Fortunately radiation accidents are infrequent occurrences, but since they have the potential of large scale events like the nuclear accidents of Chernobyl and Fukushima, preparatory planning of the medical management of radiation accident victims is very important. Radiation accidents can result in different types of radiation exposure for which the diagnostic and therapeutic measures, as well as the outcomes, differ. The clinical course of acute radiation syndrome depends on the absorbed radiation dose and its distribution. Multi-organ-involvement and multi-organ-failure need be taken into account. The most vulnerable organ system to radiation exposure is the hematopoietic system. In addition to hematopoietic syndrome, radiation induced damage to the skin plays an important role in diagnostics and the treatment of radiation accident victims. The most important therapeutic principles with special reference to hematopoietic syndrome and cutaneous radiation syndrome are reviewed. Fortunately, radiation accidents are infrequent occurrences, but since they have the potential of resulting in large scale events, such as the nuclear accidents of Chernobyl and Fukushima, preparatory planning for medical management of radiation accident victims is very important .Radiation accidents can result in radiation exposure to only a few up to several hundreds of people, depending on the type of accident and the amount of radiation exposure. Radiation exposure can occur as external exposure, for instance, from a sealed radiation source, or as internal exposure due to the intake of radionuclides. In a nuclear disaster scenario like the Chernobyl accident, a combination of external and internal radiation exposure could occur. Radiation exposure can also be categorized as either chronic or acute, depending on the period of time of radiation exposure. Another important factor that can effect treatment and outcome is whether the whole body of a person was affected homogeneously or if only localized radiation exposure of a part of the body occurred.For each of these different types of scenarios and combinations the expected consequences for the patient, depending on the absorbed radiation dose and distribution as well as diagnostic and therapeutic measures, are different. In the case of whole body exposure, all organs and organ systems are affected and, therefore, multi-organ-involvement and multi-organ-failure have always to be taken into account. Additional conventional trauma, such as wounds and burns in people with severe radiation exposure - the so-called radiation combined injury, could worsen the prognosis .There are many aspects to consider when diagnosing and managing radiation exposed patients. Acute versus chronic effects can be differentiated by the latency of manifestation of the radiation effects. Since acute effects require immediate therapeutic intervention, they should be diagnosed at an early stage. Another differentiation could be made between deterministic versus stochastic effects regarding their pathophysiological mechanisms. Deterministic radiation effects, such as the hematopoietic syndrome, occur after a threshold radiation dose is exceeded and the severity will increase with increasing radiation exposure. For stochastic effects like the development of malignant tumors on the other hand, the probability of their appearance will increase with increasing radiation exposure.Therefore, all efforts must be made to reduce the individual exposure to ionizing radiation and, thus, the absorbed dose .The identification of external contamination with radionuclides is important, since in the case of external contamination patients have to be decontaminated as soon as possible and special precautions must be taken to protect first responders, medical personnel, facilities and equipment from contamination. If patients have incorporated radionuclides, a specific de-corporation therapy must be carried out as soon as possible to reduce the resulting radiation dose. Since the de-corporation therapy has to be specific for the involved radionuclide, the identification of the radionuclide must be the initial step . Even thFor the planning of the medical management of radiation accident victims, it is crucial to estimate the severity of the radiation exposure on the basis of the individual patient's clinical signs and symptoms by means of a clinical dosimetry.After significant acute whole body or partial body radiation exposure, resulting in acute radiation induced health impairments, it is imperative that appropriate therapeutic measures be carried out as soon as possible.When dealing with specific recommendations for countermeasures against radiation-induced health impairments, the main fact is that due to the comparatively low number of radiation victims worldwide, there is a clear lack of controlled studies in this area. Therefore, established and accepted animal models , as wellDepending on the magnitude of the radiation exposure resulting in significant whole body exposure or partial body exposure, the patient will develop clinically acute radiation effects resulting in acute radiation syndrome (ARS).The biological effects of ionizing radiation will start on the cellular level by energy absorption due to several physical effects, such as the Compton process and the photoelectric process for x- or gamma-rays. The most important targets are the DNA-molecules, where direct or indirect actions of radiation could result in lesions, such as base damage, single-strand breaks and double-strand breaks. Double-strand breaks are considered the most serious DNA-lesions, since they can result in the cleavage of chromatin and might not be successfully repaired by the cell. The occurrence of DNA-lesions and, especially, of double-strand breaks will increase with increasing radiation exposure and will lead to a higher risk of cell death .The classical initial symptoms of acute radiation syndrome occur during the so-called prodromal phase. Prodromal symptoms include: anorexia, nausea, vomiting, diarrhoea, fluid loss, fever, hypotension, headache and early erythema ,9. TheseWith higher radiation exposure, disturbances of the gastrointestinal system, such as destruction of the mucosal layer can take place. A complete loss of the mucosal layer will be fatal. Very high radiation exposure can result in neurologic and cardiovascular breakdown causing death within a few days. The cutaneous syndrome can occur together with the other syndromes, but cutaneous radiation injury (CRI) could also be the consequence of external exposure to beta-radiation in the absence of other symptoms of ARS ,9.All differentiated cells and stem cell pools of the organism will be affected from acute homogeneous whole body radiation exposure resulting in multi-organ involvement (MOI) and even multi-organ failure (MOF).Pathophysiological aspects of radiation-induced MOI include systemic inflammatory response syndrome (SIRS) and consequences of cell loss due to radiation damage . TherapeClinical management of patients with acute radiation syndrome is characterized by dealing with radiation induced impairments of different organ functions, multi-organ involvement or even multi-organ failure.In the early stages of the accident situation, reliable information about physical dosimetry and results from biodosimetric methods are not always immediately available. Therefore, the estimation of radiation effects and the patient's prognosis will be based on clinical signs and symptoms as described in the METREPOL system . InsteadAs soon as reliable information about the physical dose or results from biodosimetry is available, the data should be included in therapeutic decision making and sufficient medical management. It is the prediction of expected radiation-induced impairments of organs or organ-systems that is important for this management.One of the most critical and most vulnerable organ systems to radiation exposure is the hematopoietic system, since the limited life-span of blood cells requires continuous cell divisions of hematopoietic stem cells in the bone marrow. The impairment of the hematopoiesis will result in pancytopenia of various degrees with consecutive increased risk of infection, hemorrhage and anemia. General medical management consists of barrier nursing conditions, sufficient and immediate therapy of infections or even prophylactic administration of antibiotic, and antimycotic and antiviral substances -14. SincDepending on the severity of the hematopoietic syndrome, the main therapeutic principles are replacement with blood products, such as erythrocyte concentrate, the administration of cytokines like granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the transplantation of hematopoetic stem cells (HSCT) . The souThe therapeutic use of hematopoietic factors such as G-CSF, GM-CSF, erythropoietin (EPO) and thrombopoietin (TPO) has been described in several cases -24. SincThe therapeutic use of hematopoietic factors in radiation accident victims will be considered as "off-label use". But if the development of severe neutropenia in a patient is expected, the administration of G-CSF or GM-CSF in an early stage is recommended ,8,14.If unrecoverable damage to the hematopoietic stem cell pool is noticed, a decision about the necessity of HSCT has to be made. The diagnosis, whether or not an autologous recovery of the hematopoiesis could be expected, requires specific expertise ,21,27,28In addition to hematopoetic syndrome, radiation-induced damage to the skin plays an important role in diagnosis and treatment of patients with ARS, but also in the case of local radiation injuries. The impairment of the skin could be a real challenge in the clinical management of patients with cutaneous radiation syndrome. The barrier function of the skin will be affected and inflammatory reactions will take place, which eventually might trigger the development of MOF ,32. TherThe development of acute radiation effects in radiation accident victims depends on the nature and the extent of radiation exposure. Since reliable information about the radiation exposure from physical dosimetry and results from biodosimetric methods are usually not available in accident situations, the estimation of radiation effects can be performed on the basis of clinical signs and symptoms as described in the METREPOL system.Multi-organ involvement, systemic inflammatory response syndrome and even multi-organ failure have to be considered in the clinical management of radiation accident victims.Since the hematopoietic system is most vulnerable to ionizing radiation, diagnostic and therapeutic measures dealing with the hematopoietic syndrome are most important. General measures are barrier nursing conditions, sufficient and immediate therapy of infections, or even prophylactic administration of antibiotic, antimycotic and antiviral substances. The main specific therapeutic principles are replacement with blood products, the administration of cytokines like G-CSF and GM-CSF, and the transplantation of hematopoietic stem cells.In addition to hematopoietic syndrome, radiation-induced damage to the skin plays an important role in diagnostics and treatment of patients with ARS and eventually might trigger the development of multi-organ failure.New approaches are based on the administration of stem cells, such as mesenchymal stem cells, in the case of cutaneous radiation syndrome and localized radiation injuries. Since radiation-induced multi-organ involvement or multi-organ failure will be associated with a poor prognosis in the patient, early therapeutic intervention for preventing the development of MOI and MOF seems to be one of the most important aspects for further research.From past experiences, we know that radiation accidents fortunately are rare events; therefore, the number of patients suffering from acute radiation effects and ARS is limited. However, current risk analyses of terrorist threats consider a nuclear scenario as extremely relevant. This certainly would mean that the number of victims would be in a much higher magnitude. Availability of necessary resources could be a limiting factor for the medical management of radiation accident victims. Stockpiling of essential pharmaceuticals for the treatment of radiation accident victims on a national or international level has to be considered.Prospective studies for the development of therapeutic standards for patients with ARS are extremely limited. Most of the new approaches in therapeutic measures are derived from experimental studies in animal models. Keeping these circumstances in mind, a multidisciplinary approach built on international cooperation is of the utmost importance and currently the most reasonable strategy to provide the best possible medical care for radiation accident victims. The clinical course, as well as the therapeutic regimen, of each new radiation accident victim should be documented in detail for further analysis, as in the SEARCH database .There is a strong need for internationally recognized guidelines for the treatment of severely radiation-exposed patients . FurtherARS: acute radiation syndrome; CRI: cutaneous radiation injury; CRS: cutaneous radiation syndrome; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; Gy: Gray; HSCT: hematopoetic stem cell transplantation; M-CSF: macrophage - colony-stimulating factor; METREPOL: Medical Treatment Protocols for Radiation Accident; MOI: multi-organ involvement; MOF: multi-organ failure; MSC: mesenchymal stem cells; RC: response category; Sv: Sievert; SIRS: systemic inflammatory response syndrome.The authors declare that they have no competing interests.HD and VM have made substantial contributions, drafted and revised the manuscript and both have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/9/126/prepub


The insular cortex is a multimodal brain region with regional cytoarchitectonic differences indicating various functional specializations. As a multisensory neural node, the insular cortex integrates perception, emotion, interoceptive awareness, cognition, and gustation. Regarding the latter, predominantly the anterior part of the insular cortex is regarded as the primary taste cortex. In this review, we will specifically focus on the involvement of the insula in food processing and on multimodal integration of food-related items. Influencing factors of insular activation elicited by various foods range from calorie-content to the internal physiologic state, body mass index or eating behavior. Sensory perception of food-related stimuli including seeing, smelling, and tasting elicits increased activation in the anterior and mid-dorsal part of the insular cortex. Apart from the pure sensory gustatory processing, there is also a strong association with the rewarding/hedonic aspects of food items, which is reflected in higher insular activity and stronger connections to other reward-related areas. Interestingly, the processing of food items has been found to elicit different insular activation in lean compared to obese subjects and in patients suffering from an eating disorder (anorexia nervosa (AN), bulimia nervosa (BN)). The knowledge of functional differences in the insular cortex opens up the opportunity for possible noninvasive treatment approaches for obesity and eating disorders. To target brain functions directly, real-time functional magnetic resonance imaging neurofeedback offers a state-of-the-art tool to learn to control the anterior insular cortex activity voluntarily. First evidence indicates that obese adults have an enhanced ability to regulate the anterior insular cortex. The insular cortex is embedded in the lateral sulcus of the mammalian brain. On the basis of cytoarchitectonic studies using myelin staining techniques, the insula can be subdivided in three major compartments according to the laminar structure, referred to as the anterior ventral agranular, dorsal anterior dysgranular, and posterior granular part of the insular cortex  patients exhibit increased insula activation to high-caloric food pictures in comparison to overweight and normal weight control subjects  increase after administration of 2 mL of drinking water, satiation has been associated with a decrease in insular rCBF, suggesting that the reaction of the insular cortex to sensory experiences is affected by hunger . Moreover, rtfMRI guided neurofeedback training of the insular cortex raises the possibility to modify eating behavior.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.


HMAP has progressed fruitfully inall three respects since its inception in 2000. It has established centres at theuniversities of New Hampshire (USA), Roskilde (Denmark), Hull (UK), Murdoch and Trinity College Dublin (Ireland), where faculty members – someof whom might be cast as ‘HMAP graduates’ - are responsible for leadingthe project and cultivating its distinctive approach to marine environmental issues.Here, and at numerous other educational institutions, the curricula have beenenriched by the introduction of programs of study that focus on the marinedimensions of historical ecology and environmental history. Such learning andteaching work is informed by research undertaken under the aegis of HMAP, which by2009 had generated over 200 printed and online works [www.hmapcoml.org/publications], as well as a substantialweb-based data store The articles that comprise the HMAP Collection are products of the History of MarineAnimal Populations (HMAP) project. This is an international, multidisciplinaryinitiative, the overarching aim of which is to improve knowledge and understandingof the long-term interaction of humankind with the marine environment. HMAPendeavours to attain this goal in three principal ways. First, a concerted effort isbeing made to embed the approaches and methods developed by HMAP into theinstitutional fabric of the universities that are hosting the project. This connectsclosely with the second strand of the scheme, which is designed to develop theparallel disciplines of historical marine ecology and marine environmental historythrough the sponsorship of graduate studentships, workshops, summer schools,conferences and the dissemination of research outputs. The third activity is theco-ordination of a research programme embracing the efforts of over 100 scientistsin 18 countries working in teams tasked with investigating 12 regionally-specific,two thematic and two global taxon-specific case studies [The History of Marine Animal Populations project was conceived in the late 1990s.It swiftly hatched into the historical component of the primarily science-basedCensus of Marine Life (CoML) program, which aims to assess and explain thediversity, distribution, and abundance of life in the oceans - past, present andfuture The integration of history into the science-driven CoML reflected developments infour disciplines - archaeology, history, biology and ecology - during the finalthird of the twentieth century. In essence, specialisation in these fields ofenquiry led to the emergence of a number of sub-disciplines that converged inthe 1990s to offer a multidisciplinary, or holistic, perspective on thelong-term interaction of human and marine life. Since the 1960s, for instance,developments in archaeological science have given rise to paleoecology,archaeoichthyology and paleozoology. In one example of the fruits of thesesub-disciplines, the preservation of fish scales in anaerobic bottom sedimentsoff the coast of California enabled scientists to reconstruct 1600 years ofpelagic abundances Specialist sub-disciplines have evolved within the history discipline since the1960s. Environmental history was one of these off-shoots, sprouting in the USAduring the 1970s and growing ever since, a pattern evident, albeit a littlelater, in Europe, Asia, Australia and, despite institutional problems, SouthAmerica and Africa. However, the focus of the pioneering American environmentalhistorians was strongly on human agency and perception, with ecological factorsrarely afforded an explanatory role. Moreover, the sub-discipline developed outof a strongly narrative and qualitative approach to history that had littlerapport with the quantitative approach of ecologists. The focus was very much onfrontier cultures of the prairies, bushlands, savannahs and steppes, while theoceans were largely disregarded The interest of natural scientists in the fisheries dates back to the latenineteenth century, when governments began to address the question offluctuations in catches, largely because the social and economic costs of thisunpredictability were high. Two schools of thought emerged. Some scientistsexplained the often large fluctuations and long-term declines from a singlespecies perspective. This simplicity allowed them to provide more concreteadvice to fisheries managers. Other scientists, however, saw the problem asinvolving multiple interacting species, an ecological perspective that had itsorigins in a terrestrial setting, and was now applied to the sea Fisheries biologists began to recognize the need for a more historicalperspective on some fisheries. Papers summarizing long-term landings weretherefore published, especially for fisheries where management depended on therelationships between numbers of spawners and resulting number of recruits A number of ecologists also made the historical turn. In 1995, Daniel Paulyobserved that most equilibrium or steady-state models are based on a givendataset, often established by scientists within the last generation With the long-term perspective finding favour in the marine sciences, andecological approaches assuming more importance in the analyses of archaeologistsand historians, a prospectus for a History of Marine Animal Populations projectwas issued in 1999 The initial phase of HMAP was characterized by discussions about the nature andscope of what was appropriate and possible historically and scientifically thatwould contribute to the present and future foci of the Census of Marine Life.These deliberations culminated in a workshop held in Denmark in February 2000,at which researchers from various disciplines involved in CoML sought to defineand encourage what was quickly seen to be a necessary and needed expansion ofboth environmental history and historical ecology, as well as an importantcomponent of the Census. The meeting yielded an analytical framework, a set ofhypotheses and an edited collection of papers It was agreed that the topical, spatial and temporal parameters of HMAP should bebroad: that is, the project should investigate the impact of human activity onmarine animal populations in the world's seas and oceans over the last2,000 years. But four provisos were identified. First, much of what can be knownabout the history of marine animal populations relates to the ‘humanedges’ of the ocean, the near shore and coastal waters where humans mostdirectly interacted with the sea in the past – as a source of food, ameans of transportation, a theatre of war and a recreational zone. Accordingly,most historical records concern such activities in this realm. Second, theresearch should focus on the human activity that has had the greatest impact onmarine ecosystems over historic time, the commercial fisheries conducted on thehuman edges and (for certain species) in mid-oceanic waters. Third, ingenerating knowledge about the impact and significance of the commercialfisheries, it is inevitable that analyses will be skewed towards the extractionof large animals, notably whales, large fish (such as cod and bluefin tuna), andmarketable smaller species (like herring), where the sheer size and/orcommercial value of the organisms encouraged captors to create and maintainarchival material. Fourth, moving from the unknown to the known history of theoceans requires that the approaches and methods of archaeology, history, biologyand ecology be deployed in a truly multidisciplinary way.http://hmapcoml.org/documents/Hypotheses.pdf). From this, fourbroad research questions were devised:A preliminary set of hypotheses was also formulated at the 2000 workshop fishery,as traced by Kathleen Schwerdtner Máñez and Sebastian C. A. Fersein the HMAP Collection, not only adds to HMAP's Asian case studies but alsooffers an example of the commercial pressures that have driven the majority ofthe world's fisheries over the centuries Trepang extraction enabled the people of Makassar,Indonesia, to profit from the export of a commodity that was in great demand inChina. While this rendered them vulnerable to market fluctuations, the fishingeffort was shaped by patron-client relationships and marked by the ‘rovingbandit’, or bonanza, syndrome, whereby fishers exploit stocks in alocality until they are depleted, when they move to another area. The fragilityof marine ecosystems in the face of seemingly rapacious human fishing activityis also the central theme of another HMAP Collection paper, Ruth H Thurstan andCallum Roberts's analysis of the ‘ecological meltdown’ that hasoccurred in the Firth of Clyde, Scotland, since the introduction of moreintensive fishing methods in the mid-nineteenth century The development of the Makassan sea cucumber  amounted to upwards of100,000 tonnes. Catches declined to about half of that level by 1700, and onlyincreased to about 200,000 tonnes in the late eighteenth century when theSwedish and Scottish fisheries developed apace. By 1870, total removals reacheda level of 300,000 tonnes, which equals the Total Allowable Catch for North Seaherring in 2007, as recommended by the International Council for the Explorationof the Seas. This evidence demonstrates how fishermen in the age before steamand trawl were able to remove large quantities of biomass from the sea. Whileearly modern catches seem to have been at a sustainable level, there areindications that removals at much lower levels than those recommended by modernstandards had an effect on abundance. This can be deduced by standardizing thecatching capacity of North Sea herring fishing vessels across the technologicaldivide from sail to motor-powered vessels. Even by a conservative estimate,analysis of catch-per-unit-effort indicates that stock abundance was ten timeshigher in the 1600s than in the 1950s, and already by the 1800s, well beforesteam was introduced, it had dropped to 50–60 percent of the level of theseventeenth century. Accordingly, the impact of early modern removals of herringwas much greater than historians and ecologists had previously realised With regard to the scale of activity, HMAP's North Sea researchers haveinstilled a long-term perspective into the literature. Following in the wake ofHutchings and Myers's pioneering reconstruction of catches of Atlantic codoff Newfoundland and Labrador from 1508 to 1992 A similar finding emerged from an HMAP study of the extraction of ling and codfrom the North Sea. These species are classed as ‘top predators’. Inecosystem theory, top predators play a controlling and balancing role for theabundance of other species further down the food chain, and large numbers of toppredators are a sure sign of healthy biodiversity. Human hunting tends to focuson top predators as the big fish are of the highest commercial value. At thesame time, removing the largest specimens weakens the ecosystem, for mature fishare highly important for the reproduction of the population as their eggs arehealthier and more plentiful than the spawn of younger and smaller specimens. Asthe fish continues to grow through its entire life, a decline in the length ofspecimens caught is a clear indication that fishing is changing the agestructure and viability of the stock. Historical analysis demonstrated thatwhile the average length of North Sea ling in the mid to late nineteenth centurywas about 1.5 metres, it had decreased to about 1.2 metres by the First WorldWar, and ling caught today is less than 1 metre on average. A century ago, codlanded from the North Sea was usually 1-1½ metres long, while today it isonly about 50 cm. This means that while cod used to live to an age of eight orten years, in the early twenty-first century it is caught at less than threeyears of age. As cod only spawns at the age of three years, the fisheries areclearly removing cod at a critical stage An important aspect of any long-term perspective is the measurement of changeover time. This features prominently in the contribution of Tyler D Eddy,Jonathan P.A. Gardner and Alejandro Pérez-Matus to the HMAP Collection,which focuses on the role of baselines in the management of the lobster fisheryof the Juan Fernández Archipelago, Chile trepang fishery, NewEnglanders were aware that their prey was diminishing in extent and responded bymoving to fishing grounds further offshore. By the late 1850s, many schoonerswere undertaking longer voyages to the Gulf of St Lawrence and the Grand Banks,where stocks were perceived to be larger. Another response, which was alsoevident contemporaneously in the Firth of Clyde, was the application of newtechnology. French fishermen introduced tub trawls to the Scotian Shelf fishery,and soon the Americans no longer used the traditional handlines with 2–4hooks per man, but longlines of upwards of 400–500 hooks per crewman.While the catchment area of one boat increased immensely, and catches went up inthe short run, in a matter of a few years the fish stock was showing cleardepletion signals, with smaller individuals being caught and thecatch-per-unit-effort of fishermen declining Like their counterparts in the Indonesian Spatial range is also a key theme of the research undertaken as part of the HMAPWorld Whaling case study by Tim Smith, Randall Reeves, Elizabeth Josephson andJudith Lund. This team has analyzed data relating to American offshore whalingvoyages to describe the historical distribution of five key groups of speciesthat were targeted by nineteenth-century whalers: sperm, right, humpback, grayand bowhead whales. The data are presented in the form of world maps, showingwhere the whalers went and where they encountered these species of whales The team used these offshore whaling voyage data, as well as other archivalsources from shore-based whaling operations, to develop more detaileddescriptions for several areas of the magnitude of whaling, and its impact onfor four key nineteenth-century target whales: right, sperm, gray and humpback.Right whales were the earliest target species, beginning at least by 1050 AD andcontinuing in the North Atlantic in some 33 fisheries for over 1000 years. Rightwhales were pursued in all the world's oceans, both by shore-based andoffshore whalers. Total removals of right whales in the western North Atlanticwere estimated to have been at least 5,000 animals The other major target of nineteenth-century whalers were sperm whales. The teamdrew on published and archival sources to identify more that 60 sperm whalinggrounds Humpback whales have been sought in the North Atlantic since the seventeenthcentury, with at least one fishery continuing to the present, albeit at very lowlevels. Both shore and offshore whalers pursued this species on its two NorthAtlantic breeding grounds and in all of its many feeding grounds. The teamexamined all archival information that it could find and developed estimates oftotal removals of around 30,000 animals Extinct in the North Atlantic in the 1600s, gray whales became a target ofwhaling in the North Pacific, being pursued for several centuries in both theirwestern and eastern North Pacific populations. In the eastern North Pacific,gray whaling was long conducted aboriginally on well-defined migration andfeeding grounds. In the 1850s, commercial whalers from several nations began tofocus on this species in its calving and breeding grounds in Baja California andin the North Pacific feeding grounds. American shore-based whaling alsodeveloped along the California coast. Although the total removals of easternNorth Pacific  gray whales had previously been estimated, thoseestimates were inconsistent with sightings-based estimates of current and recentabundance, and as a result pre-whaling abundance has been poorly understood. TheWorld Whaling team revisited the estimates of nineteenth-century gray whaling inthe eastern North Pacific to determine if the source of this inconsistency wasbiases in estimates of removals The HMAP Baltic case study has shed much light on the historical development offisheries in the region. Over the long term, little pressure was exerted bycommercial fishing on fish stocks in the inner parts of the Baltic. During thelate seventeenth century, for example, removals of fish biomass from the Gulf ofRiga were at least 200 times less than the level they reached in the latetwentieth century. In the earlier period, moreover, the bulk of the fishingeffort was expended in the rivers. Migratory fish species, such as sturgeon,Atlantic salmon, brown trout, whitefish, vimba bream, smelt, eel and lampreywere the most important commercial fish in the area, because they were abundant,had high commercial value and were easily available. Over time, however, fishingactivity moved downstream and into the sea. Due to intensive fishing,populations of many migratory species, especially sturgeon and Atlantic salmon,contracted considerably and they became less commercially significant, whilemarine fish, especially Baltic herring, increased in importance during thenineteenth century This follows an established pattern, for the HMAP Baltic team has utilizedlong-term perspectives to help solve other environmental issues. For instance,in the absence of historical records before 1966, fishery managers asked if therecord high cod stock in the Baltic Sea in the late 1970s and early 1980s was aunique occurrence, or whether it was likely to happen at regular intervals. Thequestion was unequivocally answered through the recovery of historical data backto 1925, which showed that abundant cod stocks corresponded to a favourablecombination of four key drivers: incursions of saline water to the brackishBaltic and hydrographic conditions that facilitated successful reproduction; lowmarine mammal predation; a highly productive environment fuelled by nutrientloading; and reduced fishing pressure. Such a conjunction of factors did nottake place at any other point in the twentieth century. While the cod biomasswas restricted from 1920 to 1950 by an abundance of marine mammals and lowecosystem productivity, in the 1950s and 1960s stock levels were depressed byhigh fishing pressure, and hydrographic conditions were rarely conducive to goodreproduction rates throughout the twentieth century, especially after 1985. Thelate 1970s and early 1980s were therefore extraordinary in that a combination ofpositive factors interacted to produce a large cod stock, a conclusion that willperhaps inform the policies and targets of fisheries managers A further notable finding of HMAP Baltic research relates to the resilience offish to broad changes in temperature and other meteorological variables.Archaeological evidence of fish fauna in the Atlantic warm period (c.7000-3900BC) infers that there were many fish species in the waters around Denmark whichare now be found in warmer waters. However, cod was very abundant in the StoneAge, even though temperatures were 2–4 degrees warmer those of the latetwentieth century, suggesting that significant cod populations can be maintainedin the Baltic region even if temperatures rise due to global warming, providedthat fishing mortalities are reduced. Climatic variables also influenced theabundance and distribution of other species. For instance, during the Little IceAge of the late seventeenth century, cold-water marine fish  sustained important fisheries in the Baltic, while the fishingseason for the major pelagic fish species was much later in the year, comparedto the much warmer conditions of the present day. Similarly, the magnitude andcomposition of catches of herring and other coastal fish (e.g. perch and ide)near Estonia in the mid and late nineteenth century, when fishing effort andmethods were constant, were chiefly governed by climatic fluctuations A decade ago, the editors of the first collection of HMAP research papersanticipated that the findings of the project's initial case studies wouldmake ‘a major contribution to knowledge and understanding of the complex,delicate and important relationship between human societies and the marineenvironment’


Pulmonary sclerosing hemangiomas (PSH) of the lung are uncommon tumors and may present cytological atypia with unusual manifestations. The development of PSH combined with other different tumors in lung is extremely rare. We report a case of coexistence of PSH and primary adenocarcinoma in a young female occurring in the same pulmonary nodular mass of right lower lobe. The solitary mass of lung was well-circumscribed on chest computed tomography (CT) and gross examination. Histologically, the mass contained two separated portions and displayed typically histological features of PSH and acinar adenocarcinoma, respectively. In PSH portion, the tumor was composed of sheets of round cells with scattered surface cuboidal cells forming small tubules. Both round and surface cells were diffusely positive for epithelial membrane antigen (EMA) and thyroid transcription factor-1 (TTF-1), but lack immunoreactivity for pancytokeratin in round cells. In adenocarcinoma portion, the tumor cells formed irregular-shaped glands with cytologically malignant cells infiltrating in fibroblastic stroma, and no TTF-1-positive round cells could be observed in this portion. Under the microscopy, there was no gradual transition of these two portions observed in mass. A diagnosis of PSH combined with primary adenocarcinoma of lung was made. There was no evidence of tumor recurrence during the period of postoperative 6-month follow-up. To our knowledge, this is the first case of coexistence of PSH and adenocarcinoma in the same nodule of lung. In addition, the biological behavior and histological differential diagnosis of this tumor were also discussed. Pulmonary sclerosing hemangioma (PSH) is an uncommon tumor and is thought to be a benign neoplasm of lung ,2. HowevA 22-year-old woman with a 4-month history of pulmonary mass was admitted to our hospital for further examination and treatment. The pulmonary mass was first detected on chest radiography when she underwent annual body examination at a local hospital Figure . For unkUnder the microscopical examination, part of nodular mass, measuring approximately 1.2 cm in longest diameter, demonstrated classical solid pattern of PSH with varying proportions of surface cuboidal cells and pale round cells. In this area, the mass was composed of sheets of round cells with scattered surface cuboidal cells forming small tubules Figure . The surThe term of "pulmonary sclerosing hemangioma (PSH)" was first used in 1956 by Liebow and Hubbell, in which sclerosing hemangioma was described as a variant of hemangioma due to prominent angiomatoid features and occurred predominantly in young or middle-aged women . HoweverIn the current study, we found that both surface and round cells in PSH portion of mass were immuno-positive for TTF-1 and EMA, but round cells were negative for pancytokeratin. These results provided useful clues not only for histogenesis but also for the diagnosis of this tumor. However, in contrast to most previous studies, the focal weak positivity of round cells, but not surface cells, for neuroendocrine marker, synaptophysin (Syn) was found in our case. This result indicated that tumor cells in PSH, in particular round cells, might have potential to neuroendocrine differentiation or represent incompletely differentiated Clara cells. It is well known that TTF-1 expressed in the non-ciliated columnar cells of the fetal lung as early as 11 weeks of gestation, and in type II pneumocytes and Clara cells of the adult lung ,14, and PSH is a distinctive lung tumor, which is composed of mixtures of papillary, solid, sclerotic, and/or hemorrhagic patterns with varying proportions of two cell types. Variable degrees of cytologic atypia were found in most PSH. The cases of atypical alveolar hyperplasia (AAH) in PSH , alveolaPSH is a clinically benign tumor and has a good prognosis after surgical resection. However, lymph node metastasis and multifocal distribution of PSH have been found in a few cases ,16,20,21We herein first reported a rare case of PSH combined with primary adenocarcinoma occurred in the same nodular mass of lung. The mass contained two separated portions and displayed typically histological features of PSH and adenocarcinoma, respectively. The precise mechanism of coexistence of PSH and adenocarcinoma in the same nodule remains unknown, and longer period of follow-up and more case investigation are necessary to better clarify the biological characteristics and clinical outcomes of this unusual tumor.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.LIU W and LI Y made contributions to acquisition of clinical data, and analysis the histological features of case by H&E staining. TIAN XY drafted the manuscript. LI Z revised manuscript critically for important intellectual content and has given final approval of the version to be published. ZHAO Y and LI B carried out the immunoassays. All authors read and approved the final manuscript.


The Ocean, which is called the “mother of origin of life,” is also the source of structurally unique natural products that are mainly accumulated in living organisms. Cyanobacteria are photosynthetic prokaryotes used as food by humans. They are excellent source of vitamins and proteins vital for life. Several of these compounds show pharmacological activities and are helpful for the invention and discovery of bioactive compounds, primarily for deadly diseases like cancer, acquired immunodeficiency syndrome (AIDS), arthritis, and so forth, while other compounds have been developed as analgesics or to treat inflammation, and so forth. They produce a large variety of bioactive compounds, including substances with anticancer and antiviral activity, UV protectants, specific inhibitors of enzymes, and potent hepatotoxins and neurotoxins. Many cyanobacteria produce compounds with potent biological activities. This paper aims to showcase the structural diversity of marine cyanobacterial secondary metabolites with a comprehensive coverage of alkaloids and other applications of cyanobacteria. Biomolecules of the NRP and hybrid polyketide-NRP structural types are important subsets of natural products utilized as therapeutic agents.Staphylococcus aureus and Staphylococcus epidermidis, including both methicillin-susceptible (MSSA & MSSE) or resistant species (MRSA & MRSE), are usually sensitive to vancomycin. Vancomycin is also effective against the anaerobes, diphtheroids, and clostridium species, including C. difficile, whereas Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. It works by causing breaks in DNA as anticancer drug. The drug is also used in the treatment of Hodgkin's lymphoma, squamous cell carcinomas, and testicular cancer, as well as in the treatment of plantar warts and as a means of effecting pleurodesis. The discovery of these unique classes of natural products from marine cyanobacteria represents an important source of novel microbial secondary metabolites, in addition to the actinomycetes and fungi, for drug discovery efforts. These include the antibiotic vancomycin, the immunosuppressive agent cyclosporine, and the anticancer agent bleomycin . VancomyAn increasing number of marine cyanobacterial compounds are found to target tubulin or actin filaments in eukaryotic cells, making them an attractive source of natural products as anticancer agents . PromineIn addition, these molecules served as a drug leading to the development of synthetic analogues, for example, compound 4, TZT-1027 , ILX-651The third generation dolastatin 15 analogue , ILX-651Prochlorococcus and Synechococcus dominate the photoautotrophic picoplankton over vast tracts of the world's oceans where they occupy a key position at the base of the marine food web and contribute significantly to global primary productivity . Th. ThcyanoCyanobacteria  provide a potential source of biologically active secondary metabolites . InvestiThe blue-green algae are among the oldest photoautotrophic organisms. Their cultivation without organic substrates can be an economical advantage over other microorganisms. In view of the growing resistance of bacteria to common antibiotics, the search for new antimicrobially active compounds has become increasingly important . ScreeniAqueous extracts and organic solvent extracts of isolated marine cyanobacteria strains were tested for antimicrobial activity against a fungus, Gram-positive and Gram-negative bacteria and for cytotoxic activity against primary rat hepatocytes and HL-60 cells . AntimicPotential commercial development of cyanobacterial compounds for nonbiomedical applications, particularly including herbicides, algaecides, and insecticides poses a potentially important opportunity to utilize the biological activity of these compounds . Aedes aegypti. The greatest inhibition, however, was associated with presence of the hepatotoxic microcystins and the neurotoxic anatoxin-a. Humpage and Falconer[Westiellopsis sp.  were larvicidal to several species of mosquito, including representatives of Aedes aegypti (a vector for Dengue Fever), Anopheles stephensi  , and Culex tritaeniorhynchus and C. quinquefasciatus  . The use of genetically engineered cyanobacteria, specifically expressing the insecticidal proteins from Bacillus thuringiensis to control mosquito larvae [Fladmark et al.. screene Falconer reportedo larvae , 45. Liko larvae , 45.Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption . From a The fact that cyanobacteria are one of the richest sources of known and novel bioactive compounds including toxins with wide pharmaceutical applications is unquestionable. Many compounds from cyanobacteria are useful for welfare of mankind. Because of high discovery rate, research should be done to unfold other hidden aspects of marine cyanobacteria. An advantage of natural products research on marine cyanobacteria is the high discovery rate (>95%) of novel compounds as compared to other traditional microbial sources. This is due largely to the unexplored nature of this group of microalgae. One of the key areas to further tap these microalgae for new chemical entities is the collection of cyanobacterial strains from unexplored localities, especially from Africa and Asia. In addition to the procurement of marine cyanobacteria from unexplored locales, the amenability of field collected strains to laboratory culture is an important factor in the drug discovery process.


Glaucoma, which affects more than 70 million people worldwide, is a heterogeneous group of disorders with a resultant common denominator; optic neuropathy, eventually leading to irreversible blindness. The clinical manifestations of primary open-angle glaucoma (POAG), the most common subtype of glaucoma, include excavation of the optic disc and progressive loss of visual field. Axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies are observed in glaucoma, in which the reduction of intraocular pressure (IOP) is known to slow progression of the disease. A pattern of localized retinal nerve fiber layer (RNFL) defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. The mechanisms of degeneration of neuronal cell bodies and their axons may differ. In this review, we addressed the molecular mechanisms of cell body death and axonal degeneration in glaucoma and proposed axonal protection in addition to cell body protection. The concept of axonal protection may become a new therapeutic strategy to prevent further axonal degeneration or revive dying axons in patients with preperimetric glaucoma. Further study will be needed to clarify whether the combination therapy of axonal protection and cell body protection will have greater protective effects in early or progressive glaucomatous optic neuropathy (GON). The axons of human retinal ganglion cells (RGCs) are approximately 50 mm in length and form synapses with cells in the lateral geniculate nucleus of the thalamus. The axons are arranged in bundles separated and ensheathed by glial cells. Upon exiting through the lamina area, the axons become myelinated with oligodendrocytes. Glaucomatous optic neuropathy (GON), the second leading cause of blindness worldwide, is a neurodegenerative disease characterized by structural damage to the optic nerve and the slow progressive death of RGCs Quigley, . PreviouRGC bodies, which carry the final neuronal output of the retina, receive visual signals from photoreceptors via the two preceding layers of neuronal cells, bipolar and amacrine cells, and transmit that information to the brain. Organelles of RGCs, including the mitochondria, endoplasmic reticulum (ER), Golgi, and cytoplasm, move from their sites of biogenesis in the cell body to distant axons and maintain the cellular environment. The cell body controls cellular organelles, and therefore cell body death influences their movements and functions  remains the main strategy to slow the progression of glaucoma. However, thinning of neurofibers and progression of visual field defects are observed even in eyes in which IOP is reduced, suggesting that disease progression is at least partially independent of IOP, especially in normal tension glaucoma , glutathione peroxidase, and catalase, and has been implicated in RGC body death  exceeds the cellular ability to neutralize and eliminate them. ROS have been implicated as crucial factors in neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases , and experimental glaucoma , an OIt has been reported that RGCs are vulnerable to oxidative stress, especially to SOD1 knockout  , vimentine, and nestin, and thickening of large cells. Upregulation of the intermediate filaments places them in contact with cytoskeletal components and the ECM, enabling them to initiate rapid cytoskeletal remodeling and exert long-term effects on tissue structure. In the retina, there is an additional glial cell type, the Müller cell, which is a specialized radial glial cell that spans the entire thickness of the retina  , and c-Jun, plays a role in NMDA-induced neurotoxicity  receptors, and kainate receptors. These receptors are encoded by at least six gene families: a single family for AMPA receptors ; two for kinate ; and three for NMDA  . IOP elevation causes stimulation of NMDA receptors in RGC bodies. Excessive levels of NMDA receptors cause apoptotic RGC death and subsequent axonal degeneration. Although the mechanism by which the stimulation of NMDA receptors occurs in high IOP-induced RGC death has not been fully elucidated, the inhibition of NMDA receptors may be important to prevent secondary degeneration in the optic nerve.Glutamate was implicated to have a role in GON in an The elimination of excessive glutamate in the retina and vitreous is also important in slowing retinal neurodegenerative disease. The glutamate transporter is the only mechanism for the removal of glutamate from the extracellular fluid in the retina Danbolt, . IncreasEndothelin (ET)-1 is a well-known, potent, long-acting vasoconstrictor peptide in the CNS which reduces blood flow in the retina. There are two distinct G-protein-coupled receptors, the ET A receptor (ETAR) and ET B receptor (ETBR) that mediate the biological effects of ET. These receptors are abundantly expressed in various ocular tissues  is a component of the mitochondrial network and plays a role in the regulation of mitochondria in RGC pathophysiology phenylphosphine borane reducing complex 1 exhibits axonal protection in the optic nerve in a hypertensive glaucoma rat model with increasing BDNF levels , a key intermediate in cellular energy homeostasis, has been suggested to play crucial roles in axonal degeneration in cultured neurons. SIRT1 is a member of a highly conserved gene family (sirtuins) encoding NADTrx has two isoforms, Trx1 and Trx2, located in the cytosol and mitochondria, respectively. Trx1 can be transported anterogradely by axoplasmic transport in the sciatic nerve (Stemme et al., The molecular mechanism of RGC death has been investigated in several laboratories. However, the molecular mechanism of local axonal degeneration in glaucoma has not been elucidated thoroughly. Our laboratory is addressing this mechanism, and its clarification may be important for developing neuroprotective agents Figure . Recent 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.


Several drug delivery systems have been proposed to overcome physiological barriers, improving ocular bioavailability. Systemic routes are seldom used due to the blood-ocular barrier. Novel drug delivery systems based on nanotechnology techniques have been developed to overcome ocular physiological barriers. This non-systematic review suggests the utilization of a transitory blood-ocular breakdown to allow the access of drugs by nanotechnology drug delivery systems via the systemic route. We discuss the possible ways to cause the breakdown of the blood-ocular barrier: acute inflammation caused by intraocular surgery, induced ocular hypotony, and the use of inflammatory mediators. The suitability of use of the systemic route and its toxic effects are also discussed in this article. Most ocular diseases are treated with topical drug applications formulated as solutions, suspensions or ointments. Ophthalmic topical formulations bear some drawbacks related to poor ocular bioavailability due to the many anatomical and physiological barriers existing in the eye . The oraThe blood ocular barrier is composed of the blood-aqueous barrier and the blood-retinal barrier, protecting the eye from entry of toxic substances and maintaining the homeostatic control that underpins the ocular physiology ,5. The bzonulae occludentes contribute to form the bulk of the blood-retinal barrier [The barrier properties of the blood-brain barrier are similar to the blood-retinal barrier. Small protein tracers like microperoxidase 19 kDa) are capable of entering the perioxonal space but not the retina , indicat barrier . The cil barrier . Thus, t kDa are There are some situations when the breakdown of the blood-ocular barrier can occur, such as ocular injuries and ocular hypotonia. Many types of ocular injuries, such as surgical and non-surgical traumas, intraocular inflammation , vascular disorders , systemic disorders  and intraocular tumors  can disturb the blood-ocular barrier, resulting in a variable inward movement of inflammatory cells and blood plasma constituents such as proteins, cytokines and growth factors  Scheme .zonulae occludentes of the ciliary body [zonulae occludentes of the retinal pigmented epithelium (Verhoeff’s membrane) and the retinal capillaries [Ocular hypotony can promote the breakdown of the blood-aqueous barrier, permitting the leakage of serum proteins into the anterior and posterior chambers through the opening of the non-fenestrated endothelial layer of the iris capillaries and the ary body  , liposomes, dendrimers, niosomes, and soluble macromolecules, amongst others. Some examples of these systems are shown in Nanoparticles are spherical particles varying in size from 10 nm to 1 µm, containing a drug molecule or not. They can be prepared using materials of different chemical classes, for example proteins, lipids, polymers or polysaccharides . The actet al. used arginine-glycide-aspartic acid peptide or dual-functionalized poly-(lactide-co-glycolide) nanoparticles to target delivery of anti-vascular endothelial growth factor (VEGF) intraceptor plasmid to choroidal neovascularization lesions in rats. They demonstrated that nanoparticles enable targeted gene delivery to the neovascular rat eye but not the control eye [Nanoparticles can have the ability to overcome physiological barriers, passing even through capillaries, and transporting the drug to specific cells or intracellular compartments by several targeting mechanisms ,32,33,34trol eye .Liposomes are membrane-like vesicles that consist of one or more concentric phospholipid or cholesterol bilayers designed to carry a drug either into the core or into the bilayer. They can have a positive, negative or neutral surface charge, depending on their chemical composition, and they present different properties, such as binding affinity .Light-targeted liposomal delivery was employed after systemic administration of thermosensitive liposomes for the diagnosis and therapy of chorioretinal neovascularization in age-related macular degeneration, showing the possibility of targeting a particular tissue . In thisDendrimers, macromolecular compounds from which a number of highly branched, tree-like arms originate in a symmetric fashion , are conNiosomes are bilayered nonionic surfactant vesicles chemically stable with the ability to carry both lipophilic and hydrophilic drugs. Niosomes are nonimmunogenetic, biodegradable and biocompatible, and show low toxicity due to their nonionic structure .in vivo [Micelles are aggregates of amphiphilic molecules dispersed in a liquid colloid. Some micelar formulations for topical applications seem to be promising, but one of the major disadvantages of micellar formation is the demicellization that happens as a result of dilution upon injection in vivo .®, a marketed treatment for neovascular age-related macular degeneration, is a nanoconjugate of an oligonucleotide (aptamer) with two polyethylene glycols (PEG) that prolongs the half-life of the drug in the vitreous humor [Macromolecules in nanometer dimensions, when present in solution, including virtually any drug, can provide special properties to the drug molecule. Macugenus humor .Our laboratory has pioneered the use of artificially made, solid nanoparticles directed to therapeutic targets, called LDE . This naConstant efforts have been made toward the development of ocular drug delivery systems with various pharmacological properties, such as increased bioavailability, prolonged drug release, compatibility with ocular tissues, ease of use in the form of eye drops causing no blurred vision or irritation and fewer instillations to obtain the intended therapeutic effect. et al. showed that piroxicam nanoparticles of Eudragit RS 100 lead to a better control of inflammatory symptoms compared with a microsuspension of piroxicam alone in rabbits with endotoxin-induced uveitis [There are some interesting studies about topical applications of nanotechnological drug delivery systems for ophthalmic treatments. Adibkia  uveitis .et al. have shown that a hyaluronic acid-chitosan nanoparticles system was successfull in transfection experiments for ocular gene therapy. The results demonstrated that bioadhesive polysaccharides, hyaluronic acid and chitosan nanoparticles were able to provide high transfection levels in cornea and conjunctiva, without affecting cell viability [De La Fuente iability .In vivo experiments showed that, following topical instillation of cyclosporin-A-loaded chitosan nanoparticles into rabbits, it was possible to achieve therapeutic concentrations in external ocular tissues  during at least 48 h while maintaining negligible cyclosporin-A levels in inner ocular structures. Additionally, the chitosan nanoparticles levels were significantly higher than those obtained following instillation of a chitosan solution containing cyclosporin A and an aqueous cyclosporin suspension [Ciclosporin-loaded nanoparticles are also used for the treatment of extraocular disorders, such as keratoconjuctivitis sicca. spension . Table 1Since studies about the use of nanosystems applied systemically for ocular permeation are still scarce, further studies on the development of nanosystems are necessary to accomplish the purpose of ocular delivery of the desired drug in an efficient and safe way. Despite the limitations of the systemic route to ocular drug delivery, researchers have made continuous efforts to develop drug delivery systems to administer drugs systemically in order to clear these barriers. Among the challenges of effective systemic nanodelivery into tissues, the limited penetration across the vascular endothelium and the uptake by the reticuloendothelial system are considerable factors. The current nanodelivery systems depend on transvascular exchange and tissue accumulation, which require high dosages to create large concentration gradients to drive nanoparticles passively across the blood-tissue interface . Neverthet al. have demonstrated that 20 nm gold nanoparticles, administered intravenously, were able to pass through the blood-retinal barrier and were distributed into all retinal layers [The use of nanoparticles that have a higher selectivity for the target tissue is a challenge to be achieved to improve systemic administration. Hence, specific targeting systems are needed to transport molecules to deeper layers of the eye, overcoming the blood-ocular barrier. Recent studies have shown promising results with systemic administration of nanoparticles. Kim l layers . The absl layers . Anotherl layers .The similarities between the blood-brain and the blood-retinal barriers allow the proposal of the hypothesis that there is the possibility of systemically administered nanoparticles also gaining the ability to pass through the ocular barrier. Dalargin, a hexapeptide analog of leucine-enkephalin containing D-alanine, which produces central nervous system analgesia, can cross the blood-brain barrier when conjugated with poly(butylcyanoacrylate) nanoparticles and accumulate in the brain of mice, but not when it administrated without nanoparticles . FurtherThe systemic use of nanoparticles in order to reach ocular tissues is attractive, but more accurate kinetics studies are needed to show the real possibility of their safety and effectiveness.In vitro experiments should have some attributes to be accurate, such as the ability to measure pathological situations separately , and the possibility to represent cell types targeted by nanoparticles through common routes of exposure  [ system) ,70.In vivo biodistribution of nanoparticles is a new and wide field of research. Several studies have been published recently describing the nanoparticle distribution, but, even though the attempts to modify their features, such as size, shape, surface coating and dosing, aiming to enhance treatment effectiveness by extending the blood circulation, nonspecific distribution has thus far been unavoidable. Excretion of nanoparticles is a concern that needs further long-term studies, since a recent study showed the variation in the levels of nanoparticle excretion dependent on time. Lastly, there is no standardized characterization of possible interaction of nanoparticles with proteins and immune cells [ne cells .A list of some examples of pharmacokinetic experimental and clinical studies using nanoparticles is summarized in in vivo. Moreover, systemic use of nanoparticles can induce changes in every organ of the human body, which may cause alterations in blood clinical chemistry, liver function, kidney function, blood cell counts, and other unknown side effects. The evaluation of systemic nanosystem toxicity is a complex task, since the drug-delivery systems have to take into account the toxicity of the polymer used, the drug, and entire system after administration The establishment of a complete risk-benefit ratio of the use of nanoparticles by systemic routes depends on the system configuration, specific materials used, dosage, and frequency of administration, besides the individual patient factors. Any change in these elements can affect the immunological response, cellular uptake, excretion, and, by consequence, the toxic effects elicited by the nanoparticle. et al. have shown the most important factors affecting nanoparticle cytotoxicity assays due to the current lack of standardized protocols, in order to improve the method that could evaluate the toxicity without false-negative or false-positive misinterpretations [New methods and biological models are necessary to increase the research in nanotoxicology. Recent toxicology studies seem to be promising to reach new evaluation standards. Kong etations .et al. have recently published an extensive review about nanoparticle biodistribution and toxicity [in vivo studies to properly investigate the innate and adaptive immune response, excretion over time and toxicity of nanoparticles. Another important point of this study is the need for more systematic in vitro approaches to improve the correlation with in vivo work, and to clarify the real nanoparticle therapeutic action and side effects [Almeida toxicity . The aut effects .et al. have shown the activity, transport and fate of silver nanoparticles at the cellular and organismic level, in conjunction with the available methods of nanoparticle characterization [Stensberg rization . They prrization .et al. have shown that the association of chemotherapeutic agents, such as carmustine, etoposide, and paclitaxel, with artificial lipid nanoemulsion (LDE) pronouncedly reduces the toxicity of those drugs while preserving or even increasing the antineoplastic activity, as shown in tumor-implanted rats and mice [Maranhão and mice ,79 and iand mice ,44,45,74et al. have shown that budesonide-PLA microparticles administered periocularly in rabbits remained at the periocular site of injection for a long time without causing local side effects, such as elevation in intraocular pressure, lens opacity or blood chemistry changes [et al. have demonstrated that periocular administered celecoxib-PLGA particles were useful sustained drug delivery systems for inhibiting diabetes-induced elevation in PGE2 and VEGF without inducing fibrotic reactions at the site of administration or damage to the retina [There are recent reports regarding the toxicity concerns of the use of nanoparticles for ophthalmic purposes. Escobar  changes . In addie retina . The systemic use of nanoparticle drug delivery systems for ophthalmic treatments is rare, equally scarce are the corresponding toxicological studies regarding this route of administration.The breakdown of the blood-ocular barrier is an attractive manner to allow the penetration of systemically applied drugs into the eye. We hypothesize that the breakdown of the blood-ocular barrier—that may occur in acute inflammation following intraocular surgeries, induced ocular hypotony and controlled use of inflammatory mediators—could allow the use of drugs carried in targeting nanosystems administered by the systemic route for ophthalmic purposes.Blood-ocular barrier breakdown can occur in some situation, such as acute inflammation caused by intraocular surgery, induced ocular hypotony, and the use of inflammatory mediators.The majority of the intraocular surgical procedures may cause a breakdown in the blood-ocular barrier, leading to increased protein content in the aqueous humor and edema of the sensory retina, due to the induced inflammation . The speThe sequence of events that follow ocular trauma includes vasodilatation, increased blood flow and hyperemia, increased permeability of blood vessels, edema, increased tissue pressure (disrupted blood-ocular barrier), and the presence of inflammatory cells .Almost all morphological, physiological and metabolic responses to trauma may be attributed to the synthesis and release of endogenous mediators, such as prostaglandins , leukotrThe mean intraocular pressure is described statistically to be around 15.9 ± 2.9 mmHg . TherefoTransient hypotonia, when it is resolved in fifteen to thirty days, is relatively common in clinical practice and usually presents no functional sequelae . On the Currently, the only possible way to induce transient ocular hypotony is by performing a paracentesis. Paracentesis is widely used in ophthalmic microsurgery  and may Induced ocular hypotony could only be considered if the paracentesis could be performed in a controlled way, with a minimal duration and extent. The leakage of aqueous through corneal paracentesis should be quick enough to decrease the intraocular pressure without causing the anterior chamber to collapse. The only justification to perform a paracentesis to induce a transitory ocular hypotony, causing the breakdown of the blood-ocular barrier, would be the availability of an effective drug that would reach long-term therapeutic levels, requiring maybe one or two procedures per year. Drugs with a short life could not be used in this scenario, since repetitive paracentesis could be associated with an unacceptable risk of infection and other potential complications. Controlled experiments investigating hypotony are scarce. Nevertheless, the occurrence of the breakdown of the ocular-blood barrier could be achieved by the induction of an iatrogenic, surgically controlled hypotony. Thus, the hypotony became a target ocular pressure through an induced condition to allow the opening of the natural vascular fenestrations into the eye. The risk of infection from a paracentesis is possibly lower than that of an intravitreal injection that penetrates into the back of the eye. However, this invasive procedure limits its use, unless one or few intravascular injections are enough to achieve the intended therapeutic response. Concomitantly, there are no current available hypotensive topical drugs that permit a potent decrease of the intraocular pressure in order to avoid a surgical procedure. Furthermore, the available systemic hypotensive drugs are nonselective and the aggressive side effects limit their current use. A model of chronic hypotony in an animal model has already been described . The devInflammatory mediators have been studied mainly in experimental uveitis models ,106,107,et al. have demonstrated the inflammatory mediators during T-cell mediated ocular inflammation, such as chemokines and their receptors and cytokines, besides indicating the cytokines as potential therapeutic targets [et al. have shown that TNFα could be a therapeutic target for the prevention of the progressive blood-retinal barrier breakdown, retinal leukostasis, and apoptosis associated with diabetic retinopathy [in vivo, few studies have evaluated the morphological and functional responses to inflammatory mediators in the eye [Foxman  targets . The acc targets . Inflamm targets . Huang einopathy . Althoug the eye . N-formylmethionyl-leucyl-phenylananine (FMLP) and chemotactic mediators were injected into the rabbit cornea, vitreous, and skin in order to induce a reaction resembling the “Arthus phenomenon” [et al. have demonstrated that topically used epinephrine can induce the partial disruption of the blood-ocular barrier due to the release of prostaglandins and other cyclooxygenase products [et al. have demonstrated that bradykinin agonist RMP-7 could, experimentally, enhance the permeability of the blood-ocular barrier [Interestingly, ocular inflammation has also been experimentally induced through the use of synthetic mediators. The complement component C5a, nomenon” . Miyake products . Elliot  barrier . This clRadix puerariae that has been investigated as a self-microemulsifying drug system. Deng et al. have shown that puerarin can penetrate the blood-ocular barrier accessing aqueous humor and vitreous humor after systemic administration [Inflammatory mediators are not the only way to promote the breakdown of the blood-ocular barrier. Puerarin is an isoflavonoid derived from stration . This phet al. have shown that Fingolimod (FTY720), a drug used in FDA phase III human multiple sclerosis trials, prevents T-cell migration to inflammatory sites by decreasing expression of the sphingosine-1 phosphate receptor generally required for egression from secondary lymphoid tissue [In the same way, recent studies have also demonstrated the possibility of rapid suppression of ocular inflammation, leading to restoration of the blood-ocular barrier. Copland d tissue . Fingolid tissue . Thus, tTherefore, the breakdown of the blood-ocular barrier could also be obtained by deliberate utilization of inflammatory mediators. However, the deliberate use of specific inflammatory mediators would only be justified based on this hypothesis, if the topical route was utilized to promote the transitory breakdown of the blood-ocular barrier. After the topical application of the inflammatory drug, the systemic administration of the specific nanosystem would be held, followed by the topical pharmacological neutralization of the inflammatory mediator previously applied, as soon as the delivery rate time of the systemic drug was concluded in order to yield therapeutic drug levels in ocular tissues.in vivo, the aqueous flare by measuring the scatter of a laser beam that is scanned into the anterior chamber. This reproducible and noninvasive procedure designed to measure the integrity of the blood-aqueous barrier is performed with a flare meter and is called tyndallometry [When the aqueous-blood barrier is broken down, there is an inward movement of plasma constituents and cells to the anterior chamber. Since 1988, it is possible to quantify, llometry ,123,124.Several methods of examination are currently used to evaluate the function of the blood-retinal barrier . VitreouThus, according to our proposition, the breakdown of the blood-ocular barrier could be monitored by the quantification of the aqueous flare and/or vitreous flare, which would help to indicate the correct time of the administration of the desired systemic medication.In summary, there are several variables that can occur in the three types of breakdown of ocular barriers, namely, in eye diseases or ocular surgeries—the intensity of inflammatory reaction; in ocular hypotony—its intensity and duration; and in the use of inflammatory mediators—the dose and specific pharmacological characteristics of the drugs. Thus, it is not currently possible to designate a preferred potential method of breakdown of the blood-ocular barrier, since the intensity and duration of the breakdown of the blood-ocular barrier are parameters highly dynamic due to the wide range of pathophysiological variables. The current absence of reliable and safe methods to induce the rupture of the blood-ocular barrier is also another important concern to establish dependable means to achieve this hypothetical goal. The current status of use or investigation of each types of breakdown of ocular barriers is summarized in The proposition presented in this article refers to the possibility of taking advantage of the breakdown of the blood-ocular barrier to use the systemic route as an alternative to access intraocular tissues. Monitoring this breakdown is currently possible, indicating the correct time to use intravascular medication. Besides the natural enhanced permeability of the blood-ocular barrier in ophthalmic surgeries, we suggest two possible ways to induce a transient, controlled breakdown of the blood-ocular barrier, both with limitations that need to be overcame.The induced breakdown of the blood-ocular barrier would be an interesting and acceptable option to facilitate the ocular access of the systemically administered nanosystem, if a topical route is chosen to administer pharmacological agents that induce it, and likewise, other topical agents are used to reverse it after the therapeutic effect is achieved. Apart from the invasive fact of the intravenous administration of the nanosystem, only non-invasive additional topical methods would be plausible to be applied concurrently. Moreover, the reversion of the breakdown of the blood-ocular barrier, when induced, would be achieved with the use of topical anti-inflammatory or anti-hypotensive drugs. The utilization of short half-life inductive drugs would be essential to carry out a self-limiting process. The pharmacological evaluation of drugs injected into the bloodstream aiming to permeate the intraocular tissues is necessary to establish their safety, especially if formulated with nanocarriers that still require additional pharmacodynamic and pharmacokinetic studies ,133. TheIn summary, the availability of new effective and safe ocular delivery systems remains a major challenge for pharmaceutical researchers. The development of methods to induce a controlled, safe and transient breakdown of the blood-ocular barrier could be a novel approach to allow the access of systemically injected drugs to the internal parts of the human eye. The ideal nanoparticle system for systemic use in order to reach the intraocular tissues is not presently available, nor is there any evidence of the facilitation of access of these nanosystems with the transient breakdown of blood-ocular barriers. However, previous studies and pathophysiological events mentioned in this article encourage us to propose this hypothesis with the aim to conceive the basis for the possible development of a viable system, allying nanoparticles properties with the facilitated permeation to intraocular tissues by taking advantage of a natural or induced breakdown of the blood-ocular barrier.The intravenous route could be reconsidered as a good alternative to complement the ophthalmic therapeutics currently in use. As the ability to deliver drugs and other compounds across the blood-ocular barrier via the systemic route for therapeutic purposes is not reached, further studies using nanoengineered technologies and focusing on the development of nanosystems with minimal toxicity and enhanced efficacy are necessary in order to expand the knowledge of the ways to selectively and efficiently overcome the blood-ocular barrier. Moreover, more detailed studies on the normal physiological and pathological conditions of the eye are essential to yield a consistent understanding of nanosystem characteristics under different circumstances in the target organ. In addition, methods to take advantage of the natural or induced breakdown of blood-ocular barriers can complement the nanotechnological properties to get easier access to nanomedicines administered systemically and targeted to the hitherto almost impervious areas of the human eye.


Hepatoid adenocarcinoma is a rare variant of extrahepatic adenocarcinoma which behaves like hepatocellular carcinoma in morphology and functionality.We present a rare case of hepatoid adenocarcinoma of the gallbladder which invades deeply the liver bed, in a 59-year-old woman. Histologically, most of the mass in the gallbladder was composed of cells with eosinophilic cytoplasm arranged in a trabecular pattern, which resembled hepatocellular carcinoma. The main differential diagnosis was hepatocellular carcinoma with invasion into the gallbladder. The gallbladder origin of the hepatoid adenocarcinoma was verified by the presence of foci of conventional adenocarcinoma, the recognition of high-grade dysplasia in the adjacent epithelium and the absence of cirrhosis. Hepatoid adenocarcinoma (HAC) is a variety of adenocarcinoma associated with hepatic differentiation. The most frequent site of this carcinoma is the stomach. Only a few cases of HAC of the gallbladder have been reported .We present a rare case of HAC of the gallbladder which, to the best of our knowledge, represents the eighth reported case in the English literature.A 59-year-old woman presented with abdominal pain and complains about general fatigue.Ultrasonography and computed tomography revealed a solid mass within the gallbladder, which infiltrates the adjacent liver without signs of cirrhosis Figure . LaboratCholecystectomy with resection of the involved liver subsegments, and regional lymph node dissection were performed.Gross examination revealed a white and yellow solid tumor, measuring 11 × 5 cm, occupying the body of the gallbladder and invading the liver bed.Microscopically, the tumor was composed mainly of "hepatoid cells", which were characterized by eosinophilic cytoplasm, enlarged nuclei, prominent nucleoi, and arranged in nests or proliferated in a trabecular and solid pattern. A few sporadic foci of adenocarcinoma were mixed with the hepatoid component. Bile plugs were recognized intracellularly and foci of high-grade dysplasia were observed in the gallbladder epithelium adjacent to the tumor Figure . The tumImmunohistochemically, the carcinoma with hepatoid features was diffusely stained for α fetoprotein (AFP), HepPar-1 Figure  and HepaOn the basis of histologic and immunohistochemical findings, the diagnosis of HAC of the gallbladder was reported. Three months postoperatively, the patient is still alive without any further therapeutic intervention.Hepatoid adenocarcinoma (HAC) is a rare variety of extrahepatic adenocarcinoma, consisting of foci of both adenomatous and hepatocellular differentiations which behave like hepatocellular carcinoma (HCC) in morphology and functionality .HAC was proposed as a specific type of primary gastric cancer by Ishikura et al. in 1985 .Since then, carcinomas with hepatoid differentiation have been described in a variety of anatomic locations including the lung, kidney, female reproductive tract, pancreas, and gallbladder, the stomach being the most prevalent site .Typically, an elevated level of serum alpha-fetoprotein (AFP) is detected, although normal levels have also been reported  and cleaAs mentioned above, HAC was named because of its characteristic histopathological features, suggesting hepatoid differentiation resembling HCC. Generally, the tumor is composed mainly of large or polygonal cells with abundant eosinophilic cytoplasm, and it proliferates in a solid or trabecular pattern, although it sometimes shows medullary proliferation .Furthermore, some parts which show papillary or tubular structures are often observed in the lamina propriae and/or submucosal areas . The recImmunohistochemically, many liver specific proteins, including AFP, albumin, transferin, PIVKA (protein induced in the absence of vitamin K), and alpha-1-antitrypsin, have been detected in the tumor cell cytoplasm. Of them, AFP is generally considered important for the diagnosis. However, it is very important to note that AFP positivity is not necessarily diagnostic of HAC, because not all HAC are associated with AFP overproduction. Therefore, the diagnosis of HAC should be made essentially by the histological features of the tumor [In addition, focal positivity with Keratin7 suggested the presence of an adenocarcinoma. CD10 positivity indicated canalicular differentiation and thus hepatocellular origin .The main differential diagnosis is HCC with invasion into the gallbladder. When HAC of the gallbladder invades the liver deeply (as in our case), differential diagnosis of these two tumours can be very difficult . To aid We present a rare case of hepatoid adenocarcinoma of the gallbladder which invades deeply the liver bed, in a 59-year-old woman. The main differential diagnosis was hepatocellular carcinoma with invasion into the gallbladder. The gallbladder origin of the hepatoid adenocarcinoma was verified by the presence of foci of conventional adenocarcinoma, the recognition of high-grade dysplasia in the adjacent epithelium and the absence of cirrhosis.A written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.SE, SC and AG formulated the manuscript, TB and NG preparated the histological figures, AA and MBA provided the clinical history and clinical figures, HM and MK participated in the design of the study. All authors read and approved the final manuscript.


The plastid signal was originally defined as a pathway that informs the nucleus of the chloroplast status and results in the modulation of expression of nuclear-encoded plastid protein genes. However, the transfer of chloroplast genes into the nuclear genome is a prerequisite in this scheme, although it should not have been established during the very early phase of chloroplast evolution. We recently demonstrated in a primitive red alga that the plastid-derived Mg-protoporphyrin IX activates nuclear DNA replication (NDR) through the stabilization of a G1 cyclin, which coordinates the timing of organelle and NDR. This mechanism apparently does not involve any transcriptional regulation in the nucleus, and could have been established prior to gene transfer events. However, a retrograde signal mediating light-responsive gene expression may have been established alongside gene transfer, because essential light sensing and regulatory systems were originally incorporated into plant cells by the photosynthetic endosymbiont. In this short article, we discuss the origins, early days and evolution of the plastid retrograde signal(s). Eukaryotic cells contain various organelles, and continuous monitoring of and responding to their status are critical functions of the nucleus for managing cell integrity. Thus, eukaryotic cells have evolved intricate signaling mechanisms from the nucleus to organelles as well as from organelles to the nucleus . Among sSince the majority of chloroplast proteins are encoded by the nuclear genome and targeted into chloroplasts after translation in the cytoplasm , communiIn plant cells, three independent organelles – chloroplasts, mitochondria, and the nucleus – each contain their own genome. While only one nucleus is usually present in a cell, dozens of chloroplasts and mitochondria are found in most land plant cells. The proliferation cycle of plant cells is defined based on the S and M phases, which correspond to NDR and cell division, respectively, as in other eukaryotic cells. Similarly, chloroplasts and mitochondria proliferate by replication of their own genomes and subsequent division, and are inherited by daughter cells through division of the cytoplasm. However, abundantly present chloroplasts and mitochondria asynchronously proliferate throughout the cell cycle phases of higher plant cells , and notArabidopsis. The authors suggested that some retrograde signal from chloroplasts might be deeply involved in the cell cycle phase transition.Microscopic analyses of ODR and NDR during leaf and root development have shown that ODR is extensively activated during the early phase of the development of these organs, while NDR appears to occur after the ODR activation phase . These oCyanidium caldarium and Cyanidioschyzon merolae, which contain only one chloroplast and one mitochondrion per cell. In these cells, ODR in the chloroplast and mitochondria occurs after the onset of the cell cycle, and NDR always occurs after ODR. Particularly unique among the unicellular red alga, Cyanidioschyzon merolae performs binary fission, and the division of each organelle occurs only once in a cell cycle  of ubiquitin ligase in darkness, which results in ubiquitination and degradation of Cyclin1 by proteasome and prevention of NDR. Light illumination activates the cell cycle and prompts entry into the S phase, however, it is ODR not NDR that is primarily activated by the light. Activation of ODR somehow results in accumulation of Mg-protoporphyrin IX (Mg-ProtoIX) very likely in the cytosol, and subsequent interaction of Mg-ProtoIX with Fbx3 prevents the ubiquitination and degradation of Cyclin1, which results in Cyclin1 accumulation, Cyclin1/CDKA activation, and finally NDR activation. In this working model, Mg-ProtoIX is produced only in the chloroplast, and thus can be considered a bona fide retrograde plastid signal. In the case of nuclear gene expression control, Mg-ProtoIX has long been suggested as a plastid retrograde signal . The mechanism for the ODR–NDR coupling described above requires basically only one specific protein, Fbx3, to be established as an additional cytoplasmic component. Providing that the evolution of Fbx3 adequately explains the chloroplast-to-nucleus DNA replication coupling, this mechanism could have been established at a very early phase of chloroplast evolution because of its extreme simplicity. In addition, it should be noted that this mechanism does not require any gene transfer events from the chloroplast to the nucleus. Since the well-known plastid retrograde signals are related to the transcriptional regulation of nuclear genes encoding chloroplast-targeted proteins, gene transfer events are prerequisite for their existence. The establishment of endosymbiosis would have been prior to such gene transfer events, and our recent findings may have supported the stabilization of the transition states. A similar coupling mechanism has also been suggested to be present in vascular plant cells . In addition, gene transfer from the chloroplast to the nuclear genome has gradually occurred. Therefore, in a later phase of chloroplast evolution, light signals should have become transmitted into the nucleus to establish light-responsive coordinated gene expression as a photosynthetic eukaryote. During the subsequent evolution, plant-type photoreceptors and light signaling pathways were likely established.Before endosymbiosis, an ancient eukaryotic cell with a nucleus and mitochondria should have some, but not so highly complicated light-responsive regulation of gene expression because it was unnecessary to respond to the light environment as a non-photosynthetic organism. Conversely, cyanobacteria, which require oxygenic photosynthesis for their survival, should have a set of photosensory and photoregulatory mechanisms. Just after endosymbiosis, during the early stages of chloroplast evolution, light-responsive gene expression derived from cyanobacteria must have been completed inside the chloroplast (symbiont), and the regulation of nuclear gene expression should have been irrespective of the light conditions. However, mutual coordination of various cellular parameters, including metabolic fluxes, must have become crucial between the chloroplast and the host cell  could be transmitted into the nucleus by some retrograde mechanisms. As a candidate mediator for chloroplast-to-nucleus signaling in vascular plant cells, Mg-ProtoIX  was examined to determine whether it could also regulate nuclear gene expression in Cyanidioschyzon merolae. As is consistent with recent negative reports for this signaling molecule , such as the two-component system inherited from cyanobacteria, might also have been responsible for light-dependent nuclear transcription via an unidentified chloroplast-to-nucleus retrograde signaling pathway(s). The establishment of a complex coordination mechanism for nuclear and organelle gene expression in response to light environments likely required a long time period. However, light-dependent nuclear transcription itself might have evolved alongside gene transfer to the nucleus. This retrograde signal(s) could be partly derived from chloroplast photosensory components including the two-component system, as well as an event of photosynthetic electron transfer. In any case, during early phases of chloroplast evolution, we expect that the development of fundamental crosstalk between the nucleus (host) and the chloroplast (symbiont) was essential to effectively respond to light environments, and to coordinate DNA replication and transcription of both genomes.In bacteria, fungi, and plants, it is well-known that two-component regulatory systems are involved in the sensing of, and regulatory responses to, various environmental stimuli. This system is normally composed of sensory histidine kinases (HKs) that perceive environmental signals and response regulators required for output regulation such as transcriptional regulation . There aectively . They arectively . Since tThe 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.