The brackish Baltic Sea hosts species of various origins and environmental tolerances. These immigrated to the sea 10,000 to 15,000 years ago or have been introduced to the area over the relatively recent history of the system. The Baltic Sea has only one known endemic species. While information on some abiotic parameters extends back as long as five centuries and first quantitative snapshot data on biota (on exploited fish populations) originate generally from the same time, international coordination of research began in the early twentieth century. Continuous, annual Baltic Sea-wide long-term datasets on several organism groups  are generally available since the mid-1950s. Based on a variety of available data sources , the Baltic Sea, incl. Kattegat, hosts altogether at least 6,065 species, including at least 1,700 phytoplankton, 442 phytobenthos, at least 1,199 zooplankton, at least 569 meiozoobenthos, 1,476 macrozoobenthos, at least 380 vertebrate parasites, about 200 fish, 3 seal, and 83 bird species. In general, but not in all organism groups, high sub-regional total species richness is associated with elevated salinity. Although in comparison with fully marine areas the Baltic Sea supports fewer species, several facets of the system's diversity remain underexplored to this day, such as micro-organisms, foraminiferans, meiobenthos and parasites. In the future, climate change and its interactions with multiple anthropogenic forcings are likely to have major impacts on the Baltic biodiversity. The Baltic Sea is very shallow, with the maximum depth of 460 m and mean depth of 60 m. It was formed after the last glaciation  and has undergone remarkable shifts in basic physicochemical characteristics during a geologically short time. The contemporary “ecological age” of the Baltic Sea is about 8,000 years  is one of the largest brackish water areas in the world, with a surface area of about 4.2×106 km2 and about 85 million people in situ  and on land .The Baltic Sea is composed of 10 regions , which could be aggregated into three macrolevel systems—the Transition Area, Baltic Proper, and Large Gulfs . Nine co3 almost equals the volume of saline water inflows from the North Sea. The major source of freshwater inflow to the Baltic comes via the Gulf of Bothnia, Gulf of Finland, and the Gulf of Riga. The upper water layer is separated from the more saline deepwater layer by a permanent halocline located at depths of about 70–100 m. There is no halocline in the shallower areas in the northeastern Baltic—for example, the Gulf of Bothnia and Gulf of Riga. A strong permanent halocline and seasonal thermocline in summer substantially hamper vertical mixing of water column, which induces formation of oxygen-depleted zones in several locations, essentially in the deep areas of the central Baltic. The water temperature regime is substantially influenced by winter severity. The first sea ice typically forms in November in the Bothnian Bay and remains there until mid-May. Duration of ice coverage decreases from north to south  from the North Sea through the Danish Straits and riverine (freshwater) inflows, which are influenced by precipitation A notable feature of the Baltic hydrography is the presence of a generally east-west and north-south salinity gradient and salinity stratification of the water column, as already indicated above. The complex hydrographic regime of the Baltic, its short, but dynamic evolution, and the human intervention resulted in the biota consisting of species of various origins and environmental tolerances that have immigrated or been artificially introduced to the area over the relatively recent history of the system. These are marine and freshwater species, migratory species, and glacial relicts. Representatives of these categories have different environmental preferences and the composition of communities therefore varies greatly in different regions of the Baltic Sea, depending primarily on salinity, water temperature, oxygen content, and nutrient concentrations.Hydrographic measurements were started in the eighteenth century, while measurements at coastal stations and on lightships were initiated in several Baltic countries in the 1890s and regular offshore observations started in the early twentieth century Dana and Gunnar Thorson (Denmark), Maria S. Merian, Prof. Albrecht Penck and Alkor (Germany), Aranda (Finland), Vejas (Lithuania), Baltica and Oceania (Poland), and Argos (Sweden).There is at least one major marine biology and fisheries institute or research laboratory in each of the countries surrounding the Baltic Sea. Several of them (including their predecessors) have over 50 years of history. Most of the Baltic countries have several research vessels. The larger vessels include, among others, The only direct activity of the Census of Marine Life program in the Baltic Sea to create new research network and datasets, and therefore contribute substantially new knowledge, was the History of Marine Animal Populations (HMAP) project. During this project, cooperation between historians and ecologists was initiated and actual research in this interdisciplinary field started. This contributed significantly to the present understanding of the Baltic Sea  in previous centuries. In addition, Baltic scientists have taken part in other Census projects, such as the Census of Marine Zooplankton (CMarZ), Natural Geography in Shore Areas (NaGISA), Arctic Ocean Diversity (ArcOD), HMAP, History of Nearshore Biodiversity (HNS), Census of the Diversity of Abyssal Marine Life (CeDAMar), and Continental Margin Ecosystems on a Worldwide Scale (COMARGE).In this study, we summarize the currrent state of knowledge of the biodiversity of the entire Baltic Sea, how this knowledge has progressed through time, and how Baltic biodiversity is influenced by hydrographic conditions, in particular, salinity as well as human impacts. As part of our synthesis, we update species lists and richness data for different organism groups and sub-regions by incorporating new information generated in recent years, based on continued taxonomic monitoring, specific targeted research and application of new molecular genetic methodologies. In addition, we provide original and yet unpublished biodiversity estimates both for relatively well-studied as well as less investigated organism groups. This knowledge should contribute to assessments of how natural and human impacts affect Baltic biodiversity, the development of biodiversity-based indicators of ecosystem status and health, a stronger taxonomic basis for understanding links between biodiversity and ecosystem functioning, and new historical baselines for management of the living marine resources.Substantial samples of phytoplankton from the Baltic Sea have been collected within the framework of national and international monitoring programs. Phytoplankton monitoring in the Baltic Sea is currently to a large extent coordinated through the HELCOM (Helsinki Commission) COMBINE  protocol . This enChanges in methodology constitute the main problem for the comparability of hundred-year-old data with recent data The history of hydrobotanical research in the Baltic Sea area dates back centuries, but even now data and comprehensiveness of information about distribution of phytobenthos communities in the area are far from sufficient. Monitoring programs, including a phytobenthos component, exist in all Baltic Sea countries, but most of these programs are targeting not changes of biodiversity itself but effects of human impact, for example eutrophication around known hot spots. Those monitoring programs, techniques used, and indicators or parameters measured are usually country or habitat specific. Few attempts to unify the monitoring methodology have been made , but so far no real intercalibration or harmonization of those techniques has been carried out. Several initiatives are conducted to coordinate the phytobenthos monitoring and mapping methods in the Baltic Sea area in several international programs . Huge effort is currently also directed toward development of efficient and reliable techniques for large-scale spatial mapping of distribution of phytobenthos communities and key species. Use of modern technology, such as underwater video, geographic information system (GIS) modeling, remote sensing, and side-scan sonar is being tested. Large-scale inventory programs have been launched in several countries  which all use the results of these new technological developments.The quantity and completeness of published data on zooplankton diversity in different areas of the Baltic Sea vary significantly. In general, biodiversity of estuarine and shallow coastal ecosystems is described better Illustrated atlases with drawings and photos of live and preserved planktonic organisms are available for the Baltic Sea. A recent series of zooplankton atlases of the Baltic Sea http://nemys.ugent.be) or detailed taxonomic publications. The current overview is based on data contained in the European Register of Marine Species (www.marbef.org) and on a literature survey and unpublished information. The major meiozoobenthic phyla are discussed in this paper in a taxonomic sequence consistent with that of Higgins and Thiel Meiozoobenthos is operationally defined as benthic invertebrates that pass through the sieves with 0.5 mm (or 1 mm) mesh size and are retained on those with 0.044 mm (or 0.063 mm) meshes Numerous literature sources were analyzed for information on macrozoobenthos distribution in the Baltic Sea. Other relevant information was captured from the IfAÖ Autecological Atlas http://www.marbef.org/data/erms.php). The taxonomic nomenclature used in the historical studies was revised before including the species in the analysis. For some species or data entries, the taxonomic assignment was highly doubtful, or not possible, when following present-day taxonomical concepts. In these cases the data were excluded. Some difficult taxonomic groups  are likely to be underrepresented because of the different expertises of the authors. At the same time, special consideration is devoted to freshwater species, including those found in the brackish and freshwater bodies adjacent to the Baltic Sea.All macrofauna species (taxon units) were identified to the lowest taxonomic level possible. The nomenclature was checked following the European Register of Marine Species . Unique ranges of taxon units were filtered out for each of the defined subregions.Monitoring of the commercially most important species  is carried out in all Baltic countries according to guidelines and procedures agreed in forums such as the International Council for the Exploration of the Sea (ICES) and the European Union . The monNerophis ophidion) are rarely caught, as are the cold-water preferring glacial relict species Information on all other fish is being obtained within coastal fish monitoring programs. These are in place in all Baltic countries, covering different parts of the Baltic Sea and various environmental conditions. The time series cover up to 22 years of annual monitoring. Fish sampling methodology is elaborated in detail and generally unified across the countries The biodiversity- and ecosystem-related research activities have generally followed a three-step plan, as identified and developed in global and Baltic HMAP workshops In addition, an important initial task was to create a dialogue among historians, archaeologists, paleoecologists, and fisheries and marine mammal ecologists. The main sources of information that were considered as potentially useful for addressing Baltic-HMAP objectives include (1) Quantitative sources such as annual tax accounts, customs rolls, household accounts, commercial catches, and scientific materials on the Baltic ecosystem and its fish populations; (2) Qualitative sources including fishing commissions' records, reports from government officers, public grants records, private sources and topographical literature; (3) Archaeological documentation, which consists mainly of subfossil fish bones and evidence of fluctuations in the productivity of the marine biotope.Baltic HMAP covers a broad range of species and populations of different origins characteristic for the Baltic Sea ; these species have different life history traits and environmental preferences in as many subsystems as possible. However, during the course of the project, the limitations of the availability of historical data became evident, and consequently, the main focus narrowed to only a few major marine species, for which the most extensive data could be recovered with the available resources. These species were cod  and herring, which have several distinct populations in the Baltic Sea.Quantitative approaches, including standard stock assessment models were applied for extending the knowledge of stock dynamics of the eastern Baltic cod in the twentieth century The main source of information on nonindigenous species in the Baltic Sea area is the Baltic Sea Alien Species Database 6 , the documented total number of cyanobacterial, phytoplankton, zooplankton, phytobenthos, zoobenthos, fish, marine mammal, and bird species as well as vertebrate parasites inhabiting the Baltic Sea is at least 6,065. Importantly, this estimate contains several yet unpublished sources for several both relatively poorly and well-studied organisms groups . However, the real estimate is most likely substantially higher as the current knowldege-level on several taxa and/or organism groups  appears to be relatively incomplete. Moreover, the estimated number of species of heterotrophic bacteria could be as high as up to 10see also . The folChecklist of Baltic Sea Phytoplankton Species comprises over 1,700 recorded species Knowledge of the taxonomy and distribution of Baltic Sea phytoplankton has increased considerably over the past three decades. The By the identified sub-regions, phytoplankton species diversity is the highest  in the Gulf of Finland and the overall sub-regional biodiversity at low salinity conditions (below 10) is about 13% lower than that in the high salinity conditions in Kattegat  At the present time, 442 species of macroalgae While the total number of phytobenthic species is rather high for the whole Baltic Sea area, the sub-regional diversity is often much lower . For insFucus radicansHELCOM Lists of Threatened and/or Declining Species and Biotopes/Habitats in the Baltic Sea AreaFucus vesiculosus and Furcellaria lumbricalis).The Baltic Sea has one known endemic phytobenthic species – Only a small number of species have significant roles in the ecosystem, providing, along with their physical structure or physiological performance, the necessary environmental support for other species. These species are able to modify the environment physically and structure the habitat to provide suitable conditions for a large number of species. In the Baltic Sea such special, structuring species are usually large perennial macroalgae on hard bottoms and phanerogams and charophytes on soft bottoms.Fucus vesiculosus, Furcellaria lumbricalis) and soft  bottoms. The decline of those communities has been described as a long-term process with duration of decades Recent trends in the phytobenthos biodiversity are described in the latest report published by HELCOM The overall species richness of micro- (20–200 µm), meso- (0.2–20.0 mm), and macrozooplankton (larger than 20 mm) in the whole Baltic Sea is 1199 species with open Baltic hosting 1031 and estuaries 168 species The sub-regional diversity of heterotrophic plankton may be best illustrated by flagellates . The higStrombidium, Strobilidium, Lohmaniella) and tintinnids – ciliates with lorica  and Litostomatea  are also rather abundant According to present-day knowledge, the most species-rich component of the Baltic Sea zooplankton is microplankton (ciliates and rotifers). The greatest overall diversity was registered in ciliates, among which 166 species are holoplanktonic, while about 650 benthopelagic species inhabit presumably the near-bottom layers and shallow waters ca e.g., . HymenosSynchaeta spp., Polyarthra spp.) and Brachionidae . These rotifers contribute significantly to the total zooplankton biomass and production, also in the open Baltic waters  in the coastal ecosystems e.g., . Rotiferc waters .Pseudocalanus spp., Temora longicornis, Acartia spp., and cladocerans Evadne nordmanni are the most important taxa in the open Baltic in biomass and production. Ctenophores Pleurobrachia pileus and copepods Eurytemora affinis play a minor role, while appendicularians Fritillaria borealis, Polychaeta larvae, cladocerans Bosmina spp., Podon spp., copepods Centropages hamatus and Bivalvia larvae range in between  dominate.There are about 40 mesozooplankton species that regularly occur in the open Baltic Sea with high abundance, 10–12 of which are dominating taxa Keratella species and several other rotifers , as well as the cladocerans Bythotrepes longimanus into the Northern Baltic Proper Pseudocalanus were substituted by Acartia species, while in the northern parts of the Baltic Proper, the dominance of Acartia spp. was replaced by the brackish-water E. affinis . At least 569 species have been identified in the Baltic meiobenthic communities, although the actual number is probably much higher (see below). In the Baltic Sea, meiobenthos is quantitatively prominent, particularly in areas below the halocline where the abundance and biomass of the macrobenthos decline sharply because of hypoxia and anoxia e.g., . On the Halammohydra octopodides, so far found living in coastal sandy sediments off the southwestern and southern Baltic coast Protohydra leuckartiChlorohydra viridissima, present in the Gulf of Riga The phylum Cnidaria is represented in the Baltic Sea by three species: Turbellarians are a common platyhelminth grouping in the Baltic meiobenthos, particularly in sublittoral sandy bottoms off the southern Baltic coast e.g., , where tThe nematodes are ubiquitous members of the meiobenthos and dominate in meiofaunal assemblages in most benthic habitats, irrespective of sediment type, depth, and oxygen situation Musellifer profundus, a species found so far at a few deep localities in the Baltic Proper Knowledge on the species richness of the Baltic gastrotrichs derives from only two publications In marine habitats, rotifers are usually associated with coastal sandy sediments. However, knowledge of rotifers occurring in the Baltic is scanty. The major accounts of rotifer species richness in the Baltic were provided in the 1940s through the 1960s Echinoderes levanderiPycnophyes maximusAn exclusively meiobenthic phylum, kinorhynchs are fairly frequently encountered in deeper parts of the Baltic Proper As no special study of meiobenthic oligochaetes has been carried out in the Baltic, it is highly probable that meiobenthic-sized representatives of the taxon are listed together with their macrobenthic counterparts. So far, lists of representatives of those families in the Baltic Sea contain about 20 species Aquatic representatives of the meiobenthic phylum Tardigrada are commonly encountered in the Baltic in sandy habitats, both littoral (beaches) and sublittoral. So far, three known species have been reported The total number of ostracod species recorded in the Baltic is 40, making those crustaceans one of the most species-rich taxa among the meiobenthos. Representatives of this taxon are found in various benthic habitats, except for deeper areas stressed by oxygen deficiency. In some parts of the Baltic, ostracods may account for most of the total meiobenthic biomass, constitute an important link in pelagic-benthic couplings, and are efficient bioturbators Because of the intensity of the research effort, the total number of harpacticoid species in the Baltic is quite high and totals 82. Harpacticoid assemblages have been identified in many areas and have been relatively well studied, particularly in the southern Baltic Halacaroid species are exclusively meiobenthic acarids that are fairly common in sandy sublittoral areas of the Baltic status quo ante for comparative studies in recent times. Particularly in respect to the EU Directives for Water Framework and Marine Strategy, a baseline is needed for the definition of pristine areas and their macrozoobenthic communities. Since the mid-1950s, scientific efforts investigating the benthic fauna of the Baltic Sea have increased rapidly, resulting in the publication of several hundred papers. A comprehensive overview of historical and current literature on macrozoobenthos is given for the German Baltic area by Gerlach, Zettler, and Röhner Regular study of macrozoobenthos in Baltic waters dates back to the end of the nineteenth century. The systematic observation of species and their distributions in the Baltic Sea began with Möbius, who published two papers on invertebrates in 1873 and 1884 In brackish water systems such as the Baltic Sea two main environmental variables  affect the composition of the benthic community and species' abundance e.g., . Within Despite of some gaps in taxonomic identification and nomenclature, and therefore also in knowledge of species distributions, it is still possible to present an extensive taxonomic list with identification in total of 1,476 species for the whole Baltic Sea . The mosBecause of the sharp increase in ship traffic and the anthropogenic use of offshore waters (such as pipelines for gas and oil and windmill farms), an enormous pressure on the environment could be observed in the last decades Gadus morhua], herring [Clupea harengus], and sprat [Sprattus sprattus]). The abundance and biomass of cod, herring, and sprat  have fluctuated substantially in the past 30–40 years  fish community comprises approximately 200 species, but only about 100 established species if the Kattegat is excluded. There are around 70 species in several sub-basins in the NE Baltic, but less than 50 species in Bothnian Bay 40 years . Cod wasPlatichthys flesus) Pleuronectes platessa) and dab (Limanda limanda) were abundant in the Bornholm Basin, but they declined in the 1950s–1970s and are rare in this area at present Some flatfish species are commercially important and the biomass appears to be moderately high, e.g., flounder (Merlangus merlangus), European anchovy (Engraulis encrasicolus), mackerel (Scomber scombrus), grey mullet (Liza ramada), and thicklip mullet (Chelon labrosus). Owing to unfavorable environmental factors, these fish are unable to form self-sustaining populations in the Baltic. In addition, there are several noncommercial fish present in the Baltic Sea, for instance gobies (Pomatoschistus spp.), three-spined stickleback (Gasterosteus aculeatus), nine-spined stickleback (Pungitius pungitus), and pipefish (Nerophis ophidion), which are successfully adapted to low-salinity conditions prevalent in near-coastal areas and play several significant roles in the food web. However, knowledge of the spatiotemporal population dynamics of these fish is relatively poor, or in some cases even absent.Various marine fish species from the North Sea migrate from time to time into the Baltic Sea. These include whiting , trout , eel (Anguilla anguilla), vimba bream (Vimba vimba), smelt (Osmerus eperlanus) are of high commercial value. Decline and or disappearance of the natural salmon stocks has been especially rapid since the late 1940s, mainly due to construction of hydroelectric power plants and river damming. However, recently some improvement is evident for the natural smolt production in the northern Baltic rivers. Sea trout populations are currently in a precarious state in the northeastern Baltic, while some improvement has been recorded in the western Baltic Several migratory species, such as salmon (Perca fluviatilis), roach (Rutilus rutilus), bream (Abramis brama), bleak , ruffe , ide (Leuciscus idus), pike (Esox lucius), and whitebream (Blicca bjoerkna). These fish are more abundant in areas where salinity is lower, such as in the northeastern Baltic Sea, including large gulfs and lagoons. Because of ongoing coastal eutrophication, as well as increased water temperatures, a significant increase in perch and roach abundance has been recorded in the Archipelago Sea during the past decade, while these and other species have significantly decreased, or even collapsed, in other areas. The suggested primary reason for the decline or collapse is excessive fishing pressure The most common and abundant freshwater species found in a majority of coastal areas of the Baltic Sea are perch (Triglopsis quadricornis), sea snail (Liparis liparis), eelpout (Zoarces viviparous), and lumpsucker (Cyclopterus lumpus), mainly inhabit the cold-water layers in deeper areas and the northeastern Baltic Sea with favorable oxygen status. Except eelpout, these fish lack any commercial importance.Relatively limited evidence on this category of fish suggests that their abundance is negatively influenced by excessive eutrophication, contamination with toxic substances, and presence of large marine predators Glacial relict species, such as fourhorned sculpin . In all of these species, local genetic populations have been detected along the salinity gradient from the Skagerrak through the Danish Straits to the northern Baltic The salinity gradient from the North Sea east and north through the Baltic also affects biodiversity within species . This is evident from recent molecular genetics studies of several fish species  than on the coastal fish. Most species exploited in the past  are still exploited at present, but sometimes in smaller quantities The long temporal perspective has enabled identification of how climate variability and change influences fish populations. For example, during the Atlantic Warm Period (roughly 7000 to 3900 B.C.), when temperatures resembled those likely to be typical in the late twenty-first century, cod were quite abundant near Bornholm. The high abundance is due partly to higher salinities, which were common at that time Phoca hispida) is an Arctic species and is therefore directly dependent on quality of ice by colonizing mainly the large gulfs in the northeastern Baltic Sea  where ice is annually formed. The main concentrations of grey seal  are found in the northern part of the Baltic Proper. The harbor seal (Phoca vitulina) is present only in the southern Baltic.The Baltic Sea is inhabited by three species of seals. Ringed seal  comprising two distinct populations: one in the Baltic Proper and the other in the Kattegat and the western Baltic  characterized by the lowest native species richness and the highest number of alien species Human-mediated biological introductions have resulted in 117 alien species being recorded, about 70 of which are known to have established self-reproducing populations  and 4. TCercopagis pengoi], zebra mussel [Dreissena polymorpha] and some Pacific salmonids [Oncorhynchus spp.]) while the Baltic has historically been and still is subject to secondary introductions from both the North Sea area and adjacent inland waters .Alien species are abundant and even dominant throughout the shallow benthic and fouling communities of the Baltic Sea—at present, no shallow-water habitat is entirely free of human-mediated invaders. Their number is the lowest in Bothnian Bay and the highest in the high-salinity Kattegat area  by rivers and canals. Some 250 rivers discharge fresh water into the Baltic from a drainage area that is four times greater than its sea surface area. Consequently, every non-native species released into the wild somewhere in the drainage basin can be transported to the sea or its most diluted coastal areas. In the peripheral parts of the drainage area of the Baltic, these species consist mainly of the Ponto-Caspian biota, whereas the northwest European river mouths host a number of marine and brackish-water aliens native to other seas P. minimum, invaded the Baltic Sea (exept the Gulf of Bothnia) in the last two decades of the twentieth century causing strong algal blooms in coastal areas Chattonella marina (now Pseudochattonella farcimen) occurred in the Gullmar fjord, Sweden, in spring 2001 Potentially toxic dinoflagellate, C. pengoi) have a high value as a food source for commercially harvested fish, such as the Baltic herring , three North-American species , the Japanese swim-bladder nematode Anguillicola crassus and the “shipworm” mollusk T. navalis, believed to be of Indo-Pacific origin. The clogging of reels and fouling of nets makes C. pengoi a potential nuisance species, this may have caused substantial economic loss in fisheries T. navalis, now fully established in the southwestern Baltic, has caused remarkable damage to submerged wooden installations (K. Hoppe unpublished) and marine archaeological objects Mnemiopsis leidyi—on the pelagic food web of the Baltic Sea seems to be spatially restricted to the southern Baltic Sea nauplii of the alien cirriped B. improvisus and larvae of jellyfish Aurelia aurita) cannibalism on larval M. leidyi was observed Alien species have no direct value as food resources in the Baltic, as none of them supports commercial fisheries and invertebrates are not harvested for food because of their small size. Some planktonic invaders , physical damage and disturbance, recreational activities, eutrophication, hazardous substances, alien species, noise pollution, hunting, and climate change All the other factors affecting the Baltic biodiversity are of relatively recent concern and have localized impact, or information on their impact is poorly documented (because the stressor is relatively recent). Although the first human-mediated introduction of species in the Baltic Sea occurred in the eleventh to twelfth century, species invasions have become a problem during the past two decades, especially with intensified invasion of alien species from the Ponto-Caspian region. In contrast with many other seas, invasion of alien species has increased both species and functional diversity of the Baltic Sea Sub-regionally balanced and representative species diversity analysis was possible to carry out for six organism groups . The steHELCOM started to establish a system of marine and coastal Baltic Sea Protected Areas (BSPAs) in 1994, with the overall aim of contributing to the protection of the entire ecosystem, including all its components and functions, and not just certain species or habitats. All contracting parties to the Helsinki Convention contributed by identifying and nominating an initial suite of 62 sites. The protected areas should therefore be well distributed across the Baltic Sea area and its different subsystems to include all species, habitats, and ecosystems The lists of threatened or declining species and biotopes or habitats of the Baltic Sea area contain 61 species G. aculeatus and P. pungitius), gobies (Pomatoschistus spp.), fourhorned sculpin (T. quadricornis), sea snail (L. liparis), and eelpout (Z. viviparus), is also scarce, despite the fact that these species may play significant roles in the ecosystem. These gaps result from a combination of lack of expertise and of relevant monitoring and research programs because of a shortage of financial resources.The Baltic Sea is one of the most intensively studied regional seas in the world; some continuous datasets go back to the early 1950s. Despite this, substantial gaps in knowledge still occur and some of the pressing issues are discussed below. So far, diversity of the biota of the Baltic Sea has been routinely described for dominant species of certain groups or size fractions that are identified and counted for monitoring purposes. Smaller organisms, like unicellular and colony-forming picocyanobacteria, which could make up a substantial part of phytoplankton biomass Nowadays, it is a common problem worldwide that professional taxonomists with extensive knowledge of the systematics of different groups of aquatic invertebrates are becoming extinct Nodularia and one genetically valid species of Anabaena exist in the Baltic Sea Marenzelleria spp. Application of various molecular techniques is an increasingly important tool in marine biodiversity studies. Several of these techniques have already been applied to study genetic diversity at different trophic levels of the Baltic Sea. For instance, case studies are available to show that two genotypes of the cyanobacteria By housing unique genes, genotypes and populations, the Baltic Sea is a vulnerable, but exceedingly valuable genetic resource Text S1Reference list of manuals and identification guides.(0.07 MB DOC)Click here for additional data file.


We have reviewed the impact of the ubiquitin proteasome system (UPS) on atherosclerosis progression of diabetic patients. A puzzle of many pieces of evidence suggests that UPS, in addition to its role in the removal of damaged proteins, is involved in a number of biological processes including inflammation, proliferation and apoptosis, all of which constitute important characteristics of atherosclerosis. From what can be gathered from the very few studies on the UPS in diabetic cardiovascular diseases published so far, the system seems to be functionally active to a different extent in the initiation, progression, and complication stage of atherosclerosis in the diabetic people. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the UPS. Nonetheless, this hypothesis may help us understand why diverse therapeutic interventions, which have in common the ability to reduce ubiquitin-proteasome activity, can impede or delay the onset of diabetes and cardiovascular diseases (CVD).People with type 2 diabetes are disproportionately affected by CVD, compared with those without diabetes . The pre Ciechanover  presenteDuring the initial insulin-resistant period, or "prediabetes," the metabolic and physiological changes proceed in parallel with the commencement of silent atherosclerosis and cardiovascular complications in genetically susceptible people, before the onset of diabetes. The spectrum of atherosclerotic disturbances associated with insulin-resistance extends beyond hyperglycemia, dyslipidemia, and inflammation. Indeed, insulin receptor signalling deregulation seems to play a crucial role in causing atherosclerosis related to insulin-resistance. Binding of insulin to its receptor stimulates phosphorylation of a set of 'insulin receptor substrate' proteins, which in turn recruit and activate a lipid kinase, phosphatidylinositol 3-kinase (PI3K) . InsulinRepeated exposure to hyperglycemia can lead to endothelial pathology that may become irreversible over time . RussellRepeated exposure to postprandial hyperglycemia and subsequently oxidative stress upregulation may contribute also the endothelial activation including the inflammatory and adhesive proprieties of endothelial cells through UPS activation. Previous reports evidenced a role for the UPS in the NFkB-dependent pro-inflammatory cytokine production, particularly under conditions of aggravated oxidative stress linked to hyperglycemia. In muscle wasting, NFkB activation was noted in the presence of aggravated oxidative stress and UPS overactivity . Also, n- production as well as ubiquitin-proteasome activity and NFkB levels were significantly higher when compared to nondiabetic patients [In middle-aged patients, the seven-year incidence of myocardial infarction among patients without diabetes who had preexisting CHDwas similar to that among patients with diabetes who did not have CHD, suggesting that type 2 diabetes may confer the same degree of risk as preexisting CHD . The isspatients . Thus, ipatients .The emerging studies, on the role of UPS in the initiation and progression of atherosclerosis process, propose a number of substances which readily penetrate the cell membrane and inhibit the proteolytic function of the proteasome complex . So far,We have reviewed the impact of diabetes progression on cardiovascular disease from endothelial dysfunction to plaque destabilization. A puzzle of many pieces of evidence suggests that UPS may be involved in the generation of insulin-resistance, diabetes, and cardiovascular disease. The UPS is the main route of cellular protein degradation. In addition to its role in the removal of damaged proteins, the UPS is involved in a number of biological processes including inflammation, proliferation, and apoptosis. From what can be gathered from the very few studies on the UPS in diabetic cardiovascular diseases published so far, the system seems to be functionally active to a different extent in the initiation, progression, and complication stage of atherosclerosis in the diabetic people. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the UPS. Nonetheless, this hypothesis may help us understand why diverse therapeutic interventions, which have in common the ability to reduce ubiquitin-proteasome activity, can impede or delay the onset of diabetes and CVD. These early findings need further attention and confirmation, importantly with regard to therapeutic intervention, which would be indicated only if the system was clearly found to be active and pathophysiologically involved. New specific and causal inhibitors of proteasome inhibitors are available and have been successfully introduced as an adjunctive treatment option in cancer. Whether this translates to the proliferative aspects of diabetic atherosclerosis remains to be cautiously awaited.The author(s) declare that they have no competing interests.All authors have equally contributed in the conception and drafting of the manuscript.


Brain-supplying arterial dissection is considered one of the most common vascular causes of stroke in younger patients. Dissections are usually preceded by trauma or mechanical stress; the vascular stressor may be trivial as this condition has been described in association with manipulation and stretching the neck. Here we describe a case of vertebral artery dissection and stroke following esophagogastroduodenoscopy. This case highlights a potentially serious complication that may occur after procedures that require hyperextension of the neck. A 74-year-old man with a past medical history of hypertension, coronary artery disease, and Barrett's esophagus presents for evaluation of gait difficulty. The day before the onset of symptoms he had a flexible fiberoptic esophagogastroduodenoscopy (EGD) under general anesthesia with intubation for symptoms of dyspepsia. After recovering from the procedure, the patient noted lack of coordination of the right hand and veering to the right when walking. There was no headache, neck pain, or history of recent trauma to the neck or head.Neurological examination showed the following signs referable to the right side: partial ptosis, a small poorly reactive pupil to light, decreased vibration and temperature sensation of the arm and leg, finger-to-nose dysmetria, and wide-based gait with veering. On brain MRI, there was an infarct of the right lateral medulla and findings consistent with vertebral artery (VA) dissection . ConventAfter atherosclerosis, dissection is a common cause of symptomatic in situ carotid artery occlusive disease . DissectOur patient had a partial lateral medullary syndrome due to brain ischemia caused by a right VA dissection in the absence of unintended head maneuvers. In this setting, we hypothesize that the EGD procedure or endotracheal intubation may have led to dissection of the right VA. Hyperextension of the neck, as may occur during intubation, EGD, difficult labor and delivery, or other medical procedures, may lead to stretching and injury of cervical vessels and cause dissection of brain-supplying arteries –6. Alter


Escherichia coli is integral for detecting chemicals over a wide range of background concentrations, ultimately allowing cells to swim towards sources of attractant and away from repellents. Its biochemical mechanism based on methylation and demethylation of chemoreceptors has long been known. Despite the importance of adaptation for cell memory and behavior, the dynamics of adaptation are difficult to reconcile with current models of precise adaptation. Here, we follow time courses of signaling in response to concentration step changes of attractant using in vivo fluorescence resonance energy transfer measurements. Specifically, we use a condensed representation of adaptation time courses for efficient evaluation of different adaptation models. To quantitatively explain the data, we finally develop a dynamic model for signaling and adaptation based on the attractant flow in the experiment, signaling by cooperative receptor complexes, and multiple layers of feedback regulation for adaptation. We experimentally confirm the predicted effects of changing the enzyme-expression level and bypassing the negative feedback for demethylation. Our data analysis suggests significant imprecision in adaptation for large additions. Furthermore, our model predicts highly regulated, ultrafast adaptation in response to removal of attractant, which may be useful for fast reorientation of the cell and noise reduction in adaptation.Adaptation of the chemotaxis sensory pathway of the bacterium  Bacterial chemotaxis is a paradigm for sensory systems, and thus has attracted immense interest from biologists and modelers alike. Using this pathway, cells can sense chemical molecules in their environment, and bias their movement towards nutrients and away from toxins. To avoid over- or understimulation of the signaling pathway, receptors adapt to current external conditions by covalent receptor modification, ultimately allowing cells to chemotax over a wide range of background concentrations. While the robustness and precision in adaptation was previously explained, we quantify the dynamics of adaptation, important for cell memory and behavior, as well as noise filtering in the pathway. Specifically, we study the intracellular signaling response and subsequent adaptation to concentration step changes in attractant chemicals. We combine measurements of signaling in living cells with a dynamic model for strongly coupled receptors, even including the effects of concentration flow in the experiment. Using a novel way of summarizing time-dependent data, we derive a new adaptation model, predicting additional layers of feedback regulation. As a consequence, adaptation to sudden exposure of unfavorable conditions is very fast, which may be useful for a quick reorientation and escape of the cell. Escherichia coliin vivo fluorescence resonance energy transfer (FRET) measurements and quantitative modeling to address this problem.Cells are able to sense and respond to various external stimuli. To extend the working range of their sensory pathways, biochemical mechanisms allow for adaptation to persistent stimulation, resulting in only a transient response. The dynamics of adaptation are important as they often represent the cells' memory of previous environmental conditions, directly affecting cellular behavior E. coli allows cells to sense chemicals and to swim towards more favorable environments by successive periods of straight swimming (running) and random reorientation (tumbling). Transmembrane chemoreceptors, including the highly abundant Tar and Tsr receptors, cluster at the cell poles and act as “antennas” to detect various attractants (e.g. certain amino acids and sugars) and repellents  with high sensitivity The chemotaxis pathway in E. coli is based on reversible methylation and demethylation of receptors at specific modification sites, catalyzed by enzymes CheR and phosphorylated CheB (CheB-P), respectively. Tar and Tsr receptors have four major modification sites. In addition, the Tsr receptor has two minor modification sites which are methylated less strongly Adaptation in i) Despite their importance for cell behavior, memory and noise filtering, the dynamics of adaptation and the methylation level are largely unknown. This is because the methylation level is difficult to measure precisely, relying on quantification of receptor protein and radioactively-labeled methylation substrate (methionine) incorporated into receptors ii) The molecular mechanism of adaptation, in particular demethylation, remains unclear. While CheR binds strongly to the tether, suggested to increase its concentration in the vicinity of methyl-accepting sites in vivo FRET experiments, monitoring receptor activity upon stimulation, is ideally suited to study the adaptation dynamics and address these questions.Although a lot is known about the components of the chemotaxis pathway, several open questions remain to be answered in adaptation.  model was used to successfully describe the signaling of two-state receptor complexes, formed by 10–20 strongly interacting receptor dimers in vivo FRET data obtained from cells adapted to ambient concentrations of attractant Inset). To analyze the adaptation dynamics, we use the data collapse, a condensed representation of time courses. This data collapse enables us to evaluate the effect of ligand flow and adaptation imprecision, to infer the kinetics of the receptor methylation level, as well as to efficiently compare adaptation models from the literature to experimental data. Finally, we experimentally test two predictions to validate our adaptation model. We change the adapted receptor activity, and use a non-regulatable CheB mutant to bypass its negative feedback on the receptor activity. Our combined study of experiments and modeling shows that adaptation is relatively imprecise at the receptor level for large stimuli, and that demethylation is more tightly regulated than previously thought. This leads to very short tumbles for sudden occurrences of unfavorable conditions, allowing cells to quickly reorient their swimming direction after a short tumble.Here, we use in vivo ratio. Using a two-state assumption, the activity of a receptor complex is given by its probability to be in on (active), which depends on the free-energy difference on and off (inactive) state on state, and one from attractant binding at MeAsp concentration off state. The free-energy difference on and off states, respectively. Most of these parameters were determined previously , with the dynamic effects of adaptation by receptor modification, as well as ligand concentration flow. In the static MWC model, mixed receptor complexes composed of Tar (aspartate receptor) and Tsr  are considered in their E. coli, we also found the phosphorylation reactions are sufficiently fast to assume that concentrations of phosphorylated (and unphosphorylated) proteins are in quasi-steady state. Furthermore, the concentrations of activated proteins are approximately proportional to the receptor complex activity. Both these conditions allow us to use the receptor complex activity as a substitute for the down-stream activity measured by FRET reducing the number of model parameters for fitting to data greatly . Note that the asymmetry between slow adaptation of inactive and active receptors, respectively, cannot simply be changed by adjusting the rate constants of methylation and demethylation individually, since they are constrained by the adapted activity Adaptation occurs on a similar time scale as the kinetics of the MeAsp concentration flow. In experiments, changes in MeAsp concentration are established over several seconds, due to the finite flow speed and mixing effects in the flow chamber. In our model, we assume exponentially rising and falling concentration changes upon addition and removal in line with previous measurements by Sourjik and Berg  [23]. Adrses cf.  where adrses cf. Inset. Nin vivo FRET . Note, however, that responses eventually do saturate according to the dynamic MWC model for even larger concentration step changes due to the presence of Tsr receptors . Hence, the rate of activity change is a function off and on state, respectively. Inset shows the experimental rate of activity change as extracted from our quantitative time-course data from FRET for different concentration step changes at an ambient concentration. We observe that, in contrast to the prediction of the model, the rate of activity change depends on the magnitude of the concentration step changes. For addition of large concentration step changes (blue symbols), the rate is reduced and the activity stays below the pre-stimulus value. Furthermore, for total removal of MeAsp concentration , the magnitude of the rate is reduced and the activity remains above the pre-stimulus value.The short-term behavior in the time-course data  is essenInset.To explain the deviations from the predicted data collapse, we consider the effects of MeAsp flow and imprecise adaptation in our model. According to Eq. 3, each of the two effects contribute independently to the rate of activity change. First, we include the MeAsp flow for concentration step changes as described, and simulate time courses based on the precise adaptation model  the signaling activity of two-state mixed chemoreceptor complexes in response to added or removed attractant concentration step changes based on the Monod-Wyman-Changeux model, (ii) the kinetics of the ligand concentration in the flow chamber, and (iii) a detailed mechanism for adaptation, including multiple layers of feedback regulation and imprecise adaptation. In particular, we find that the finite ligand flow speed and fast, activated demethylation explains for the first time the gradually reduced amplitudes in removal dose-response curves for increasing ambient concentrations  are integrated at the level of the free-energy of a receptor complex, which determines its activity. However, the imprecision of adaptation we found in FRET time courses at large MeAsp concentrations is in contrast to earlier experiments, which showed that the frequency of tumbling adapts precisely to aspartate, but not serine E. coli were used. Wild-type strain 1 (WT1) is VS104 D56E. The D56E mutation was introduced into CheB by PCR. It prevents CheB phosphorylation, but allows protein to retain basal level of activity. Cells were grown at 275 rpm in a rotary shaker to mid-exponential phase (D56E mutant) the native level of CheB.Two different wild-type strains of The experimental procedures follow those detailed by Sourjik and Berg on and off states of the complex. The indexes Inset of This model describes the response of adapted mixed receptor complexes to instantaneous MeAsp concentration step changes iles cf. , with  aThe dynamic MWC model combines the static MWC model with a dynamical model for adaptation. In our model for precise adaptation, the rate of change of the average receptor methylation level We incorporate the effect of imprecise adaptation, as suggested by time courses cf. , by makiTo calculate the rate of activity change, the time courses for adaptation to step concentration changes were smoothed by averaging every 20 subsequent data points starting approximately 10 s after the step onset. The derivative Text S1Supplementary information.(0.52 MB PDF)Click here for additional data file.


The Situs viscerum inversus associated with anomalies of intestinal rotation and fixation is an extremely rare condition. To the authors’ knowledge, this is the first report of colon cancer associated with intestinal malrotation and mesenterium ileocolicum commune.A 34-year-old man with a 2-month history of diarrhea associated with abdominal pain and weight loss underwent abdominal ultrasonography, colonscopy with biopsies and abdominal computed tomography scan with intravenous contrast. A right colonic neoplasm was diagnosed, observed only at surgery, as neither computed tomography or ultrasonography showed the intestinal malrotation. Particularly, the third and the fourth part of the duodenum descended vertically, without Treitz’s ligament in support to the duodeno-jejunal flexure. The small bowel and the colon were located in the right and left side of the abdominal cavity, respectively.The anomaly of situs viscerum inversus influenced the surgical strategy in this case because of the vascular and lymphatic anomalies. Lymphatic vessels were therefore marked with subserosal injection of patent blue in the proximity of the tumor. Subsequently, right colectomy was performed. Colectomy extended from the distal ileum to the descending colon, by ligature of the right colic artery and vein at the origin from the superior mesenteric vessels. Patent blue guided lymphadenectomy was also performed with curative intent. Finally, a mechanical ileo-colic anastomosis was carried out. After right colectomy and ileo-descending anastomosis, the Ladd’s procedure for intestinal malrotation was unnecessary. The authors believe that this strategy, despite the anatomical difficulties, represents an effective procedure for the radical surgical treatment of the right colon cancer associated with anomalies of intestinal rotation and fixation. The right position of the organs, called situs viscerum solitus (SVS), can have some changes during the embryonic development, leading to an anatomical abnormality called situs viscerum inversus (SVI). The situs viscerum inversus totalis (SVIT) represents the most common condition, with an incidence varying from 1 in 4000 to 1 in 50000 live births , being cIn this report we describe a rare case of colon cancer associated with intestinal malrotation and mesenterium ileocolicum commune.A 34-years-old Caucasian male of Italian nationality was admitted to our department complaining for a 2-months history of diarrhea associated with abdominal pain, progressing from the upper to the lower abdomen, and weight loss. The patient did not report any other previous disease or surgery.Moreover, no familiarity for metabolic or neoplastic diseases was found. The patient denied alcohol or tobacco use. Clinical examination revealed a distended abdomen, increased bowel sounds and a lightly painful mass at the left lower quadrant of the abdomen. Abdominal ultrasonography (US) showed a mass of 9 × 5 cm of mixed echogenicity in the proximity of the sigmoid colon with some hypoechoic lymph nodes of increased volume in the adipose adjacent tissue. Colonscopy with biopsy was performed because of the presumed diagnosis of intestinal neoplasm. Interestingly, at endoscopy, a polypoid vegetating mass, involving the 2/3 of the intestinal circumference was found, whereas, in the remaining colonic segments, no signs of mucosal injury were reported. At histopathologic standard examination, the mass showed microscopic aspects of adenocarcinoma. The abdominal computer tomography (CT) with intravenous contrast showed some thickened ileal loops and increased in volume mesenteric lymph nodes . At routHowever, the supramesocolic organs maintained their normal position.The presence of this anatomical abnormality strongly influenced some aspects of the surgical strategy. First of all, we decided, because of the associated vascular and lymphatic anomalies, to mark lymphatic vessels with peritumoral subserosal injection of patent blue violet, at the four cardinal points, to achieve a radical lymph node dissection. Therefore, right colectomy, extended from the distal ileum to the descending colon, by ligature of the right colic artery and vein at the origin from the superior mesenteric vessels, and patent blue guided lymphadenectomy, were performed, with curative intent. Subsequently, a mechanical ileo-colic anastomosis was carried out.We did not perform the Ladd’s procedure  for the Pathological examination revealed well-differentiated adenocarcinoma of the caecum infiltrating the subserosal layer without nodal involvement. The patient had an uneventful postoperative course.Only several cases of colon cancer complicated by intestinal and vascular anomalies are reported in medical literature -8 and noAlthough the intestinal malrotation has long been recognized as a cause of intestinal obstruction in infants, it often remains asymptomatic in the adults and its real incidence is indeterminable . MoreoveAlthough the available literature suggests that the diagnosis of rotational anomalies can be made by means of barium enema , in the As regards the surgical technique, we preferred the laparotomy approach for two reasons. Firstly, nowadays, the laparoscopic approach is still not considered the gold standard for the treatment of the advanced colon cancer. Although the long-term outcome after laparoscopic and open surgery for colon cancer seems to be comparable, the choice of the best surgical approach is still source of doubts and the long-term oncological outcome, cost effectiveness and the impact on the patients’ quality of life should be defined by large-scale prospective randomized trials . SecondlAt surgery, a radical and curative resection was obtained in spite of the anatomic anomalies and the altered vascular and lymphatic flow. Indeed, the extension of the lymphadenectomy was guided by the intraoperative injection of patent blue violet in the peritumoral subserosal layer, allowing an oncologically correct nodal dissection.Moreover, the anomalous absence of a “true” transverse colon influenced the margins of resection that were extended from the distal ileum to the descending colon, including the short segment of large intestine that connected the ascending to the descending colon.The surgical treatment of choice for the intestinal malrotation is the Ladd’s procedure. This includes the division of the Ladd’s band, the mobilization of the right colon and duodenum, the division of adhesions to the mesenteric base and appendectomy .Obviously, the right colectomy performed for colon cancer and the presence of a floating duodenum, in the absence of a Treitz’s ligament attaching the duodeno-ingiunal junction, made the Ladd’s procedure unnecessary.The intestinal malrotation associated with mesenterium commune influenced the surgical strategy for the treatment of the associated colon cancer, because of the vascular and lymphatic anomalies. We believe that our case, despite the anatomical difficulties, illustrates an effective procedure for the oncologically correct surgical treatment of the colon cancer associated with anomalies of intestinal rotation and fixation.


Lipoprotein glomerulopathy is a glomerulonephritis which was described for the first time by Saito in 1989 and is currently acknowledged as a separate nosological entity. It is histologically characterized by a marked dilatation of the glomerular capillaries and the presence of lipoprotein thrombi in the glomerular lumens. The dyslipidemic profile is similar to that of type III dyslipoproteinemia with Apolipoprotein E values that are often high; proteinuria and renal dysfunction are present. Proteinuria often does not respond to steroid and cytostatic treatments.The phenotypic expression of lipoprotein glomerulopathy is most probably correlated to a genetic alteration of the lipoprotein metabolism (mutation of the Apolipoprotein E coding gene). In literature, lipoprotein glomerulopathies have mainly been reported in Japanese and Chinese subjects, except for three cases in the Caucasian race, reported in France and the USA.MODENA), and treated successfully with low density lipoprotein-apheresis with the Heparin induced extracorporeal lipoprotein precipitation system. After a first phase of therapeutic protocol with statins, the patient was admitted for nephrotic syndrome, renal failure and hypertension. Since conventional treatment alone was not able to control dyslipidemia, aphaeretic treatment with heparin-induced Extracorporeal Lipoprotein Precipitation - apheresis (HELP-apheresis) was started to maintain angiotensin converting enzyme inhibitor therapy for the treatment of hypertension. Treatment with HELP-apheresis led to a complete remission of the proteinuria in a very short time (four months), as well as control of hypercholesterolemia and renal function recovery.We describe the case of a 60-year-old female, Caucasian patient suffering from lipoprotein glomerulopathy, carrier of a new mutation on the Apolipoprotein E gene (Apolipoprotein EAccording to this case of lipoprotein glomerulopathy, we believe that renal damage expressed by proteinuria correlates to the levels of lipids and, furthermore, the treatment with HELP-apheresis, by lowering low-density lipoprotein cholesterol and triglycerides, may be considered as a therapeutic option in synergy with pharmacological treatment in the treatment of lipoprotein glomerulopathy. Glomerular damage is frequently caused by fat deposits in various anomalies of lipid metabolism , with a glomerulonephritis. This develops into glomerulosclerosis with severe nephrotic syndrome. From an initial asymptomatic proteinuria, chronic renal failure develops gradually as the atherosclerotic process advances.The accumulation of lipids in the renal glomerule is a rare condition, described for the first time by Saito in 1989 . The mutant Apo E  as well as the difficulty to reach the diagnosis (the sequence of the ApoE gene in 2007 made it possible for a complete diagnosis of LPG to be confirmed). In July 2005, after the poor response of the patient to lipid-lowering drugs, we decided to start with an LDL-Apheresis protocol as possible treatment instead of ApoE and TG to stop the glomerular damage. In patients with familial hypercholesterolemia, kidneys are frequently damaged by fat deposits leading to glomerulonephritis which develops into glomerulosclerosis with severe nephrotic syndrome. The direct negative effects of lipids and pro-inflammatory markers on the renal arteries endothelium are due to the formation of free radicals because of oxidized LDL (oxLDL). This induces an inflammatory condition with an impairment of the endothelial function. There is glomerular damage and passive filtration of lipoproteins in the mesangium with active phagocytosis by a part of the mesangial cells and macrophages which, by releasing cytokines and growth factors, increase mesangial proliferation . In pati2) and increasing Prostaglandin I2. LDL apheresis has also been used to increase the response to steroid therapy by removing the VLDL, which induces a reduction of dose-dependent specific binding sites for the dexamethasone on smooth muscle cells [LDL apheresis has been used in the treatment of steroid-resistant nephrotic syndromes ,14. It hle cells .A potential advantage of HELP-apheresis versus dextran sulfate columns in the treatment of LPG may be related to the use of high heparin dosages. Heparin may activate LPL and HTGL and easily remove lipoproteins rich of TG like VLDL and IDL that are generally elevated in LPG. Another potential advantage of HELP-apheresis versus dextran sulfate may be the dialysis circuit present in the HELP-Plasmat Futura machine. This plasmatic dialysis process, fundamental to restoring the plasmatic physiological pH and the balance of fluid, is also able to slightly correct impaired renal parameters such as creatinine, urea, and uric acid, as reported by Thiery . FurtherThe experience in this case of LPG leads us to believe that the renal damage expressed by proteinuria correlates with the levels of lipids. The selective removal of LDL-cholesterol, Lp(a), TG and fibrinogen through HELP-apheresis and pharmacological treatment led to the clinical remission of proteinuria, thereby improving the renal function parameters . This clinical improvement may be also explained by considering the capability of the HELP dialysis circuit to correct impaired renal parameters. This specific tool probably makes HELP-apheresis a first choice apheretic treatment for drugs-resistant LPG or nephrotic syndrome. HELP-apheresis allowed the patient to maintain the use of the ACE-inhibitor and to reduce the administration of statins at a lower dosage.Finally, HELP-apheresis may be considered a therapeutic option in synergy with pharmacological therapy in the treatment of LPG.ApoE: Apolipoprotein E; ApoB: Apolipoprotein B; PG: Lipoprotein Glomerulopathy; HELP.: Heparin induced Extracorporeal Lipoprotein Precipitation; LPL: Lipoprotein Lipase; HTGL: Hepatic Triglyceride Lipase: TG: Triglycerides; ox-LDL: Oxidazed LDL; LDL: Low density lipoprotein.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.LF, ML, RM, AA performed the clinical work and made the diagnosis. RG, RN, PR performed the LDL-Apheretic therapy. RG, LF, ML, RM acquired, analyzed and interpreted the patient data and helped to draft the manuscript. RG reviewed the literature and drafted the manuscript. All authors read and approved the final manuscript.


Venous thromboembolism (VTE) is an important cause of avoidable morbidity and mortality. However, routine prophylaxis for at-risk patients is underused. Recent guidelines issued by an international consensus group, including the International Union of Angiology (IUA), recommend use of low-molecular-weight heparins (LMWHs) for the treatment of acute VTE and prevention of recurrence, and for prophylaxis in surgical and medical patients. This review highlights current inadequacies in the provision of thromboprophylaxis, and considers the clinical implications of the European guidelines on the prevention and treatment of VTE. Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is an important cause of avoidable morbidity and mortality. Generally, massive PE occurs without warning. For patients dying in hospital as a result of PE, a diagnosis of PE has not even been considered in 70–80% of cases prior to death -4. AlthoThere is a strong association between asymptomatic DVT and the subsequent development of symptomatic VTE . HoweverThis review aims to highlight the need for greater efforts in preventing VTE and considers the clinical implications of the recent European guidelines on the prevention and treatment of VTE.Risk factors for VTE are well known Table . PatientThe risks of VTE in surgical patients and the need for appropriate thromboprophylaxis have long been recognised. The risks are particularly high for orthopaedic surgery, where routine use of thromboprophylaxis is standard practice. Non-orthopaedic surgical patients are classified as being at high, medium or low risk of developing VTE on the basis of known risk factors  and low-molecular-weight heparins (LMWHs) when used for prophylaxis in general surgical patients . LDUH orThe European guidelines recommend specific prophylactic approaches for each type of orthopaedic surgery . For exaPatients with VTE receive anticoagulants to treat the acute event and prevent fatal PE, and also to minimise the risks of developing post-thrombotic syndrome and recurrent VTE. For many years, unfractionated heparin (UFH) has been the standard treatment for acute VTE. However, clinical trial data show that LMWHs are more effective than UFH for the initial treatment of VTE and are associated with less major bleeding ,27. As aOn the basis of data from two clinical trials ,30, fondIn patients with cancer, the IUA guidelines recommend either LMWH or UFH for initial treatment of VTE (Grade A), but note that outpatient therapy with LMWH is preferred, particularly in patients with a reduced life expectancy in whom quality of life becomes a priority . Recent LMWHs are manufactured by a variety of different methods, and each LMWH has a unique chemical structure that confers specific pharmacokinetic and pharmacodynamic properties. Regulatory bodies in Europe and North America regard LMWHs as distinct chemical entities, and advise that they should not be used interchangeably ,34. VeryIn the absence of sufficient comparative data, each LMWH should be dosed according to the labelling and recommendations issued by the manufacturer. Thus, the clinical results from one LMWH should not be extrapolated to another. Adopting an evidence-based approach to patient management is essential in the use of LMWHs, and only doses of drugs that have been adequately evaluated in well-designed clinical trials should be considered for use in a particular indication.Despite the existence of comprehensive consensus guidelines for the prevention and treatment of VTE ,12,13, tImproving compliance with thromboprophylaxis guidelines is a complex task that needs to include improved thrombotic risk-assessment methods, familiarisation of clinicians with current best practice, and facilitation of appropriate prescribing of prophylaxis . SeveralThe author declares that they have no competing interests.Risk categories in non-orthopaedic surgical patients . ReproduClick here for file


In an influenza pandemic, the benefit of vaccines and antiviral medications will be constrained by limitations on supplies and effectiveness. Non-pharmaceutical public health interventions will therefore be vital in curtailing disease spread. However, the most comprehensive assessments of the literature to date recognize the generally poor quality of evidence on which to base non-pharmaceutical pandemic planning decisions. In light of the need to prepare for a possible pandemic despite concerns about the poor quality of the literature, combining available evidence with expert opinion about the relative merits of non-pharmaceutical interventions for pandemic influenza may lead to a more informed and widely accepted set of recommendations. We evaluated the evidence base for non-pharmaceutical public health interventions. Then, based on the collective evidence, we identified a set of recommendations for and against interventions that are specific to both the setting in which an intervention may be used and the pandemic phase, and which can be used by policymakers to prepare for a pandemic until scientific evidence can definitively respond to planners' needs.Building on reviews of past pandemics and recent historical inquiries, we evaluated the relative merits of non-pharmaceutical interventions by combining available evidence from the literature with qualitative and quantitative expert opinion. Specifically, we reviewed the recent scientific literature regarding the prevention of human-to-human transmission of pandemic influenza, convened a meeting of experts from multiple disciplines, and elicited expert recommendation about the use of non-pharmaceutical public health interventions in a variety of settings  and pandemic phases .The literature contained a dearth of evidence on the efficacy or effectiveness of most non-pharmaceutical interventions for influenza. In an effort to inform decision-making in the absence of strong scientific evidence, the experts ultimately endorsed hand hygiene and respiratory etiquette, surveillance and case reporting, and rapid viral diagnosis in all settings and during all pandemic phases. They also encouraged patient and provider use of masks and other personal protective equipment as well as voluntary self-isolation of patients during all pandemic phases. Other non-pharmaceutical interventions including mask-use and other personal protective equipment for the general public, school and workplace closures early in an epidemic, and mandatory travel restrictions were rejected as likely to be ineffective, infeasible, or unacceptable to the public.The demand for scientific evidence on non-pharmaceutical public health interventions for influenza is pervasive, and present policy recommendations must rely heavily on expert judgment. In the absence of a definitive science base, our assessment of the evidence identified areas for further investigation as well as non-pharmaceutical public health interventions that experts believe are likely to be beneficial, feasible and widely acceptable in an influenza pandemic. Ongoing concerns about the emergence of an influenza pandemic continue as the number of avian and human infections with the H5N1 virus mount . AdequatAt the request of the US. Department of Health and Human Services, we evaluated the evidence base for non-pharmaceutical public health interventions by reviewing recent published literature, including historical reviews, convening a meeting of experts, and formally eliciting and quantifying expert opinion about the relative efficacy and effectiveness of specific non-pharmaceutical interventions for pandemic influenza. Based on this collective evidence, we identified a set of recommendations for and against interventions that are specific to both the setting in which an intervention may be used and the pandemic phase, and which can be used by policymakers to prepare for a pandemic until scientific evidence can definitively respond to planners' needs. We also identified important areas of uncertainty that warrant further research.Nature, Journal of the American Medical Association, New England Journal of Medicine, Annals of Internal Medicine, British Medical Journal, Science, Lancet, Emerging Infectious Diseases, Journal of Infectious Disease, and Clinical Infectious Disease. Finally, we included additional literature identified by manual review of references lists of selected articles. The search identified 2,552 titles, of which 168 were eventually selected based on general relevance. Exclusion criteria are presented in Table We identified scientific articles through a MEDLINE search that combined communicable and infectious disease with non-vaccine and non-pharmaceutical intervention search terms. We searched various combinations of the Medical Subject Headings (MeSH) headings in biomedical and infections control journals back to 1966 [see Additional file While completing the literature review, we convened a meeting of experts on January 17 and 18, 2006, in Arlington, VA. Attendees represented a broad range of disciplines, including biomedical research, virology, clinical practice, infection control, epidemiology, public health, ethics, law, history, and health policy. All panelists excepting one were based in North America. Participants identified a set of non-pharmaceutical public health interventions that could potentially mitigate an influenza pandemic and grouped them into four categories: (1) infection control and prevention to reduce transmission when contact occurs between infected and uninfected individuals; (2) patient management to reduce contact between infected and uninfected individuals; 3) contact management to reduce contact between possibly infected and uninfected individuals; and (4) voluntary and mandatory community restrictions to reduce contact between groups that may contain infected persons  and various aspects of effectiveness . The latter included feasibility, cost, logistics, operational and infrastructure constraints, and acceptability in terms of concerns surrounding legality and ethics, equity, public confidence, and potential unintended consequences. In their deliberations, the experts also considered the different settings in which these interventions might be applied . They also considered the epidemic phases in which the use of these interventions should be evaluated .Following the meeting, we asked each expert to rate 200 unique intervention-setting-phase triads identified during the meeting based on the totality of their knowledge. Thirteen of seventeen responded. Ratings were on a scale of 1 to 5, with 1 being 'not recommended' and 5 being 'strongly recommended'. We scored the ratings using an adaptation of the RAND/UCLA Appropriateness Method ,13. We fOur formal ratings of the articles revealed few high quality studies to inform the evidence base for non-pharmaceutical interventions for influenza. The majority of topically relevant articles we identified were narrative reviews, case reports, observational studies or expert opinion, editorials and commentaries Table . We founIn light of the evident lack of scientific evidence about specific non-pharmaceutical interventions in the context of seasonal or pandemic influenza, there was limited directly useable information from the majority of the studies identified in the formal Medline search. For this reason, we turned to expert opinion to inform and categorize the findings . Expert Hospital-based infection control measures such as hand hygiene and respiratory etiquette to prevent the spread of infection are widely supported in the literature and broadly accepted -20. ManyThe experts recommended rigorous and routine hand hygiene as an important strategy for healthcare workers and the general public in all settings and at all phases of a pandemic, including prior to a pandemic  to control influenza transmission during the influenza season . But expmandatory isolation in any specific setting. This was because of the inconclusive nature of the evidence, the concern that healthcare facilities are likely to be rapidly overwhelmed, and that overflow into difficult to manage public settings such as arenas would be less effective. Moreover, mandatory isolation outside of healthcare settings, even if effective and enforceable, raises a range of legal, political and ethical issues that can, at a minimum, erode public acceptance of these policies. Despite the skepticism about mandatory isolation strategies, voluntary self-isolation in the home was recommended for all phases of a US pandemic.The amount of influenza virus shed by symptomatic individuals is greater than in the asymptomatic phase, but viral shedding typically begins shortly after infection and before the onset of symptoms. This limits the efficacy of isolation except for individuals completely quarantined almost immediately after contact with an infected person . HoweverWith the exception of some evidence from SARS, we did not find any published data that directly support the use of masks, respirators, or other personal protective equipment by the public, or other steps such as disinfecting surfaces beyond usual practices. The expert's views were mixed. There was uncertainty regarding requirements for masks or respirators because of uncertainty about the relative roles of droplet versus aerosol transmission. Concerns about supply, competency in mask and especially respirator fitting and use, adherence by the public, and social impact of mask-wearing all served to undermine the panel's confidence in the feasibility and acceptability of widespread use. On the survey, experts recommended against the use of masks or respirators by the public prior to the arrival of pandemic influenza and in the early localized phase. For similar reasons, experts recommended against the public use of other protective equipment such as gowns, gloves and protective eye wear.Although social distancing measures such as workplace closures, limitations on location-based gatherings and events, and mandated travel restrictions have been a recent focus of investigation, and some of these measures were implemented in Asia and North America during SARS, their effectiveness in an influenza outbreak has not yet been established ,8,48. DeThe experts generally thought that community restrictions could be considered on a case-by-case basis, for example, cancellation of an event to which thousands would travel. However, efforts to forcibly limit public assembly or movement were seen as legally and ethically problematic, especially when there is limited scientific evidence supporting such restrictions. There are also important practical and logistical limitations to mandatory long-term community restrictions and compulsory quarantine, in addition to the problem of likely public opposition to such measures ,53,54. TConsistent with the literature, the experts contended that widespread and sustained screening of travelers would ultimately be impractical and inefficient as long as detecting asymptomatic shedding is not feasible. Difficulties with the rapid diagnosis of influenza means that travel bans and screening programs risk detaining a large number of symptomatic persons who do not have influenza. There is also the possibility of such measures leading to an international backlash, decreasing cooperation at a time when increased is needed. However, voluntary measures and guidelines would likely be more acceptable and thus more effective. The experts recommended against any mandatory travel restrictions in the advanced phases of a pandemic and did not recommend restrictions on domestic or international departures or entry screening when a pandemic is in the early localized phase.We evaluated the evidence-base for non-pharmaceutical public health interventions in an influenza pandemic by reviewing the recent scientific literature, convening a multidisciplinary meeting of experts, and eliciting expert knowledge qualitatively and quantitatively. Despite the poor quality of the evidence, the use of expert opinion has enabled us to identify strategies that are likely to help slow influenza transmission in a pandemic setting and also do no harm. Our findings highlight the importance of specifying the setting in which a non-pharmaceutical public health intervention will be used, as well as when its use should be considered. Although the interplay of these factors and deep uncertainty about the relative efficacy or effectiveness of specific non-pharmaceutical public health interventions prevents us from conclusively pinpointing an optimal set of non-pharmaceutical public health interventions for every circumstance, our study provides some important insights about pandemic planning.Consistent with others, we found that the published literature revealed scant confirmatory evidence on efficacy and overall effectiveness of non-pharmaceutical public health interventions in an influenza pandemic, effectively forcing policymakers to turn to expert opinion,9. Some First, policymakers should actively promote personal responsibility for slowing spread of infection through good hand hygiene and respiratory etiquette in all settings and at all times. Use of disinfectant hand soaps and alcohol-based rubs should also be encouraged. Second, developing the capability and capacity for early rapid viral diagnosis should be a high priority. Third, healthcare providers need to be better trained to maximize the effectiveness of infection control measures, including use of masks, respirators, and other personal protective equipment. It may be reasonable to recommend limited use of personal protective measures in certain other settings such as mask-wearing by the ill or perhaps surface disinfection of very heavily trafficked public areas. However, other use of personal protective equipment by the general public is not recommended at this time. Fourth, and also consistent with other studies, we founds that widespread government mandates to segregate individuals, including isolation, quarantine, sheltering, location-based community restrictions, and travel restrictions, are less likely than voluntary measures to be recommended, especially over the longer-term. InsteadThe demand for scientific evidence on non-pharmaceutical public health interventions for influenza is pervasive, and policy recommendations must rely heavily on expert judgment. In the absence of a definitive science base, our assessment of the evidence identified areas for further investigation as well as non-pharmaceutical public health interventions that experts believe are likely to be beneficial, feasible, and socially and politically acceptable in an influenza pandemic. Taken together, the literature and expert opinion reveal the kinds of explicit judgments required to translate existing knowledge into policy-relevant terms. These findings should be considered in forming national, state, local, and facility pandemic plans.The author(s) declare that they have no competing interests.JEA designed and carried out the literature review, designed and conducted the expert panel and drafted the manuscript. NL conceived of the study, and participated in its design and coordination, conducted the expert panel, and helped to draft the manuscript. JW conceived of the study, and participated in its design and coordination, and helped to draft the manuscript. SAB designed the literature review, designed and conducted the expert panel, designed the follow-up expert survey and analysis plan, and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Search terms. The file contains a brief paragraph of the Medline search terms.Click here for fileComplete list of final articles reviewed and classified (N = 168). This file contains a complete list of the final set of articles from our search that were reviewed and classified.Click here for file


Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy–Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct or analysis. The rapidly evolving evidence on genetic associations is crucial to integrating human genomics into the practice of medicine and public health ,2. GenetDespite the many similarities between genetic association studies and ‘classical’ observational epidemiologic studies  of lifestyle and environmental factors, genetic association studies present several specific challenges including an unprecedented volume of new data ,6 and thAlthough several commentaries on the conduct, appraisal and/or reporting of genetic association studies have so far been published –39, theiDespite increasing recognition of these problems, the quality of reporting genetic association studies needs to be improved –49. For The main goal of this article is to propose and justify a set of guiding principles for reporting results of genetic association studies. The epidemiology community has recently developed the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement for cross-sectional, case-control and cohort studies ,56. GiveA multidisciplinary group developed the STREGA Statement by using literature review, workshop presentations and discussion and iterative electronic correspondence after the workshop. Thirty-three of 74 invitees participated in the STREGA workshop in Ottawa, Ontario, Canada, in June, 2006. Participants included epidemiologists, geneticists, statisticians, journal editors and graduate students.Before the workshop, an electronic search was performed to identify existing reporting guidance for genetic association studies. Workshop participants were also asked to identify any additional guidance. They prepared brief presentations on existing reporting guidelines, empirical evidence on reporting of genetic association studies, the development of the STROBE Statement and several key areas for discussion that were identified on the basis of consultations before the workshop. These areas included the selection and participation of study participants, rationale for choice of genes and variants investigated, genotyping errors, methods for inferring haplotypes, population stratification, assessment of Hardy–Weinberg equilibrium (HWE), multiple testing, reporting of quantitative (continuous) outcomes, selectively reporting study results, joint effects and inference of causation in single studies. Additional resources to inform workshop participants were the HuGENet handbook ,58, examIn Recommendation for reporting of methods [, item 8 frequencies and disease risks differ. When the groups compared in the study differ in their proportions of the population subgroups, an association between the genotype and the disease being investigated may reflect the genotype being an indicator identifying a population subgroup rather than a causal variant. In this situation, population subgroup is a confounder because it is associated with both genotype frequency and disease risk. The potential implications of population stratification for the validity of genetic association studies have been debated –83. ModeRecommendation for reporting of methods [, item 12A haplotype is a combination of specific alleles at neighbouring genes that tends to be inherited together. There has been considerable interest in modelling haplotype variation within candidate genes. Typically, the number of haplotypes observed within a gene is much smaller than the theoretical number of all possible haplotypes ,107. MotIn most current large-scale genetic association studies, data are collected as unphased multilocus genotypes . It is common in such studies to use statistical methods to estimate haplotypes –111 and Information on common patterns of genetic variation revealed by the International Haplotype Map (HapMap) Project  can be aRecommendation for reporting of methods [, item 12Hardy–Weinberg equilibrium has become widely accepted as an underlying model in population genetics after Hardy  and WeinP-value threshold were set. There is no consensus on the appropriate P-value threshold for HWE-related quality control in this setting. So, we recommend that investigators state which threshold they have used, if any, to exclude specific polymorphisms from further consideration. For SNPs with low minor allele frequencies, substantially more significant results than expected by chance have been observed and the distribution of alleles at these loci has often been found to show departure from HWE.For massive-testing platforms, such as genome-wide association studies, it might be expected that many false-positive violations of HWE would occur if a lenient P-values for each SNP are ranked in order from the smallest to the largest and plotted against the expected null distribution [For genome-wide association studies, another approach that has been used to detect errors or peculiarities in the data set  has been to construct quantile-quantile (Q/Q) plots whereby observed association statistics or calculated ribution ,130. TheRecommendation: State if the study is the first report of a genetic association, a replication effort, or both , item 3.Articles that present and synthesize data from several studies in a single report are becoming more common. In particular, many genome-wide association analyses describe several different study populations, sometimes with different study designs and genotyping platforms and in various stages of discovery and replication ,130. WheThe choices made for study design, conduct and data analysis potentially influence the magnitude and direction of results of genetic association studies. However, the empirical evidence on these effects is insufficient. Transparency of reporting is thus essential for developing a better evidence base . TranspaThe STREGA Statement proposes a minimum checklist of items for reporting genetic association studies. The statement has several strengths. First, it is based on existing guidance on reporting observational studies (STROBE). Second, it was developed from discussions of an interdisciplinary group that included epidemiologists, geneticists, statisticians, journal editors and graduate students, thus reflecting a broad collaborative approach in terminology accessible to scientists from diverse disciplines. Finally, it explicitly describes the rationale for the decisions  and has http://www.strega-statement.org/. We welcome comments, which will be used to refine future versions of the recommendations. We note that little is known about the most effective ways to apply reporting guidelines in practice and that therefore it has been suggested that editors and authors collect, analyse and report their experiences in using such guidelines [The STREGA recommendations are available at: idelines . We considelines . We emphWe hope that the recommendations stimulate transparent and improved reporting of genetic association studies. In turn, better reporting of original studies would facilitate the synthesis of available research results and the further development of study methods in genetic epidemiology with the ultimate goal of improving the understanding of the role of genetic factors in the cause of diseases.


Aaron Douglas, a native of Kansas, studied art in Nebraska before going to Paris and finally settling in New York City, where he became part of the flourishing art scene of the 1920s and 1930s known as Harlem Renaissance. Douglas drew inspiration from this powerful cultural movement that encompassed all fields of art and advocated celebration of African cultural identity and heritage  and African sculpture, was greatly influenced by German-born American artist Winold Reiss (1886–1953). Reiss, son of celebrated architectural designer Fritz Reiss, was a master painter of folk themes. His work captured ethnic and local characteristics in portraits of powerful universal appeal and showcased Pueblo and African cultures in the same way Paul Gauguin’s work showcased Far Eastern culture  allows uninterrupted concentration on the strict geometric definition of space. The transparent, overlapping geometric forms define the desired perspective. The ark is thrust to the foreground, preceded only by the prominent African mask, which firmly anchors the viewer into a geographic and chronological milieu. Sharp lightening strikes, terse animals heading for cover, and a focused crew advancing the vessel’s final course bespeak highest emergency.Cataclysmic disasters fill the pages of human history, from Moses to “the little Dutch boy.” The stuff of nightmares, these disasters touch a chord because they reach beyond individual tragedy to massive plight of global proportions. Like other universal themes, the ark derives its appeal from broad applicability: haven of last resort protects those inside from impending disaster for the greater good.Our times, plagued by (among other pestilences) the relentless emergence of global communicable disease, have constructed their own version of the ark, quarantine. But in this modern version, those sealed inside the vessel are not saved; they perish for the common good. Modern quarantine  protects the whole from the damaged parts. Still, the infected are sealed in the ark to ensure long-term survival of the herd.