From dynamic self-organization to avalanching instabilities in soft-granular threads.

We study the dynamics of threads of monodisperse droplets, including droplet chains and multi-chains, in which the droplets are interconnected by capillary bridges of another immiscible liquid phase. This system represents wet soft-granular matter - a class of granular materials in which the grains are soft and wetted by thin fluid films-with other examples including wet granular hydrogels or foams. In contrast to wet granular matter with rigid grains (e.g., wet sand), studied previously, the deformability of the grains raises the number of available metastable states and facilitates rearrangements which allow for reorganization and self-assembly of the system under external drive, e.g., applied via viscous forces. We use a co-flow configuration to generate a variety of unique low-dimensional regular granular patterns, intermediate between 1D and 2D, ranging from linear chains and chains with periodically occurring folds to multi-chains and segmented structures including chains of finite length. In particular, we observe that the partially folded chains self-organize via limit cycle of displacements and rearrangements occurring at a frequency self-adapted to the rate of build-up of compressive strain in the chain induced by the viscous forces. Upon weakening of the capillary arrest of the droplets, we observe spontaneous fluidization of the quasi-solid structures and avalanches of rearrangements. We identify two types of fluidization-induced instabilities and rationalize them in terms of a competition between advection and propagation. While we use aqueous droplets as the grains we demonstrate that the reported mechanisms of adaptive self-assembly apply to other types of soft granular systems including foams and microgels. We discuss possible application of the reported quasi-1D compartmentalized structures in tissue engineering, bioprinting and materials science.

Pregnancy-associated plasma protein A mRNA expression as a marker for differentiated thyroid cancer: results from a "surgical" and a "cytological" series.

PURPOSE: Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase initially described for its role during pregnancy. PAPPA regulates IGF ligands 1 (IGF1) bioavailability through the degradation of IGF-binding protein 4 (IGFBP4). After the cleavage of IGFBP4, free IGF1 is able to bind IGF1 receptors (IGF1R) triggering the downstream signaling. Recently, PAPPA expression has been linked with development of several cancers. No data have been published on thyroid cancer, yet. METHODS: We evaluated PAPPA, insulin-like growth factor (IGF1), IGF1 receptors (IGF1R) and IGF-binding protein 4 (IGFBP4) mRNA expression levels in a "Surgical series" of 94 thyroid nodules (64 cancers, 16 follicular adenomas and 14 hyperplastic nodules) and in a "Cytological series" of 80 nodules from 74 patients underwent to fine-needle aspiration cytology (FNAC). In tissues, PAPPA was also evaluated by western blot. RESULTS: We found that PAPPA expression was increased in thyroid cancer specimen at mRNA and protein levels and that, adenomas and hyperplastic nodules had an expression similar to normal tissues. When applied on thyroid cytologies, PAPPA expression was able to discriminate benign from malignant nodules contributing to pre-surgical classification of the nodules. We calculated a cut-off with a good specificity (91%) which reached 100% when combined with molecular biology. CONCLUSION: These results show that PAPPA could represent a promising diagnostic marker for differentiated thyroid cancer.

Comparison of in situ sediment remediation amendments: Risk perspectives from species sensitivity distribution.

Contaminated sediment is a major issue for aquatic environments, but attention must be kept even during remediation activities that can negatively affect resident biota especially when applied in situ. For the first time, the species sensitivity distribution (SSD) approach was applied to amendments used for in situ sediment remediation considering 39 papers including both freshwater (F) and saltwater (S) effect data (i.e. n = 17 only F, n = 19 only S, and n = 3 both F and S). Toxicity data related to the application of activated carbon (AC), nano-Zero-Valent-Iron (nZVI), apatite (A), organoclay (OC) and zeolite (Z) were collected and analyzed. SSD curves were constructed by lognormal model providing comprehensive comparisons of the sensitivities of different species to the relative testing methods. Results indicated that Bacteria were the most sensitive group of testing organisms, while Crustaceans were the less sensitive. The hazardous concentration for 5% of the affected species (HC5) were derived to determine the concentration protecting 95% of the species. OC, A and Z presented both acute and chronic toxicity. The HC5 values in descending order are: AC (4.79 g/L) > nZVI (0.02 g/L) > OC, A and Z (1.77E-04 g/L). AC and nZVI can be considered safer than OC, A and Z in sediment remediation activities, even if in situ long-term effects remained still underexplored.

Development and preliminary evaluation of a communication skills training programme for hospital physicians by a specialized palliative care service: the 'Teach to Talk' programme.

BACKGROUND: There is widespread agreement about the importance of communication skills training (CST) for healthcare professionals caring for cancer patients. Communication can be effectively learned and improved through specific CST. Existing CSTs have some limitations with regard to transferring the learning to the workplace. The aim of the study is developing, piloting, and preliminarily assessing a CST programme for hospital physicians caring for advanced cancer patients to improve communication competences. METHODS: This is a Phase 0-I study that follows the Medical Research Council framework; this paper describes the following sections: a literature review on CST, the development of the Teach to Talk training programme (TtT), the development of a procedure for assessing the quality of the implementation process and assessing the feasibility of the implementation process, and the pilot programme. The study was performed at a 900-bed public hospital. The programme was implemented by the Specialized Palliative Care Service. The programme was proposed to 19 physicians from 2 departments. RESULTS: The different components of the training course were identified, and a set of quality indicators was developed. The TtT programme was implemented; all the physicians attended the lesson, videos, and role-playing sessions. Only 25% of the physicians participated in the bedside training. It was more challenging to involve Haematology physicians in the programme. CONCLUSIONS: The programme was completed as established for one of the two departments in which it was piloted. Thus, in spite of the good feedback from the trainees, a re-piloting of a different training program will be developed, considering in particular the bed side component. The program should be tailored on specific communication attitude and believes, probably different between different specialties.

Preventing action slows down performance in perceptual judgment.

Action and vision are known to be tightly coupled with each other. In a previous study, we found that repeatedly grasping an object without any visual feedback might result in a perceptual aftereffect when the object was visually presented in the context of a perceptual judgement task. In this study, we explored whether and how such an effect could be modulated by presenting the object behind a transparent barrier. Our conjecture was that if perceptual judgment relies, in part at least, on the same processes and representations as those involved in action, then one should expect to find a slowdown in judgment performance when the target object looks to be out of reach. And this was what we actually found. This indicates that not only acting upon an object but also being prevented from acting upon it can affect how the object is perceptually judged.

Sentinel node biopsy versus elective neck dissection in early-stage oral cancer: a systematic review.

PURPOSE: To provide a summary of the evidence on the comparative effectiveness of two surgical treatment strategies, sentinel node biopsy (SNB) and elective neck dissection (END), in patients with T1-T2 oral cancer and clinically negative (cN0) neck, in terms of overall survival (OS), disease-free survival (DFS) and neck recurrence rates (NRRs). METHODS: A systematic review was performed by including studies published up to April 2019. Meta-analysis was performed to compare NRRs between SNB and END. A narrative summary of the results was generated for OS, DFS and morbidity outcomes. The certainty of evidence was assessed according to the GRADE methodology. RESULTS: No randomized studies were retrieved. Five observational studies were included in the comparative effectiveness analysis and four observational studies were included in the comparative morbidity analysis. The pooled risk ratio showed no differences in NRRs between SNB and END (10.5% vs 11.6%; pooled RR 1.09; 95% CI 0.67-1.76). No differences in OS or DFS between the two treatments were found. SNB appears to be associated with a lower rate of postoperative complications and lower shoulder dysfunction than END. Conversely, the results of the quality of life (QoL) questionnaires are not sufficient to advocate a particular strategy. CONCLUSION: Our review highlights the lack of well conducted and randomized studies comparing SNB to END, leading to poor clinical evidence. Although our findings suggest no significant differences in OS, DFS and NRR between the two strategies, the certainty of our evidence is too low to make it useful for clinical decision making.

Isotopic biomonitoring of N pollution in rivers embedded in complex human landscapes.

The dynamic and hierarchical structure of rivers, together with disruption of the natural river continuum by human activities, makes it difficult to identify and locate sources of nutrient pollution affecting receiving waters and observe its dispersion, thus impairing monitoring efforts. The identification of reliable indicators of anthropogenic nitrogen inputs in catchments is therefore key to achieving effective management of polluted rivers. We tested the capacity of N isotopic signatures (δ15N) of epilithon and snails to provide useful indications of organic and inorganic anthropogenic N inputs in three Mediterranean rivers differing in terms of surrounding land use and physicochemical conditions. We used a combined approach based on (i) analysis of nutrient concentrations in water, (ii) CORINE land cover classification and drainage patterns in catchments and (iii) isotopic analysis of river biota to verify whether isotopic variations were indicative of anthropic activities in the watershed, the associated alteration of water quality, and the consequent impact on snail abundance and diversity. Variation in the δ15N of epilithon within and between rivers reflected localised and diffuse N inputs from inorganic and organic sources. Negative epilithon δ15N values (<0‰) indicated inorganic pollution from agriculture. Values between 4‰ and 8‰ and those above 8‰ respectively indicated moderate organic pollution from urban areas, and high organic pollution, mostly from waste waters. The diversity and abundance of snails decreased with increasing water pollution. While their isotopic variations reflected between-river differences, they failed to indicate within-river variations in anthropogenic N inputs, since the proportion of epilithon in their diet varied along the rivers. Concluding, epilithon was a reliable indicator of anthropogenic N sources across a wide range of nutrient concentrations and anthropogenic inputs, and the proposed approach allowed us to determine the nature of nitrogen pollutants, their sources, location and dispersion along rivers embedded in complex human landscapes.

The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

The 2018 ISDE achalasia guidelines

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Pathologist's assistant (PathA) and his/her role in the surgical pathology department: a systematic review and a narrative synthesis.

In recent decades, various highly qualified individuals have increasingly performed tasks that have historically been handled by physicians with the aim of reducing their workload. Over time, however, these "physician assistants" or "physician extenders" have gained more and more responsibilities, showing that specific tasks can be performed equally skilfully by specialised health care professionals. The pathologist's assistant (PathA) is a highly qualified technician who works alongside the pathologist and is responsible for the grossing and autopsies. This profession was developed in the USA, with formal training programmes starting in 1970 when Dr. Kinney, director of the Department of Pathology of Duke University, Durham, NC, started the first dedicated course. Most institutes in the USA and Canada currently employ these technical personnel for grossing, and numerous papers published over the years demonstrate the quality of the assistance provided by the PathA, which is equal to or sometimes even better than the performance of pathologists. The PathA can be employed to carry out a wide range of tasks to assist the pathologist, such as grossing (the description and reduction of surgical specimens), judicial autopsies and administrative and supervisory practices within the laboratory or assistance in research, although the diagnosis is always the pathologist's responsibility. Since this role has already been consolidated in North America, part of the relevant literature is altogether out of date. However, the situation is different in Europe, where there is an increasing interest in PathA, mainly because of the benefits of their inclusion in anatomic pathology laboratories. In the UK, biomedical scientists (BMS, the British equivalent of PathA) are involved in many tasks both in surgical pathology and in cytopathology, which are generally performed by medically trained staff. Several papers have been recently published to highlight the role of BMS with the broader public. This report aimed to conduct a systematic review of all the articles published about the PathA/BMS and to perform a narrative synthesis. The results may contribute to the evidence for including the PAthA/BMS within a surgical pathology laboratory organisation.

Hyaluronan: an overview.

Hyaluronic acid (HA) is a polyanionic natural polymer occurring as a linear polysaccharide composed of glucuronic acid and N-acetylglucosamine repeats. Hyaluronic acid has a wide range of applications with its excellent physicochemical properties such as biodegradability, biocompatibility, non-toxicity, non-immunogenicity and serves as an excellent tool in biomedical applications such as osteoarthritis surgery, ocular surgery, plastic surgery, tissue engineering and drug delivery. This work provides an overview on hyaluronic acid, its chemistry and biochemistry and its medical applications.

Long-term wireless pH monitoring of the distal esophagus: prolonging the test beyond 48 hours is unnecessary and may be misleading.

Wireless pH monitoring of the esophagus has been widely used to detect GERD for more than a decade. It is generally well tolerated and accepted by patients, but it is still unclear whether prolonging a recording beyond the usual 48 hours can improve the test's diagnostic value. The aim of this study is to examine the diagnostic yield of 96-hour pH monitoring vis-à-vis 24- and 48-hour tests, and to ascertain whether any gain in diagnostic terms was of genuine clinical utility. Patients with suspected GERD underwent 4-day PPI-off wireless pH monitoring of the distal esophagus. The capsule was inserted under endoscopic control, 6 cm above the squamocolumnar junction. Average acid exposure time was calculated after 24, 48, and 96 hours of recording. Ninety-nine patients completed the 96 hour test, and formed the study sample. The wireless test method was used in 42 patients (42.4%) unable to tolerate the traditional pH-monitoring catheter, and in 57 (57.6%) with a previous negative pH study despite symptoms suggestive of GERD. On complete analysis, 47 patients (47.5%) had a pathological test result: 19 patients within the first 24 hours (19.2%, 24 hour group); another 16 after 48 hours (+16.2%, 48 hour group), and a further 12 (+12.1%, 96 hour group) only after 96 hours of monitoring. All 47 patients with an abnormal acid exposure were offered and accepted surgery (10 patients) or medical therapy (37 patients). Clinical follow-up was obtained in all patients with a positive Bravo test result after a median 67 months (IQR: 38-98) using a validated symptom questionnaire. A good outcome after fundoplication or medical therapy was achieved in 73.7% of patients in the 24 hour group, in 62.5% of those in the 48 hour group, and in only 25% of those in the 96 hour group, P = 0.02. Long-term wireless pH monitoring enables an increase in the diagnostic yield over traditional 24- and 48-hour pH studies, but prolonging the test may constitute an unwanted bias and prompt the recruitment of more complex patients, in whom the outcome of surgical or medical therapy may prove less than satisfactory. These findings should be taken into account when establishing the guidelines for assessing GERD with such long-term pH monitoring methods.

Economic evaluation of the randomized European Achalasia trial comparing pneumodilation with Laparoscopic Heller myotomy.

BACKGROUND: A recent multicenter randomized trial in achalasia patients has shown that pneumatic dilation resulted in equivalent relief of symptoms compared to laparoscopic Heller myotomy. Additionally, the cost of each treatment should be also taken in consideration. Therefore, the aim of the present study was to perform an economic analysis of the European achalasia trial. METHODS: Patients with newly diagnosed achalasia were enrolled from to 2003 to 2008 in 14 centers in five European countries and were randomly assigned to either pneumatic dilation (PD) or laparoscopic Heller (LHM). The economic analysis was performed in the three centers in three different countries where most patients were enrolled (Amsterdam [NL], Leuven, [B] and Padova [I]) and then applied to all patients included in the study. The total raw costs of the two treatments per patient include the initial costs, the costs of complications, and the costs of retreatments. RESULTS: Two hundred and one patients, 107 (57 males and 50 females, mean age 46 CI: 43-49 years) were randomized to LHM and 94 (59 males and 34 females, mean age 46 CI 43-50 years) to PD. The total cost of PD per patient was quite comparable in the three different centers; €3397 in Padova, €3259 in Amsterdam and €3792 in Leuven. For LHM, the total costs per patient were highest in Amsterdam: €4488 in Padova, €6720 in Amsterdam, and €5856 in Leuven. CONCLUSION: In conclusion, the strategy of treating achalasia starting with PD appears the most economic approach, independent of the health system.

C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition.

Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients' samples and by in silico analysis on an independent patient cohort from Taylor's platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients' risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring.

Multicenter Ozone Study in oldEr Subjects (MOSES): Part 1. Effects of Exposure to Low Concentrations of Ozone on Respiratory and Cardiovascular Outcomes.

INTRODUCTION: Exposure to air pollution is a well-established risk factor for cardiovascular morbidity and mortality. Most of the evidence supporting an association between air pollution and adverse cardiovascular effects involves exposure to particulate matter (PM). To date, little attention has been paid to acute cardiovascular responses to ozone, in part due to the notion that ozone causes primarily local effects on lung function, which are the basis for the current ozone National Ambient Air Quality Standards (NAAQS). There is evidence from a few epidemiological studies of adverse health effects of chronic exposure to ambient ozone, including increased risk of mortality from cardiovascular disease. However, in contrast to the well-established association between ambient ozone and various nonfatal adverse respiratory effects, the observational evidence for impacts of acute (previous few days) increases in ambient ozone levels on total cardiovascular mortality and morbidity is mixed.Ozone is a prototypic oxidant gas that reacts with constituents of the respiratory tract lining fluid to generate reactive oxygen species (ROS) that can overwhelm antioxidant defenses and cause local oxidative stress. Pathways by which ozone could cause cardiovascular dysfunction include alterations in autonomic balance, systemic inflammation, and oxidative stress. These initial responses could lead ultimately to arrhythmias, endothelial dysfunction, acute arterial vasoconstriction, and procoagulant activity. Individuals with impaired antioxidant defenses, such as those with the null variant of glutathione S-transferase mu 1 (GSTM1), may be at increased risk for acute health effects.The Multicenter Ozone Study in oldEr Subjects (MOSES) was a controlled human exposure study designed to evaluate whether short-term exposure of older, healthy individuals to ambient levels of ozone induces acute cardiovascular responses. The study was designed to test the a priori hypothesis that short-term exposure to ambient levels of ozone would induce acute cardiovascular responses through the following mechanisms: autonomic imbalance, systemic inflammation, and development of a prothrombotic vascular state. We also postulated a priori the confirmatory hypothesis that exposure to ozone would induce airway inflammation, lung injury, and lung function decrements. Finally, we postulated the secondary hypotheses that ozone-induced acute cardiovascular responses would be associated with: (a) increased systemic oxidative stress and lung effects, and (b) the GSTM1-null genotype. METHODS: The study was conducted at three clinical centers with a separate Data Coordinating and Analysis Center (DCAC) using a common protocol. All procedures were approved by the institutional review boards (IRBs) of the participating centers. Healthy volunteers 55 to 70 years of age were recruited. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures (SOPs) and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits, each consisting of the pre-exposure day, the exposure day, and the post-exposure day. The subjects spent the night in a nearby hotel the night of the pre-exposure day.On exposure days, the subjects were exposed for three hours in random order to 0 ppb ozone (clean air), 70 ppb ozone, and 120 ppm ozone, alternating 15 minutes of moderate exercise with 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after, each exposure. The endpoints included: (1) electrocardiographic changes (continuous Holter monitoring: heart rate variability [HRV], repolarization, and arrhythmia); (2) markers of inflammation and oxidative stress (C-reactive protein [CRP], interleukin-6 [IL-6], 8-isoprostane, nitrotyrosine, and P-selectin); (3) vascular function measures (blood pressure [BP], flow-mediated dilatation [FMD] of the brachial artery, and endothelin-1 [ET-1]; (4) venous blood markers of platelet activation, thrombosis, and microparticle-associated tissue factor activity (MP-TFA); (5) pulmonary function (spirometry); (6) markers of airway epithelial cell injury (increases in plasma club cell protein 16 [CC16] and sputum total protein); and (7) markers of lung inflammation in sputum (polymorphonuclear leukocytes [PMN], IL-6, interleukin-8 [IL-8], and tumor necrosis factor-alpha [TNF-α]). Sputum was collected only at 22 hours after exposure.The analyses of the continuous electrocardiographic monitoring, the brachial artery ultrasound (BAU) images, and the blood and sputum samples were carried out by core laboratories. The results of all analyses were submitted directly to the DCAC.The variables analyzed in the statistical models were represented as changes from pre-exposure to post-exposure (post-exposure minus pre-exposure). Mixed-effect linear models were used to evaluate the impact of exposure to ozone on the prespecified primary and secondary continuous outcomes. Site and time (when multiple measurements were taken) were controlled for in the models. Three separate interaction models were constructed for each outcome: ozone concentration by subject sex; ozone concentration by subject age; and ozone concentration by subject GSTM1 status (null or sufficient). Because of the issue of multiple comparisons, the statistical significance threshold was set a priori at P < 0.01. RESULTS: Subject recruitment started in June 2012, and the first subject was randomized on July 25, 2012. Subject recruitment ended on December 31, 2014, and testing of all subjects was completed by April 30, 2015. A total of 87 subjects completed all three exposures. The mean age was 59.9 ± 4.5 years, 60% of the subjects were female, 88% were white, and 57% were GSTM1 null. Mean baseline body mass index (BMI), BP, cholesterol (total and low-density lipoprotein), and lung function were all within the normal range.We found no significant effects of ozone exposure on any of the primary or secondary endpoints for autonomic function, repolarization, ST segment change, or arrhythmia. Ozone exposure also did not cause significant changes in the primary endpoints for systemic inflammation (CRP) and vascular function (systolic blood pressure [SBP] and FMD) or secondary endpoints for systemic inflammation and oxidative stress (IL-6, P-selectin, and 8-isoprostane). Ozone did cause changes in two secondary endpoints: a significant increase in plasma ET-1 (P = 0.008) and a marginally significant decrease in nitrotyrosine (P = 0.017). Lastly, ozone exposure did not affect the primary prothrombotic endpoints (MP-TFA and monocyte-platelet conjugate count) or any secondary markers of prothrombotic vascular status (platelet activation, circulating microparticles [MPs], von Willebrand factor [vWF], or fibrinogen.).Although our hypothesis focused on possible acute cardiovascular effects of exposure to low levels of ozone, we recognized that the initial effects of inhaled ozone involve the lower airways. Therefore, we looked for: (a) changes in lung function, which are known to occur during exposure to ozone and are maximal at the end of exposure; and (b) markers of airway injury and inflammation. We found an increase in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) after exposure to 0 ppb ozone, likely due to the effects of exercise. The FEV1 increased significantly 15 minutes after 0 ppb exposure (85 mL; 95% confidence interval [CI], 64 to 106; P < 0.001), and remained significantly increased from pre-exposure at 22 hours (45 mL; 95% CI, 26 to 64; P < 0.001). The increase in FVC followed a similar pattern. The increase in FEV1 and FVC were attenuated in a dose-response manner by exposure to 70 and 120 ppb ozone. We also observed a significant ozone-induced increase in the percentage of sputum PMN 22 hours after exposure at 120 ppb compared to 0 ppb exposure (P = 0.003). Plasma CC16 also increased significantly after exposure to 120 ppb (P < 0.001). Sputum IL-6, IL-8, and TNF-α concentrations were not significantly different after ozone exposure. We found no significant interactions with sex, age, or GSTM1 status regarding the effect of ozone on lung function, percentage of sputum PMN, or plasma CC16. CONCLUSIONS: In this multicenter clinical study of older healthy subjects, ozone exposure caused concentration-related reductions in lung function and presented evidence for airway inflammation and injury. However, there was no convincing evidence for effects on cardiovascular function. Blood levels of the potent vasoconstrictor, ET-1, increased with ozone exposure (with marginal statistical significance), but there were no effects on BP, FMD, or other markers of vascular function. Blood levels of nitrotyrosine decreased with ozone exposure, the opposite of our hypothesis. Our study does not support acute cardiovascular effects of low-level ozone exposure in healthy older subjects. Inclusion of only healthy older individuals is a major limitation, which may affect the generalizability of our findings. We cannot exclude the possibility of effects with higher ozone exposure concentrations or more prolonged exposure, or the possibility that subjects with underlying vascular disease, such as hypertension or diabetes, would show effects under these conditions.

Marine microorganisms as a promising and sustainable source of bioactive molecules.

There is an urgent need to discover new drug entities due to the increased incidence of severe diseases as cancer and neurodegenerative pathologies, and reducing efficacy of existing antibiotics. Recently, there is a renewed interest in exploring the marine habitat for new pharmaceuticals also thanks to the advancement in cultivation technologies and in molecular biology techniques. Microorganisms represent a still poorly explored resource for drug discovery. The possibility of obtaining a continuous source of bioactives from marine microorganisms, more amenable to culturing compared to macro-organisms, may be able to meet the challenging demands of pharmaceutical industries. This would enable a more environmentally-friendly approach to drug discovery and overcome the over-utilization of marine resources and the use of destructive collection practices. The importance of the topic is underlined by the number of EU projects funded aimed at improving the exploitation of marine organisms for drug discovery.

Papillary type 2 versus clear cell renal cell carcinoma: Survival outcomes.

AIM: To compare the cancer specific survival (CSS) between p2-RCC and a Propensity Score Matched (PSM) cohort of cc-RCC patients. METHODS: Fifty-five (4.6%) patients with p2-RCC and 920 cc-RCC patients were identified within a prospectively maintained institutional dataset of 1205 histologically proved RCC patients treated with either RN or PN. Univariable and multivariable Cox regression analyses were used to identify predictors of CSS after surgical treatment. A 1:2 PSM analysis based on independent predictors of oncologic outcomes was employed and CSS was compared between PSM selected cc-RCC patients using Kaplan-Meier and Cox regression analysis. RESULTS: Overall, 55 (4.6%) p2-RCC and 920 (76.3%) cc-RCC patients were selected from the database; p2-RCC were significantly larger (p = 0.001), more frequently locally advanced (p < 0.001) and node positive (p < 0.001) and had significantly higher Fuhrman grade (p < 0.001) than cc-RCC. On multivariable Cox regression analysis age (p = 0.025), histologic subtype (p = 0.029), pN stage (p = 0.006), size, pT stage, cM stage, sarcomatoid features and Fuhrman grade (all p < 0.001) were independent predictors of CSS. After applying the PSM, 82 cc-RCC selected cases were comparable to 41 p2-RCC for age (p = 0.81), tumor size (p = 0.39), pT (p = 1.00) and pN (p = 0.62) stages, cM stage (p = 0.71) and Fuhrman grade (p = 1). In this PSM cohort, 5 yr CSS was significantly lower in the p2-RCC (63% vs 72.4%; p = 0.047). At multivariable Cox analysis p2 histology was an independent predictor of CSM (HR 2.46, 95% CI 1.04-5.83; p = 0.041). CONCLUSIONS: We confirmed the tendency of p2-RCC to present as locally advanced and metastatic disease more frequently than cc-RCC and demonstrated p2-RCC histology as an independent predictor of worse oncologic outcomes.

The GerdQ questionnaire and high resolution manometry support the hypothesis that proton pump inhibitor-responsive oesophageal eosinophilia is a GERD-related phenomenon.

BACKGROUND: Little is known about the relationship between proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE), eosinophilic esophagitis (EoE) and gastro-oesophageal reflux disease (GERD). AIM: To compare high resolution manometry features and symptom profiles of patients with EoE, PPI-REE and GERD. METHODS: Consecutive patients diagnosed with EoE or PPI-REE according to international criteria (presence of at least one typical symptom of oesophageal dysfunction; at least 15 eosinophils per high-power field at mid/proximal oesophagus, persistence or resolution of eosinophils after an 8-week PPI trial), and a group of patients with proven GERD and oesophageal eosinophilia, prospectively completed the GerdQ questionnaire and underwent high resolution manometry. RESULTS: Thirty-five patients with EoE, 17 with PPI-REE and 27 with GERD were enrolled. When compared to GERD, both EoE and PPI-REE had higher rates of dysphagia (15% vs. 94% vs. 88%, P < 0.0001), patients with EoE reported heartburn and regurgitation less frequently (26% vs. 85%, and 17% vs. 74%, respectively; P < 0.001 for each and had lower GerdQ score [1 (0-6) vs. 8 (6-12), P < 0.001] than GERD patients. There was no significant difference comparing PPI-REE and GERD patients. Patients with PPI-REE had a higher prevalence of erosive oesophagitis than patients with EoE (35% vs. 9%, P = 0.04), which was similar to that of GERD (48%, P = 0.54). Patients with EoE had a lower frequency of high resolution manometry features associated with GERD than patients with PPI-REE. There was no significant difference between PPI-REE and GERD patients. CONCLUSION: GERD, as assessed by GerdQ and high resolution manometry is common in patients with PPI-REE, which may share similar pathogenic mechanisms.