Concurrence of adenocarcinoma and large-cell neuroendocrine carcinoma of the stomach is a rare condition. Here, we report a case of gastric collision tumour with large-cell neuroendocrine carcinoma and adenocarcinoma. A 71-year-old Peruvian man presented with nausea, epigastric pain, and weight loss for seven months. An Endoscopic evaluation revealed a huge ulcerative and infiltrative mass in the upper and middle third of the stomach. The patient underwent a D2 total gastrectomy. Microscopically, two separated and attached ulcerative lesions were recognised. The proximal to the cardial lesion showed neuroendocrine morphology and immunoreactivity for synaptophysin, and the other a moderated tubular adenocarcinoma Borrmann type III. Both lesions invaded serosa and lymph nodes metastases were found in 17 of 41 lymph nodes retrieved (one lymph node with neuroendocrine metastatic deposits). Adenocarcinomas are largely the most common gastric malignant tumour and concurrent or synchronous presentation in the same stomach of different histological type tumours rarely occurs. Lewin proposed a nomenclature for these neoplasms: (a) Composite tumours for the mixture of exocrine and endocrine components; (b) Collision tumours, where the exocrine and endocrine components differ and are juxtaposed and finally; (c) Amphicrine cell tumours, where the endocrine and exocrine cells constituents are present within the same cell, exhibiting dual differentiation , 2.Collision tumours are neoplasms consisting of two distinct cell populations, developing in juxtaposition to one another, without areas of intermingling . These tA 71-year-old man was admitted to our outpatient clinic, with nausea, epigastric pain, and weight loss that had lasted for seven months. Laboratory findings showed anaemia. The patient underwent an endoscopic evaluation, which revealed a huge ulcerative and infiltrative mass in the upper and middle third of the stomach and the biopsy specimen taken showed a moderated tubular adenocarcinoma. Contrast-enhanced computerised tomography (CT) scan revealed a thick engrossment of the two upper thirds of the stomach with enlarged perigastric lymph nodes and not liver, nor peritoneal metastases findings were shown. The patient underwent a D2 total gastrectomy with distal pancreatectomy and splenectomy. At surgery, the tumour was located in the upper two-thirds of the posterior wall of the stomach with enlarged lymph nodes at the lesser curvature and celiac trunk. There was serosal invasion and fixation to the anterior surface of the pancreas body. No liver or peritoneal metastases were found.On gross examination of the specimen, we identified two attached ulcerative tumours located on the posterior wall of the stomach . The proThe neuroendocrine phenotype of the large-cell neuroendocrine carcinoma was immunohistochemically confirmed with synaptophysin, which stain all . AdditioThe tumour cells invaded veins as well as lymphatic nodes. Regional lymph node metastasis was detected in 17 out of 41 lymph nodes. Sections showed adenocarcinoma in all lymph nodes retrieved, but only one lymph node showed metastasis from the neuroendocrine carcinoma.Gastric large-cell neuroendocrine carcinomas (LCNECs) are a rare type of tumours that account for less than 1.5% of all types of gastric cancers and have a very poor prognosis . These aOn the other hand, adenocarcinomas account to up to 95% of all malignancies found in the stomach and are by far the most studied type of gastric tumour . It is kThe prognosis of the patient will be determined by the aggressiveness and extension of the tumour with deeper invasion of the gastric wall and the proportion of lymph node metastases. In this case, the most aggressive lesion was the adenocarcinoma, which showed serosal exposure and great proportion of lymph node metastases. This tumour was classified as a stage IIIC, using the criteria established by the American Joint Commission on Cancer (TNM), indicating that surgery was the first choice of treatment . The casTo our knowledge, there are fewer than 40 cases of reported collision tumours with the characteristics given , 12. TheAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.The authors declare that they have no conflict of interest.


Seagrasses and associated macrophytes are important components of coastal systems as ecosystem engineers, habitat formers, and providers of food and shelter for other organisms. The positive impacts of seagrass vegetation on zoobenthic abundance and diversity (as compared to bare sands) are well documented, but only in surveys performed in summer, which is the season of maximum canopy development. Here we present the results of the first study of the relationship between the seasonal variability of seagrass vegetation and persistence and magnitude of contrasts in faunal communities between vegetated and bare sediments. The composition, abundance, biomass, and diversity of macrozoobenthos in both habitats were compared five times throughout the year in temperate eelgrass meadows in the southern Baltic Sea. Significant positive effects of macrophyte cover on invertebrate density and biomass were recorded only in June, July, and October when the seagrass canopy was relatively well developed. The effects of vegetation cover on faunal species richness, diversity, and composition persisted throughout the year, but the magnitude of these effects varied seasonally and followed changes in macrophyte biomass. The strongest effects were observed in July and coincided with maximums in seagrass biomass and the diversity and biomass of other macrophytes. These observations indicate that in temperate, clearly seasonal systems the assessment of macrophyte impact cannot be based solely on observations performed in just one season, especially when that season is the one in which macrophyte growth is at its maximum. The widely held belief that macrophyte cover strongly influences benthic fauna in marine coastal habitats, which is based on summer surveys, should be revisited and complemented with information obtained in other seasons. Posidonia oceanica and Zostera noltii vegetated sediments and on bare sand in the Mediterranean Sea based on a study performed in two seasons - summer and winter. Some indication of seasonality in the importance of seagrass vegetation for associated fauna is reported by Berkenbusch et al. Zostera novazelandica as the best explaining factor for macrofaunal community structure in summer at the seagrass growing optimum, while it is much less important in fall. The lack of the seasonal aspect in the rich literature on seagrass influences on zoobenthic communities is a significant gap in understanding the functioning of these systems.Seagrasses and associated macrophytes are important structural and functional components of coastal ecosystems in temperate and tropical seas. They are classic examples of marine ecosystem engineers Callianassa filholi on intertidal flats persisted throughout the year, but the magnitude of impact varied seasonally correspondingly to changes in bioturbator density. Regarding seagrasses, Hasegawa et al. Zostera marina  was season dependent and followed temporal changes in seagrass canopy development. These reports support Fortino's Ecosystem engineer effects can depend on the quantitative characteristics of engineering species populations Z. marina compared to P. oceanica; Z. marina in northwest Europe and North America were even reported to employ annual or semi-annual life histories; when no or only a small percentage of vegetative shoots survive winter, and the persistence of a population relies on extensive seed production and new recruitment each spring Seagrass and associated macrophyte canopies can vary substantially in annual cycles Duarte Z. marina meadows are consistent across different seasons; 2) if the persistence and magnitude of these differences mirror seasonal changes in macrophyte cover quantitative and qualitative characteristics. In this paper, we present the first analyses of the relationship between the temporal variability of macrophyte vegetation in a seagrass meadow and its impacts on associated fauna.Jankowska et al. The collection of macrophytes, sediment and macrofauna samples undertaken for this research was approved by collection permits issued to a “ZOSTERA. Restitution of key elements of the inner Puck Bay ecosystem,” project (no. POIS.05.01.00-00-205/09-00) coordinated by Center of Coordination of Environmental Projects and Regional Directorate of Environmental Protection and Nature Conservation at the Pomeranian Voivodship.Zostera marina meadows were present in the Puck Lagoon and the outer Puck Bay in the 1950s, but from the late 1950s to the 1980s degradation of the meadows and the gradual replacement of eelgrass by filamentous algae and Zanichella palustris was observed Z. marina meadows are growing in size The samples were collected in the Puck Bay, which is a shallow embayment in the southwestern part of the Gulf of Gdańsk  separated from the open sea by the Hel Peninsula. The eight-kilometer Ryf Mew sandbank divides the bay into two parts: the inner Puck Lagoon and the outer Puck Bay. The depths and bottom morphology of these two parts of the bay differ. The outer Puck Bay is notably deeper at an average depth of 20.5 m, while the Puck Lagoon is considerably shallower with an average depth of 3.1 m http://www.smhi.se/oceanografi/iceservice/is_prod_en.php). However, high concentrations of chlorophyll a in the surface sediments at this sampling time Two localities were selected for sampling: 1) RM – located in Puck Lagoon close to the shallows of the Ryf Mew sandbank at a depth of 3 m ; 2) JAS – located in the outer part of the Puck Bay east of Jastarnia at a depth of 1.5 m , and photosynthetic pigment concentrations (upper 2 cm). The samples for macrofauna were sieved through 0.5 mm mesh and then fixed in 4% formaldehyde. The sediment samples for photosynthetic pigment analyses were frozen at −80°C.At each sampling location five replicate sets of samples were collected from the vegetated seabed and bare sand. Each set of samples included one collected with a 15 cm diameter large core for macrozoobenthos and three sediment samples collected with a 2 cm diameter small core. Sediment samples were collected to analyze grain size (upper 10 cm), POC and TN concentrations, δ15N, and δ 13C in sediments were analyzed using an Elemental Analyzer Flash EA 1112 Series combined with an Isotopic Ratio Mass Spectrometer IRMS Delta V Advantage . To determine the grain-size distribution, sediment samples were dried  and sieved through mesh sizes at thirteen 0.5 phi intervals In the laboratory, chlorophyll a and pheopigment concentrations were assessed with the spectrophotometric method S), species diversity measured with the Shannon-Wiener diversity loge based index (H), and evenness of distribution of individuals among taxa expressed by the Pielou index (J), were calculated for all macrobenthic samples. Differences in macrozoobenthic univariate characteristics  among the five months (Mt) and between the two stations (St), and two bottom types  were tested using the three-way PERMANOVA model based on a similarity matrix created from the Euclidean distances among samples. The PERMANOVA routine does not rely on the assumption of normally distributed data and uses permutations to test null hypotheses. Unbiased estimates of each of the components of variation (CV) were calculated from mean squares to compare the amount of variation that is attributable to different terms in the model. When a significant effect of Bt and significant interaction of BtxMt were detected, pairwise tests for differences between bottom types within the five months were performed. The magnitude of the effect of vegetation on macrofauna univariate characteristics in different months was estimated using of the veg/bare ratio, which is the ratio of the mean recorded on vegetated bottom to that on bare sand.Species richness, defined as the number of taxa in a sample (a priori groups) was used to visualize the variability along the two axes that best discriminated groups of samples defined by bottom type and month. When the significant effect of Bt and the significant interaction of BtxMt was detected by the main PERMANOVA test, pairwise tests for differences between bottom types in the five months were performed. The magnitude of the effects of vegetation on the macrobenthic community composition in different months was estimated with the distance (Bray Curtis index) between centroids representing the fauna collected from two bottom types. An nMDS plot of Bray-Curtis similarities between averaged species abundances in groups of samples defined by two sites, two bottom types, and five months was constructed to visualize multivariate variability among these groups of samples.Bray-Curtis similarities were calculated for presence/absence data (pr/ab), double root transformed, and untransformed data (nonTR) of macrobenthic species abundances in the samples. The three-way PERMANOVA model, with the three factors of Mt, St, and Bt, was applied to the similarity matrices. The patterns of macrobenthic composition were visualized with PCO plot. In addition, CAP , photosynthetic pigments , and the granulometric characteristics of sediments . These variables were tested preliminarily for collinearity using Draftsman plot and the Spearman correlation matrix. Based on the results, only six quantitative variables were left for further analysis . The forward selection procedure was used to determine the best combination of predictor variables Relationships between environmental variables and macrobenthic community composition were investigated using the Distance-based Linear Models (DISTLM) procedure in PERMANOVA+ For samples collected on vegetated bottom the DISTLM analyses was used to explore the relationships between macrophyte biometrics and macrozoobenthic community characteristics. The original data set included 6 quantitative variables: total macrophyte biomass, seagrass above ground biomass, total seagrass biomass, seagrass shoot density, algal biomass and algal species richness. These variables were tested preliminarily for collinearity using Draftsman plot and the Spearman correlation matrix. Based on the results, seagrass total biomass was excluded from further analysis. Similarity matrix created from the Euclidean distances among samples was used for macrozoobenthic univariate characteristics  while Bray-Curtis similarities of double-root transformed data of species abundances in samples were used for the analyses focused on faunal species composition. The forward selection procedure was used to determine the best combination of predictor variables.The SIMPER procedure was applied to identify species that were responsible for differences in macrobenthic communities between bare sand and vegetated bottom. SIMPER analysis was performed on Bray-Curtis similarities of both double-root transformed and presence absence data. The SIMPER procedure is based on the breakdown of average dissimilarity between groups into separate contributions from each species Z. marina was recorded. The highest biomass and species diversity (six species) was recorded in JUL. Brown filamentous algae Pilayella litoralis comprised from 30% to 80% of the total biomass of macrophytes accompanying eelgrass in this meadow. Further details of macrophyte vegetation trait variability at the studied stations are reported by Jankowska et al. Similar seasonal patterns were observed for all measured seagrass vegetation characteristics  with minimum values recorded in MAR and maximum in JUL . The bio−2), the highest mean density and high variability was observed in JUL on the vegetated bottom at the RM site . The very high mean biomass and highest variability in values were recorded in JUN and JUL in vegetated sediment at the JAS site . The factor of bottom type had the strongest effect on macrobenthic biomass  differed significantly among months, bottom types, and stations  than at the RM site  was higher in samples collected at the JAS site than at RM, but this difference was not consistent throughout the sampling period as was indicated by the significant effects of months and significant MtxSt interaction  and the highest in July , and station had the strongest effect (as indicated by the highest CV). H at the JAS site was 1.62 on average (±0.33 SD), while at RM it was 1.03 (±0.27 SD). H was significantly higher on vegetated bottoms than on bare sand, but this effect did not interact with the effect of month  of Bt, St, and Mt on macrobenthic community composition . Bottom The significant interaction of BtxMt  suggesteDISTLM analyses confirmed significant effects of all seven environmental variables on macrobenthic community structure . DISTLM In the vegetated bottom, macrophyte biometrics explained from 10 (density) to 27% (species richness) of variation in macrozoobenthic community characteristics . None ofTheodoxus fluviatilis, Idotea balthica, Idotea chelipes, Mytilus edulis, and Chironomidae larvae were identified by SIMPER as discriminating the two bottom types in both analyses; they occurred both with higher frequencies and higher densities on vegetated bottoms. None of the discriminating species was found only in samples collected from one bottom type. For most species, higher average densities were recorded on vegetated bottoms, with only Macoma balthica occurring with higher numbers on bare sand.SIMPER analyses of double root transformed data identified nine species of cont% equal to or higher than 4%. These species altogether contributed to about 45% of the total dissimilarity between vegetated and bare sediments . Ten speThis is the first study of natural seagrass and bare sediment communities that provides evidence that the persistence and magnitude of the impact of macrophyte cover on zoobenthos can be seasonally dependent. The significant positive effects of macrophyte vegetation on invertebrate density and biomass were recorded only in June, July, and October, which are the months when the seagrass canopy is relatively well developed. The strongest contrasts in macrofaunal characteristics between vegetated and unvegetated sediments were observed in July and coincided with the maximum peak in all quantitative characteristics of macrophyte vegetation – seagrass biomass, shoot density, and the biomass and diversity of other associated macrophytes. The vegetation effects on faunal species richness, diversity, and composition persisted throughout the year, but the magnitude of these effects varied seasonally in parallel with the pattern of macrophyte cover seasonal development. Again, the strongest effects (i.e. largest contrasts between the two habitats) were documented in July.Cymodocea nodosa in the Lagoon of Venice. They found no significant difference between these two treatments in March, while significantly higher standing stocks and diversity of the fauna in the vegetated plot were noted in September, when seagrass shoot density was two times and leaf biomass was seven times higher than in early spring. A few studies conducted in natural seagrass beds also showed that seasonal changes in the quantitative characteristics of faunal assemblages mirrored seasonal variability in seagrass vegetation. For example, maximum values of mollusc species richness and abundance in Mediterranean Posidonia oceanica meadows occurred in summer months and coincided with the peaks in seagrass shoot density and leaf length Caulerpa prolifera meadow −2. Several studies report that the engineering effects of seagrass are density dependent. Gacia et al. Z. marina beds off the Isles of Scilly Z. marina meadows off southwest England for both infaunal Season-related differences in the effects of seagrass cover on fauna are suggested by Pranovi et al. Zostera beds had higher habitat complexity, higher food availability, higher organic carbon content, lower flow velocity, finer sediments, higher shelter, lower predation, lower competition, enhanced deposition, and higher sediment stability. It is usually hard to separate the effects of these possible mechanisms and factors when identifying differences between vegetated and bare sands 13C differed significantly between the bare sand and vegetated bottom at both stations, but the magnitude of these differences remained stable throughout the year and did not follow seasonal variability in seagrass biomass 2 values indicated their contributions were rather small. Herkul & Kotta Z. marina on sediment characteristics and faunal communities in the northern Baltic Sea. They found sea grass removal had a moderate effect on sediment granulometry (decreased fine grain size fraction), organic matter content, and macrofaunal communities (decreased density and diversity). However, their experiments also included the artificial addition of sand to the seagrass meadow sediments, and this manipulation had no significant effect on the associated macrofauna. These results corroborate our notion that the modification of sediment characteristics is of lesser importance for seagrass meadow macrofauna than other factors, most probably the habitat complexity provided by the vegetation.Bostrom & Bonsdorff Zostera marina were the most pronounced, but seagrass is not the only phytal element that changed seasonally in the studied meadows. Both the diversity and biomass of other macrophytes changed alongside eelgrass cover seasonal development. In winter, Z. marina was the only component of the vegetation, while in summer it was accompanied by six other macrophyte species representing a variety of morphological forms, which together comprised a considerable percentage of the total macrophyte biomass. Habitat structural complexity, which is a key characteristic of seagrass meadows, is produced by a three-dimensional net of interlacing stems, leaves, roots, and rhizomes with a number of gaps and crevices providing a variety of microhabitats to marine infaunal and epifaunal invertebrates in situ observations and experimental surveys Platichthys flesus, Anguilla anguilla, Pomatoschistus minutus, P. microps, Neogobius melanostomus, Zoarces viviparous, Rutilus rutilus) in the Puck Bay is much higher than in the northern Baltic Sea coastal areas Seasonal changes in Zostera is not an important direct provider of organic carbon to macrobenthic invertebrates in the Baltic Sea benthic system. In Swedish Baltic Sea coastal waters, Jephson et al. Rissoa sp. and Theodoxus fluviatilis, and only the former occurs in the Puck Bay. On the other hand, they did identify a number of grazers that depend on the epiphyte algae that accompany Z. marina in seagrass meadows. Seagrasses are rarely treated as preferred food, mostly because of their low nitrogen and high cellulose content as well as the presence of condensed tannins and phenolic acids that can be toxic to herbivores Macoma balthica was the only dominant species that occurred with higher densities on bare sand. In a settlement experiment in the Archipelago Sea, Bostrom et al. Z. marina vegetation can actually inhibit the settlement of the larvae of the bivalves M. balthica and Cerastoderma glaucum. They also reported that post-settlement transportation of bivalves by resuspension events and secondary settlements of larger individuals were much more common on bare sands and seagrass patches than in continuous Z. marina vegetation. These effects were particularly strong for M. balthicaMacoma, the mussel Mytilus edulis occurs almost exclusively in seagrass beds, and seagrass vegetation has been shown to collect drifting clumps of mussels, and, thus, facilitate the post-recruitment settlement of Mytilus populations Theodoxus fluviatilis was among the species that most strongly discriminated the two communities, both with regard to abundances  and frequencies of occurrence (presence/absence data). The strong preference of Th. fluviatilis for seagrass beds is not surprising, as this species can use seagrass tissue as a direct food source Idotea chelipes, Idotea balthica) and amphipod  species were important components of the seagrass communities in the Puck Bay. These are small mesograzers that feed on seagrass epiphytes The differences in macrobenthic community composition between vegetated and unvegetated sediments in the Puck Bay were produced by shifts in the dominance of co-occurring species rather than a complete change in species composition. Bivalve molluscs that are important components of the Puck Bay macrozoobenthos in terms of both abundance and biomass occurred at different abundances in seagrass meadows and on bare sand. The temporal and spatial variability of macrozoobenthos was higher on bare sand than on vegetated bottoms. This was indicated by the larger dispersion of bare sand samples both on PCO ordination, and on CAP ordination plotted along the strongest gradients produced by months and stations . This paIn this study we have demonstrated that the effects of macrophytes on associated benthic communities in the southern Baltic Sea are seasonally depended. The positive effects of macrophyte cover on the univariate and multivariate characteristics of macrobenthic fauna were either weaker or could not be detected in late fall and early spring when macrophyte vegetation was least developed in terms of both biomass and taxonomic diversity. These findings indicate that in temperate, clearly seasonal systems the assessment of the ecosystem engineer impact cannot be based solely on observations performed in one season only. The common notion that macrophyte cover has a strong influence on benthic fauna in marine coastal habitats is actually mostly based on surveys performed in summer when macrophyte cover is best developed. Thus, the effects of macrophytes can be overestimated to some extent. More studies of seagrass systems performed in other seasons, especially in winter, are strongly recommended if we are to better understand the actual role of macrophyte vegetation in structuring macrozoobenthic communities.Table S1Taxonomic composition and densities of taxa in samples collected at two stations, on two bottom types and in five months. Average values for replicate samples collected at the same stations, bottom types  and months are presented.(XLSX)Click here for additional data file.


Importance: Utilizing social media in an emergency can enhance abilities to locate and evacuate casualties more rapidly and effectively, and can contribute towards saving lives following a disaster, through better coordination and collaboration between search and rescue teams.Objective: An exercise was conducted in order to test a standard operating procedure (SOP) designed to leverage social media use in response to an earthquake, and study whether social media can improve joint Israeli-Jordanian search and rescue operations following a regional earthquake.Design: First responders from both Jordan and Israel were divided into two mixed groups of eight people each, representing joint (Israeli-Jordanian) EMS teams. Simulated patients were dispersed throughout the Ben-Gurion University Campus. The first search and rescue team used conventional methods, while the second team also used social media channels (Facebook and Twitter) to leverage search and rescue operations.Participants: Eighteen EMS and medical professionals from Israel and Jordan, which are members of the Emergency Response Development and Strategy Forum working group, participated in the exercise.Results: The social media team found significantly more mock casualties, 21 out of 22 (95.45%) while the no-media team found only 19 out of 22 (86.36%). Fourteen patients (63.63%) were found by the social media team earlier than the no-media team. The differences between the two groups were analyzed using the Mann-Whitney U-test, and evacuation proved to be significantly quicker in the group that had access to social media. The differences between the three injury severities groups' extraction times in each group were analyzed using the Kruskal-Wallis test for variance. Injury severity influenced the evacuation times in the social media team but no such difference was noted in the no-media team.Conclusions: Utilizing social media in an emergency situation enables to locate and evacuate casualties more rapidly and effectively. Social media can contribute towards saving lives during a disaster, in national and bi-national circumstances. Due to the small numbers in the groups, this finding requires further verification on a larger study cohort. The DSF is comprised of emergency management experts from Jordan and Israel, consisting of field practitioners from emergency medical services (EMS), senior policy makers as well as academic researchers. In order to study the contribution of social media for managing a potential earthquake in the region, a joint exercise was developed and implemented. The exercise provided an opportunity for Jordanian and Israeli EMS personnel to collaborate in order to respond to a simulated disaster. First responders from both Jordan and Israel were divided into two mixed groups of eight people each, representing joint (Israeli-Jordanian) EMS teams. The exercise's objective was to verify and test a standard operating procedure (SOP) designed to leverage social media in response to an earthquake. The exercise was conducted at the campus of the Joyce and Irving Goldman Medical School and Health Sciences in Ben-Gurion University of the Negev in Beer-Sheba (BGU). Figure 1 shows the map of BGU’s main campus, where the black dashed rectangle indicates the location of the Health Sciences campus where the exercise was held. Simulated patients were dispersed throughout the campus and its six buildings, coordinated through the faculty administration office. They were placed in class rooms, staff offices, corridors and in open spaces.Both teams were sent out to "search and rescue" mock casualties throughout the campus. The first team ("No Media Team" - NMT) used only conventional methods of search and rescue, mainly spreading staff simultaneously to different locations to verify reconnaissance of all casualties, communicating through radio and cellular channels, as well as with the Zello (http://zello.com/) push-to-talk (PTT) application, which provided a walkie-talkie experience. The second team  used both conventional methods as well as social media channels (Facebook and Twitter) to leverage their search and rescue operations. Both teams were briefed regarding the exercise and its goals.Figure 2 describe the involved players, the operational model, and the information flow of the exercise. The solid lines represent direct command and control actions, while the dashed lines signify information flow  and communication channels. The exercise included five types of participants: 1) Players- personnel who have an active role in responding to the simulated emergency and perform their regular roles and responsibilities during the exercise. 2) Controllers- who set up and operate the exercise site, plan and manage its execution, and simulate roles of response individuals and agencies not represented in the exercise. 3) Simulators- control staff personnel who operate out of the Simulation Cell, enacting roles in accordance with instructions and information provided in the Master Scenario Events List (MSEL). 4) Evaluators- who assess and document participants’ performance based on established emergency plans and exercise evaluation criteria. 5) Simulants- volunteers who simulate specific roles during the exercise, mainly the mock casualties.Both the NMT and SMT operated under the same hierarchical structure, which included a control center, incident commander, triage center and two SAR teams. The control center managed the work and progress of the entire team’s operation during the exercise. Each control center was allocated an office in which they deployed an operation center. An incident commander was appointed by each team whose responsibility was to coordinate search and rescue operations of the SAR teams from the field.A Facebook Group was created for the purpose of the exercise, but only the participants of the social media team were approved to join it. The Simulation Cell, which was in charge for role-playing nonparticipating organizations or individuals and for information dissemination to the exercise participants used a Twitter account that provided a conduit through which they could publish information. The exercise duration was planned for 90 minutes, or until one of the teams has found all of the mock casualties. All information and directions to the participants were communicated from the Simulation Cell, according to a predefined MSEL, which included a scripted chronological sequence of events and actions to be injected into the exercise by the simulation cell. The command center of both teams updated in real time a spreadsheet, through Google Docs [1]. This spreadsheet was visible to the exercise directors sitting in the exercise headquarters. The SMT were encouraged to use social media for both receiving and updating information during the exercise. Active interaction with the Simulation Cell was rewarded as it provided more operational information. Twenty two students representing mock casualties, were assigned with injury tags describing their medical condition, and were distributed to 20 different locations in a radius of approximately two square kilometers within the campus. Both exercise teams were instructed to locate and extract the casualties, implement triage processes, state the injury severity (severe/moderate/mild) and "evacuate" the mock casualties to a hospital according to priorities . Furthermore, they were instructed to record the location of each simulated casualty, time of extraction and evacuation, and the ID of each simulated patient. Only mock casualties with smartphones were allowed to publish information  on Facebook. This information could include a general description of their location (i.e. second floor of the X building), without specifying their exact position. Also, they could upload photos of their location using their smartphones. The simulation cell could publish additional information concerning the casualties' locations, but only items that would in such situations be published by bystanders. The SMT team was encouraged to read the tweets and Facebook posts and coordinate their search and rescue efforts accordingly.Minimum, maximum and mean times (duration) in minutes from exercise commencement to the extraction were calculated and compared between groups. In addition, the total number of casualties found and rescued by each group was compared. Statistical Package for the Social Sciences (SPSS) 18 was used for the analysis. As the number of records was small (22 maximum) and normalcy could not be assumed, a non-parametric (Mann-Whitney) test was used to compare between the groups. An additional comparison was conducted between the three levels of injury severity within the casualties' array of each team. A non-parametric test  was used to compare the three injury severity groups' extraction times between media groups.During the exercise, the Simulation Cell published location based information, through both the Facebook group and the Twitter account, regarding the possible location of the simulated casualties. Six of the eight SMT members had a smartphone with which they could check the above mentioned social media channels for information throughout the exercise. Two team members mentioned that they had difficulties using both Facebook and Twitter concurrently on their smartphone, as it required them to switch between the applications repeatedly. Up to the end of the exercise, the SMT found 21 out of 22 (95.45%) simulated patients, while the NMT found only 19 out of 22 (86.36%). Furthermore, the SMT found the first patient five minutes earlier than the NMT, and the last patient seven minutes earlier than the NMT: ten minutes versus 15 minutes for first patient and 55 minutes versus 62 minutes for last patient. Time statistics are presented in table 1.Figure 1 summarizes and compares both teams' patient location and extraction times.The dotted line represents the median time of the NMT, until which the SMT located and rescued 17 simulated patients (77.27%) while the NMT located 8 patients (36.36%). Fourteen patients (63.63%) were found by the SMT earlier than the NMT . Only four patients (18.18%) were located by the NMT prior to their location by the SMT. The gap between the solid (SMT) and the dotted (NMT) lines demonstrates the difference between the median extraction times of each group.The differences between the two groups were analyzed using the Mann-Whitney U-test; the null hypothesis being that there would be no difference in the distribution of times to evacuation between the two groups. This hypothesis was rejected as statistically significant differences were identified (p=0.011). Evacuation proved to be significantly quicker in the group that had access to social media.Each team nominated a medical professional who was responsible for the simulated patient's medical triage following extraction. Patient severity was assigned as one of three categories: Severe, Moderate, and Mild.Before comparing the times to evacuation by severity category, we compared severity assignment between media availability groups in order to verify that there were no significant differences between the groups in regard to mock patient severity. A chi-square test confirmed that no significant differences existed in severity between the SMT and NMT in regard to the assignment of severity categories.The differences between the three injury severities groups' extraction times in each social media group were then analyzed using the Kruskal-Wallis test for variance.The null hypothesis was that the distribution of the time would be the same across the categories of severity. This hypothesis was rejected in the SMT (p=0.029) and retained in the NMT (p=0.762) meaning that injury severity influenced the evacuation times in the SMT team but no such difference was observed in the NMT team.Recurrence of preventable dysfunction during disasters, as was displayed in Hurricane Sandy (2012), Hurricane Katrina (2005) and Tropical Storm Allison (2001), displays the vital need for raising awareness and increase emergency preparedness ,Rescue time is a crucial lifesaving component in responding to earthquakes Exercises that leverage and integrate social media expose the practitioners to these mechanisms, emphasizing their challenges and opportunities. Social media should be integrated into disaster management activities The exercise enabled to compare performance of two first responders' teams, engaging in identical tasks, utilizing similar manpower and logistic resources, differing solely in the availability of social media capacities. Thus, the advantages achieved through the use of the social media in the search and rescue activities could be well displayed and understood. While most of the former studies focused on the integration of one specific type of social media and its influence on staff performance, the present study used both Facebook and Twitter[1] as channels for information dissemination. Abbasi, et al. The significant gaps in performance between the two groups  displayed that social media may and should have a major impact on the search and rescue operations as means of intra and inter-team collaboration, sharing information and optimizing resources utilization. This media can facilitate not only local and national response, but also a cross-border regional response, enabling to overcome obstacles such as language barriers or different modes of operation ,,Communication is one of the fundamental tools of emergency management. Communication systems must be able to withstand a disaster and enable devices to function effectively even when communication networks have collapsed Although this study and exercise were carefully planned and executed, two limitations should be noted. The first one is the limited, relatively small number of mock casualties that prevented use of statistical tests that are based on normal distribution. Second, although various severe disasters that occurred worldwide in recent years have demonstrated the internet's survivability, communication and power infrastructures may collapse, thus making social media unavailable.Social media provides a standardized and familiar platform that can serve to create bridges, offering options for cooperation, coordination and collaboration in order to improve preparedness and response to emergencies. Utilizing social media in an emergency, as was well displayed during the exercise conducted in the present study, enabled to locate and evacuate casualties more rapidly and effectively. Thus, social media can contribute towards saving lives during a disaster. Nevertheless, it is recommended that the social media emergency exercise be further implemented and validated in other emergency scenarios.The authors have declared that no competing interests exist.


Mycobacterium tuberculosis typically affects the lungs, causing tuberculosis, but can occasionally spread to the CNS via the bloodstream, leading to tuberculous meningitis (TBM), a life-threatening complication. A key pathological feature of TBM is the formation of granulomas – collections of immune cells – in the brain or meninges (connective tissue layers that envelop the CNS). Little is known about the role of granulomas in the early phases of TBM development. Astrid van der Sar and colleagues sought to explore the pathogenesis of CNS granuloma formation at different developmental stages, using a well-established zebrafish model of tuberculosis in which infection is caused by Mycobacterium marinum, a close relative of M. tuberculosis. The authors first confirmed that M. marinum infection induces TBM in adult zebrafish and then looked at earlier stages of development. To determine the optimum mode of inoculation in zebrafish embryos, they used local and systemic inoculation routes; infection via the bloodstream or directly into the CNS resulted in the formation of CNS granulomas. Interestingly, granulomas formed regardless of whether infection occurred before or after development of the blood-brain barrier, indicating that the pathogen can efficiently cross this barrier. Inactivation of the mycobacterial ESX-1 virulence secretion system, which is important for pathogenesis, resulted in the formation of smaller clusters with a high number of phagocytosed bacteria. However, migration of bacteria from the bloodstream to the brain did not seem to be affected, suggesting that the ESX-1 locus is dispensable for migration. This study shows that the zebrafish-M. marinum model provides an effective tool for characterisation of host-pathogen interactions in granuloma formation. This model could be used to explore the pathogenesis of TBM and pinpoint potential markers for early disease diagnosis and treatment. 1111Page


In the past decade, rapid advances in genomic technologies have dramatically changed the genetic studies of complex diseases. Genome-wide association studies (GWAS) have been widely used in dissecting genetic structure of complex diseases. As of December 18th, 2014, A Catalog of Published Genome-Wide Association Studies (GWAS) had reported significant association of 15,177 SNPs with more than 700 traits in 2,087 publications T[P, respectively. A breeding equation is given byH is a heritability matrix and denoted byWhere Suppose that the phenotype can) be decomposed as a summation of additive effect, dominant effect and environment effect:kP byA, D and E represent the genetic additive, dominant and environmental effect, respectively. Denote the covariance matrix between the breeding value and phenotype values byIt is known thatIt follows from thi trait iih is a function of the genetic covariance between the thi trait and other traits. In other words, the heritability of each trait is influenced by its correlation with other multiple traits. This clearly demonstrates that the trait by trait genetic study will overlook the influence of other traits. The missing heritability may be due to trait by trait genetic analysis. The joint genetic analysis of multiple traits may increase the heritability.There has been increasingly consensus that individual genetic and epigenetic variants, individual genes, individual linear pathway and individual trait analysis cannot capture the intrinsic genetic and epigenetic complexity of multiple phenotypes.To completely capture the heritability, the right research direction is to jointly investigate genetic, expression, miRNA, epigenetic, metabolic variants, physiological traits, medical imaging measurements and environments in multiple traits which are often interactively organized networks. Integrative analysis of genetic, epigenetic, imaging and environmental variation in multiple phenotypes will fully uncover the heritability and facilitate the understanding the mechanism of the complex diseases. The popular methods for integrative analysis are mainly based on correlation and association analysis. These methods cannot efficiently detect, distinguish and characterize the true biological, mediated and spurious pleiotropic effects. Therefore, these approaches may not provide clear biologically or clinical relevant information that allows the mechanisms of genetic effects to be discovered and understood. To overcome these limitations, developing a new framework and novel statistical methods for inferring causal networks of genotype-phenotypes with NGS data and detecting, distinguishing and characterizing the true biological pleiotropic, mediated pleiotropic and spurious pleiotropic effects of genetic variants are urgently needed.An essential issue for using causal graphs to study genetics of multiple phenotypes is how to accurately and efficiently estimate the structure of causal graph from observational data. Structure learning of casual graphs has been shown to be NP-hard. Early methods for structure learning mainly focused on approximation algorithms, but such methods are unable to ensure the generation of the true causal graph. To obtain the causal graph from observation data as close to the biological causal graph as possible, “score and search”-based methods for exact learning causal graphs of genotype-phenotype to find the best-scoring structures for a given dataset are being developed. The accurate and robust estimation of the genotype-phenotype causal networks by the “score and search” methods will shift the paradigm of genetic studies of correlated multiple phenotypes from association analysis to causal inference, and dramatically facilitate discovery of the mechanism underlying multiple traits.Although their application to genome-wide genotype-phenotype network construction is difficult due to computational limitations, the “score and search” based causal inference methods are suitable to the phenome-wide association studies where starting phenomics, defined as the unbiased study of a large number of phenotypes in a population. We study the complex networks between multiple expressed phenotypes and genetic variants. Since the number of genetic variants in the phenome-wide association is quite limited and hence the size of the genotype-phenotype network is limited, the required computational time of construction of genotype-phenotype networks using causal inference is in the range the current computer system can reach. Advances in biosensors and sequencing technologies generate large amounts of phenotype and genetic data. Causal genetic and epigenetic network analysis may emerge as a new paradigm of genetic studies of complex traits. The main purpose of this editorial is to stimulate discussion about what are the optimal strategies to facilitate the development of a new generation of genetic analysis. I hope that more and more real data analysis in the future will greatly increase the confidence in causal inference for genotype-phenotype studies.


Stem cells are defined by their unique ability to self-renew and their multipotent differentiation capacity, thus maintaining tissue homeostasis throughout the life of a multicellular organism. Stem cells reside in niches characterized by hypoxia and low reactive oxygen species (ROS), both of which are critical for maintaining the potential for self-renewal and stemness. Until recently, the focus in stem cell biology has been on the adverse effects of ROS, particularly the damaging effects of ROS accumulation on tissue aging and the development of cancer. However, it has become increasingly clear that, in some cases, redox status plays an important role in stem cell maintenance, that is, regulation of the cell cycle. In fact, ROS at low levels function as signaling molecules to mediate cell proliferation, migration, and differentiation and gene expression. ROS levels in stem and progenitor cells have a clear correlation with cellular functions and are regulated by a fine-tuning of the balance between ROS-generating and antioxidant defense systems.This special issue tries to fully decipher the underlying molecular mechanisms involved in the maintenance of stem cell self-renewal, which is critical to address the important role of redox homeostasis in the regulation of both self-renewal and differentiation of stem cells.The safe use of stem cells for clinical applications still requires culture improvements to obtain functional cells. The review of S. Sart et al. investigates the roles of ROS in the maintenance of self-renewal, proliferation, and differentiation of mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs) and highlights that the tight control of stem cell microenvironment, including cell organization, metabolic, and mechanical environments, may be an effective approach to regulate endogenous ROS generation. While high levels of ROS have detrimental effects on stem cells through the induction of oxidative stress, physiological levels of ROS play an important role in the regulation of stem cell fate decision. Mild levels of ROS act as secondary messengers by interfering with various signaling pathways that regulate stem cell proliferation, survival, and differentiation. However, the contribution of the specific site of ROS production and the specific type of ROS to the regulation of stem cell fate requires further delineation. In addition, the exact threshold levels of ROS discerning between the role as damaging molecules or as enhancers of stem cell signaling pathway are not clearly defined. Combined with accurate ROS measurement, regulation of biochemical and biomechanical environment of stem cells to modulate redox status can lead to the controlled proliferation and differentiation of stem cells towards various biomedical applications.Regarding the site of ROS production and the damaging role of ROS in human stem cells the article of T. Maraldi et al. suggests a particular role of NAD(P)H oxidase enzyme family. In this study they show that Nox4 nuclear expression depends on the donor and it correlates with the expression of redox transcription factors involved in stemness regulation and with the differentiation potential. Taken together, these results suggest that nuclear Nox4 regulation may have important effects on stem cell capability through modulation of transcription factors and DNA damage and the extensive donor-to-donor heterogeneity.The study of O. G. Lyublinskaya et al. focuses on the involvement of ROS in the process of MSCs “waking up” and entering the cell cycle after the quiescence. Using human endometrial MSCs, they showed that intracellular basal ROS levels are positively correlated with the proliferative status of the cell cultures. In fact, they observed that physiologically relevant levels of ROS are required for the initiation of human MSC proliferation and that low levels of ROS due to the antioxidant treatment can block the stem cell self-renewal.Despite many attractive advantages of MSCs, replicative senescence of MSCs occurs, eventually decreasing their functional capacities. MSC aging is proposed to potentially contribute to organism aging leading to loss of tissue homeostasis. It is essential to consider the role of ROS in the aging process of MSCs since MSCs and their regenerative potential have revealed a critical therapeutic approach to aging. In lung diseases, the excessive amount of ROS from the ambient air might be associated with respiratory failure through unsuspected mechanisms that regulate declines in the residual stem cell function with age. However, the review of S.-R. Yang concludes that much work remains to be done to understand the ROS-mediated mechanisms that regulate residual stem cells. Elucidating these mechanisms will be critical to understand how stem cell based or antioxidant therapies are effective in certain tissues including lungs.Regarding the role of ROS in the differentiation process the article of S. Kostyuk et al. describes that GC-rich fragments in the pool of cell-free DNA (cfDNA), circulating throughout the bloodstream of both healthy people and patients with various diseases, can potentially induce oxidative stress and DNA damage response and affect the direction of MSCs differentiation in human adipose-derived MSCs. Such a response may be one of the causes of obesity or osteoporosis.Similar to normal stem cells, cancer stem cells (CSCs) also show lower intracellular ROS levels, suggesting that maintenance of a reduced intracellular environment is associated with an undifferentiated state. CSCs are responsible for cancer recurrence after chemotherapy or radiotherapy. However, the role of ROS in CSCs remains poorly understood and intensive research is desperately needed.The review of S. Ding focuses on ROS generation and removal in CSCs and their effects on CSC self-renewal and differentiation through the modulating of ROS-dependent cellular processes. While information on ROS regulation in CSCs are limited, there is fast emerging evidence that ROS may play essential role in the self-renew and differentiation ability of CSCs. The review concludes that targeting CSCs via ROS and antioxidant enzymes regulation holds a great promise in cancer therapy.Similarly, the review of J. Liu and Z. Wang analyses the particular role of ROS in CSCs. Increasing evidence proposes that a low concentration of ROS can maintain the stemness of CSCs and contribute to tumorigenesis and development. Various systems exist for the regulation of ROS in CSCs. For example, under hypoxic environment, increased levels of ROS induce the expression of HIFs in CSCs, resulting in the upregulation of CSC markers and the reduction of intracellular ROS level and thus facilitating CSCs survival and proliferation. Consequently, the induction of oxidative stress appears to be a promising approach for the preferential killing of cancer cells, including CSCs. In addition, a more detailed investigation of therapies with direct or indirect effects on ROS will help to define a made-to-order therapeutic schedule with a lower tendency toward promoting the development of resistance to treatment.Tullia MaraldiTullia MaraldiCristina AngeloniCristina AngeloniElisa GiannoniElisa GiannoniChristian SellChristian Sell


Macrophages as innate immune cells and fast responders to antigens play a central role in protecting the body from the luminal content at a huge interface. Chronic inflammation in inflammatory bowel diseases massively alters the number and the subset diversity of intestinal macrophages. We here address the diversity within the human intestinal macrophage compartment at the level of similarities and differences between homeostasis and chronic intestinal inflammation as well as between UC and CD, including the potential role of macrophage subsets for intestinal fibrosis. Hallmark of macrophages is their enormous plasticity, i.e., their capacity to integrate signals from their environment thereby changing their phenotype and functions. Tissue-resident macrophages located directly beneath the surface epithelium in gut homeostasis are mostly tolerogenic. The total number of macrophages increases with luminal contents entering the mucosa through a broken intestinal barrier in ulcerative colitis (UC) as well as in Crohn’s disease (CD). Although not fully understood, the resulting mixtures of tissue-resident and tissue-infiltrating macrophages in both entities are diverse with respect to their phenotypes and their distribution. Macrophages in UC mainly act within the intestinal mucosa. In CD, macrophages can also be found in the muscularis and the mesenteric fat tissue compartment. Taken together, the present knowledge on human intestinal macrophages so far provides a good starting point to dig deeper into the similarities and differences of functional subsets and to finally use their phenotypical diversity as markers for complex local milieus in health and disease. The gastrointestinal tract is the largest immune compartment of the human body. The major function of the intestinal immune cells is to maintain the integrity of the body at the huge interface between external stimuli that include food components and the intestinal microflora. Chronic inflammation in inflammatory bowel diseases (IBD) profoundly alters the composition of all local immune-cell compartments. Macrophages are part of the innate immune system and instrumental in controlling the barrier function in the small and the large intestine. The macrophages integrate signals from their environment, thereby changing their phenotype and function. The present knowledge about intestinal macrophages is predominantly based on mouse studies. Even the finding of the gut as the largest reservoir of tissue-resident macrophages within the body  remains In terms of a first-line defense, tissue-resident intestinal macrophages contribute to the gut homeostasis by eliminating invading pathogens without inducing an inflammatory response of the lymphocytes within the lamina propria. Positioned directly beneath the surface epithelium, the macrophages in intestinal tissues are the first immune-cell population encountering foreign material, e.g., luminal bacteria or food antigens randomly passing the epithelial barrier Figure A. Whethein situ γ or phorbol myristate acetate in vitro did not produce IL-10 -8 and transforming growth factor (TGF)β . Additioin situ . While min situ , 13, humin situ . By contce IL-10 .A hallmark of macrophages is their plasticity as well as the ability to change phenotype and function according to the immediate environment. This has been demonstrated systemically by recent work from Xue and colleagues who defined a core transcriptome network for human and murine macrophages .Hence, it is not surprising that small intestinal macrophages are different from large intestinal macrophages. These two organs have a distinct architecture, exert different functions, and host diverse microbiota. For example, macrophages from healthy jejunum show high expression of human leukocyte antigen (HLA)-DR and very low expression of CD14 and the low-affinity human immunoglobulin (Ig)G receptor CD16 . Here, t+ macrophages massively infiltrate the intestinal mucosa in IBD and diffusely spread throughout the thickened mucosa and submucosa but differ with regard to the subset composition and function in UC , while intermediate monocytes (CD14hiCD16+) were increased  is involved in the release of retinoic acid, which has immunomodulatory properties and is mandatory in the induction of forkhead-box protein 3+ Tregs , 60. Dirpatients . While Tpatients , 63. TakCX3CR1 and the T300A mutation in the autophagy-related ATG16L1 link to macrophage functions (Specific for CD and relying on the presence of numerous M2 macrophages, the hyperplastic mesenteric fat tissue beyond the transmural inflammation could be defined as a second protective barrier from invading luminal contents . In the unctions , 67. An unctions –70. Fibrunctions  that takunctions . The tyrunctions  regulateunctions . Other sunctions . The pleunctions . In combunctions .+ macrophages enhanced the proliferation of stem cells in response to the epithelial injury in UC (+ macrophages are found in colorectal cancer (Macrophages carrying the mannose receptor CD206 and considered wound-healing macrophages  are incrry in UC . Relatinl cancer .Taken together, many open questions remain with regard to specifics of the involvement of different subpopulations of human macrophages in the pathogenesis and the chronicity of UC and CD. Further dissecting the diversity and the local distribution of functional macrophages in human gut tissues will help to define the clinical relevance of the macrophage subset.AK, UE, LK, and BS summarized the content of the manuscript. AK and UE wrote the manuscript, and BS and LK discussed and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Respiratory syncytial virus (RSV) is the most significant cause of acute respiratory tract infections in infants and young children worldwide. RSV accounts for approximately 70% of hospitalizations for bronchiolitis and 40% of pneumonia among infants <1 year of life.RSV infection seems to be associated with recurrent wheezing during the first decade of life and impaired respiratory health-related quality of life in adults .Universal prevention of RSV infection is based on environmental prophylaxis aimed at minimizing the spread of the virus good hand hygiene in the home, and limiting direct contact of high-risk children with other children and adults with respiratory tract infections. Exposure to tobacco smoke should be avoid in family with infants, breastfeeding should be encouraged.Pharmacological prophylaxis is based on the administration of palivizumab  during the epidemic period to the children at risk .Palivizumab is a humanized monoclonal antibody directed to an epitope in the A antigenic site of F protein of RSV. It is designed to provide passive immunity against RSV and thereby prevent or reduce the severity of RSV infection .The aim of this work is to provide Italian neonatologists shared recommendations regarding palivizumab use in premature and other at-risk infants in the light of new emerging evidence.The peak incidence of severe RSV disease occurs between 2 and 3 months of age. The risk of serious RSV illness is highest among preterm neonates, children with chronic lung disease, congenital heart disease .The children with the above mentioned clinical conditions, particularly in cases of hospitalization, are more likely to require admission to an intensive care unit and need mechanical ventilation. In addition they have high rates of re-hospitalization for lower respiratory tract infections ,6.Therefore, all these categories of infants are likely to benefit from prophylaxis, and have been included in the recommendations. Specific recommendations are provided according to gestational age at birthRSV infections occur most frequently during the period between October-March.According to this observation, prophylaxis with Palivizumab is indicated in this 5-6 months long seasonal window of RSV infection.The duration of prophylaxis  depends on the underlying condition.Palivizumab is clinically effective; however, the cost is very high. In our opinion strict criteria for patient selection and reduced drug costs would improve the cost-effectiveness of the prophylaxis .


A 64-year-old smoking male presented with an abrupt onset of pruritic erythematous plaques predominantly in a sternal distribution for 2 weeks. Subsequently, a crop of tense vesicles and bullae appeared over these lesions. Physical examination revealed bullous lesions localized on the sternal region. Nikolsky sign and bulla spread sign were negative. Also, the patient presented ulcerated lesion of the midportion of lower lip. The histology of lip biopsy showed squamous cell carcinoma. The general investigations didn't reveal any metastasis. Besides, Histopathological examination of bullous lesions revealed a sub-epidermal blister with abundant fibrin, neutrophils, and eosinophils in the blister cavity suggestive of BP. Direct immunofluorescence revealed linear deposits of IgG and C3 along the basement membrane zone without intercellular deposits. Salt split skin technique by direct immunofluorescence, showed immunoreactants on both, epidermal and dermal sides of the split confirming BP as the diagnosis. The BP was treated by dermo-steroids and the patient was refered for oncological surgery and radiotherapy for the squamous cell carcinoma of the lip. The association of BP with cutaneous malignancies has always been a matter of debate with no consensus reached. Despite many published case reports and trials, a definite association is lacking. The time of presentation of malignancy can be variable, with malignancy presenting either before, concurrently or after the appearance of BP. BP has been reported with various malignancies especially of the gastrointestinal tract. To the best of our knowledge, this is the first report of BP associated with squamous cell carcinoma of the lower lip.


Lagopus muta pyrenaica) is the southernmost subspecies of the species in Europe and is considered threatened as a consequence of changes in landscape, human pressure, climate change, and low genetic diversity. Previous studies have shown a relationship between the date of snowmelt and reproductive success in the Pyrenean ptarmigan. It is well established that birds laying early in the breeding season have higher reproductive success, but the specific mechanism for this relationship is debated. We present an explicative model of the relationship between snowmelt date and breeding success mediated by food quality for grouse in alpine environments. From microhistological analyses of 121 faecal samples collected during three years in the Canigou Massif (Eastern Pyrenees), and the assessment of the chemical composition of the main dietary components, we estimated the potential quality of individual diets. Potential dietary quality was correlated with free-urate faecal N, a proxy of the digestible protein content ingested by ptarmigan, and both were correlated with phenological stage of consumed plants, which in turn depends on snowmelt date. Our findings suggest that the average snowmelt date is subject to a strong interannual variability influencing laying date. In years of early snowmelt, hens benefit from a longer period of high quality food resources potentially leading to a higher breeding success. On the contrary, in years of late snowmelt, hens begin their breeding period in poorer nutrient condition because the peaks of protein content of their main food items are delayed with respect to laying date, hence reducing breeding performance. We discuss the possible mismatch between breeding and snowmelt timing.The Pyrenean rock ptarmigan ( Lagopus muta pyrenaica) was positively associated with the early appearance of snow-free ground ) an advancement of the peak abundance of their prey (caterpillars) in relation to laying date, caused a decrease in their reproductive success [Various studies demonstrate an advance in the phenology of plants and animals as a result of climate change ,88–90. I success ,91. In tA decline in snow pack and an advance in snowmelt date have been observed over the last 50 years in the Pyrenees . AccordiIn temperate ecosystems, temperature increase tends to have a direct influence on the start of the growing season . In alpiIn this study, we found that free-urate faecal N content was related to the protein content of the ptarmigan diet. Therefore, the number of breeding periods analysed (only three years) is insufficient to find conclusive relationships between the N content of the ptarmigan diet during the post-melting period and their reproductive success. We need to further investigate the relationships between diet, plant phenology, weather and reproductive success of ptarmigan to consolidate the assumptions proposed in this work. An individual survey of diet quality of females during the breeding season related to reproductive success would likely be required. The understanding of such relationships will allow the development of models that predict the potential impact of climate change on the population dynamics of the Pyrenean rock ptarmigan and other alpine birds.S1 FigEach point corresponds to a single faecal sample. Arrows indicate the date of snowmelt at nearest weather station.(TIF)Click here for additional data file.S1 TableWinter period comprises from September to date of snowmelt. Diet items are leaves unless otherwise indicated.(PDF)Click here for additional data file.


Undifferentiated chest pain is one of the most common complaints in the acute care setting. Type B aortic dissection is an important cause of chest pain and a complex clinical entity, which carries significant morbidity and mortality and requires accurate clinical and radiological evaluation.Imaging technologies have become an irreplaceable tool to establish the diagnosis of aortic dissection and to plan treatment strategies. Computed tomography is an important component in this process, replacing catheter-based angiography as the most commonly used preoperative and postoperative imaging modality for the thoracic aorta. The use of functional imaging methods, such as magnetic resonance imaging and echocardiography is evolving. These methods are able to provide the clinically relevant anatomical, hemodynamic and biomechanical information that is necessary for accurate diagnosis, risk stratification and patient selection for treatment.Advanced image acquisition equipment and expertise are increasingly available in a growing number of institutions and as a consequence, existing strategies for the management of type B dissection are rapidly evolving. Undifferentiated chest pain is one of the most common complaints in the acute care setting, accounting for over 5 million emergency department visits in the USA each year . The cosAcute type B aortic dissection results in an intense inflammatory process and the development of complex hemodynamics that interrelate the true and false lumens , 5. The The growing availability and technical advances in modern imaging provide a way to develop an understanding of the complex mechanisms that govern aortic dissection . PatientComputed tomography (CT) angiography, magnetic resonance (MR) angiography and echocardiography are the techniques most commonly used in clinical practice for the assessment of aortic dissection Table .Table 1CComputed tomography (CT) angiography is widely available, has a rapid acquisition time, provides images with high spatial resolution and is the most commonly used imaging modality for anatomical evaluation of the thoracic aorta. State of the art scanners include multi-slice, multi-detector and multi-source technologies. This new technology results in a proportional decrease in the scanner time, which allows improved vascular opacification, with less contrast media, less aortic motion and fewer breathing artefacts . The CT Various CT protocols exist for evaluating patients with non-specific acute chest pain. Bolus tracking technology is the most commonly used technique to visualize the vessels. The length and density of the contrast agent bolus are important parameters in the optimization of this type of imaging, as both will affect the amount of contrast in the image . The timThe CT data can be acquired with reference to the electrocardiogram (ECG) signal to provide images of each phase of the cardiac cycle. This allows the acquisition of multiple three-dimensional (3D) images over time, so-called four-dimensional (4D) imaging. This, however, significantly increases the dose of ionizing radiation compared with conventional static scanning . The verIntraoperative CT utilizes cone beam reconstruction software and flat-panel detectors to generate CT-like images from rotational angiographic image acquisitions. This modality can be performed immediately in the operating theatre after completion of the endovascular procedure and offers the same benefits as CT imaging in terms of image quality and ability to reformat the image data in any plane . The mosMagnetic resonance imaging has some advantages over CT including superior soft tissue contrast, the absence of ionizing radiation and the ability to depict and quantify functional parameters . CombiniFirst pass MRI is routinely used to measure false lumen thrombosis, where the image acquisition is timed according to the arrival of the contrast bolus in the proximal unaffected aorta and thrombosis is assumed to be present when there is no contrast agent in the false lumen. Recent studies have shown, however, that the flow rates in the false lumen are highly variable and often very slow , 19. A rPhase contrast (PC) sequences can be used to assess blood flow and velocity. They can also be used to acquire 3D velocity information  for each voxel, within a 3D volume over time . This acquisition offers the potential to study aortic hemodynamics, flow patterns and derived vessel wall parameters, such as wall shear stress. This technique can help to identify entry tears between the true and false lumens and to stratify patients according to the risk of aneurysm formation , 20. DynBlack blood sequences can be used to assess the vessel wall, to evaluate hematoma and thrombus in the aortic wall and false lumen, respectively . The 4D-Ultrasound techniques have relatively low spatial resolution compared with CT and MR imaging but they can provide functional information with high temporal resolution. A high clinical index of suspicion after a negative result from the first diagnostic investigation may warrant subsequent second or third imaging modalities. Transthoracic echocardiography (TTE) is useful in hemodynamically unstable patients because it is portable, rapid and the patient is still accessible during the acquisition of the imaging data . This moTransesophageal echocardiography (TEE) has a high accuracy for the diagnosis of aortic dissection and provides excellent anatomical and functional imaging of the descending thoracic aorta  involves the use of a probe that is advanced under fluoroscopic guidance. This technology is able to provide dynamic information regarding the true and false lumens and can detect false lumen thrombosis with higher sensitivity and specificity than TEE . The IVUPositron emission tomography (PET) is a functional imaging technique that works by measuring the distribution in the body of the tracer F-fluorodeoxyglucose (FDG). This is a glucose analog and has an increased uptake in cells with a high metabolic demand, such as inflammatory cells and cells in areas of acute injury. The use of FDG-PET scans, as well as higher resolution dual-modality scanning (PET/CT and PET/MRI), can therefore detect areas of inflammation and acute injury in large vessels and organs and has several applications that are being developed in aortic dissection. One such application is in the assessment of dissection chronicity, an important feature in deciding on treatment as well as predicting outcome , 28. AcuImaging plays an important role in diagnosis, risk stratification and selection of the appropriate treatment in patients with thoracic aortic dissection. The decision of which diagnostic technique should be used depends on the availability of these techniques in the emergency situation and on local expertise. Future imaging techniques in aortic dissection should be used to detect early subclinical pathological changes and to identify patients who would benefit from early intervention.


Rationale: Endometrial cancer recorded a peak incidence in ages 60-64 years in Romania. Since 2013, an increased trend of endometrial cancer occurrence has been registered in urban areas as compared with rural ones. Unfortunately, most of the cancer cases are diagnosed too late, in an advanced stage of the disease, resulting into diminished lifetime expectancy. The first part of the article concentrated on issues such as: the description of the study, results, and discussions regarding the study, definitions and terms, risk factors specific for endometrial carcinomas, presentation of the activities of the Program, etc. Objective: Drafting a national program that will serve as an early diagnosis method of endometrial cancer. This second part of the study continues with the presentation of the activities of the Program, analyzes the human resources and materials needed to implement the Program, presents the strategies and the indicators specific for the implementation of the project.Methods and Results: A standardization of the diagnostic steps was proposed and the focus was on 4 key elements for the early diagnosis of endometrial cancer: The first steps were approached in the first part of the study and the second part of the study investigated the proper monitoring of precursor endometrial lesions or cancer associated endometrial lesions and screening high risk populations . Discussion: Improving medical practice based on diagnostic algorithms and programs improves and increases the lifetime expectancy, due to the fact that endometrial cancer is early diagnosed and treated before it causes serious health problems or even death.Abbreviations: ASCCP = American Society for Colposcopy and Cervical Pathology, CT = Computerized Tomography, HNPCC = Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome), IHC = Immunohistochemistry, MSI = Microsatellites instability, MSI-H/ MSI-L = high (positive test)/ low (negative test) microsatellites instability, PCR = Polymerase chain reaction, MRI = Magnetic Resonance Imaging, SGO = Society of Gynecologic Oncologists, SHG = Sonohysterography, TVUS = Transvaginal ultrasound The First Part of the article can be found Journal of Medicine and Life, vol. VIII, issue 3, 2015.5. Investigation of the particularities/ anomalies of the cervical cytology examination1]. The sensitivity of cervical cytologic examination in detecting the endometrial carcinoma varies between 26 and 60% for the endometrioid type, up to 100% for the serous papillary carcinoma with clear cells, the sensitivity increasing with the tumor degree . The presence of malignant cells in the cervical cytology examination represents a prediction factor for a severe myometrial invasion, ganglions metastasis, unfavorable prognosis, and a high risk of recurrence [4]. Rarely, the atypical glandular cells have been associated with tubal, ovarian, vaginal, colonic and breast cancer. The incidence of atypical glandular cells in the cervical cytology examination is of 0,1-2,1% and is associated in 30% of the cases with premalignant/ malignant lesions . The etiological evaluation stage for adenocarcinoma obligatorily contains atypical endometrial cells and atypical glandular cells, colposcopy with endocervical curettage, high risk HPV testing and endometrial biopsy (ASCCP). The benign/ normal endometrial cells with a supplementary exploration indication are examined by an endometrial biopsy. Patients, who have been histologically confirmed to suffer from endometrial cancer, go to stage IV and V of the diagnosis of the disease. Patients without intraepithelial cervical lesions, carcinoma in situ, and adenocarcinoma should do a co-testing (Pap + high risk HPV testing) at 12 and 24 months, whose negative result will reintegrate the patient in the standard screening program. The abnormal co-testing imposes colposcopy followed by an endometrial biopsy, which will be repeated in case a colposcopy diagnosis will not be obtained. Patients with AGC-NOS/ persistent endocervical AGC without diagnosis after repeating the colposcopy and the endometrial biopsy need conization. In the presence of symptoms, persistent endometrial AGC imposes an annual biopsy repeating and examination in order to detect a primary/ secondary tubal, ovarian, pelvic, or abdominal cancer . In favor of neoplasia – AGC, the carcinoma in situ or the adenocarcinoma with an unclear diagnosis after anterior investigations need a diagnosis excision procedure (preferably conization), endocervical curettage of the remaining cervix and endometrial curettage. The lack of specification of the diagnosis imposes the ultrasound investigation of the tubes and ovaries in search of lesions at this level :Amsterdam II Criteria [- Minimum 3 relatives cu Lynch-associated cancer  - One of the relatives must be a Ist degree relative with the other two- Minimum 2 successive generations affected - Minimum a case of cancer diagnosed under the age of 50 years- Familial adenomatous polyposis must be excluded from the category of colorectal cancer - Tomors should be examined from a histopathological point of view8] for MSI testing of colorectal tumors are the following: The revised Bethesda Criteria  regarding the evaluation of the Lynch syndrome: SGO Guidelines . Most of the experts recommend the MSI/ IHC testing of all the colorectal or endometrial cancers. The certainty diagnosis of Lynch syndrome is based on the genetic determination of the germinal line mutation of one of the MMR or EPCAM genes. Due to the fact that the testing of the germinal line of all the patients suspect of Lynch syndrome is very expensive, a sequential genetic evaluation, which starts with PCR tumor testing for MSI (MSI-H = positive test) and/ or by immunohistochemistry for the MMR genes expression (loss of the proteins color = positive test), should be undergone . After the family planning, patients with a certain genetic diagnosis of Lynch syndrome, are recommended total hysterectomy with bilateral adnexectomy in order to reduce the risk (Cancer Genetics Consortium) [12] .The management of the patients with Lynch syndrome includes observation by screening, chemoprevention, and surgery in order to reduce risk. Screening for endometrial cancer consists of an endometrial biopsy annually performed starting with 30-35 years old or 5-10 years before the earliest age for the diagnosis of a cancer form associated to Lynch (HNPCC) syndrome in the family   are the following:The clinical diagnosis criteria of Cowden syndrome [Major criteria:- Breast cancer - Endometrial cancer - Thyroid (follicular) cancer - Gastrointestinal hamartomas - Lhermitte-Duclos disease (in adults)- Macrocephaly - Macular pigmentation of the pineal gland - Multiple cutaneous-mucous lesions (any of the following): • Multiple trichilemmomas  • Acral keratosis • Cutaneous-mucous neuromas (≥ 3)• Buccal papillomas , multiple (≥ 3)• Biopsy/ dermatological diagnosis proof Minor criteria:- Autistic type specter of affections - Colon cancer - Esophageal glycogenic acanthosis (≥ 3)- Lipomas (≥ 3)- Mental retardation (IQ < 75)- Carcinoma of the renal cells - Testicular lipomatosis - Thyroid cancer (papillary/ follicular type of the papillary one) - Structural thyroid lesions  - Vascular anomalies . The individual operational diagnosis (any of the following): 1. three or more major criteria, among which one is obligatorily macrocephaly, Lhermitte-Duclos disease or gastrointestinal hamartomas 2. two major criteria and three minor criteria The operational diagnosis in families with a person who meets the individual diagnosis criteria or with a PTEN genetic mutation diagnosis: 1. any two major criteria with/ without minor criteria 2. one major criterion and two minor criteria3. three minor criteria. Standard: The testing criteria for Cowden syndrome  are the following:- A person who comes from a family with a known PTEN mutation - Individual diagnosis criteria for Cowden syndrome: Bannayan-Riley-Ruvalcaba syndrome/ Lhermitte-Duclos adult disease/ autism and macrocephaly/ two or more trichilemmomas proven by biopsy/ two or more major criteria among which one is macrocephaly/ three major criteria without macrocephaly/ one major criteria and three or more minor criteria/ four or more minor criteria. - Persons with high risk: persons with relatives diagnosed with Cowden syndrome/ PTEN hamartoma tumor syndrome/ Bannayan-Riley-Ruvalcaba syndrome untested genetically and which presents any major criteria or two minor criteria. The persons who meet the testing criteria are directed to undergo a genetic consultation and testing  for PTEN mutation. Patients with Cowden syndrome must be informed regarding the risks and are advised to promptly present to a specialty examination in case abnormal uterine bleedings appear. The hysterectomy option must be discussed. They must be completely physically examined annually. Screening by endometrial biopsy is recommended starting with 35-40 years old or 5 years earlier as compared to the age the first case of endometrial cancer was diagnosed in a family member. Postmenopausal women are recommended annual transvaginal ultrasound. 8. The awareness of the women regarding the bleeding anomalies and addressing to the family physicianOn the occasion of the annual/ triennial visit to the physician for the evaluation of the health state, the family physician must perform an anamnesis of the patient according to her age, the variables with concern to the menses/ menopause and the possibility of some bleedings. Moreover, the family physician must counsel the patient regarding the recognizing of a pathological bleeding and the importance of immediately addressing the doctor. On the visit, the family physician can give the patient a flyer with general information regarding abnormal bleeding. Human resources and materials necessary to implement the program Strategies for the implementation of the program• checklist/ prioritized schemes of specific interventions; • identifying the problems in adopting the recommendations and offering personalized solutions; • integrating the recommendations in the current medical practice conditions in gynecology; • identifying the systems and technical solutions of compliance to the application of recommendations of the program;• developing and creating interdisciplinary teams  for the study of the optimum application methods. The studies regarding the implementation of guidelines and recommendations have shown a raise in their acceptance and application, in the conditions of their substantiation by clear profs and the compatibility with the current rules and practices, in the absence of the need of acquiring new technical abilities, in the absence of controversies generating and in the conditions of a better clinical application.The tools proposed were generated based on the personal clinical experience and the literature review. In order to turn into medical practice algorithms a group of experts should validate them. Once validated, the tools can be shared with OG specialists and the family physicians . The successful criteria for the implementation of the adequate medical practice are the following: - systematic sharing with the physicians  - organizing discussions/ professional forums for the implementation of the new practices - evaluating the implementation of the practices Monitoring indicators specific for the implementation of the projectAdministrative issuesPatients with abnormal uterine bleeding and the ones with particularities/ anomalies of the cervical cytology examination can address the family physician or the gynecologist. The initial evaluation stage can be performed in any medical unit by the family physician or the gynecologist. The cases of patients with abnormal uterine bleeding or the ones with particularities/ anomalies of the cervical cytology examination, who are suspected of endometrial cancer, based on the initial evaluation stage, cases with precursor endometrial lesions/ associated with endometrial cancer which were diagnosed and treated, being in the monitoring period and the high-risk population , are evaluated by the gynecologist in outpatient or in a hospital, which must have a department of imagistic explorations and a laboratory of pathological anatomy. The laboratory of pathological anatomy must ensure the possibility of undergoing paraffin, ice, and immunohistochemistry examinations. The cases of patients with acute abnormal uterine bleeding or hemodynamically unstable are evaluated by the gynecologist in an emergency hospital unit. The patients diagnosed with endometrial cancer must be guided to do pre-therapeutic psychological counseling. Patients with endometrial cancer, which appeared while suffering from Lynch syndrome (HNPCC) or Cowden syndrome, must be guided, together with the family members, towards undergoing a genetic consultation and genetic examination specific for the mutations of MMR and PTEN genes.The conduct of the patients diagnosed with endometrial cancer is established by an interdisciplinary collaboration between surgeon, oncologist, and pathologist. Patients diagnosed with endometrial cancer will be surgically treated in a hospital unit by a gynecologist who has a gynecology complementary studies certificate or by a mixed team made up of a gynecologist-oncological surgery specialist.The monitorization indicators specific to the program are the following: a. number of OG who have received the information and the tools  b. number of family physicians who have received the information and the tools  c. number of patients with a correct medical history regarding the abnormal bleedings at the MF level  d. % of patients counseled at the MF level regarding the abnormal bleedings from the total eligible patients recorded  e. number of patients who are at risk and who take part in screening for endometrial cancer  The evaluation indicators should reflect the degree in which the proposed tools determine modifications in the management of the cases and should be systematically evidenced  at the level of each provider of medical services.Some proposed indicators are the following: a. % of cases with abnormal bleeding, investigated according to the practice algorithm b. % of cases with anomalies of the cervical cytology examination, investigated according to the practice algorithm c. % of cases with precursor endometrial lesions/ associated to endometrial cancer, investigated according to the practice algorithm  d. % of cases with Lynch and Cowden syndrome, identified before the appearance of endometrial cancer  e. % of cases of endometrial cancer discovered in stage I of the disease f. post-diagnosis survival of patients with endometrial cancer.