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The growing penetration of non-programmable renewable energy sources and the consequent fluctuations in energy prices and availability lead to the need to enhance energy system flexibility and synergies between different energy vectors. This can be reached through sector integration. Among the most relevant technologies used for this purpose, Power-to-Gas systems allow excess renewable electricity to be converted directly into fuels that can be then stored or used. A smart energy system, however, which includes these innovative solutions, requires intelligent management methods to optimize its operation. This work investigates the operational strategy of energy systems integrated with Power-to-Gas solutions for seasonal storage, by developing an optimization model for the system, formulated as Mixed-Integer Linear Programming problem. The algorithm tackles the uncertain nature of future disturbances, such as energy needs, generation and price using two-stage stochastic programming. The algorithm is tested on grid-connected and 100% renewable energy supply case studies. The novel stochastic algorithm allows a more robust optimization compared to a deterministic optimization, and system management is ensured under several future disturbances realization. Furthermore, the integration of Power-to-Gas solutions warrants the energy security of the energy systems and acts as a buffer to forestall unpredictable behavior of the disturbances.

Background: FGFR1 regulates cell–cell adhesion and extracellular matrix architecture and acts as oncogene in several cancers. Potential cancer driver mutations of FGFR1 occur in neuroblastoma (NB), a neural crest-derived pediatric tumor arising in sympathetic nervous system, but so far they have not been studied experimentally. We investigated the driver-oncogene role of FGFR1 and the implication of N546K mutation in therapy-resistance in NB cells. Methods: Public datasets were used to predict the correlation of FGFR1 expression with NB clinical outcomes. Whole genome sequencing data of 19 paired diagnostic and relapse NB samples were used to find somatic mutations. In NB cell lines, silencing by short hairpin RNA and transient overexpression of FGFR1 were performed to evaluate the effect of the identified mutation by cell growth, invasion and cologenicity assays. HEK293, SHSY5Y and SKNBE2 were selected to investigate subcellular wild-type and mutated protein localization. FGFR1 inhibitor (AZD4547), alone or in combination with PI3K inhibitor (GDC0941), was used to rescue malignant phenotypes induced by overexpression of FGFR1 wild-type and mutated protein. Results: High FGFR1 expression correlated with low relapse-free survival in two independent NB gene expression datasets. In addition, we found the somatic mutation N546K, the most recurrent point mutation of FGFR1 in all cancers and already reported in NB, in one out of 19 matched primary and recurrent tumors. Loss of FGFR1 function attenuated invasion and cologenicity in NB cells, whereas FGFR1 overexpression enhanced oncogenicity. The overexpression of FGFR1N546K protein showed a higher nuclear localization compared to wild-type protein and increased cellular invasion and cologenicity. Moreover, N546K mutation caused the failure in response to treatment with FGFR1 inhibitor by activation of ERK, STAT3 and AKT pathways. The combination of FGFR1 and PI3K pathway inhibitors was effective in reducing the invasive a

The climate change includes a decrease in seawater pH, and an increase in its temperature. It is possible that the marine fish sperm cells, which are released to the sea at spawning, can be affected by these expected changes on the water, and become unable of fulfill its role on fertilization. For that reason, different seawater pH has been tested in 3 aquaculture marine species: the European eel (Anguilla anguilla), the European seabass (Dicentrarchus labrax), and the Senegalese sole (Solea senegalensis), and their sperm motility parameters analyzed by a CASA-mot system. In the European eel, tested seawater pH, from 6.5 to 9.5, affected sperm motility and other kinetic parameters like MP, FA, VCL, VAP, LIN, STR, WOB, ALH and BFC. pH values lower than 7.8 or higher than 8.2 caused lower values of motility and the rest of kinetic parameters. The longevity was not affected by pH from 7.6 to 8.2. In other experiment a seawater pH of 7.8 caused lower motility, FA, VSL, VAP and LIN than a seawater with pH 8.2. The effect of the water temperature was tested, by comparing activation with seawater at 4 °C (our control) and at 23-24 °C. The spermatozoa beating cross frequency (BCF) was the only parameter significantly affected, being lower at 23 °C than at 4 °C. In other experiment where we combined 2 temperatures (4, 24 °C) and two pH (7.8, 8.2), a significant interaction was observed, and in general the worst results were obtained with seawater at 4 °C and at pH 7.8. Considering all these data, it seems that the seawater pH has a deeper effect on the eel sperm motility than a high temperature. Regarding European sea bass and Senegalese sole, motility and other sperm parameters were not affected by seawater temperature in the pH range from 6.5 to 9.5, thus indicating that ocean acidification would not affect their behavior. The differences found between these species, evolutively and ecologically differents, could reflect different activation mechanisms of the spermatozoa m

La grande sfida che ci pone la fragilità è la difficoltà a ricondurla a un singolo dominio perché connette le dimensioni biologica e soggettiva di perdita di resistenza e di capacità di adattamento ad eventi stressogeni, a cambiamenti, perché non è peculiare di un'unica fascia di età, anche se fortemente influenzata dall'età avanzata, perché non equivalente alla cronicità, alla politologia e non significa disabilità o non autosufficienza, di cui è però un precursore. Quindi una condizione multifattoriale nella quale intervengono fortemente molti determinanti della salute che se individuata precocemente, trattata e gestita può, in alcuni casi, regredire e/o rallentare il suo decorso. Per questi motivi il Gruppo di Lavoro Primary Health Care di SItI ha deciso, dopo la stesura del position paper La Fragilità in una prospettiva di Sanità Pubblica: principi e strumenti per un approccio "life course" orientato alla prevenzione, di dar voce, in un volume, a tutti i professionisti coinvolti e ai cittadini sui modi per definire e riconoscere la fragilità secondo un approccio multidimensionale che possa diventare guida, riflessione e formazione sulla fragilità ad ampio spettro. In particolare il progetto editoriale si rivolge agli operatori della salute per orientarli, attraverso l'acquisizione di competenze specifiche, nelle attività di prevenzione, monitoraggio, coordinamento ed integrazione dei servizi che si rivolgono a questa ampia fascia di popolazione. Si sono volutamente mantenute le posizioni diversificate degli autori per offrire, in un'unica raccolta, visioni differenti e comunque in evoluzione fra professionisti e ricercatori con estrazioni ed esperienze variegate per sottolineare la necessità di un approccio interdisciplinare ad una tematica che approda a servizi e attività che vanno dal livello territoriale a quello specialistico e "super-specialistico", ma soprattutto che coinvolgono tutta la comunità in una rete di relazioni formali ed i

Background High-risk neuroblastomas (HR-NBs) are rare, aggressive pediatric cancers characterized by resistance to therapy and relapse in more than 30% of cases, despite using an aggressive therapeutic protocol including targeting of GD2. The mechanisms responsible for therapy resistance are unclear and might include the presence of GD2neg/low NB variants and/or the expression of immune checkpoint ligands such as B7-H3. Method Here, we describe a multiparametric flow cytometry (MFC) combining the acquisition of 10 6 nucleated singlets, Syto16pos CD45neg CD56pos cells, and the analysis of GD2 and B7-H3 surface expression. 41 bone marrow (BM) aspirates from 25 patients with NB, at the onset or relapse, are analyzed, comparing results with cytomorphological analysis (CA) and/or immunohistochemistry (IHC). Spike in experiments assesses the sensitivity of MFC. Kaplan-Meier analysis on 498 primary NBs selects novel prognostic markers possibly integrating the MFC panel. Results No false positive are detected, and MFC shows high sensitivity (0.0005%). Optimized MFC identifies CD45negCD56pos NB cells in 11 out of 12 (91.6%) of BM indicated as infiltrated by CA, 7 of which coexpress high levels of GD2 and B7-H3. MFC detects CD45negCD56posGD2neg/low NB variants expressing high surface levels of B7-H3 in two patients with HR-NB (stage M) diagnosed at 53 and 139 months of age. One of them has a non-MYCN amplified tumor with unusual THpos PHOX2Bneg phenotype, which relapsed 141 months post-diagnosis with BM infiltration and a humerus lesion. All GD2neg/low NB variants are detected in patients at relapse. Kaplan-Meier analysis highlights an interesting dichotomous prognostic value of MML5, ULBPs, PVR, B7-H6, and CD47, ligands involved in NB recognition by the immune system. Conclusions Our study validates a sensitive MFC analysis providing information on GD2 and B7-H3 surface expression and allowing fast, specific and sensitive evaluation of BM tumor burden. With other routinely u

The sexual maturation of the European eel (A. anguilla) has been traditionally induced by hormonal treatments, requiring weekly handling and causing fish stress. The osmotic pumps (OP) were tested as an alternative method for induction of maturation of eel males and females. Males were divided in Control, OP-100 and OP-200 groups (n=10/group). The control group received weekly injections of recombinant hCG (1.5 IU/g fish) for 15 weeks. The induction of sexual maturation of OP groups was carried out by implanted hCGrec-loaded osmotic pumps (ALZET 1004 and 2006). Sperm samples were weekly collected by stripping and several sperm parameters were evaluated by CASA. Biometric parameters such as fin color and gonadosomatic index were evaluated as key indicators of maturation. Blood samples were taken and 11-ketotestosterone levels determined by a specific EIA. Osmotic pumps induced the maturation and spermiation in males, but without the required intensity to produce a sufficient quantity of gametes (sperm volume, density) or quality parameters (motility) for aquaculture purposes. Eel females were divided in Control (n=11) and OP-2ML4 group (n=10). The control group received weekly injections carp pituitary extract (CPE; 20 mg/kg fish) for 15-20 weeks. The OP2ML4 group was implanted with a CPE-loaded OP ALZET 2ML4. The females were weekly monitored and those riped were induced to spawn and artificial fertilization was performed. The gonadosomatic index was also evaluated. The results showed that OP evoked an unusual early maturation in some females, evidencing that this method might become a viable alternative for eel hatchery procedures.

The European eel (A. anguilla) is a valued species targeted for aquaculture production. However, it is considered a critically endangered species and its reproduction in captivity seems to be the only alternative to solve both economic and ecological problems. Although it is possible to obtain eel gametes for artificial fertilization, it requires longterm hormonal treatments. Recent studies found that cold seawater stimulates the brainpituitary-gonad axis in eel males, inducing the start of spermatogenesis. These results suggested that cold seawater could be used as a pre-treatment before the standard hormonal therapy applied to induce sexual maturation, to obtain higher sperm quantity and quality. Thus, our study evaluates the effects of cold seawater pre-treatments of different duration (1, 2 and 4-weeks) on reproductive performance of eel males. Biometric parameters from control and pre-treated fish were measured. Blood and testis samples were collected for steroid (T, 11-KT and E2) and histology analyses, respectively. Once eels were spermiating, sperm parameters were evaluated using a CASA system. Eel males pre-treated with cold temperature showed increased biometric indexes, androgens and E2 plasma levels. Males maintained at 10 ºC for 4-weeks showed a significantly higher percentage of differentiated type A spermatogonia in comparison to undifferentiated ones. However, the low sperm quality found in the pre-treated groups revealed that pretreatments followed by recombinant human chorionic gonadotropin (rechCG) treatment at high temperatures impairs spermatogenesis. Cold temperature pre-treated males had a time-dependent and fast response to rechCG treatment, but their spermiation period was shorter and sperm parameters were significantly lower. Further research is needed to study the effect of thermic pre-treatments on gene regulation controlling spermatogenesis.

[Introduction]: The European eel (Anguilla anguilla) is a highly valued species targeted for aquaculture production. However, it is considered a critically endangered species by CITES, and reproduction in captivity seems to be the only realistic alternative to solve both economic and ecological problems (Asturiano, 2020). It is possible to obtain gametes for artificial fertilization but it requires hormonal treatment, which is a time-consuming and expensive process (Gallego et al., 2012). Moreover, the variable response to these treatments results in high mortality rates during the early stages of development, which could be caused (at least in part) by low sperm quality and uncontrolled epigenetic factors (Herráez et al., 2017). Considering the environmental conditions experienced during eels oceanic migration, the effects of low temperature combined with hormonal treatment have been used to better understand the onset of eel maturation (Peñaranda et al., 2016). Thus, the present study considers the use of low temperature as a pre-treatment before starting a standard hormonal treatment and evaluates its impact on eel maturation and male reproductive performance., [Material and Methods]: Eighty-eight male European eels were maintained for 3-4 days in freshwater at 20 ºC. Then, 6 males were sacrificed, as initial control, and the rest were changed to seawater at 10 ºC, except the control group, which was changed to seawater but maintained at 20 ºC. Low water temperature pre-treatments were applied during 1, 2 or 4 weeks to groups of 20 males. Once finished each pre-treatment, 8 fish per group were sacrificed for sampling. The temperature of the water of the remaining males was increased to 20 ºC in 3-4 days and they started receiving standard hormonal treatment (weekly administration of recombinant chorionic human gonadotropin, rhCG; Ovitrelle, Spain, 1.5 IU/g fish). From sacrificed fish (controls and pre-treated) biometric parameters were measured. Blood and testis samples were used to perform steroid (T, 11-KT and E2) analyses and histology, respectively. Once eels were spermiating, sperm volume, motility and kinetic parameters were evaluated weekly using a CASA system., [Results]: The eye, fin and hepatosomatic indexes from 1-week, 2- and 4-weeks pre-treated fish were significantly higher than those of the control group. The gonadosomatic indexes registered in the control group were unusually high and significantly differed with 1-week pre-treatment group but not with the 2- and 4-weeks groups. Androgen levels (T, 11-KT) were significantly higher after 4-weeks of pre-treatment in comparison with the control. The E2 levels did not show the same increasing profile. The control and 1-week pre-treated males showed significantly higher percentages of undifferentiated and differentiated type A spermatogonia in comparison with early spermatogonia type B. The males after 2- and 4-weeks of pre-treatment revealed a significantly increased proportion of differentiated spermatogonia type A. After the rhCG treatment, males from the 4-weeks pre-treatment group started to produce sperm earlier than males from the other groups. The sperm volume in the 4-weeks pre-treatment group increased during the first weeks of spermiation and in the control group at the end of the experiment, but no significant differences were found. Sperm motility and kinetics parameters were low in pre-treated groups throughout the whole experiment while in the control group increased significantly at the end of the hormonal treatment., [Discussion]: The onset of maturation in the European eel is controlled by environmental conditions found during their migration. The application of pre-treatments can be important to induce maturation in aquaculture eels, which do not encounter these conditions (Palstra and van den Thillart, 2009). Several factors such as temperature, salinity, forced swimming and pressure have been used as part of pre-treatments applied to eels (reviewed by Asturiano et al., 2020). Rozenfeld et al. (2019) evaluated the effects of cold seawater in European eel maturation without hormonal treatment. In eels treated at 10 ºC, the T and 11-KT levels were higher and there was an increase in the proliferation of differentiated type A spermatogonia. Our results also corroborate that low-temperature pre-treatment (4-weeks at 10 °C) induces an early sexual development, thus leading to the release of androgens which promote the proliferation of type A spermatogonia. However, the low sperm quality found in the pre-treated groups revealed that thermal pre-treatment followed by rhCG treatment at high temperatures impairs spermatogenesis. Low-temperature pre-treatments induce testis cell proliferation and synchronization but inhibit further maturation. Peñaranda et al. (2016) suggested that low seawater temperature inhibits the gene expression of enzymes responsible for the synthesis of maturation-inducing steroids (MIS) during eels oceanic migration. Thus, the premature maturation of the testis is prevented before eels arrive to the spawning areas and a temperature threshold is reached allowing the change of the steroidogenic pathway to change from androgens to MIS. In our experiment, lowtemperature pre-treated males had a time-dependent and fast response to rhCG treatment (in comparison with control males maintained at 20 °C), but their spermiation period was shorter and their sperm motility parameters were significantly lower. If this is evidencing a lower rate of gene expression in the test

The increased average life expectancy, not followed by an increase in healthy life years, results in a growing prevalence of frailty, with a significant change in the health needs of the population. Consequently, frailty can be considered an important threat to public health that can be labeled as the future cornerstone of public health. The purpose of this paper is to provide an overview of the concept of frailty that shows how public health language, logic and tools should intervene in the definition of frailty and the related health needs in order to promote a deeper knowledge of the considered condition, its prevention and its management at the individual and population level. Social and environmental determinants of health get a relevant role according to the biopsychosocial definition of frailty. In fact following this approach this condition is reported as multidimensional syndrome. For this reason, different screening and evaluation tools have been developed to investigate the different domains and to allow an early identification of this condition which is essential to help patients in regaining functionality and in the prevention of associated negative outcomes. n addition to these individual assessment systems, from a public health perspective, it is also necessary to have risk stratification tools that can read and evaluate the whole population in order to plan and organize services intended for a community. The characterization of the need for health of the "frail" people does not require a univocal definition that fits all health and social contexts, but rather a sharing among all professionals about the ways to define and recognize frailty according to a multidimensional approach. The training lever represents a qualifying element for Public Health to develop policies, programs and interventions intended for all professional actors involved in the treatment of frailty as well as for patients and their caregivers. The participation of the caregivers an

The contribution of coding mutations to oncogenesis has been largely clarified, whereas little is known about somatic mutations in noncoding DNA and their role in driving tumors remains controversial. Here, we used an alternative approach to interpret the functional significance of noncoding somatic mutations in promoting tumorigenesis. Noncoding somatic mutations of 151 neuroblastomas were integrated with ENCODE data to locate somatic mutations in regulatory elements specifically active in neuroblastoma cells, nonspecifically active in neuroblastoma cells, and nonactive. Within these types of elements, transcription factors (TF) were identified whose binding sites were enriched or depleted in mutations. For these TFs, a gene expression signature was built to assess their implication in neuroblastoma. DNA- and RNA-sequencing data were integrated to assess the effects of those mutations on mRNA levels. The pathogenicity of mutations was significantly higher in transcription factor binding site (TFBS) of regulatory elements specifically active in neuroblastoma cells, as compared with the others. Within these elements, there were 18 over-represented TFs involved mainly in cell-cycle phase transitions and 15 under-represented TFs primarily regulating cell differentiation. A gene expression signature based on over-represented TFs correlated with poor survival and unfavorable prognostic markers. Moreover, recurrent mutations in TFBS of over-represented TFs such as EZH2 affected MCF2L and ADP-ribosylhydrolase like 1 expression, among the others. We propose a novel approach to study the involvement of regulatory variants in neuroblastoma that could be extended to other cancers and provide further evidence that alterations of gene expression may have relevant effects in neuroblastoma development.

Across the world, life expectancy is increasing. However, the years of life gained do not always correspond to healthy life years, potentially leading to an increase in frailty. Given the extent of population aging, the association between frailty and age and the impact of frailty on adverse outcomes for older people, frailty is increasingly being recognized to be a significant public health concern. Early identification of the condition is important to help older adults regain function and to prevent the negative outcomes associated with the syndrome. Despite the importance of diagnosing frailty, there is no definitive evidence or consensus of whether screening should be routinely implemented. A broad range of screening and assessment instruments have been developed taking a biopsychosocial approach, characterizing frailty as a dynamic state resulting from deficits in any of the physical, psychological and social domains, which contribute to health. All these aspects of frailty should be identified and addressed using an integrated and holistic approach to care. To achieve this goal, public health and primary health care (PHC) need to become the fulcrum through which care is offered, not only to older people and those that are frail, but to all individuals, favoring a life-course and patient-centered approach centered around integrated, community-based care. Public health personnel should be trained to address frailty not merely from a clinical perspective, but also in a societal context. Interventions should be delivered in the individuals' environment and within their social networks. Furthermore, public health professionals should contribute to education and training on frailty at a community level, fostering community-based interventions to support older adults and their caregivers to prevent and manage frailty. The purpose of this paper is to offer an overview of the concept of frailty for a public health audience in order to raise awareness of the multidimens

On May 30th, 2017 at about 21h 09m 17s UTC a green bright fireball crossed the sky of north-eastern Italy. The fireball path was observed from some all-sky cameras starting from a mean altitude of $81.1 \pm 0.2$ km (Lat. $44.369^{\circ} \pm 0.002^{\circ}$ N; Long. $11.859^{\circ} \pm 0.002^{\circ}$ E) and extinct at $23.3 \pm 0.2$ km (Lat. $45.246^{\circ} \pm 0.002^{\circ}$ N; Long. $12.046^{\circ} \pm 0.002^{\circ}$ E), between the Italian cities of Venice and Padua. In this paper, on the basis of simple physical models, we will compute the atmospheric trajectory, analize the meteoroid atmospheric dynamics, the dark flight phase (with the strewn field) and compute the best heliocentric orbit of the progenitor body. Search for meteorites on the ground has not produced any results so far., Comment: 19 pages, 17 figures. Accepted for publication in The European Physical Journal PLUS

On May 30th, 2017 at about 21h 09m 17s UTC a green bright fireball crossed the sky of north-eastern Italy. The fireball path was observed from some all-sky cameras starting from a mean altitude of $81.1 \pm 0.2$ km (Lat. $44.369^{\circ} \pm 0.002^{\circ}$ N; Long. $11.859^{\circ} \pm 0.002^{\circ}$ E) and extinct at $23.3 \pm 0.2$ km (Lat. $45.246^{\circ} \pm 0.002^{\circ}$ N; Long. $12.046^{\circ} \pm 0.002^{\circ}$ E), between the Italian cities of Venice and Padua. In this paper, on the basis of simple physical models, we will compute the atmospheric trajectory, analize the meteoroid atmospheric dynamics, the dark flight phase (with the strewn field) and compute the best heliocentric orbit of the progenitor body. Search for meteorites on the ground has not produced any results so far., Comment: 19 pages, 17 figures. Accepted for publication in The European Physical Journal PLUS

Background Quinidine at high dose is suggested as antiarrhythmic treatment in patients with Brugada Syndrome (BrS), but its efficacy to prevent life-threatening arrhythmic events (LAE) in this population is unproven and its use limited by frequent side effects. We assessed whether low-dose quinidine in patients with BrS reduces the following: (1) the occurrence of LAEs at follow-up, as compared to no therapy, in a population of both high-risk survivors of LAE and lower risk patients asymptomatic for LAEs and (2) the arrhythmic burden in the high-risk group of cardiac arrest survivors. Methods We compared the clinical course of 53 patients with BrS treated with quinidine to that of 441 untreated controls, matched by sex, age, symptoms, and the duration of observation. Furthermore, we calculated the annual incidence of LAE off-quinidine and on-quinidine in 123 patients with BrS who were cardiac arrest survivors. Results Fifty-three patients with BrS (89% males, median age 39.8 years) received quinidine (439±115 mg/d) for 5.0±3.7 years. Therapy was stopped in 3 cases (6%) for side effects. Quinidine reduced by 26% the risk of experiencing an LAE in cases versus controls (hazard ratio, 0.74; 95% CI, 0.22-2.48; P=0.62). Furthermore, in 27 of 123 patients with BrS symptomatic for LAEs who were treated for 7.0±3.5 years, the annual rate of LAEs decreased from 14.7% while off-quinidine to 3.9% while on-quinidine (P=0.03). Of note, recurrent LAEs were recorded in 4 (15%) cardiac arrest survivors while on-quinidine. Conclusions We demonstrated for the first time in the long-term that low-dose quinidine reduces recurrent LAEs in patients with BrS who had already survived an LAE, with few side effects. Remarkably, 15% of patients symptomatic for LAEs experience recurrent life-threatening arrhythmias while on-treatment, suggesting that quinidine cannot replace implantable defibrillators in high-risk subjects. Visual Overview A visual overview is available for this article.

Background: Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). Objectives: This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. Methods: Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. Results: The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LTQ3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). Conclusions: The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS

We show that when a derivative portfolio has different correlated underlyings, hedging using classical greeks (first-order derivatives) is not the best possible choice. We first show how to adjust greeks to take correlation into account and reduce P&L volatility. Then we embed correlation-adjusted greeks in a global hedging strategy that reduces cost of hedging without increasing P&L volatility, by optimization of hedge re-adjustments. The strategy is justified in terms of a balance between transaction costs and risk-aversion, but, unlike more complex proposals from previous literature, it is completely defined by observable parameters, geometrically intuitive, and easy to implement for an arbitrary number of risk factors. We test our findings on a CVA hedging example. We first consider daily re-hedging: in this test, correlation-adjusted greeks allow the reduction of P&L volatility by more than 30% compared to standard deltas. Then we apply our general strategy to a context where a CVA portfolio is exposed to both credit and interest rate risk. The strategy keeps P&L volatility in line with daily standard delta-hedging, but with massive cost-saving: only six rebalances of the illiquid credit hedge are performed, over a period of six months.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined. Objectives This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy. Methods We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals. Results A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p < 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated. Conclusions The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular

Angiostatin effectively blocks tumor angiogenesis through still poorly understood mechanisms. Given the close association between immune and vascular regulation, we investigated the effects of angiostatin on angiogenesis-associated leukocytes. Angiostatin inhibited the migration of monocytes and, even more markedly, neutrophils. Angiostatin blocked chemotaxis of neutrophils to CXCR2 chemokine receptor agonists (IL-8, MIP-2, and GRO alpha), formyl-Met-Leu-Phe (fMLP), and 12-O-tetradecanoylphorbol 13-acetate, and repressed fMLP-induced mitochondrial activity. Two different angiostatin forms (kringles 1-4 and 1-3) were effective, whereas whole plasminogen had no effect. IL-8, MIP-2, and GRO alpha induced intense angiogenic reactions in vivo, but no angiogenic response to these factors was observed in neutropenic mice, demonstrating an essential role for neutrophils. Angiostatin potently inhibited chemokine-induced angiogenesis in vivo, and consistent with in vitro observations, both angiostatin forms were active and whole plasminogen had little effect. Angiostatin inhibition of angiogenesis in vivo was accompanied by a striking reduction in the number of recruited leukocytes. In vivo, the inflammatory agent lipopolysaccharide also induced extensive leukocyte infiltration and angiogenesis that were blocked by angiostatin. Neutrophils expressed mRNAs for ATP synthase and angiomotin, two known angiostatin receptors. These data show that angiostatin directly inhibits neutrophil migration and neutrophil-mediated angiogenesis and indicate that angiostatin might inhibit inflammation.

Since its discovery in mammals as a key-hormone in reproduction and metabolism, leptin has been identified in an increasing number of tetrapods and teleosts. Tetrapods possess only one leptin gene, while most teleosts possess two leptin genes, as a result of the teleost third whole genome duplication event (3R). Leptin acts through a specific receptor (LEPR). In the European and Japanese eels, we identified two leptin genes, and for the first time in vertebrates, two LEPR genes. Synteny analyses indicated that eel LEPRa and LEPRb result from teleost 3R. LEPRb seems to have been lost in the teleost lineage shortly after the elopomorph divergence. Quantitative PCRs revealed a wide distribution of leptins and LEPRs in the European eel, including tissues involved in metabolism and reproduction. Noticeably, leptin1 was expressed in fat tissue, while leptin2 in the liver, reflecting subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential increases in the expression of leptins and LEPRs in the BPG-liver axis. Leptin2 was strikingly upregulated in the liver, the central organ of the reproductive metabolic challenge in teleosts. LEPRs were differentially regulated during sexual maturation, which may have contributed to the conservation of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated leptins and leptin receptors as a result of 3R

Kaposi's sarcoma (KS) is a multifocal lesion that develops with high incidence in AIDS patients and is characterized by prominent angiogenesis. Both HHV8 and HIV are involved in the etiogenesis of epidemic KS, where imbalances between angiogenesis inducers and inhibitors appear to play a role. We have developed numerous primary cultures from Kaposi's sarcoma biopsies and studied factors involved in the induction and inhibition of KS associated angiogenesis. An immortal cell line developed in our laboratory, KS-Imm, gives rise to hemorrhagic tumors that resemble undifferentiated nodular KS when injected in nude mice. KS-CM supernatants, KS-Imm cells and purified HIV-Tat have been used to stimulate endothelial cells in vitro and angiogenesis in vivo in order to screen for anti-angiogenic compounds. We have tested several molecules for their capability to inhibit KS associated angiogenesis and tumor growth, such as class I interferons, retinoids, thrombospondin, somatostatin and N-acetyl-cysteine. Here we review the results obtained.