussion: Our results confirm previous studies showing that sleep disturbances are common in MCI, and this may be due to an ongoing neurodegenerative process rather than a symptom of cognitive impairment. Future research with objective sleep measurements are needed in MCI as well as interventions to improve sleep with the aim of preventing cognitive decline.

Blood MCP-1 levels are increased in chronic obstructive pulmonary disease patients with prevalent emphysema.

Background and aimsChronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by different phenotypes with either bronchial airways alterations or emphysema prevailing. As blood biomarkers could be clinically useful for COPD stratification, we aimed at investigating the levels of blood biomarkers in COPD patients differentiated by phenotype: prevalent chronic airway disease versus emphysema.MethodsIn 23 COPD patients with prevalent airway disease (COPD-B), 22 COPD patients with prevalent emphysema (COPD-E), 9 control smokers (CSs), and 18 control nonsmokers (CNSs), we analyzed the expression levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, epidermal growth factor (EGF), monocyte chemotactic protein (MCP)-1, and vascular endothelial growth factor by enzyme-linked immunosorbent assay in plasma/serum; glutathione peroxidase and superoxide dismutase (SOD)-1 by immunochemical kits in plasma; and free F2-isoprostanes (F2-IsoPs) by gas chromatography in plasma.ResultsF2-IsoPs level was increased in COPD-B and COPD-E compared with CSs and CNSs; in addition, CS showed higher levels than CNSs; SOD1 level was lower in COPD-B and COPD-E than that in CNSs. Interestingly, MCP-1 level was higher only in COPD-E versus CSs and CNSs; EGF and IL-8 levels were higher in COPD-B and COPD-E versus CNSs; IL-6 level was increased in all three smoking groups (COPD-B, COPD-E, and CSs) versus CNS; IFN-γ and IL-1α levels were higher in CSs than in CNSs; and IL-1α level was also higher in CSs versus COPD-B and COPD-E. In all subjects, F2-IsoPs level correlated positively and significantly with MCP-1, IL-2, IL-1β, IFN-γ, and TNF-α and negatively with SOD1. When correlations were restricted to COPD-E and COPD-B groups, F2-IsoPs maintained the positive associations with IFN-γ, TNF-α, and IL-2.ConclusionWe did not find any specific blood biomarkers that could differentiate COPD patients with prevalent airway disease from those with prevalent emphysema. The MCP-1 increase in COPD-E, associated with the imbalance of oxidant/antioxidant markers, may play a role in inducing emphysema.

The experience of accreditation of the Reggio Emilia Research Hospital with the OECI model.

The research hospital Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) of Reggio Emilia has a unique organization that involves a recently recognized IRCCS in oncology within a preexisting general hospital. The IRCCS of Reggio Emilia joined the "Tailored Accreditation Model for Comprehensive Cancer Centers: Validation through the Applicability of the Experimental OECI-based Model to the Network of Cancer IRCCS of the Alliance Against Cancer" and applied the accreditation & designation (A&D) Organisation of European Cancer Institutes (OECI) model in 2013. Before that accreditation, it had never been accredited according to international accreditation systems concerning cancer. By December 2015, the IRCCS of Reggio Emilia completed the first steps of the A&D OECI process (self-assessment period, peer review visit, implementation of the improvement plan). In December 2014, OECI confirmed the accreditation of our IRCCS and its designation as a Clinical Cancer Center and proposed a revisit at 2 years for upgrading the designation to Comprehensive Cancer Center (CCC). On the whole, the results given by adhesion to the A&D-OECI project are numerous and positive, under different points of view, formal (European accreditation and designation as a Clinical Cancer Center with possible upgrade to CCC) and substantial (involvement of professionals, attention to ongoing improvement, work on the sectors mainly of interest). The balance between the advantages and disadvantages linked to this accreditation model was positive. Following our experience, we conclude that the model was useful also for our kind of IRCCS, with its features useful for investigating all the sectors of the patient care pathway and research and necessity to stimulate change.

The organization of clinical trials for oncology at IRCCS Istituto Nazionale Tumori "Fondazione G. Pascale" Napoli and the impact of the OECI accreditation process.

The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori "Fondazione G. Pascale" (INT-Pascale) is the largest Clinical Care and Research Cancer Center in Southern Italy. The mission is prevention, diagnosis, and care of cancer and innovative research in oncology. In 2013, INT-Pascale joined the Organisation of European Cancer Institutes (OECI) accreditation and classification project along with other Italian IRCCS cancer centers. One of the major OECI requirements that a cancer center must fulfill in order to achieve and maintain OECI certification is a strong emphasis in translational and clinical research: increasing the number of patients enrolled in clinical trials, establishing easily accessible databases for operators, and informing all possible stakeholders, including patients. A characterizing theme of INT-Pascale is a strong commitment to clinical experimental studies. In the 2007-2014 period, 440 clinical trials were activated at INT-Pascale; in this period, the number of clinical trials and observational studies has had an increment achieving in 2014, respectively, the share of 60 clinical trials and 35 observational studies activated. Optimization of clinical trials management and dissemination of the clinical research culture at INT-Pascale are main objectives to be achieved through several actions and procedures being implemented as a component of the OECI improvement plan. Participation in the OECI program has represented an important challenge to improve quality and processes related to promoting, prioritizing, and monitoring clinical trials at INT-Pascale.

MR blockade protects against diet induced obesity, adipocyte dysfunction and cardiac inflammation in mice, through browning of the adipose organ and modulation of autophagy

Obesity is a key factor in the development of insulin resistance (IR), cardiovascular disease, hypertension, type 2 diabetes etc. Given the near epidemic incidence of obesity in western society there is a clear need for effective treatment options. Mineralocorticoid receptor (MR) blockade has shown significant promise in transgenic mouse models of obesity in limiting IR and adipocyte dysfunction, a disease that is independent of classical MR actions (renal). Female 10-weekold C57bl6 mice were fed with normal chow or a high fat (HF) diet for 12 weeks. Mice fed HF diet were concomitantly treated for 12 weeks with drospirenone (DRSP, 6 mg/kg/day), a potent MR antagonist with antiadipogenic activity, or spironolactone (SPIRO, 20 mg/kg/day). Mice fed HF diet showed a significant increase in total body weight, fat mass, mean adipocyte size, expression of white adipose tissue (WAT) marker genes and showed impaired glucose tolerance after intraperitoneal plasma glucose tolerance test. DRSP and SPIRO prevented weight gain and white fat mass expansion induced by HF diet in parametrial, perivescical, and inguinal depots without affecting interscapular fat pad weight. Magnetic Resonance Imaging (MRI) confirmed that MR antagonists blocked the HF dietdriven expansion of abdomino-pelvic (parametrial and perivescical) fat volume. High levels of MR mRNA were detected in all depots of adipose tissue. HF fed mice showed no increase in heart or kidney weight and tissue fibrosis. Cardiac macrophage recruitment and osteopontin staining was increased in hearts of HF fed mice and reversed by both MR antagonists. Moreover, both DRSP and SPIRO prevented the impaired glucose tolerance in mice fed HF diet, and countered HF diet-induced up-regulation of WAT markers transcripts and adipocyte hypertrophy. Importantly, MR antagonists increased uncoupling protein 1 (UCP-1) positive brown-like adipocyte content in WAT, and improved metabolic activity of adipose tissue, as indicated by PET/CT imaging. In keeping with this, MR antagonism significantly increased expression of brown-like adipocyte marker genes such PRDM16, CIDEA, beta-3 adrenergic receptor (ADRB3) and UCP-1 in all WAT depots analysed. In exploring the mechanism, we demonstrated that MR antagonism induced brown adipose tissue (BAT) markers, and reduced the autophagic rate, a key remodelling process in adipocyte differentiation, in WAT depots in vivo as well as in primary cultured adipocytes. We conclude that adipocyte MR regulates BAT-like remodeling of WAT through modulation of autophagy. MR blockade therefore has promise as a novel therapeutic option for the prevention of metabolic dysfunctions and the cardiac consequences of obesity. doi:10.1016/j.ijcme.2015.05.012 Transcriptional control of ICAM-1 in human coronary artery endothelial cells by Mineralocorticoid Receptor (MR): Implications for the protective effects of MR antagonists in cardiovascular diseases V. Marzolla, A. Armani, A. Fabbri, I.Z. Jaffe, M. Caprio Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy Department of Medicina dei Sistemi, Endocrinology Unit, S. Eugenio & CTO A. Alesini Hospitals, University Tor Vergata, Rome, Italy Molecular Cardiology Research Institute, Tufts Medical Center, Boston,

Transcriptional control of ICAM-1 in human coronary artery endothelial cells by Mineralocorticoid Receptor (MR): Implications for the protective effects of MR antagonists in cardiovascular diseases

Obesity is a key factor in the development of insulin resistance (IR), cardiovascular disease, hypertension, type 2 diabetes etc. Given the near epidemic incidence of obesity in western society there is a clear need for effective treatment options. Mineralocorticoid receptor (MR) blockade has shown significant promise in transgenic mouse models of obesity in limiting IR and adipocyte dysfunction, a disease that is independent of classical MR actions (renal). Female 10-weekold C57bl6 mice were fed with normal chow or a high fat (HF) diet for 12 weeks. Mice fed HF diet were concomitantly treated for 12 weeks with drospirenone (DRSP, 6 mg/kg/day), a potent MR antagonist with antiadipogenic activity, or spironolactone (SPIRO, 20 mg/kg/day). Mice fed HF diet showed a significant increase in total body weight, fat mass, mean adipocyte size, expression of white adipose tissue (WAT) marker genes and showed impaired glucose tolerance after intraperitoneal plasma glucose tolerance test. DRSP and SPIRO prevented weight gain and white fat mass expansion induced by HF diet in parametrial, perivescical, and inguinal depots without affecting interscapular fat pad weight. Magnetic Resonance Imaging (MRI) confirmed that MR antagonists blocked the HF dietdriven expansion of abdomino-pelvic (parametrial and perivescical) fat volume. High levels of MR mRNA were detected in all depots of adipose tissue. HF fed mice showed no increase in heart or kidney weight and tissue fibrosis. Cardiac macrophage recruitment and osteopontin staining was increased in hearts of HF fed mice and reversed by both MR antagonists. Moreover, both DRSP and SPIRO prevented the impaired glucose tolerance in mice fed HF diet, and countered HF diet-induced up-regulation of WAT markers transcripts and adipocyte hypertrophy. Importantly, MR antagonists increased uncoupling protein 1 (UCP-1) positive brown-like adipocyte content in WAT, and improved metabolic activity of adipose tissue, as indicated by PET/CT imaging. In keeping with this, MR antagonism significantly increased expression of brown-like adipocyte marker genes such PRDM16, CIDEA, beta-3 adrenergic receptor (ADRB3) and UCP-1 in all WAT depots analysed. In exploring the mechanism, we demonstrated that MR antagonism induced brown adipose tissue (BAT) markers, and reduced the autophagic rate, a key remodelling process in adipocyte differentiation, in WAT depots in vivo as well as in primary cultured adipocytes. We conclude that adipocyte MR regulates BAT-like remodeling of WAT through modulation of autophagy. MR blockade therefore has promise as a novel therapeutic option for the prevention of metabolic dysfunctions and the cardiac consequences of obesity. doi:10.1016/j.ijcme.2015.05.012 Transcriptional control of ICAM-1 in human coronary artery endothelial cells by Mineralocorticoid Receptor (MR): Implications for the protective effects of MR antagonists in cardiovascular diseases V. Marzolla, A. Armani, A. Fabbri, I.Z. Jaffe, M. Caprio Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy Department of Medicina dei Sistemi, Endocrinology Unit, S. Eugenio & CTO A. Alesini Hospitals, University Tor Vergata, Rome, Italy Molecular Cardiology Research Institute, Tufts Medical Center, Boston,

Mutations of the Mitochondrial-tRNA Modifier MTO1 Cause Hypertrophic Cardiomyopathy and Lactic Acidosis

Dysfunction of mitochondrial respiration is an increasingly recognized cause of isolated hypertrophic cardiomyopathy. To gain insight into the genetic origin of this condition, we used next-generation exome sequencing to identify mutations in MTO1, which encodes mitochondrial translation optimization 1. Two affected siblings carried a maternal c.1858dup (p.Arg620Lysfs(∗)8) frameshift and a paternal c.1282G>A (p.Ala428Thr) missense mutation. A third unrelated individual was homozygous for the latter change. In both humans and yeast, MTO1 increases the accuracy and efficiency of mtDNA translation by catalyzing the 5-carboxymethylaminomethylation of the wobble uridine base in three mitochondrial tRNAs (mt-tRNAs). Accordingly, mutant muscle and fibroblasts showed variably combined reduction in mtDNA-dependent respiratory chain activities. Reduced respiration in mutant cells was corrected by expressing a wild-type MTO1 cDNA. Conversely, defective respiration of a yeast mto1Δ strain failed to be corrected by an Mto1(Pro622∗) variant, equivalent to human MTO1(Arg620Lysfs∗8), whereas incomplete correction was achieved by an Mto1(Ala431Thr) variant, corresponding to human MTO1(Ala428Thr). The respiratory yeast phenotype was dramatically worsened in stress conditions and in the presence of a paromomycin-resistant (P(R)) mitochondrial rRNA mutation. Lastly, in vivo mtDNA translation was impaired in the mutant yeast strains.

Launch of the ComNet (comet network) project on the comet assay in human population studies during the International Comet Assay Workshop meeting in Kusadasi, Turkey (September 13-16, 2011)

To whom correspondence should be addressed. Clinical and MolecularEpidemiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) SanRaffaele Pisana, Via di Val Cannuta, 247, 00166 Rome, Italy. Tel: þ39 0652253418; Fax: þ39 06 52255668; Email: stefano.bonassi@sanraffaele.itReceived on December 27, 2011; revised on February 22, 2012;accepted on February 23, 2012

Late-onset hereditary spastic paraplegia with thin corpus callosum caused by a new SPG3A mutation

Mutations in the SPG3A gene cause the most frequent autosomal dominant (AD) type of pure hereditary spastic paraplegia (HSP) with very early onset [1, 2]. Here, we report a novel disease-associated mutation in the SPG3A gene in an immigrant South African Zulu family with ADHSP and atypical clinical characteristics. Individuals were clinically evaluated by two neurologists with a proven experience in HSPs (A.O., G.B.). The proband (Fig. 1a, II:3) was a 68-year-old male. He had had progressive walking disturbance from the age of 56 years and a hoist had been required from the age of 66 years. A recent neurological examination disclosed moderate disease severity (SPRS [3] score 35/52) and mild mental retardation (WAIS-R IQ [4] score 62). Furthermore, the patient reported urinary incontinence due to sphincter incompetence. Brain MRI showed a thin corpus callosum (TCC) without cerebellar involvement or white matter abnormalities (Fig. 1b). The spinal cord MRI demonstrated no abnormal signal intensity or atrophy. Similar clinical features, including a late-onset of the disease (55 ± 5.6 years, mean ± SD), mental impairment and the occurrence of TCC, were observed in the other family members (Table 1). After informed consent was given by participants, genomic DNA was isolated from blood samples and subject to linkage analyses at all currently known ADHSP loci (OMIM web site: http://www.ncbi.nlm.nih.gov/omim). HSP gene sequences were studied by direct sequencing. The PCR-RFLP method was used for segregation analysis as described previously [5]. Significant two-point lod scores were obtained at the microsatellite markers of the SPG3A region (Zmax = 4.11 for D14S269 at h = 0.0), while linkage to the other known ADHSP loci was excluded. Sequence analysis of SPG3A demonstrated a novel heterozygous change in exon 12 (c.1246 C[T), resulting in the change of amino acid arginine to cysteine at codon 416 (R416C). The PCR-RFLP analyses showed that all affected family members carried the mutation in SPG3A, while the unaffected members did not (Fig. 1). The mutation was absent in 400 control chromosomes from unrelated South African Zulu individuals. In addition, sequence analyses of the known genes causing HSP with mental retardation and TCC (SPG1, SPG7, SPG11, SPG15 and SPG21) showed no pathological nucleotide changes. We detected a novel R416C missense mutation in a South African Zulu family with ADHSP. The genetic variation fell on exon 12, in accordance with the literature indicating a frequency of 35% for SPG3A mutations in this exon [2], and the R416C amino acid change could exert its pathogenic effect by generating an aberrant secondary A. Orlacchio (&) P. Montieri C. Babalini F. Gaudiello G. Bernardi Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, 64 Via del Fosso di Fiorano, 00143 Rome, Italy e-mail: a.orlacchio@hsantalucia.it

Close Encounters of the Third Kind

Following vascular injury, endothelial cells become activated in the attempt to repave the damaged luminal surface. In addition, a physical interaction is established not only among the denuded subendothelial matrix, activated platelets, and circulating inflammatory cells but also with the progenitor cells (PCs).1 Endothelial survival, proliferation, and migration, necessary for re-coverage of exposed lamina, are aided by CD34+ PCs that express the vascular endothelial growth factor (VEGF) receptor-2/kinase-insert domain receptor (KDR). However, whether these cells enter the peripheral circulation as a predefined population or acquire their final antigenic phenotype on homing to the peripheral vasculature remains a matter of debate. See accompanying article on page 408 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , de Boer et al propose that human CD34+/KDR+ cells are generated from circulating CD34+ cells after immobilization on activated platelets.2 By using an ex vivo flow model, the authors show that activated platelets favor the homing of CD34+ cells to sites of vascular injury and that, on cell immobilization, KDR is rapidly translocated from an endosomal compartment to the cell surface. Presumably, PCs shed afterward to “carry the message” into the circulation. It is noteworthy that de Boer et al also report an increased coexpression of KDR on CD34+ cells in type-2 diabetes, which was reduced by aspirin treatment. The authors conclude that their data might have implications for the identification of patients with subclinical vascular injury, on the basis of the hypothesis that activated/injured endothelium provides more opportunity …

Large Pituitary Hyperplasia in Severe Primary Hypothyroidism

Endocrinology and Diabetology Unit (E.P., A.T., B.A., S.C.), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Donato, 20097 San Donato Milanese, Milan, Italy; Department of Medical-Surgical Sciences (E.P., B.A., S.C.), University of Milan, 20097 San Donato Milanese, Milan, Italy; Department of Neurosurgery (M.L.), IRCCS Fondazione Ca’ Granda Policlinico, 20122 Milano, Milan, Italy; and Endocrinology Unit (A.G.L.), Department of Medical Sciences, University of Milan, IRCCS Fondazione Ca’ Granda Policlinico, 20122 Milan, Italy

Prevention and Diagnosis of Ventilator-Associated Pneumonia

Prevention and Diagnosis of Ventilator-Associated Pneumonia