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Among cardiovascular diseases, hypertension is one of the main risk factors predisposing to fatal complications. Oxidative stress and chronic inflammation have been identified as potentially responsible for the development of endothelial damage and vascular stiffness, two of the primum movens of hypertension and cardiovascular diseases. Based on these data, we conducted an open-label randomized study, first, to evaluate the endothelial damage and vascular stiffness in hypertense patients; second, to test the effect of supplementation with a physiological antioxidant (melatonin 1 mg/day for 1 year) in patients with essential hypertension vs. hypertensive controls. Twenty-three patients of either gender were enrolled and randomized 1:1 in two groups (control and supplemented group). The plasmatic total antioxidant capacity (as a marker of oxidative stress), blood pressure, arterial stiffness, and peripheral endothelial function were evaluated at the beginning of the study and after 1 year in both groups. Our results showed that arterial stiffness improved significantly (p = 0.022) in supplemented patients. The endothelial function increased too, even if not significantly (p = 0.688), after 1 year of melatonin administration. Moreover, the supplemented group showed a significative reduction in TAC levels (p = 0.041) correlated with the improvement of arterial stiffness. These data suggest that melatonin may play an important role in reducing the serum levels of TAC and, consequently, in improving arterial stiffness.

Background Minimally invasive adrenalectomy represents the treatment of choice of pheochromocytoma (PCC). For large or invasive PCCs, an open approach is currently recommended, in order to ensure complete tumor resection, prevent tumor rupture, avoid local recurrence, and limit perioperative hemodynamic instability. The aim of this study is to analyze perioperative outcomes of laparoscopic adrenalectomies (LAs) for large adrenal PCCs. Methods All consecutive LAs for PCC performed at a single institution between 1998 and 2020 were included. Two groups were defined: lesions larger (group 1) and smaller (group 2) than 5 cm. Short-term outcomes were compared in order to find any significant difference between the two groups. Outcomes One hundred fourteen patients underwent LA during the study period: 46 for lesions larger and 68 for lesions smaller than 5 cm. No significant differences were found in patients’ characteristics, median operative time, conversion rate, intraoperative hemodynamic and metabolic parameters, postoperative intensive care unit (ICU) admission rate, complications rate, and length of hospital stay. Long-term oncologic outcomes were similar, with a recurrence rate of 5.1% in group 1 vs 3.6% in group 2 (p = 1). Conclusion Minimally invasive adrenalectomy seems to be safe and effective even in large PCC. The recommendation to prefer an open approach for large PCCs should probably be reconsidered.

Autism spectrum disorder (ASD) identifies a neurodevelopmental disease defined by social impairments and repetitive or stereotyped behaviors. The etiology of ASD remains unclear; it primarily affects the brain, but a link between gastrointestinal (GI) diseases, inflammatory mucosal pathology and this disorder has been suggested. In particular, a central role seems to be played by an imbalance in pro-and anti-inflammatory cytokines, oxidative stress, and apoptosis. Toll-like receptor 4 (TLR4) is a protein of innate immunity responsible for the regulation and maintenance of intestinal homeostasis. Through histochemical and immunohistochemical evaluations we analyzed the intestinal morphology and the immunopositivity of TLR4 and of other pro-inflammatory and apoptotic proteins in BTBR T+Itpr3tf/J mice. Morphological data showed that the mucosal tunica presented longer intestinal villi. The length of the villi and the epithelial surface determine the exchanges of the intestinal mucosa with luminal contents, modifying the microbiota composition. The biochemical and immunohistochemical results indicated a close relationship among the increase of TLR4 and the activation of NF-kB subunits (p65 and p50) and pro-inflammatory and apoptotic proteins, such as cyclooxygenase-2, interleukin-1β, inducible nitric oxide synthase, tumor nuclear factor—alpha, caspase-3, caspase-8. These preliminary results require more in-depth study but they suggest the TLR4 signaling pathway as a possible target for therapeutic approaches to reduce GI disorders in ASD.

The project of Contrada Bricconi started out as Giacomo Perletti’s dream. Born in 1986, he is a farmer and the symbol of the great passion that has driven the development project of a farm that has existed since 2010, which was when an agreement was signed between the newly founded company and the municipality of Oltressenda Alta. The agreement provided for the concession of some buildings owned by the municipality in Contrada Bricconi, an ancient stone farm settlement dating back to the 15th century and located at around 900 meters above sea level, on the border of the Parco delle Orobie Bergamasche in Val Zurio, a valley situated at the side of the Serio River basin. Since that day, the company has seen a surprising convergence of multiple people, institutions, and initiatives. Over the years, they have contributed to the realization of an ambitious project aimed at reintroducing an agricultural activity in the contrada, which had been in a state of semi-abandonment, redeveloping the existing buildings while preserving the landscape, offering the appropriate catering and hospitality for the mountain context, ensuring the economic sustainability of the new-born company. The history of Contrada Bricconi tries to teach that the landscape is itself the product of a rural society that has shaped the vegetation, topography, infrastructures, and settlements over the centuries. The return of agricultural activities in the mountains, albeit intervening on pre-existing ecological and social balances, is essential to ensure the preservation of the local heritage, which needs people’s presence and work to survive.

The intestinal epithelium plays a key role in managing the relationship with the environment, the internal and external inputs, and their changes. One percent of the gut epithelium is represented by the enteroendocrine cells. Among the enteroendocrine cells, a group of specific cells characterized by the presence of yellow granules, the enterochromaffin cells, has been identified. These granules contain many secretion products. Studies showed that these cells are involved in gastrointestinal inflammatory conditions and hyperalgesia; their number increases in these conditions both in affected and not-affected zones of the gut. Moreover, they are involved in the preservation and modulation of the intestinal function and motility, and they sense metabolic–nutritional alterations. Sometimes, they are confused or mixed with other enteroendocrine cells, and it is difficult to define their activity. However, it is known that they change their functions during diseases; they increased in number, but their involvement is related mainly to some secretion products (serotonin, melatonin, substance P). The mechanisms linked to these alterations are not well investigated. Herein, we provide an up-to-date highlight of the main findings about these cells, from their discovery to today. We emphasized their origin, morphology, and their link with diet to better evaluate their role for preventing or treating metabolic disorders considering that these diseases are currently a public health burden.

Aims Arterial hypertension, especially if not well-controlled, is one of the main risk factors predisposing to fatal cardiovascular diseases (CVDs). Moreover, the diagnosis of essential hypertension are increasing, therefore oxidative stress and chronic inflammation have also been identified as potential responsible for the development of endothelial damage. Among all the molecules, melatonin (MT) was chosen for its role as a powerful antioxidant and anti-inflammatory endogenous molecule. This trial aims to evaluate the early intervention at the base of the inflammatory and oxidative cascade (that results in the development of hypertension), to restore an oxidative balance leading to positive results even at the endothelial and vascular level using MT in addition to anti-hypertensive therapy. Methods The trial is randomized, prospective and monocentric control. We enrolled 23 patients with hypertension in absence of other cardiovascular or autoimmune diseases that could alter the oxidative background, from March 2018 to April 2019 (recruitment period). Patients were randomly assigned to two groups: ‘melatonin group’ (in which 16 patients add 1 mg/day of melatonin for a year, to their already settled therapy), and a ‘control’ group (consisting of 7 patients with no changes in their therapy). The average follow-up was 1 year from randomisation. Patients were evaluated before and after a period of 1 year through MT plasma concentration and serum antioxidant capacity (TAC) by specific quantitative ELISA method. Therefore endothelial dysfunction and arterial stiffness were evaluated too (using the non-invasive methods of EndoPAT and SphygmoCor). Results In ‘melatonin group’ arterial stiffness index statistically decreased (P 0.022), according to a significant increase in plasma melatonin values (P 0.003) and significant decrease in TAC levels (P 0.041) despite the ‘control’ group. The improvement of endothelial function was not significant (P 0.688). Blood pressure had not a significative improvement too (P 0.401). Conclusions Data obtained could confirm the hypothesis of activation of plasma antioxidant system against a situation of altered oxidative balance. In fact, it is possible to hypothesize a correlation between TAC and arterial stiffness that confirm the antioxidant role of MT. The combination between antihypertensive therapy and antioxidant supplementation is able to improve the vascular stiffness. Data obtained are still preliminary and present some limitations but we can think of proposing this trial as a future basis for other extensive and prolonged studies.

Summary Background Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. Methods NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov ( NCT02790996 ). Findings Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). Interpretation In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. Funding EU Seventh Framework Programme for research, technological development and demonstration.

To assess ductal size correlated to spontaneous closure, pharmacological or surgical treatment; to index ductal diameter to body weight and body surface area; to evaluate the morbidities.Retrospective study on preterms ≤32 weeks, birth weight ≤1500 g, extremely low birth weight (ELBW) and very low birth weight (VLBW). Inclusion criteria: patent ductus arteriosus (PDA) with a diameter ≥1 millimeter (mm) at 72 h from birth; need for ibuprofen treatment on the basis of a hemodynamically significant ductus arteriosus (HsPDA).One hundred infants with the diagnosis of PDA have been included. We observed a prevalence of spontaneous closure in 34% of newborns (41.3% VLBW versus 26.7% ELBW). The percentage of response to a single course of ibuprofen was of 62% (68.5% ELBW versus 54.3% VLBW). The mean of absolute ductal diameter was of 2.26 ± 0.62 mm in ELBW and 2.18 ± 0.42 mm in VLBW. The indexing of ductus size to body weight demonstrated a higher value in ELBW than VLBW (2.76 ± 0.97 mm/kg versus 1.84 ± 0.40 mm/kg).Our results confirmed that HsPDA can develop in presence of a ductus1.5 mm as absolute value or1.4 mm/kg as indexed to body weight. In ELBW infants the ductal size indexed for body weight and body surface area could be more predictive of spontaneous closure or need for pharmacological treatment compared to the absolute value of ductal size. A strong association between HsPDA and short- or long-term morbidities was confirmed particularly in ELBW.

Nowadays, it is known that the sex differences regard many organs, e.g., liver, vessels, pancreas, lungs, bronchi and also the brain. Sex differences are not just a matter of ethical and moral principles, as they are central to explain many still unknown diseases and their understanding is a prerequisite to develop an effective therapy for each individual. This review reports on those sex differences that are not only macroscopic and morphological, but also involve molecular and functional dimorphism in the brain. It will recapitulate the main structural differences between male and female brain including the neurotransmission systems; in particular, the main objective is to identify a correlation, already known or to be investigated in the future, between the differences that characterize male and female brains from a morphological and biochemical point of view and neurological syndromes. This correlation could provide a starting point for future scientific research aimed to investigate and define a personalized therapy.

Simple Summary Despite recent advances in surgical techniques and in anticancer drugs, and the adoption of perioperative treatments mostly based on conventional chemotherapy, the prognosis of advanced and metastatic gastric cancer remains poor. In the last decade, the addition of molecular therapy did not show any significant survival advantage, and the first reports available documented an increase of the rate of severe adverse effects and related mortality. We conducted a literature search for randomized trials investigating novel molecular agents as compared to conventional chemotherapy. The outcomes were patients’ survival and the rates of tumor response and of severe adverse effects (SAE). Although we did not find an increase of SAE, the survival benefits of novel molecular therapies available to date for advanced and metastatic gastric cancer were rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number. Abstract Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs recently investigated. PubMed, Embase and Cochrane Library were searched for phase III randomized controlled trials published from January 2016 to December 2020. Patients in the experimental arm received molecular therapy with or without conventional chemotherapy, while those in the control arm had conventional chemotherapy alone. The primary outcomes were overall and progression-free survival. The secondary outcomes were the rate of tumor response, severe adverse effects, and quality of life. Eight studies with a total of 4223 enrolled patients were included. The overall and progression-free survival of molecular and conventional therapy were comparable. Most of these trials did not find a significant difference in tumor response rate and in the number of severe adverse effects and related deaths between the experimental and control arms. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number.

Today, talking about metabolic syndrome (MetS) and oxidative stress, can be risky [...]

The LARS score is an internationally well-accepted questionnaire to assess low anterior resection syndrome, but currently there is no formally validated Italian version. The purpose of this study was to test the reliability and validity of the Italian version among Italian patients submitted to sphincter-sparing surgery for rectal cancer. The English version of the LARS score was translated into Italian following the forward-and-back translation process. A total of 147 patients filled out our version. Among them, 40 patients answered the questionnaire twice for the test-retest reliability phase. The validity of the LARS score was tested using convergent and discriminant validity indicators by correlating the EORTC QLQ-C30 and QLQ-CR29 questionnaires. The LARS score capability to differentiate groups of patients with different demographic or clinical features was also assessed. The test-retest reliability was excellent in 87.5% of patients, remained in the same LARS category in both tests. The convergent validity phase showed a relevant relationship of the LARS score with the EORTC domains, which was significant for 7 of 15 EORTC QLQ-C30 subscales, and for 14 of 29 EORTC QLQ-CR29 subscales. The LARS score was able to discriminate patients who received radiotherapy (p = 0.0026), TME vs. PME (p = 0.0060), tumour site at < 10 cm from the anal verge (p = 0.0030) and history of protective stoma (p < 0.0001). The Italian version of the LARS score is a valid and reliable tool for measuring LARS in Italian patients after SSS for rectal cancer.

Atherosclerosis represents one of the main risk factors for the development of cardiovascular diseases. Their etiologies have been studied in recent years in order to better define therapeutic targets for intervention and to identify diagnostic methods. Two different subtypes of macrophages, M1 and M2, have been described in physiological conditions. They can also be found in the atherosclerotic process, where they both have opposite roles in disease progression. Perivascular brown adipose tissue is also involved in inflammation and endothelial damage. In this work, we provide insights into the protective role of melatonin in the atherosclerotic process by morphological and 18F-FDG-PET/CT analyses. In particular, we examined the effects of melatonin on pathways that are linked to atherosclerosis development. We showed that melatonin, by suppressing M1 activity, reduced inflammation and directed macrophage polarization toward the M2 macrophage subtype. Moreover, melatonin preserved the activity of perivascular brown adipose tissue. In addition, 18F-FDG uptake is very high in mice treated with melatonin, confirming that other factors may alter 18F-FDG distribution. In conclusion, we showed that melatonin affects inflammatory pathways that have been linked to atherosclerosis, assessed the relationships of the 18F-FDG PET/CT parameters with macrophage markers and the production of their cytokines, which that have been defined by morphological evaluations.

Emerging evidence suggests that red blood cells (RBCs) are involved in many functions essential for life. Nuclear factor-kB (NF-kB), nitric oxide synthases (inducible nitric oxide synthase -iNOS-, endothelial nitric oxide synthase -eNOS-) and interleukin-1β (-IL-1β-) are all proteins that have been identified in RBCs. In nucleated cells, such as white blood cells (WBCs), these proteins have well investigated roles, linked to stress and inflammation. It is not the same in erythrocytes, for this reason, we considered obese patients for studying the morphology of RBCs. We studied a possible correlation between their morphological changes and several protein expressions. Moreover, we compared the results about the aforementioned proteins and antioxidant markers with those obtained in WBCs from healthy and obese patients before and after omega-3 polyunsaturated fatty acid supplementation. This latter scientific point is important in order to determine whether there are differences in the expression of nucleated and anucleated cells. The morphology of RBCs changed in obese patients, but it is significantly restored after six weeks of supplementation. The expression of antioxidant enzymes changed in RBCs and WBCs in obesity but all proteins restore their positivity after supplementation. We found that: the presence of NF-kB, antioxidant enzymes and eNOS in healthy RBCs could indicate a role of these proteins as regulators of cellular metabolism; obese WBCs showed a higher NF-kB, iNOS and IL-1β positivity, whereas eNOS presence did not significantly change in these cells. We tried to explain the different positivity of NF-kB, proposing a dual role for this protein, as prolifespan and as proinflammatory processes, depending on examined cells. In conclusion, we have considered the literature that focuses on the omega-6/omega-3 ratio. The ratio changed from the past, especially in people whose diet is strongly westernized worsening the state of health of the patient and leading to an higher incidence of obesity. Our study hypothesizes that the supplementation could help to restore the correct ratio.

Autism spectrum disorder is a neurodevelopmental syndrome with a complicated etiology and could be responsible for disrupted gastrointestinal tract microbiota. The aim of this work was to study intestinal samples from an autistic animal model (BTBR mouse strain) to better describe gastrointestinal alterations. We performed a morphological and biological evaluation of small intestine samples. In terms of morphology, we studied the goblet cells, cells of intestinal mucosal responsible for the production and maintenance of the protective mucous blanket. Alterations in their secretion may indicate an altered rate of mucus synthesis and this is one of the possible causes of gastrointestinal problems. In terms of biological evaluation, impaired regulation of glucose homeostasis regulated by sodium-glucose transporters has been suggested as an important component of obesity and associated comorbidities, therefore, this study analyzed the expression of sodium/glucose transporter-1 and -3 in BTBR mice to better define their role. We demonstrated that, in BTBR mice as compared to C57BL/6J (B6) strain animals: (1) The goblet cells had different protein content in their vesicles and apparently a larger number of Golgi cisternae, (2) the expression and level of sodium/glucose transporters were higher. These findings could suggest new possible targets in autism spectrum disorder to maintain mucus barrier function.

The thesis studies ski resorts planned and built at high altitude after the Second World War in the Franco-Italian Alps.The two national contexts, different for economic history, politics and geographical location, now share similar problems, which look to the future of a tourism model based on mass attendance, long stays and an offer concentrated around skiing. Indeed, climatic hazards, changes in the modes and times of tourist use, ageing of structures and infrastructures, are only some of the challenges which these places are facing today. Several researchers from various disciplines then suggested that the station could be rethought in continuity with the territory, the latter included in its economic, geographical or administrative nature.The research aims at investigating these questions in the field of architecture and through a historical study. By questioning the relationships established between the station and the territory (in its spatial, environmental and landscape components) during the design, construction and evolution process, the wish is to go beyond a reading of high mountain tourist establishments as decontextualized objects.Working on the spatial coordinate of the territory, we formulate the hypothesis that the establishment of winter sports resorts has led to large-scale transformations, and that, at the same time, the environmental, historical, economic and geomorphological characteristics of the sites concerned have played an active role in the design and construction process.Working on the temporal coordinate of the territory, we assume that the history of the winter sports resorts built in the 1960s and 1970s is only one step in the long process of transforming high-altitude sites for tourism. In this perspective, the history of activities preceding tourism, located in the same places, plays a decisive role.We rely on a method developed by environmental historians such as William Cronon, who considers the history of a territory as the result of interactions between human actions and natural data over a long period of time. The work is carried out through the study of four cases: Pila and Sansicario, in the Italian Alps; Chamrousse and La Plagne in the French Alps. We mobilize a corpus mainly constituted by documents belonging to different archival collections (local authorities, architects and urban planners, technicians), which we process by analyzing textual, graphic and cartographic documents, as well as by re-drawing and constructing chronosystem systemic timelines.In addition to give a contribution to the understanding of the history of tourism development in high mountain areas, we hope, through this work, to contribute to the debate on the methodological issues of research in the history of architecture., La thèse étudie les stations de sports d’hiver planifiées et construites en haute altitude après la Seconde Guerre mondiale dans les Alpes franco-italiennes.Les deux contextes nationaux, différents du fait de leurs histoires économiques, politiques et situations géographiques, partagent aujourd’hui des problèmes similaires. Ceux-ci concernent le futur d’un modèle touristique basé sur une fréquentation massive, de longs séjours et une offre concentrée autour de la pratique du ski. En effet, l’aléa climatique, le changement dans les modes et les temps de la fréquentation touristique, le vieillissement des structures et infrastructures, représentent seulement une partie des enjeux auxquels ces lieux se confrontent. Plusieurs chercheurs provenant de diverses disciplines suggèrent alors de repenser la station comme étant en continuité avec le territoire d’implantation, ce dernier compris dans sa nature économique, géographique ou administrative.La recherche, menée dans le domaine de l’architecture, souhaite contribuer à la réflexion autour de ces questionnements par une étude historique. En interrogeant les relations établies entre la station et le territoire (dans ses composantes spatiales, environnementales, paysagères), durant le processus de conception, de construction et d’évolution, nous souhaitons aller au-delà d’une lecture des établissements touristiques de haute montagne considérés comme des objets décontextualisés.En nous appuyant sur la coordonnée spatiale du territoire, nous formulons l’hypothèse que l’implantation des stations de sports d’hiver a entrainé des transformations à grande échelle, et que, en même temps, les caractères environnementaux, historiques, économiques, géomorphologiques des sites concernés ont joué un rôle actif dans le processus de conception et construction.À partir de la coordonnée temporelle du territoire, nous supposons que l’histoire des stations de sports d’hiver construites dans les années 1960 et 1970 n’est qu’une étape dans le processus long de transformation touristique des sites de haute altitude. Dans cette perspective, l’histoire des activités précédentes au tourisme, implantées sur les mêmes lieux, joue un rôle décisif.Le travail se déroule à travers l’étude de quatre cas : Pila et Sansicario, dans les Alpes italiennes ; Chamrousse et La Plagne dans les Alpes françaises. Pour cela, nous nous appuyons sur une méthode mise en place par les historiens de l’environnement, tels que William Cronon, qui considèrent l’histoire d’un territoire comme le résultat des interactions entre activités humaines et données naturelles, sur un temps long. Nous mobilisons un corpus principalement constitué de documents appartenant à différents fonds d’archives (des collectivités territoriales, des architectes et urbanistes, des techniciens), que nous traitons par l’analyse de documents textuels, graphiques et cartographiques qui le composent, ainsi que par le re-dessin et la construction de frises chrono-systémiques.Au-delà de contribuer à la compréhension de l’histoire de la mise en tourisme des territoires de haute montagne nous souhaitons, par ce travail, participer à la réflexion autour des enjeux méthodologiques de la recherche en histoire de l’architecture.

Liver diseases are classified as acute and chronic hepatic failures. In particular, chronic pathologies are the most common diseases in the World. Chronic pathologies of liver disease are the most common diseases in the world. There are many causes that induce a progressive and irreversible degeneration of the hepatic parenchyma, but, in general, they lead to the destruction of the normal balance between reactive oxygen stress (ROS) formation and ROS degradation within the liver. The prevalence of disabling diseases, including the hepatic diseases, is increasingly widespread, and it is important to find a safe, inexpensive, accessible and effective way to face this condition. Many recent studies have focused on different natural antioxidants, which could restore the physiological hepatic environment, thereby allowing the normal functioning of this organ. Natural products have been used to discover new leads for treating several diseases; among them, it is important to emphasize curcumin, which is a polyphenol obtained from Curcuma longa Linn, a plant naturally found throughout tropical and subtropical regions of the world.

Based on small studies and not on statistically valid clinical trials, guidelines for neonatal transfusions remain controversial and practices vary greatly. Premature infants and critically ill neonates in the neonatal intensive care unit (NICU) often require blood transfusions and extremely preterm neonates receive at least one red blood cell transfusion during their hospital stay. Transfusions to neonates convey both benefits and risks and consequently it is imperative to establish specific guidelines to improve practice and avoid unnecessary transfusions. Appropriate and lifesaving platelet transfusion in thrombocytopenic bleeding neonates pertains to 2% of all neonates in NICUs. Inversely, 98% of platelet transfusions are given prophylactically, in the absence of bleeding, with the assumption that this reduces the risk of a serious hemorrhage. To date, no evidence base is available for assigning a platelet transfusion trigger to NICU patients. Each NICU should approve specific guidelines that best suit its local clinical practice. Therefore, whatever guidelines are chosen in deciding when to transfuse, what is most important is to adhere strictly to the guidelines adopted, thus limiting unnecessary transfusions that convey no benefits and carry both known and unknown risks.

For years the thymus gland (TG) and the pineal gland (PG) have been subject of increasingly in-depth studies, but only recently a link that can associate the activities of the two organs has been identified. Considering, on the one hand, the well-known immune activity of thymus and, on the other, the increasingly emerging immunological roles of circadian oscillators and the rhythmically secreted main pineal product, melatonin, many studies aimed to analyse the possible existence of an interaction between these two systems. Moreover, data confirmed that the immune system is functionally associated with the nervous and endocrine systems determining an integrated dynamic network. In addition, recent researches showed a similar, characteristic involution process both in TG and PG. Since the second half of the 20th century, evidence led to the definition of an effectively interacting thymus-pineal axis (TG-PG axis), but much has to be done. In this sense, the aim of this review is to summarize what is actually known about this topic, focusing on the impact of the TG-PG axis on human life and ageing. We would like to give more emphasis to the implications of this dynamical interaction in a possible therapeutic strategy for human health. Moreover, we focused on all the products of TG and PG in order to collect what is known about the role of peptides other than melatonin. The results available today are often unclear and not linear. These peptides have not been well studied and defined over the years. In this review we hope to awake the interest of the scientific community in them and in their future pharmacological applications.

Infants born prematurely before 37 weeks of gestational age (GA) have particular anatomical, immunological and metabolic characteristics that predispose them, even in the absence of diseases at birth, to severe morbidity. Respiratory syncytial virus (RSV) is the leading cause of hospitalization for lower respiratory tract infections (LRTI) in the first year of life, as well as an important cause of respiratory outcomes as recurrent wheezing in industrialized countries or mortality in developing countries. Prematurity is an important risk factor for hospitalization for severe RSV disease, but epidemiological, environmental and demographic risk factors also play a role in RSV infection. Currently, there is no effective antiviral therapy for the treatment of RSV infection, nor the possibility of using maternal immunization or vaccination of children to prevent infection, although numerous preclinical and clinical studies are still ongoing. Passive immunization with palivizumab has been shown to be safe and effective in preventing RSV hospitalization in children at greater risk of contracting a serious infection. Costs associated with palivizumab prophylaxis and its monthly intramuscularly administration has prompted many health institutions of different countries to implement specific recommendations, with the aim of protecting at risk infants for whom RSV infection is likely to cause serious illness or death. The cost-effectiveness ratio of prophylaxis, related to reduce hospitalization costs and the impact of the burden of RSV disease worldwide, greatly affects the drafting and the adoption of specific recommendations and the adherence to them, concerning the passive immunization with palivizumab.

Objective: To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. Study design: This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. Results: Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. Conclusion: Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. Trial registration: isrctn.org: ISRCTN53107700.

Neonatal sepsis is frequently accompanied by significant and sometimes life-threatening coagulopathy. More complete understanding is needed of the molecular and cellular mechanisms underlying the interaction of the inflammatory and hemostatic systems. Such information may help focus future studies toward novel ways to improve the outcome of neonates who develop septic coagulopathy.

As the incidence rates of neonatal invasive fungal infection (IFI) have been increasing over the last years, research efforts have been addressed towards identifying both effective preventative strategies, and efficacious and well-tolerated antifungal drugs. Historically, the first options in treatment of neonatal IFI have been –and currently are- fluconazole and amphotericin B. However, these two drugs carry limitations both in efficacy and in putative toxicity. Recently, new therapeutic alternatives have drawn the neonatologists’ attention. Echinocandins are a new class of antifungal drugs with characteristics that might better meet the needs of this particular population of patients. Caspofungin, Micafungin and Anidulafungin have inherent good activities both against biofilms, and against natively fluconazole-resistent strains of Candida spp, thus overcoming two of the major weaknesses of the commonly used antifungal drugs in nurseries. Caspofungin and Micafungin have been recently studied in neonatal populations. The kinetics and appropriate dosing of this agent in premature and term infants have been described, but ongoing further studies are needed to better address this area. Extrapolation of data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both Caspofungin and Micafungin are effective and well tolerated also in neonates. Further studies properly designed for neonatal populations will better address long-term safety and echological issues related to Echinocandin use in neonates.

Summary Background Liposomal amphotericin B (LAMB) is frequently administered in NICU to preterm infants Aim To assess the occurrence of renal function impairment related to LAMB in a 10-year cohort of VLBW neonates treated with this drug. Methods Through database search of clinical charts, all VLBW neonates admitted to a 3 rd level NICU in the years 1998–2007 and undergoing treatment with LAMB were identified. The occurrence of LAMB-attributable renal toxicity was investigated; infants withdrawn from treatment for development of adverse effects or toxicity were identified. Results In the study period, 71 of 792 admitted VLBW neonates (8.9%) underwent antifungal treatment with LAMB administered at the recommended dosages (3-to-5 mg/kg/day). Mean duration of treatment was 14 (±9) days, mean cumulative dose given was 58 (±25) mg/kg per infant. Renal compromise, defined as hypokalaemia, and/or elevated creatinine serum levels, and/or decreased urine output, occurred in 2 of 71 (2.8%) treated patients, by 5 (±3) mean days after treatment initiation. In both patients LAMB was withdrawn; renal function impairment was only mild and transient, and normal renal function was restored at discharge. No other significant adverse effects were recorded in any treated neonate. Conclusions LAMB is generally safe and well tolerated in VLBW neonates. The occurrence of LAMB-related nephrotoxicity appears to be uncommon, mild and transient.

As the incidence rates of neonatal systemic fungal infections (SFI) have been increasing over the last years, research efforts have been addressed towards identifying both effective preventative strategies, and efficacious and well-tolerated antifungal drugs. Historically, the first options in treatment of neonatal SFI have been#x2013; and currently are#x2013; fluconazole and amphotericin B. However, these two drugs carry limitations both in efficacy and in putative toxicity. Recently, new therapeutic alternatives have drawn the neonatologists' attention. Echinocandins are a new class of antifungal drugs with characteristics that might better meet the needs of this particular population of patients. Caspofungin (CSP), micafungin (MICA), and anidulafungin have inherent good activities both against biofilms, and against natively fluconazole-resistant strains of Candida spp, thus overcoming two of the major weaknesses of the commonly used antifungal drugs in nurseries. CSP and MICA have been recently studied in neonatal populations. The kinetics and appropriate dosing of this agent in premature and term infants have been described, but ongoing further studies are needed to better address this area. Case-report series show clinical efficacy and tolerability in critical neonatal patients given CSP and MICA. In addition, extrapolation of data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both CSP and MICA are effective and well tolerated also in neonates. Further studies properly designed for neonatal populations will better address long-term safety and ecological issues related to echinocandin use in neonates.

Fungal-related morbidity and mortality is a major concern for most neonatal intensive care units (NICUs) worldwide. Incidence rates are increasing and might be higher than reported due to the challenges associated with diagnosing fungal infections. As preterm neonates display clinical characteristics that make them prone to Candida spp infections, and there is a high frequency of severe neurodevelopmental sequelae in those who survive neonatal fungal infections, specific prevention – rather than empiric or pre-emptive treatment – should be the optimal strategy. Besides stewardship of drug use and efforts to minimize invasive cares, pharmacological prevention with use of fluconazole has proved highly effective in decreasing the rates of fungal sepsis in very low birth weight (VLBW) neonates. Alternative options needing further and more conclusive assessments include use of nystatin, bovine lactoferrin or probiotics.

An episode of sepsis occurs in 20 to 40% of all preterm patients, and such figures have been reported constantly increasing in Neonatal Intensive Care Units. Neonatal sepsis include bloodstream, urine, cerebrospinal, peritoneal infections, infections starting from burns and wounds, or from any other usually sterile sites. Many specific risk factors account for the increased risk of sepsis, including employment of broad-spectrum antibiotics selecting resistant microflora, parenteral nutrition, acid inhibitors and steroids, as well as the systematic and long-lasting use of invasive management. In preterm neonates, loss of gut commensals such as bifidobacteria and lactobacilli, due to the difficulties in oral feeding, or a slower acquisition of them, translates into an increased susceptibility to pathogenic gut colonization. Prompt diagnosis, effective treatment, and specific prophylaxis with antibacterial and antifungal drugs are the milestones of management of these life-threatening events. This article discusses the recent advances in prevention and shows how fluconazole for prevention of fungal sepsis, probiotics for prevention of necrotizing enterocolitis, and bovine lactoferrin for prevention of bacterial sepsis may be considered as effective preventive strategies.

Renal diseases interfere with the regulation of several metabolic pathways including dyslipidemia. The latter includes increased triglycerides, very low-density lipoprotein levels and decreased high-density lipoproteins. These lipoproteins change during renal injury. Apolipoprotein-E deficient mice (ApoE(-/-)) are considered a very well accepted model of hypercholesterolemia with marked renal pathological alterations. Ghrelin hormone is mainly secreted from the stomach when the stomach is empty, but it is also found in the kidney. In this organ it has autocrine and/or paracrine roles determining glomerular filtration rate, tubular phosphate and sodium reabsorption. Interestingly, it has been demonstrated that ghrelin levels increase after fasting. This mechanism induces an interaction with sirtuin 1 (SIRT1)/p53 pathway suggesting a link between ghrelin and SIRT1 in the regulation of salt and water metabolism. The mechanisms of ghrelin-induced SIRT1 expression are not yet fully understood. Recent studies indicate that SIRT1 exerts renoprotective properties against kidney diseases. This could be a very interesting point for underlining the important role of the ghrelin-SIRT1 system. Water movement across biological cell membranes is enhanced or facilitated by tetrameric membrane-bound channels, named aquaporin (AQP) family, and in particular, AQP1 and AQP2 proteins. In this study, we evaluated the possible pathway existing among the ghrelin/SIRT1/AQP1/AQP2 system in APOE(-/-) mice in order to clarify or stress the role played by said system in renal diseases associated to aging with or without comorbities. The results could provide a basis for considering ghrelin as a new target for therapeutic strategies of renal injury.