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In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

In electron beam welding a very intense pencil beam of electrons is driven onto the base metal, to melt it and produce the welding. In the interaction of the beam with the metal, strong bremsstrahlung emission of X-ray is generated. Here the generation is evaluated, and the KERMA in air at 1 m is predicted. Results show that a significant radiation hazard is present and serious radiation protection measures are needed.

Klinefelter syndrome is a frequent cause of hypogonadism, but despite hundreds of publications on different aspects of Klinefelter syndrome, only a few studies dealt with sexual dysfunction. In particular, testosterone is critical for various aspects of sexual response, but its role on sexuality in Klinefelter syndrome patients is debatable and no studies have evaluated the efficacy of testosterone treatment on sexual dysfunction in these subjects. Furthermore, the impact of psychological and relational aspects on sexual function of Klinefelter syndrome subjects is poorly defined. In this study, we aimed to determine the presence and type of sexual dysfunctions in Klinefelter syndrome subjects; to correlate them with testosterone levels and psychosexological and relational domains; and to evaluate the effects of testosterone therapy. We studied 62 non-mosaic naïve Klinefelter syndrome patients and 60 age-matched controls by means of medical history, psychosexological history, 15-item International Index of Erectile Function questionnaire, endocrine assessment, and dynamic penile color Doppler ultrasound. Twenty-five hypogonadal Klinefelter syndrome patients were studied after 6 months of testosterone replacement therapy. Klinefelter syndrome subjects have reduced 15-item International Index of Erectile Function scores regarding sexual desire, intercourse satisfaction, and overall satisfaction with respect to controls, and these aspects were significantly associated with testosterone levels. Klinefelter syndrome subjects had also higher prevalence of erectile dysfunction, but no relation with testosterone levels was evident. A high prevalence of a range of psychological disturbances was present in Klinefelter syndrome subjects with erectile dysfunction with respect to those without erectile dysfunction. No statistical difference in the prevalence of premature and delayed ejaculation was observed between Klinefelter syndrome and control subjects. Testosterone replacement therapy improved sexual desire, intercourse satisfaction, and overall satisfaction scores, but had no effect on erectile function. Penile color Doppler ultrasound was normal in all subjects. This study shows that sexual dysfunction in Klinefelter syndrome is multifactorial and related only in part to hypogonadism and largely to psychological disturbances. Evaluation and therapy of sexual dysfunction should include a combined andrological and psychosexological approach.

The study focuses on some reproductive aspects of Norway lobster (Nephrops norvegicus L., 1758) females landed in two Adriatic harbors (Ancona and Giulianova) and coming from two different fishing areas. The ovarian maturation showed a peak in May for Ancona's samples and in June for Giulianova's ones. Berried females were more frequent in autumn in both areas. The estimated carapace length at first maturity was 29.62 mm in Ancona and 23.31 mm in Giulianova.

Background The value of adding carboplatin (Cb) to neoadjuvant chemotherapy for TNBC is debated. Current evidence supports the association between Cb use and increased pathological complete response (pCR) rate. However, treatment schedules and doses adopted in randomized trials were not always consistent with those used in clinical practice. Methods Clinicopathological data of TNBC (ER & PgR Results 166 patients were included: 61% treated with AT, 39% with AT+Cb (all patients in this group received Cb AUC2 weekly administered concomitantly to the taxane segment). Main characteristics: median age 50 yrs, ductal histology 93%, grade 3 90%, cT > 2cm 86%, cN + 57%, median TILs 10%, median Ki67 60%, BRCA mutated 10%. After propensity score matching, pCR rate was significantly higher for AT+Cb vs AT: 52% vs 31% (OR 2.39 95%CI 1.04-5.50, p = 0.040). In multivariable analysis, treatment with AT+Cb maintained an independent association with pCR: OR 2.51 95%CI 1.03-6.11, P = 0.043. The achievement of pCR was significantly associated with improved disease-free survival (HR 0.16, 95%CI 0.06-0.45). No difference in DFS was observed comparing AT+Cb vs AT: HR 0.99, 95%CI 0.44-2.25. Conclusions We confirmed in a clinical practice setting the association of Cb-containing neoadjuvant chemotherapy with higher pCR rates. Additional data are needed to clarify the impact on long-term survival. These data support the conditional positive recommendation for Cb inclusion in neoadjuvant chemotherapy for TNBC provided by the Italian Association of Medical Oncology Guidelines on Breast Cancer. Funding Has not received any funding. Disclosure M.V. Dieci: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Celgene; Advisory / Consultancy: Genomic Health. V. Guarneri: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

Purpose: To evaluate the outcome of selective arterial embolization with N-2-butyl-cyanoacrylate for aneurysmal bone cysts. Methods: We retrospectively studied 102 patients (72 male, 30 female; mean age, 16 years; range, 3–60 years) with aneurysmal bone cysts treated with embolization with N-2-butyl-cyanoacrylate. Mean follow-up was seven years (range, 3–13 years); no patient was lost to follow-up. We evaluated healing and recurrences of the lesions, complications and cost of the procedures, and recurrences with respect to age and gender of the patients, and size and location of the lesions. Results: Embolization was feasible in 88 patients (86.3%), and not feasible in 14 patients (13.6%) because feeding arteries were not identified or the spinal artery of Adamkiewicz was recognized at the embolization field. Seventy two patients (81.8%) experienced complete healing of their lesions after a single (50 patients, 56.8%), a second (17 patients, 19.3%) or a third embolization (5 patients, 5.7%). Sixteen patients (18.2%) experienced recurrence within four months (range, 3–9 months) after embolization; these patients underwent surgical treatment. Recurrences were more common in patients younger than 15 years of age and cysts larger than 6 cm, without any difference with respect to gender and location. Four patients (4.5%) experienced a complication including skin necrosis, sciatic nerve paresthesias, and femoral artery pseudoaneurysm. The cost estimate was 3000 euro per procedure. Conclusion: Embolization of aneurysmal bone cysts with N-2-butyl-cyanoacrylate is associated with good results and low complication rates, however, experience, technical skills, and knowledge of the vascular anatomy of the area is necessary. © 2016, SICOT aisbl.

At present, the assessment and management of Adriatic Sea fishery resources are based on data that do not fully account for the complex spatial patterns arising from fleet behavior and/or species' behavior and biology, mainly because logbooks do not guarantee adequate coverage of the fishing activity exerted by the fleet. For data collection, the Adriatic Sea is divided into two management areas (namely {FAO} Geographical Sub-Areas-GSAs). To account for these spatial patterns while using the data available, we propose a method for estimating the monthly landings of Italian trawlers operating in the Adriatic Sea at a higher spatial resolution than the GSA. We use a stepwise approach based on the combined analysis of questionnaire-derived vessel-specific landings and the spatial activity of the vessels with respect to a set of fishing grounds. Thus, we sequentially 1) analyze the available vessel monitoring system data, 2) partition the study area into fishing grounds (the origin of the landings), 3) cross analyze vessel-specific fishing efforts with the available vessel-specific monthly landings to estimate the {LPUE} of each fishing ground, and 4) estimate the monthly landings (by vessel, fishing ground, and harbor) for the whole fleet and the monthly fluxes between fishing grounds (origin) and landing harbors (the destination of the landings). We apply the method to two species: the Norway lobster and the European hake. For both species, we find a few fishing grounds to be consistently more productive than others and the landings per harbor to vary greatly but with few harbors regularly receiving a significant share. In particular, the results suggest that the Pomo/Jabuka pit area represents a critical area for both species. Additional outcomes include a detailed characterization of the activity of the Adriatic bottom trawling fleet, highlighting the strengths and shortcomings of the official data available. We discuss the results in the context of the current management paradigm.

In this paper, the results of a research regarding the transit network of the city of Bologna are presented in order to highlight those factors affecting the reliability of a transit service at high frequency. In literature, several authors relate bus service reliability to the variability of travel time performance (Polus, 1978; Sterman and Schofer, 1976); others with the adherence to schedules (Bates et al., 2001), others to the maintenance of the designed service frequency (Janos and Furth, 2002), others with the waiting time at the bus stops (Bowman and Turnquist, 1981), and others to the impossibility of getting on the bus because of capacity issues (Chapman, 1976). Anyway, the reliability of a transit service is a key element both for users - real and potential ones - and providers. Low service reliability implies the reduction of the service quality perceived by users causing an increase of the amount of time passengers must wait at a bus stop as well as the comfort reduction due to vehicles’ overcrowding (Bates et al., 2001; Rietvield et al., 2001; TCRP, 1999; Prioni and Hensher, 2000; Welding, 1957; Turnquist, 1978). From providers perspective, low service reliability means a reduction of the veh-km delivered and an inefficient utilization of the fleet: some buses travels full of passengers whereas others are empty. This implies the need of additional vehicles to be provided, thus increasing the operating costs. Moreover, as reliability decrease, public transport demand will decrease too thus engendering a lower income for the service provider. The reliability is strictly related to the bunching phenomenon. Bus bunching refers to a group of two or more transit vehicles scheduled to be evenly spaced along the same route, which run in the same location at the same time. This occurs when at least one of the vehicles is unable to keep its schedule because of the interaction with other vehicles of the traffic steam, presence of signalized intersections along the route, demand increase, etc., which implies a bus to be early/late with respect to the planned schedule. Theoretically, the driver should try to adjust the bus speed in relation to the gap with the preceding bus; although it represents one of the most important hypothesis of bunching simulation models, this procedure, which requires driver knows the position of the preceding vehicles, is not usually adopted (Nagatani, 2001). This research provides a general analysis based on reliability, identifying and discussing its determinants. The relative importance of each determinant is analyzed through a survey conducted along two of the main bus routes of the Bologna transit network. This analysis could allow providers identifying appropriate strategies, preventive or corrective ones, in order to improve the service reliability.

Recent experiments in the Current Drive Experiment-Upgrade (CDX-U) provide a first-ever test of large area liquid lithium surfaces as a tokamak first wall to gain engineering experience with a liquid metal first wall and to investigate whether very low recycling plasma regimes can be accessed with lithium walls. The CDX-U is a compact (R = 34 cm, a = 22 cm, Btoroidal = 2 kG, IP = 100 kA, Te(0) ∼ 100 eV, ne(0) ∼ 5 × 10 19 m −3 ) spherical torus at the Princeton Plasma Physics Laboratory. A toroidal liquid lithium pool limiter with an area of 2000 cm 2 (half the total plasma limiting surface) has been installed in CDX-U. Tokamak discharges which used the liquid lithium pool limiter required a fourfold lower loop voltage to sustain the plasma current, and a factor of 5–8 increase in gas fuelling to achieve a comparable density, indicating that recycling is strongly reduced. Modelling of the discharges demonstrated that the lithium limited discharges are consistent with Zeffective < 1.2 (compared with 2.4 for the pre-lithium discharges), a broadened current channel and a 25% increase in the core electron temperature. Spectroscopic measurements indicate that edge oxygen and carbon radiation are strongly reduced.

Spectral purity and source stability represent two of the primary goals in the design of high performance frequency synthesizer for modern radar systems. This paper presents a new X-band High Stable Synthesizer (HSS) architecture, which combines Phase Lock Loop (PLL), Direct Digital Synthesis (DDS) and multiplier techniques, in order to cope with low phase noise and frequency agility requirements of the next radar generations. This synthesizer offers frequency coverage in X band with a percentage bandwidth of a minimum of 10%, with fast switching time, high digitally-tunable resolution and very low phase noise. The achievement of such performance has been demonstrated by experimental results measured on a laboratory demonstrator: they show a lock-in time within 10 us and a phase noise improvement up to 30 dB compared to the current state of art Frequency Generation Unit (FGU). Moreover, for its versatility, the architecture is able to provide an intermediate output covering the needs for new S-L band application.

Recent interest in a severe accident management scheme known as ‘In-Yessel Retention’ has created the need to establish the coolability limits of large, inverted geometries. In this paper, full-scale simulations conducted at UCSB's ULPU facility are examined at the microscopic level. Because of the peculiar geometry, it has become possible to directly visualize the boiling transition phenomenon, and with the help of microthermocouples to quantitatively identify the mechanism of dryout. Altogether, a new boiling transition regime was identified, with a significant coupling between overall systems dynamics and the microphenomena. This leads the way to the a priori prediction of critical heat flux and factors that may influence it.

The ACOPO experiment simulates natural convection heat transfer from volumetrically heated pools at a half-scale reactor lower head geometry (hemispherical). New data for internal Rayleigh numbers of up to 1016 are presented, correlated and discussed, in relation to other available correlations. These ACOPO results confirm a key component of the in-vessel retention severe accident management strategy for an AP600-like design, as recently established in DOE/ID-10460.

The conditions of the MAGICO-2000 experiment are extended to more broadly investigate the regimes of premixing, and the corresponding internal structures of mixing zones. With the help of the data and numerical simulations using the computer code PM-ALPHA, we can distinguish extremes of behavior dominated by inertia and thermal effects—we name these the inertia and thermal regimes, respectively. This is an important distinction that should guide future experiments aimed at code verification in this area. Interesting intermediate behaviors are also delineated and discussed.

Lower head integrity under steam explosion loads in an AP600-like reactor design is considered. The assessment is the second part of an evaluation of the in-vessel retention idea as a severe accident management concept, the first part (DOE:ID-10460) dealing with thermal loads. The assessment is conducted in terms of the risk oriented accident analysis methodology (ROAAM), and includes the comprehensive evaluation of all relevant severe accident scenarios, melt conditions and timing of release from the core region, fully three-dimensional mixing and explosion wave dynamics, and lower head fragility under local, dynamic loading. All of these factors are brought together in a ROAAM probabilistic framework to evaluate failure likelihood. The conclusion is that failure is 'physically unreasonable'. © 1999 Elsevier Science S.A. All rights reserved.

An overall verification approach for the PM-ALPHA code is presented and implemented. The approach consists of a stepwise testing procedure focused principally on the multifield aspects of the premixing phenomenon. Breakup is treated empirically, but it is shown that, through reasonable choices of the breakup parameters, consistent interpretations of existing integral premixing experiments can be obtained. The present capability is deemed adequate for bounding energetics evaluations.

As computations of transient, multidimensional, multiphase flows are becoming increasingly more realistic, so increases the demand for their detailed experimental validation. Key in this task is the evolution of flow patterns, and the usual approaches of local measurements are inherently limited in meeting this demand. In this paper, we demonstrate the particular suitability of flash X-ray radiography, and the feasibility of reliably quantifying the radiographs of flow regions of various sizes, from microscopic to rather large scale.

This work addresses certain fundamental aspects of the premixing phase of steam explosions. At issue are the multifield interaction aspects under highly transient, multidimensional conditions and in the presence of strong phase changes. They are addressed in an experiment (the MAGICO-2000) involving well-characterized particle clouds mixing with water and detailed measurements on both external and internal characteristics of the mixing zone. Both cold and hot (up to 1500°C) particle clouds are considered in conjunction with saturated and subcooled water pools. The PM-ALPHA code is used as an aid in interpreting the experimental results and the exercise reveals good predictive capabilities for it.

The ACOPO experiment simulates natural convection heat transfer from volumetrically heated pools, at a half-scale reactor lower head geometry (hemispherical). Data for Rayleigh numbers of up to 2·1016, from the first round of experiments, are presented in this paper. The results are in substantial agreement with those of the mini-ACOPO proof-of-concept experiment. Moreover, it is shown that these ACOPO results confirm a key component of the in-vessel retention capability for an AP600-like design, as recently established in DOE/ID-10460.

This work discusses certain fundamental aspects in the mixing of particle clouds plunging into water. In particular, the momentum transfer in the isothermal interaction is considered here, as part of a broader investigation involving very high-temperature particles and thus heat transfer and phase change, as related to the premixing phase of steam explosions. The focus is on the multifield behaviour, and the investigation is carried out experimentally in the MAGICO-2000 facility: we observe front advancements, mixing region evolution and water displacements. The effect of particle volume fraction, density, inlet velocity and pool geometry are analyzed. Measurements are taken by means of high-speed videos and X-ray radiography: the latter allows us to map the interior of the mixing region, highlighting interesting features of the interaction. All results are compared to the numerical simulations obtained with the PM-ALPHA code, and the exercise reveals good predictive capabilities for it.

Three recently published premixing experiments, the Magico, mixa , and Faro , are discussed comparatively, and two of them, the Magico and Faro , are analyzed with the help of the computer code Pm-alpha . The results of these analyses are shown to provide quantitative interpretations of the data, and to suggest conditions/measurements in further experiments to enhance the insights thus obtained. Also, a quantitative radiography technique is described and applied to Magico for the measurement of chordal-averaged void fractions in the mixing zone. The results are in excellent agreement with Pm-Alpha predictions, thus confirming the previously reported good comparisons with the local (point) measurements of Flute .

The thermal field in a reactor vessel downcomer and resulting thermal/stress response in the adjacent reactor vessel wall during high-pressure safety injection are examined, especially with regard to departures from one-dimensional behavior. Similarity solutions for the stratification (in the cold leg) that creates the downcomer plumes, and scaling considerations for the thermal conduction and stress fields in the vessel wall are developed to provide generalized criteria for the adequacy of the one-dimensional treatment.

This paper describes the first attempt to experimentally quantify the multiphase transient associated with the premixing of steam explosions — a hot particulated (heavy) phase falling, in film boiling, into a coolant pool, which is thus forced to rapid vaporization. The process is characterized by mixing-zone-averaged and local void-fraction transients, as well as mixing-front advancement histories, and the data are found to be in good agreement with predictions carried out with our PM-ALPHA code. In particular, these tests confirm the predicted water depletion phenomenon which is a crucial factor in limiting the energetics of large-scale steam explosions.

The ambient air of urban centres is polluted with potentially toxic chemicals mostly arising from the combustion or fuels used for transport, heating and industrial activities. Alongside the risk to the general public, atmospheric pollution could be considered an occupational health hazard to professional groups, such us traffic police or professional drivers working in urban areas. Molecular epidemiology can facilitate health risk assessment by investigating the relationship between exposure to environmental pollutants and quantification of biomarkers that lie on the pathway of carcinogenesis upstream of clinical disease. In particularly, biomarkers of early effects and susceptibility are playing an increase role in the investigation of the impact of air pollution on human carcinogenesis.

From 1989 to 1995, 4,053 meningococcal strains with a clinical information form were sent to the National Reference Center for Meningococci (NRCM). Among these strains 569 meningococci (14.04%) were isolated from secretions of the bronchopulmonary tract by expectoration or fibroscopy protected or not from contamination by microflora. Fifteen observations associated an infection of bronchopulmonary syndrome and a meningococcemia without any other symptoms. These patients were in general elderly (mean = 71.3 years old) except for two cases: one of them presented sickle cell anemia and the other was very young (13 months). In all cases, there were signs of clinical and X-ray pneumopathies. Among the fifteen cases described, eight cases occurred during the winter, and four during the spring. Twelve were described in countries north of the Loire. Serogroup Y was isolated six times, serogroup B four times and serogroup C three times. The small quantity of cases did not permit us to study the distribution of serotype and serosubtype. Three patients, aged 92, 86 and 74 years old, died from the meningococcal infection.

The efficacy of external flooding of a reactor vessel as a severe accident management strategy is assessed for an AP600-like reactor design. The overall approach is based on the Risk Oriented Accident Analysis Methodology (ROAAM), and the assessment includes consideration of bounding scenarios and sensitivity studies, as well as arbitrary parametric evaluations that allow the delineation of the failure boundaries. Quantification of the input parameters is carried out for an AP600-like design, and the results of the assessment demonstrate that lower head failure is physically unreasonable. Use of this conclusion for any specific application is subject to verifying the required reliability of the depressurization and cavity-flooding systems, and to showing the appropriateness (in relation to the database presented here, or by further testing as necessary) of the thermal insulation design and of the external surface properties of the lower head, including any applicable coatings. The AP600 is particularly favorable to in-vessel retention. Some ideas to enhance the assessment basis as well as performance in this respect, for applications to larger and/or higher power density reactors are also provided.

The efficacy of external flooding of a reactor vessel as a severe accident management strategy is assessed for an AP600-like reactor design. The overall approach is based on the Risk Oriented Accident Analysis Methodology (ROAAM), and the assessment includes consideration of bounding scenarios and sensitivity studies, as well as arbitrary parametric evaluations that allow the delineation of the failure boundaries. Quantification of the input parameters is carried out for an AP600-like design, and the results of the assessment demonstrate that lower head failure is physically unreasonable. Use of this conclusion for any specific application is subject to verifying the required reliability of the depressurization and cavity-flooding systems, and to showing the appropriateness (in relation to the database presented here, or by further testing as necessary) of the thermal insulation design and of the external surface properties of the lower head, including any applicable coatings. The AP600 is particularly favorable to in-vessel retention. Some ideas to enhance the assessment basis as well as performance in this respect, for applications to larger and/or higher power density reactors are also provided.

Our initial experience with four minor resections for one malignant and three benign lesions is reported. Dissection was accomplished by mechanical fragmentation and hydrojet. Coagulation was effectively achieved by the argon beam system. Larger vessels were clipped. Three patients were treated laparoscopically and were rapidly discharged after an uneventful postoperative course. The other patient (small hepatocellular carcinoma in cirrhotic liver) had an intraoperative cardiac arrest, probably due to gas embolism. After restoration of normal cardiac activity, the operation was completed after conversion to an open approach. When using the argon coagulator it is necessary to prevent excessive intra-abdominal pressure due to the flow of argon gas and to avoid injury to the hepatic veins, which may cause gas embolism.

Simplified parietal cell vagotomies (Taylor's and Hill-Barker's procedures) were proposed more than a decade ago to make the operation easier and faster. Efficacy and safety have proven to be as good as with proximal gastric vagotomy. The Hill-Barker operation is particularly simplified by the laparoscopic approach, which enables the procedure to be performed very precisely. The limited trauma of minimally invasive vagotomy has increased the interest in peptic ulcer surgery, especially for patients with chronic duodenal ulcer disease who cannot or do not want to take long-term continuous medication, or who are resistant to it. We describe our technique of performing the laparoscopic Hill-Barker procedure. Our initial results with eleven patients show no operative mortality and minimal morbidity with early discharge and ulcer of all patients. Of the 9 cases which are evaluable, 8 are pain-free and one had an ulcer recurrence after incomplete vagotomy.

Limb-girdle muscular dystrophies (LGMDs) are clinically and genetically heterogeneous diseases presenting with a wide clinical spectrum. Autosomal dominant LGMDs represent about 10–15% of LGMDs and include disorders due to defects of DNAJB6, transportin-3 (TNPO3), HNRNPDL, Calpain-3 (CAPN3), and Bethlem myopathy. This review article aims to describe the clinical spectrum of LGMD D2 TNPO3-related, a rare disease due to heterozygous mutation in theTNPO3gene.TNPO3encodes for transportin-3, which belongs to the importin beta family and transports into the nucleus serine/arginine-rich (SR) proteins, such as splicing factors, and HIV-1 proteins, thus contributing to viral infection. The purpose of this review is to present and compare the clinical features and the genetic and histopathological findings described in LGMD D2, performing a comparative analytical description of all the families and sporadic cases identified. Even if the causative gene and mutations of this disease have been identified, the pathogenic mechanisms are still an open issue; therefore, we will present an overview of the hypotheses that explain the pathology of LGMD D2 TNPO3-related.

Oxidative stress plays a major role in the pathophysiology of cardiac disorders, but the experimental data on the protective effects of exogenous antioxidants are controversial. A promising cardioprotective strategy may be through the induction of the endogenous antioxidants and phase II enzymes by chemical inducers. Sulforaphane is an isothiocyanate derived from cruciferous vegetables, and it has gained attention mainly as a potential chemopreventive agent in part through the induction of detoxifying enzymes. Accordingly, this study was undertaken to investigate the time-dependent induction of gene transcription, protein expression, and enzyme activity of antioxidant and phase II enzymes [glutathione reductase, glutathione-S-transferase, glutathione peroxidase, NAD(P)H:quinone oxidoreductase-1, thioredoxin reductase] by sulforaphane in cultured rat neonatal cardiomyocytes. The potential cardioprotective action of sulforaphane was confirmed by the decrease in intracellular reactive oxygen species production, the increase in cell viability, and the decrease in DNA fragmentation after long-term treatment accompanied by the induction of antioxidants and phase II enzymes in cardiomyocytes.

This report is part of a biomarker study conducted in an Italian population with exposure to environmental benzene ranging from 1.43 to 31.41 μg/m 3 (values from personal sampling). DNA damage induced by benzene is the crucial mechanism of its genotoxicity, which leads to chronic benzene poisoning, haematotoxicity and leukaemia. Therefore, genetic variation in DNA-repair genes may modulate susceptibility to benzene-induced DNA damage. In light of this, the effects of polymorphisms in DNA-repair genes ( APEX1 , hOGG1 , NBS1 , XPD , XRCC1 , and XRCC3 ) on micronucleus (MN) formation as a biomarker of early biological effects were evaluated. A significantly higher median MN frequency was recorded in traffic wardens than in controls. However, none of the analysed polymorphisms was significantly associated with the median MN frequency. A gene–gender interaction was observed for the APEX1 genotype. The APEX1 variant genotype was associated with significantly lower median MN frequency in men , not in women. Statistical analysis did not reveal any association between the score of the protective alleles – hypothetically pushing the pathway towards optimal DNA-damage repair – and MN. Even though there are some limitations in the study, our results indicate that the general population may be exposed to benzene concentrations higher than the threshold level for air-quality standards in the European Union of 10 μg/m 3 . Furthermore, urban traffic wardens are exposed to significantly higher levels of benzene than individuals spending most of the time indoors. This higher exposure may contribute to DNA damage, suggesting that benzene might be implicated both as an environmental and occupational risk factor in leukaemia and other haematological diseases. In conclusion, this study suggest the need for (i) regular monitoring of traffic wardens for possible exposure to benzene, as a precautionary step to reduce the associated health risks, and (ii) more comprehensive studies in order to better elucidate the involvement of APEX1 genotypes in benzene genotoxicity.

Lo studio sulle attività alieutiche nei secoli dell'età moderna consente di ricostruire una specifica storia del Mediterraneo che trova nel Cinquecento un'epoca di transizione tra antiche e nuove maniere di pescare. La ricerca sulle fonti archivistiche ha restituito un quadro assai efficace dell'evoluzione della pesca dal XVI al XIX secolo che permette di seguire il passaggio dalla pratiche piscatorie svolte prevalentemente in prossimità della costa, a tecniche di pesca a strascico in alto mare esercitate con l'ausilio di tipi navali e attrezzature fino a quel momento mai sperimentati. L'aumento della produzione sollecita anche una migliore organizzazione dello smercio del pesce con l'utilizzo di ghiaccio per bloccare il facile deperimento del prodotto (conserve, neviere) e favorirne il trasporto sulle lunghe distanze. Nonostante le non poche problematiche sociali e organizzative del settore si avvia la trasformazione del commercio ittico che porta fra Sette e Novecento, in virtù del significativo allargamento della rete distributiva del prodotto fresco, anche un radicale cambiamento nelle abitudini alimentari.

La biodiversità assicura il mantenimento della vita sul nostro pianeta e per questo motivo la sua conservazione è un obiettivo prioritario ed irrinunciabile, a partire dalla funzione di stabilizzatore nel mantenimento degli equilibri climatici sia a scala locale che planetaria. Dalla diversità biologica dipende la capacità dei sistemi naturali di fornire quei servizi che sorreggono anche la vita del genere umano. La sostenibilità ecologica riassume lo scopo di rendere compatibili le politiche economiche con la salvaguardia dell’ambiente, delle sue risorse tanto a livello territoriale locale quanto su scala globale. La promozione di una nuova sensibilità collettiva e l’adozione di nuove strategie per la protezione dell’ambiente è resa necessaria dalla presa di coscienza dei limiti delle risorse naturali di fronte ai massicci interventi di sfruttamento dovuti alle attività umane. La cultura della sostenibilità attraverso l’educazione ambientale offre gli strumenti necessari per una lettura e comprensione dell’ambiente e dei suoi valori, allo scopo di favorire il recupero delle risorse naturali esistenti ed un loro uso sostenibile.

Sulforaphane (SF), a naturally occurring isothiocyanate abundant in Cruciferous vegetables, has gained attention as a potential chemopreventive compound (1) thanks to its ability to induce several classes of genes implicated in reactive oxygen species (ROS) and electrophiles detoxification. Antioxidant responsive element (ARE)- mediated gene induction is a pivotal mechanism of cellular defence against the toxicity of electrophiles and ROS. The transcription factor NF-E2-related factor-2 (Nrf2), is essential for the up-regulation of these genes. Nrf2 phosphorylation by protein kinases such as Akt kinase, extracellular-signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and protein kinase C (PKC) influence the activation of the Nrf2/ARE pathway (2, 3). Recently, we have demonstrated that SF elicits cardioprotective activity by up-regulating a battery of antioxidants and phase II enzymes (4). The aim of this study was to verify SF mechanism of action leading to cardioprotection by investigating the effect of SF treatment on Nrf2 activation in primary cultures of neonatal rat cardiomyocytes. In particular we focused our attention on the ability of SF to activate different mitogen–activated protein kinases (MAPK) related to Nrf2 translocation to the nucleus. Cultured rat cardiomyocytes, prepared and grown as previously reported (5), were supplemented with 5 μM SF for different times. Western blot analyses of Nrf2, phsopho-p38, phospho-JNK, phospho-Akt, phospho-ERK1/2 were performed using specific antibodies and following the manufacturer’s recommended protocols. Nrf2 translocation to the nucleus was evaluated by immunoblotting of different cellular fractions. The expression of Nrf2 was determined by RT-PCR. SF was able to modulate MAPK phosphorylation and Nrf2 translocation to the nucleus. This translocation was blocked by cell treatment with specific MAPK inhibitors demonstrating that Nrf2 activation is mediated by these pathways. SF was also able to up-regulate Nrf2 expression. So, the cardioprotective activity of SF could be ascribed to its ability to modulate both MAPK signaling pathways and Nrf2 expression. This research was supported by MIUR-COFIN and Fondazione del Monte di Bologna e Ravenna 1. Y. Zhang, et al. (1992) Proc Natl Acad Sci U S A. 89, 2399-403. 2. J. D. Hayes, et al. (2001) Cancer Lett. 174, 103-13. 3. T. Nguyen, et al. (2004) Free Radic Biol Med. 37, 433-41. 4. C. Angeloni, et al. (2007) Proc Nutr Soc. 66, 111A. 5. S. Hrelia, et al. (2002) Biochim Biophys Acta. 1567, 150-6.

A promising strategy for protecting cardiac cells against oxidative damage may be through the induction of endogenous phase 2 enzymes. Sulforaphane (SF), a naturally occurring isothiocyanate from Brassicaceae, demonstrated a strong chemopreventive effect mediated by Nuclear factor E2-related factor-2 (Nrf2), a transcription factor that binds to the Antioxidatn responsive Element orchestrating antioxidant and cytoprotective responses. No data are available to support a similar role of SF in cardioprotection. Using cultured rat cardiomyocytes we have characterized the time-dependent gene induction of phase 2 enzymes and Nrf2 elicited by SF, the corresponding protein expression and Nrf2 translocation to the nucleus. Methods: Cultured rat cardiomyocytes were supplemented with 5 mM SF for different times (6-48 h). The gene induction of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), NAD(P)H-quinone reductase 1 (NQO1), thioredoxine reductase (TR) and Nrf2 were determined by RT-PCR. Western blot analyses of GR, GST, GPx, TR, NQO1 and Nrf2 were performed using specific antibodies. Nrf2 translocation to the nucleus was evaluated by laser confocal microscopy. Results: Both the mRNA and protein levels of GR, GST, NQO1 and TR significantly increased after SF supplementation in a time-dependent manner. GR, GST, NQO1 mRNA increased after 3h treatment, while all protein expressions appear significantly different from unsupplemented cells only at longer exposure times (24, 48h) apart of NQO1 and TR which expressions increased after 6h and 12h respectively. This is probably due to the delay between gene induction and active protein synthesis and confirm our previous data on the time course of phase 2 enzymes activities (1). GPx was not affected by SF at any time point. SF caused an increase of Nrf2 mRNA and laser confocal microscopy evidenced its nuclear translocation. In this study we have demonstrated that SF modulates phase 2 enzymes and Nrf2 induction in cardiomyocytes, eliciting an indirect antioxidant activity to counteract oxidative stress that characterizes many cardiovascular diseases. Supported by MIUR (PRIN 2005) and Fondazione del Monte di Bologna e Ravenna 1. E. Leoncini et al., Nutrition, Oxygen Biology and Medicine (P.Cillard, L.Packer et al eds)2007,55

The ambient air of urban centres is polluted with potentially toxic chemicals mostly arising from the combustion or fuels used for transport. Among these compounds, benzene raises particular concern due to its haematoxicity and leukaemogenic risks. Although limits of benzene in air have been established in the European Union (5 μg/m3), individual exposure levels—and therefore risk estimates—cannot merely be extrapolated from environmental concentrations. Molecular epidemiology can facilitate health risk assessment by investigating the relationship between exposure to environmental pollutants and quantification of biomarkers that lie on the pathway of carcinogenesis upstream of clinical disease. We review the available for biomarker studies regarding health risks linked to environmental benzene exposure, and make some suggestions for future work.