Numerous studies have been conducted in developed countries to evaluate the impact of interventions designed to reduce hospital admissions or length of stay (LOS) amongst frail older people. In this study, we have undertaken a systematic review of the recent international literature (2007-present) to help improve our understanding about the impact of these interventions.We systematically searched the following databases: PubMed/Medline, PsycINFO, CINAHL, BioMed Central and Kings Fund library. Studies were limited to publications from the period 2007-present and a total of 514 studies were identified.A total of 48 studies were included for full review consisting of 11 meta-analyses, 9 systematic reviews, 5 structured literature reviews, 8 randomised controlled trials and 15 other studies. We classified interventions into those which aimed to prevent admission, interventions in hospital, and those which aimed to support early discharge.Reducing unnecessary use of acute hospital beds by older people requires an integrated approach across hospital and community settings. A stronger evidence base has emerged in recent years about a broad range of interventions which may be effective. Local agencies need to work together to implement these interventions to create a sustainable health care system for older people. There is an emerging consensus about the definition of frailty in older people and its association with increased hospital admissions due to falls, confusion and loss of mobility and with increased length of stay once admitted to hospital . FurtherIn this study, we have undertaken a systematic review of the recent international literature (2007-present) to help improve our understanding about the interventions which appear to work and those which have been less successful in reducing hospital bed use.We systematically searched the following databases: PubMed / Medline, PsycINFO, CINAHL, BioMed Central and Kings Fund library using the following search filters; older people/frail older people/elderly people/geriatrics and hospital admission rates/hospital length of stay/hospital bed use/early supported discharge/admission avoidance/intermediate care. Studies were limited to publications from the period 2007-present. A total of 514 studies were identified. Following a review of study abstracts, we excluded those which did not include older people or frail older people as the main target population, studies which only included older people with specific long-term conditions and studies of lower quality, for example, single case studies, audit studies and those which did not include a comparison population.A total of 48 studies were included for full review consisting of 11 meta-analyses, 9 systematic reviews, 5 structured literature reviews, 8 randomised controlled trials and 15 other studies . With only 1 exception , evidencWe assessed the impact of the studies based on the reported findings as follows: Positive - statistically significant positive impact on hospital admissions/readmissions and/or length of stay; Equivocal - some positive but not statistically significant impact; Negative - no impact. We classified interventions into those which aimed to prevent admission  intervenWe found evidence for the effectiveness of care coordination, preventive health checks and care home liaison in the prevention of admission to hospital. Within the hospital setting, there was an evidence for the effectiveness of geriatric assessment units and orthogeriatric units targeting frail older people in reducing the length of stay. For services which linked hospital- and community-based care, including discharge planning, information sharing and rehabilitation services provided in the person's home, there was an evidence of effectiveness in reducing length of stay and preventing readmission to hospital.There were a series of interventions where there was no evidence of impact on hospital bed use. These included multi-factorial falls prevention services, day hospital services, medication reviews, exercise programmes in the community, nutritional enhancement in hospital and nurse-led transitional care units.Our search for peer-reviewed publications about interventions for reducing hospital bed use by frail older people published since 2007 revealed a large number of studies. There may be further studies which were not captured by our search terms. As the majority of studies we identified were secondary reviews, our study covers a substantial body of evidence from peer-reviewed research on this topic.We have found that the evidence base has strengthened for many interventions in hospital and community settings. These include: targeted preventive health checks, care coordination for frail older people, when embedded within integrated health and social care teams, hospital geriatric assessment and orthogeriatric units, community-based rehabilitation services and better integration of acute and post-acute care through discharge planning and joined up information systems.We have found no evidence to support multi-factorial falls prevention services, community-based medicines reviews, day hospital services, exercise interventions in hospital and nurse-led transitional care, but there were fewer studies of these interventions. It may be that with further development, some of these interventions may prove effective. Studies of association have shown that falls , polyphaDespite huge expectations, telehealth and telecare have not been shown to be effective in the randomised trials. In a recently published randomised trial of telehealth  (the WhoOther factors associated with increased bed use include advanced old age ,61, poorEffective interventions had common features including anticipatory care targeting older people at risk of adverse outcomes in all settings and well-integrated multidisciplinary practice and inter-agency working. We conclude that services should be developed as a whole system including preventive care, acute hospital care and community care. A shared information system should be created to support patient flow through the system.Reducing unnecessary use of acute hospital beds by older people requires an integrated approach across hospital and community settings. A stronger evidence base has emerged in recent years about a broad range of interventions which may be effective. Local agencies need to work together to implement these interventions to create a sustainable health care system for older people.


Partitiviridae, Totiviridae, Endornaviridae, Chrysoviridae, and other related unclassified dsRNA viruses are generally associated with symptomless or persistent infections of their hosts. These characteristics indicate that samples or materials derived from eukaryotic organisms used to construct cDNA libraries and EST sequencing might carry these viruses, which were not easily detected by the researchers. Therefore, the EST databases may include numerous unknown viral sequences. In this study, we performed in silico cloning, a procedure for obtaining full or partial cDNA sequence of a gene by bioinformatics analysis, using known dsRNA viral sequences as queries to search against NCBI Expressed Sequence Tag (EST) database. From this analysis, we obtained 119 novel virus-like sequences related to members of the families, Endornaviridae, Chrysoviridae, Partitiviridae, and Totiviridae. Many of them were identified in cDNA libraries of eukaryotic lineages, which were not known to be hosts for these viruses. Furthermore, comprehensive phylogenetic analysis of these newly discovered virus-like sequences with known dsRNA viruses revealed that these dsRNA viruses may have co-evolved with respective host supergroups over a long evolutionary time while potential horizontal transmissions of viruses between different host supergroups also is possible. We also found that some of the plant partitiviruses may have originated from fungal viruses by horizontal transmissions. These findings extend our knowledge of the diversity and possible host range of dsRNA viruses and offer insight into the origin and evolution of relevant viruses with their hosts.Genome sequence of viruses can contribute greatly to the study of viral evolution, diversity and the interaction between viruses and hosts. Traditional molecular cloning methods for obtaining RNA viral genomes are time-consuming and often difficult because many viruses occur in extremely low titers. DsRNA viruses in the families,  The genome sequence of viruses can contribute greatly to the study of viral evolution, diversity and interactions between viruses and their hosts. Traditional methods for obtaining RNA viral sequences include the use of techniques such as dsRNA isolation, cDNA library construction and molecular cloning Birnaviridae, Picobirnaviridae, Reoviridae, Endornaviridae, Chrysoviridae, Partitiviridae, and TotiviridaeTotiviridae possess a monopartite genome encoding, in most cases, only a capsid protein (CP) and an RNA-dependent RNA polymerase (RdRp) Partitiviridae infect fungi, plants or apicomplexan protozoa and possess a bipartite genome separately encoding the CP and RdRp Chrysoviridae encompasses viruses with quadripartite genomes that code for RdRp, CP, and two unknown proteins P3 and P4 Endornaviridae comprise large dsRNAs encoding a single long polypeptide with typical viral RNA helicases (Hels), UDP-glucosyltransferases (UGTs), and RdRps Double-stranded (ds) viruses infecting eukaryotes are grouped into seven families: Partitiviridae. Indeed, recent phylogenetic analyses based on amino acid sequences of RdRps of partitiviruses suggest that partitiviral horizontal transmission between fungi and plants may have occurred The partitiviruses, totiviruses, chrysoviruses, and endornaviruses as well as other related unclassified dsRNA viruses do not have extracellular routes for infection and are transmitted vertically via cell division or horizontally via cell fusions. Therefore, it has been suggested that these viruses may have co-evolved with their hosts in silico cloning, a procedure of obtaining full or partial cDNA sequence of a gene by bioinformatics analysis, using the known dsRNA viral sequences as queries to search against NCBI Expressed Sequence Tag (EST) database. In this study, we obtained numerous virus-like sequences related to members of families Endornaviridae, Chrysoviridae, Partitiviridae, and Totiviridae. Many of them were discovered from eukaryotic lineages that were not known to be hosts to these viruses. Furthermore, we conducted comprehensive phylogenetic analysis with these newly identified virus-like sequences and known dsRNA viruses. Results from this study extended our knowledge of the diversity and possible host range of dsRNA viruses and offered insight into the origin and evolution of relevant viruses with their hosts.Considering that many dsRNA viruses are associated with symptomless or persistent infections of their hosts, samples or materials derived from eukaryotic organisms used to construct cDNA libraries for EST sequencing may carry viruses. Viral RNAs may have been cloned and sequenced together with host RNAs. Therefore, the EST databases may include numerous viral ESTs that are treated as contaminating sequences. These viral ESTs, however, are important to understand the host range and evolution of dsRNA viruses. With this in mind, we performed in silico cloning method, we obtained 91 virus-like sequences (contigs or singletons) that were most closely related to members of the family Partitiviridae  and sea radish (R. raphanistrum subsp. maritimus) have high sequence identity (>90% aa) to RdRp or CP of R. sativus cryptic virus 2 (RsCV-2) and RsCV-3, two partitiviruses reported in cultivated radish R. sativus-root cv. Yidianhong, respectively, suggesting that the same or similar viruses infected different host species.Most of these virus-like sequences shared low amino acid (aa) identities (<60%) with those of known partitiviruses, suggesting that they may represent new viral species in the Three partitivirus-like sequences were identified in the cDNA libraries of plant samples infected by fungi. These sequences were either from fungal viruses or plant viruses. In addition, since mycoviruses are commonly found in different species of endophytic fungi of grasses Totiviridae were discovered from cDNA libraries of plant, rust fungi, arthropods and diatoms  with known totiviruses, suggesting that they may represent the genomes of novel totivirus-like species.Eight virus-like sequences that were distinctly related to members of the family  diatoms . The CP-Antonospora locustae) also was related to these four plant viruses (Fourteen virus-like sequences from plant cDNA libraries were closely related to Southern tomato virus (STV) and three other related unclassified viruses isolated from plants  viruses .Artemisia annua) and garden zinnia (Zinnia violacea) (One chrysovirus RdRp-like and two p3 protein-like sequences were found in cDNA libraries of sweet wormwood (iolacea) . These tEndornaviridae from cDNA libraries of animals, protozoans, and plants  and pig roundworm (Ascaris suum) were most closely related to integrated viral sequences in animal genomes  but their phylogenies seem not to be topologically congruent with that of their hosts, suggesting that these plant partitiviruses may not be ancient origin. Considering that the branches of fungal viruses were generally locating at the base of plant viral clades  and 3, iOnychiurus arcticus) and slender oat (Avena barbata) clustered together in clade III (Schistosoma mansoni) and twisted-wing parasite (Mengenilla chobauti) were most closely related to those of certain fungal viruses in clade I and III  clustered with those of two fungal endornaviruses of Helicobasidium mompa and thereby possibly evolved from fungal viruses. The virus-like sequence from white spruce (Picea glauca) was distantly related to other endornavirus-like sequences, possibly representing a new dsRNA viral lineage related to endornaviruses.Phylogenetic analysis of endornavirus-like sequences shown that the plant viral sequences were generally clustered together and fungal viral sequences were generally branched at the base of plant viral clusters . This isectively . The virThe dsRNA virus-like sequences discovered here are either from integrated viral sequences or infecting viruses. Although it is not certain whether all of the virus-like sequences are indeed derived from the annotated host organisms, they may indicate the potential hosts for these viruses and extend the possible host range of viruses.Partitiviridae commonly occur in plants and fungi. To date, only one member of this family, the Cryptosporidium parvum virus 1, was found to infect apicomplexan protozoa of genus Cryptosporidium. The discovery of partitivirus-like sequences from animal cDNA libraries in this study together with our previous finding of endogenous partitiviral sequences in arthropod genomes Members of the family Totiviruses are known to infect fungi and protozoa and recently found in arthropods Chrysoviridae are fungi, Anthurium mosaic-associated virus, a chryso-like virus infecting monocots is available in the database. Furthermore, we discovered three chryso-like sequences from two dicot plant species, suggesting that plants also are possible hosts of chrysoviruses.Though the only known hosts of viruses in the family Endornaviruses were originally discovered in plants and later found in fungi and Stramenopiles Altogether, totiviruses and STV-like viruses have the broadest host range, including four of the five supergroups of eukaryotes: Unikonta, Plantae, Chromalveolata and Excavata Partitiviridae and Totiviridae have been revealed to be ancient and antedate the radiation of eukaryotic supergroups The partiti-, toti-, chryso-, and endornaviruses have similar features that they are transmitted vertically via spores and do not have extracellular routes for infection and have little or no effects on their hosts silico cloning approach, we discovered numerous novel virus-like sequences from NCBI EST database, representing members of families Partitiviridae, Totiviridae, Endornaviridae, and Chrysoviridae. The new sequences identified in this study are either from novel viruses or from known but yet unsequenced viruses. These viral sequences provide extended the potential host range of related viruses and help to shed light on their origin and evolution.In this study, by using the in Birnaviridae, Picobirnaviridae and Reoviridae. It is possible that samples for cDNA library construction containing viruses are easily detected due to the fact that these viruses generally cause serious disease on their hosts.We failed to find EST sequences similar to three other dsRNA families, in silico cloning approach may has a broad application prospect in plant virology. In fact, similar approaches were used to identify several families of plant positive-sense ssRNA viruses. Numerous EST sequences similar to these viruses were also found. Many of them may belong to new species or genera. We also found many plant virus-like sequences from cDNA libraries of insects and nematodes, suggesting new viral vectors or new host range for these plant viral lineages .This method we used seemed to be more effective for identification of plant viruses. Considering the extensive diversity of plant viruses and the rapid increase of plant EST sequencing, the in silico cloning approach for discovery of novel dsRNA viral sequences. By using this method, we obtained 91 partitivirus-like, 22 toti- or STV-like, 3 chrysovirus-like and 3 endornavirus-like novel sequences. Some of these virus-like sequences were discovered from eukaryotic lineages which are not known to be hosts for these viruses. Furthermore, phylogenetic analysis of these new virus-like sequences with those of known dsRNA viruses revealed that these viruses may have co-evolved with respective host supergroups over a long evolutionary time frame while potential viral horizontal transmission was also likely to be occurred between different host supergroups. The phylogenetic analysis also revealed that some of plant partitiviruses may have originated from mycoviruses by interkingdom host jumping. Our findings extend the diversity and possible host range of dsRNA viruses and offers insight into the origin and evolution of relevant viruses with their hosts.In this study, we demonstrated the application of the Birnaviridae, Picobirnaviridae, Reoviridae Endornaviridae, Chrysoviridae, Partitiviridae, and Totiviridae from viral genome databases at the NCBI website (http://www.ncbi.nlm.nih.gov/genomes/GenomesHome.cgi?taxid=10239). These viral sequences were then used as seed queries to search against the NCBI EST database by Netblast (blastcl3) program with tBLASTn strategy. All non-redundant matches from these searches with E-values≤1e-5 were extracted and were divided into different groups according to different sources of species. The ESTs in each group were used to construct contigs with CAP3 sequence assembly program where overlapping regions of EST sequences show at least 97% sequence identity. The resulting contigs and singletons were used as BLASTx queries against the non-redundant (NR) protein database to confirm the assembly quality and the relationships between these and the known viruses. If the contigs and singletons from one species have high sequence identity (95% DNA) with the reported viruses in the same species, these sequences were discarded and not analyses further. The analyses were completed by March 2011.We firstly selected and downloaded the protein sequences derived from representative viruses in each genus of dsRNA families, The software package DNAMAN 7  was used for sequence annotations, including nucleotide statistics and ORF searching. The putative peptides of viral contigs and singletons were obtained according to BLASTx hits and ORF predictions were checked manually. Multiple alignments of protein sequences were constructed using COBALT Maximum likelihood (ML) phylogenies were estimated using amino acid sequence alignments with PhyML-mixtures Data S1Summary of virus-like EST sequences obtained by cloning in silico.(XLS)Click here for additional data file.


Stem cells have the potential to generate a renewable source of cells for regenerative medicine due to their ability to self-renew and differentiate to various functional cell types of the adult organism. The extracellular microenvironment plays a pivotal role in controlling stem cell fate responses. Therefore, identification of appropriate environmental stimuli that supports cellular proliferation and lineage-specific differentiation is critical for the clinical application of the stem cell therapies.Traditional methods for stem cells culture offer limited manipulation and control of the extracellular microenvironment. Micro engineering approaches are emerging as powerful tools to control stem cell-microenvironment interactions and for performing high-throughput stem cell experiments.In this review, we provided an overview of the application of technologies such as surface micropatterning, microfluidics, and engineered biomaterials for directing stem cell behavior and determining the molecular cues that regulate cell fate decisions.Stem cells have enormous potential for therapeutic and pharmaceutical applications, because they can give rise to various cell types. Despite their therapeutic potential, many challenges, including the lack of control of the stem cell microenvironment remain. Thus, a greater understanding of stem cell biology that can be used to expand and differentiate embryonic and adult stem cells in a directed manner offers great potential for tissue repair and regenerative medicine. Stem cells are primitive cells found in many multi-cellular organisms. Self-renewal and potency are two defining properties of stem cells. Self-renewal is the ability to perform numerous cell cycle divisions, each resulting in two identical daughter cells, while differentiation potency defines the differentiation capability of stem cells into mature cell types. The two main categories of mammalian stem cells are: embryonic stem (ES) cells, which are derived from blastocysts, and adult stem cells, which are found in adult tissues. ES cells have the potential to differentiate into all mature cell types except extra embryonic tissue . ES cellHere, we provide a brief overview of the applications of micro scale technologies and their applications for regulating the behavior of stem cells.ES cell fates  are regulated by both intrinsic and extrinsic factors , 31. To The proliferation and differentiation of ES cells can be controlled by regulating homotypic (contact with the same cell type) and heterotypic (contact with other cell types) cell-cell contact. These interactions can be manipulated by patterning cells within geometrically defined adhesive regions on two-dimensional (2D) surfaces , 32, 33.Micro-fabricated parylene-C stencils were also used to pattern and immobilize ES cells  as well Micro scale technologies are enabling tools for directing stem cell differentiation and studying cell-matrix interactions, because they are able to generate miniaturized microarrays that can be used to perform high-throughput experiments. For example, a high-throughput polymer microarray was fabricated by using robotic spotters for analyzing various ES cell-biomaterial interactions . Within In vivo, cells are embedded in a 3D complex matrix with a well-defined geometry, which provides physical and chemical support and mediates the exchange of soluble nutrients and waste. To mimic living tissues, 3D scaffolds have been widely used in tissue engineering applications to provide cells with a suitable growth environment in vitro, with optimal oxygen levels, effective nutrient transport as well as physical and chemical cues . Micro-fAdult stem cells are an attractive cell source for regenerative medicine. Despite their significance, adult stem cells isolated from adult tissues exhibit limited proliferation capacity in vitro . The limCell patterning on 2D surfaces is important for directing adult stem cell fates , becauseThe design of patterned scaffolds which possess the ability to differentiate adult stem cells into various lineages is a promising approach for controlling stem cell behaviors. Previously, a layer-by-layer laser micro fabrication approach has been used to create spatially patterned scaffolds of photocrosslinkable polymers , 56. ThiSince these cells potentially have the ability to regenerate the smooth muscle cells of the vessel, they may be useful in various clinical applications. Overall, it appears that micro engineered scaffolds can be used to provide a 3D microenvironment for adult stem cells. In particular, the 3D microarchitecture of the stem cell niche in the body provides biological necessity to use scaffolds. The future of this research seems promising in generating micro scale scaffolds that can be used to study biological mechanisms of cell response as well as therapeutic tissue engineered constructs.Stem cells have enormous potential for therapeutic and pharmaceutical applications, because they can give rise to various cell types. Despite their therapeutic potential, many challenges, including the lack of control of the stem cell microenvironment remain. Thus, a greater understanding of stem cell biology that can be used to expand and differentiate embryonic and adult stem cells in a directed manner offers great potential for tissue repair and regenerative medicine. These challenges may be addressed by using micro engineering approaches such as surface patterning, high-throughput microarrays, microfluidics, and 3D biodegradable scaffolds . As it c


Many trace elements, among which metals, are indispensable for proper functioning of a myriad of biochemical reactions, more particularly as enzyme cofactors. This is particularly true for the vast set of processes involved in regulation of glucose homeostasis, being it in glucose metabolism itself or in hormonal control, especially insulin. The role and importance of trace elements such as chromium, zinc, selenium, lithium and vanadium are much less evident and subjected to chronic debate. This review updates our actual knowledge concerning these five trace elements. A careful survey of the literature shows that while theoretical postulates from some key roles of these elements had led to real hopes for therapy of insulin resistance and diabetes, the limited experience based on available data indicates that beneficial effects and use of most of them are subjected to caution, given the narrow window between safe and unsafe doses. Clear therapeutic benefit in these pathologies is presently doubtful but some data indicate that these metals may have a clinical interest in patients presenting deficiencies in individual metal levels. The same holds true for an association of some trace elements such as chromium or zinc with oral antidiabetics. However, this area is essentially unexplored in adequate clinical trials, which are worth being performed. Many trace elements, among which metals, involved as cofactors in myriads of biochemical-especially-enzymatic reactions. As such they play cardinal roles in many physiological processes, in particular immunity and metabolism. A good example to illustrate their important contribution is magnesium: low magnesium levels have been associated with increased type 2 diabetes ,2, whereTrace elements have been identified for long time as potential candidates for improving metabolic disorders like prediabetes  or diabetes. In parallel with increasing comprehension of cellular and biochemical mechanisms leading to-or aggravating- these metabolic disorders, identifying the cellular targets and sites of action of trace elements has reactivated interest in their therapeutic potential. Activation of insulin receptor signalling (chromium), antioxidant properties  or inhibition of phosphatases (vanadium) thus appeared promising in view of the key importance of these processes in glucose homeostasis and insulin sensitivity. Indeed insulin receptor/postreceptor signalling defects are considered to underlie glycemic dysregulation and insulin resistance, although the precise causal defects must still be unravelled ,5. PrediThe present review updates our actual state of knowledge about those five trace elements which have a therapeutic potential in insulin resistance and diabetes, describing their mechanisms of action and their efficacy in both animal and human investigations.The importance of chromium (Cr) for glucose metabolic regulation has been seen in clinical states of relatively severe Cr deficiency, characterized by impaired glucose tolerance, fasting hyperglycaemia and eventually lipid disorders ,11. SeveCr has no effect in healthy individuals and, because these are not Cr-deficient, there is no need for supplementation. Cr has been administered and tested in various forms such as Cr-chloride, Cr-nicotinate, Cr-proprionate, Cr-histidinate or Cr-picolinate, the latter being by far the best investigated form because of its solubility in water at neutral pH. However in acidic milieu it hydrolyzes and it has been shown that only about 1% of absorbed Cr is found in the bloodstream . Most ofSeveral mechanistic studies showed improvements in insulin receptor/postreceptor signalling, leading to increased glucose transport by enhanced activity of the hormone-sensitive GLUT-4 transporters. These effects can be due to the receptor itself, its control mechanisms or its immediate environment in the cell membrane. Cr-picolinate was shown to induce various effects: increase in AMPKinase and p38 MAPkinase activities , increasFinally, one should mention that Cr can bind directly to insulin, in particular to insulin dimers , therebyThe appearance of glucose intolerance or even fasting hyperglycaemia in demonstrated cases of Cr deficiency have rapidly led to investigations on the potential of Cr supplementation in insulin resistance and diabetes. Furthermore, diabetic patients have about 1/3 less Cr in various biological samples -33. The As for many therapeutic trials, concern must be raised as to the concentrations used. Especially in vitro and in animals studies are usually performed with irrelevant concentrations of the active compound, leading to so-called "pharmacological" effects. Accordingly these data should be viewed with appropriate caution. In vitro many beneficial effects of Cr salts have been reported for insulin resistance or diabetes; Cr chloride increased glucose transport in fat and muscle cells as well as in cardiomyocytes ,25,35. TIn animals Cr-picolinate reduced AUC for glucose in type1 diabetic rats . InsulinIn addition to positive effects on glucose and insulin metabolic profiles, some studies also reported reduction in triglycerides  and stimIn contrast to animal studies, human studies look much more controversial. This may be due to large differences in Cr administration protocols. Positive reports with Cr exist in type2 diabetics treated with sulfonylureas  or in coBased on mechanistic hypotheses (see below) the best application might be insulin resistance , although this is also controversial: reduction in insulin resistance was observed in diabetics ,59 but aZinc (Zn) is an essential micronutrient which has an important role in the functioning of hundreds of enzymes , in insuSevere Zn deficiency is not frequent but concerns have nevertheless been raised about Zn levels in diabetic patients because of increased excretion due to polyuria. Whereas some studies have reported Zn deficiency in type 2 diabetes ,76-78, oSeveral modes of action have been described to explain the improved action of insulin by Zn. It appears that Zn can have direct insulin-like effects, which may be due to inhibition of the important glycogen-regulating enzyme GSK3 . Other mZn is a remarkable antioxidant: it acts at specific sites where it can compete for iron and copper; it further binds to SH groups in proteins, protecting them from oxidation . Becauseof Zn for 3 months reduced proteinuria  is an adipokine which stimulates energy expenditure in skeletal muscle and brown adipose tissue, resulting in reductions in body weight, glycaemia, triglycerides and NEFAs as found in ob/ob mice. It increases the pancreatic insulin content and improves the glucose tolerance test . Its levZn-dithiocarbamate and a complex of Zn with garlic-originated allixin improved diabetes in KK mice ,112.Selenium (Se) is relatively well absorbed from diet, better so if it is in an organic form . It actsIn view of the potent antioxidant ,123 and In vitro Se inhibited hyperglycaemia or hyperinsulinaemia-induced expression of adhesion molecules via reduction in p38MAPkinase . It alsoIn type 1 diabetic rats Na-selenite protected mitochondria from oxidative stress . AnotherIn humans lower levels of sialic acid and triglycerides were reported in young adults having the highest dietary Se intake . ReductiVanadium (Va) has been known for about one century to possess antidiabetic properties . HoweverVa is usually described as "insulin mimetic", in view of several in vitro experiments looking at insulin receptor signaling. The most evident mechanisms is an inhibition of phosphotyrosine phosphatases, leading to increased phosphorylation of IRS-1, PKB, GSK3 and FOXO1 ,142. InhIn animals; many positive reports exist showing beneficial effects of various Va salts in mild or severe diabetes. For example, Va sulphate or more elaborated organic complexes such as bisoxovanadium [BMOV] have proven efficacy in both type 1 and type 2 models ,147. MorIn humans many trials were performed. However, as exposed in a review , almost Lithium (Li) is a complex trace element mainly used in neurological disorders and more particularly for treating mood and bipolar disorders. Its clinical management is difficult and Li is likely toxic ,157.The interest in Li is based on its ability to inhibit GSK3 ,159, a kIn vitro Li increased both basal and insulin-stimulated glucose transport, as well as glycogen synthesis in soleus muscle of insulin resistant, obese Zucker rats . The effIn vivo Li paradoxically increased glycaemia when administered intravenously to diabetic rats, as shown by increases in glucagon . AnotherAltogether these data do not support the use of lithium in diabetes despite a cellular target (GSK3) which is potentially of particular interest.As a whole, this review shows that trace element supplementation as monotherapy is of weak efficacy in diabetes and hardly efficacious in prediabetic states. The global outcome in humans is somewhat frustrating in view of the logical good expectations from mechanistic effects of these metals at key steps of glucose and insulin regulatory control . As suchAlthough surprisingly few data are available, our belief is that trace elements are of benefit in certain conditions: individual reports indeed suggest that they are of value in situations of trace element deficiency and possibly also in combination with either other trace elements or antioxidants or oral antidiabetics ,173. In The authors declare that they have no competing interests.NW wrote the manuscript and performed the literature review. JR revised the manuscript and made modifications of intellectual content. Both authors read and approved the final manuscript.


Pheochromocytomas are catecholamine producing tumors arising mostly from chromaffin cells of the adrenal medulla. The most common clinical presentation is hypertension, mainly in the form of paroxymal episodes. Cardiovascular manifestations include malignant arrhythmia and catecholamine cardiomyopathy, mimicking acute coronary syndromes and acute heart failure.There are reports of pheochromocytomas presenting as acute coronary syndrome and rapidly leading to cardiogenic shock; the failure of intensive medical treatment in these cases has prompted the need for emergency adrenalectomy as the only remaining option. We report on a case of complicated pheochromocytoma presenting as cardiogenic shock, in which emergency adrenalectomy was performed following a total lack of response to intensive medical treatment. Pheochromocytomas are catecholamine-producing tumors arising mostly from chromaffin cells of the adrenal medulla.The most common clinical presentation is hypertension, mainly in the form of paroxymal episodes. Cardiovascular manifestations include malignant arrhythmia and catecholamine cardiomyopathy, mimicking acute coronary syndromes and acute heart failure. Pheochromocytoma may constitue a clear medical emergency, and differential diagnosis poses a major challenge.There are reports of pheochromocytomas presenting as acute coronary syndrome and rapidly leading to cardiogenic shock; the failure of intensive medical treatment in these cases has prompted the need for emergency adrenalectomy as the only remaining option.The literature contains few papers discussing the emergency surgical treatment of pheochromocytoma. We report on a case of complicated pheochromocytoma presenting as cardiogenic shock, in which emergency adrenalectomy was performed following a total lack of response to intensive medical treatment.The patient was a 31-year-old male, with no known drug allergies. Pulmonary emphysema and an esophageal fistula had been diagnosed 7 years earlier. The patient had a recently diagnosed difficult to treat hypertension with bisoprolol and enalapril and for the last year had suffered exertional dyspnea  and a number of similar episodes classed as anxiety attacks.The patient came to the Emergency Service complaining of occipital headache, chest pain and tightness, palpitations, dyspnea and throat constriction, all of a few hours' standing; no sweating, nausea or vomiting.Findings at physical examination were blood pressure 144/85, heart rate 98, Sat O2 100%. The patient was conscious, alert, cooperative, eupneic at rest; with hydration and perfusion satisfactory. Neurological findings were normal, without nuchal rigidity. Cardiorespiratory examination revealed rhythmic heart sounds, without murmurs and normal breath sounds. Abdomen was soft, with normal sounds, non-tender, without megalies or masses and no signs of peritonism. Lower limbs did not show edema or signs of deep-vein thrombosis. Echocardiogram revealed sinus rhythm, 70 bpm, axis normal, no repolarization defects and chest X-ray had not significant findings.During his stay in the Emergency Unit, the patient was given sublingual lorazepam for suspected anxiety symptoms. He later displayed intense chest pain, vomiting and profuse sweating, a marked deterioration in general condition and poor peripheral perfusion. A repeat ECG revealed ST segment depression in V1, V2, V3 and V4 tracings. Troponine was elevated  and emergency vs. delayed surgery. Since no ECMO system was immediately available it was decided, following consultation with the duty surgeon and careful risk assessment , that emergency surgery should be performed.Under general anesthetic, an anterior peritoneal approach through left subcostal laparotomy incision was performed; following by careful separation of surrounding structures, early ligature of the ipsilateral adrenal vein and tumor removal plus adrenalectomy figure  AlthoughHistopathology was reported as a multifocal pheochromocytoma with focal necrosis and hemorrhage. Post-surgical clinical progress was good. The hydroelectrolytic balance was restored under constant monitoring. After 12 hours, the patient was extubated, the intra-aortic balloon was withdrawn and vasoactive amine thearpy was stopped. Five days after surgery, the patient was transferred to the ward, where oral tolerance therapy was started. He was then placed in the care of the Endocrinology Unit, for subsequent observation  has been reported in autopsy studies, suggesting that many tumors are missed, resulting in sudden death or premature mortality .Sporadic forms of pheochromocytoma are the most common (90%), and are usually diagnosed in individuals aged 40-50 years. However, hereditary forms can also occur, in association with familial syndromes ; these are usually diagnosed before age 40, and in most cases require genetic testing.Pheochromocytoma is often referred to as the great mimic, and differential diagnosis is rendered complex by the very wide range of clinical symptoms reported  Whilst pPheochromocytoma may present as a real medical emergency, mainly where there are complications . Some paThe serious and potentially lethal cardiovascular complications of these tumors are due to the potent effects of secreted catecholamines . PheochrOther cardiovascular complications of pheochromocytoma include sudden death, heart failure due to toxic cardiomyopathy, hypertensive encephalopathy, acute cerebrovascular accident or neurogenic pulmonary edema -10.The most appropriate diagnostic tests for patients with suspected pheochromocytoma remain a matter of some debate. Biochemical presentation of excessive production of catecholamines is an essential step for the diagnosis of pheochromocytoma. Traditional biochemical tests include meaurements of urinary and plasma catecholamines, urinary metanephrines (normetanephrin and metanephrine), and urinary vanillylmandelic acid (VMA); these tests have a sensitivity of over 76%. Measurements of plasma-free metanephrines (normetanephrine and metanephrine) represent a more recently available test. However, since catecholamine release is often paroxysmal, a single measurement may give a false sense of security. Sensitivity may be improved by repeating tests two or more times, and especially following a paroxysmal episode.Other valuable diagnostic procedures include nuclear magnetic resonance imaging  and radio-labeled metaiodobenzylguanidine (MIBG) scanning, due to the particular affinity of this substance for chromaffin tissues. Complete abdominal CT scan may be very valuable in emergency situations; given a strong clinical suspicion, the presence of an adrenal mass is highly indicative of pheochromocytoma.With regard to surgical treatment, elective surgery is the ideal option, accompanied by appropriate preoperative medical treatment; if the procedure is undertaken by an experienced anesthesiologist and a skilled surgeon, operative mortality is less than 1% . HoweverThe major aim of medical pretreatment is to prevent catecholamine-induced, serious, and potentially life-threatening complications during surgery, including hypertensive crises, cardiac arrhythmias, pulmonary edema and cardiac ischemia. Traditional management strategies include the blockade of alpha-adrenoceptors; phenoxy-benzamine is mostly preferred for this purpose, since it blocks alpha-adrenoceptors non-competitively, although doxazosin is also widely used. Other alternative drugs for preoperative management are labetalol  or calcium-channel blockers (dihydropiridines), used either alone or in combination with adrenoceptor blockers. Metirosine , which blocks catecholamine synthesis, is also occasionally used.Medical treatment usually lasts for around 10-14 days. The alpha-adrenoceptor blocker dose is periodically increased, and a beta-adrenoceptor blocker is added after the first few days of alpha-adrenergic blockade; this treatment is particularly useful in patients with tachyarrhythmias. Additional preoperative measures include increasing salt and fluid intake (to reduce the risk of orthostatic and postoperative hypotension), maintaining blood pressure at or below 160/90 mm Hg, reducing the frequency of ventricular extrasystoles (<1 every 5 minutes) and avoiding electrocardiographic ST segment changes and T-wave inversions for one week prior to surgery .Any rise in blood pressure during surgery can be controlled by bolus or by continuous infusion of phentolamine, sodium nitroprusside or nicardipine, whilst tachyarrhythmias can be treated by infusion of esmolol.Laparoscopic removal of adrenal and extra-adrenal pheochromocytomas is now the preferred surgical technique at experienced centers, since it reduces postoperative morbidity, hospital stay, and expense compared with laparotomy -15, withAfter surgery, patients need to be under close surveillance for the first 24 hours, either in a recovery room or in the intensive care unit. The two major postoperative complications are hypotension and hypoglycemia. Postoperative hypotension is due to the abrupt fall in circulating catecholamines after tumor removal in the continuing presence of alpha-adrenoceptor blockade (by phenoxybenzamine). Treatment consists of fluid replacement and occasionally intravenous ephedrine. If ephedrine infusion is ineffective, vasopressin might be used. The risk of hypoglycemia is related to rebound hyperinsulinemia due to the recovery of insulin release after tumor removal.Although there are few reports in the literature, tumor removal is known to prompt a reversal of cardiomyopathy and associated symptoms ,17; howeA number of authors have reported on the use of extracorporeal membrane oxygenation (ECMO) as a rescue strategy in patients with pheochromocytoma presenting with acute cardiogenic shock not responding to intensive medical treatment, as an intermediate step prior to elective surgery -20.With regard to the timing of surgery, a number of authors recommend emergency adrenalectomy whenever there is progressive deterioration of the patient's hemodynamic status or multiple organ failure despite maximal medical treatment ,22.The initial rapid differential diagnosis in a young patient displaying clinical symptoms of acute coronary syndrome progressing to acute heart failure led to diagnostic imaging procedures which revealed a complicated adrenal pheochromocytoma; emergency surgery was seen as the only viable option, given clinical evidence of cardiogenic shock not responding to inotropic sympathomimetic drugs or emergency implantation of intra-aortic balloon pump counterpulsation. Although the first option was to continue intensive medical therapy and apply extracorporeal membrane oxygenation, the patient's declining hemodynamic status - coupled with the fact that no ECMO system was immediately available - finally led to emergency surgery within the first 24-48 hours. Good perioperative anesthesia management and a laparotomy-based surgical approach - due to the patient's unstable condition - enabled tumor removal and, within a few days, complete reversal of clinical symptoms and progressive patient recovery. Therefore, we remark the importance of emergency adrenalectomy in patients with a complicated adrenal pheochromocytoma.Written informed consent was obtained from the patient for publication of this case report and anny accompanying images. A copy of the written consent is available for review by Editor-in-Chief of this journal.The authors declare that they have no competing interests.CL and OG conceived and drafted the article. JMS and SR participated in the design of the study and review the article. FJP, RC and CL operated the patient and review the case report.


Some patients with chronic ischemic left ventricular dysfunction have shown significant improvements of contractility with favorable long-term prognosis after revascularization. Several imaging techniques are available for the assessment of viable myocardium, based on the detection of preserved perfusion, preserved glucose metabolism, intact cell membrane and mitochondria, and presence of contractile reserve. Nuclear cardiology techniques, dobutamine echocardiography and positron emission tomography are used to assess myocardial viability. In recent years, new advances have improved methods of detecting myocardial viability. This paper summarizes the pathophysiology, methods, and impact of detection of myocardial viability, concentrating on recent advances in such methods. We reviewed the literature using search engines MIDLINE, SCOUPS, and EMBASE from 1988 to February 2012. We used key words: myocardial viability, hibernation, stunning, and ischemic cardiomyopathy. Recent studies showed that the presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and LV dysfunction, but the assessment of myocardial viability did not identify patients with survival benefit from revascularization, as compared with medical therapy alone. This topic is still debatable and needs more evidence. Coronary artery disease (CAD) remains a principal cause of morbidity and mortality worldwide . Many suThe first view of adaptation involves dedifferentiation or embryonic regression, the so called “smart heart” hypothesis . The proStunning is another form of reversible segmental myocardial dysfunction in the setting of normal myocardial perfusion. Heyndrickx et al.  observedClassically, hibernation was thought to occur with sustained hypoperfusion, especially during tachycardia but with adequate residual flow to allow survival of the tissue in the lack of contractile activity . In contIt was originally assumed that the recovery of function when hibernating myocardium is revascularized must indicate that structural changes are absent or minimal, as had been found in experimental models of stunned myocardium. However, since the early 1980s, it has been known that chronically dysfunctional myocardial segments demonstrate distinct morphological changes that can be verified by both the light and the electron microscope .One prominent feature of the changes seen in cardiomyocytes, by light microscope, is the loss of contractile material, which is replaced with an amorphous, strongly Periodic Acid-Schiff (PAS)-positive material typical of glycogen in addition to variable intracellular fibrosis , 20. TheThe differentiation of viable from nonviable myocardium is therefore highly relevant in patients who are being considered for revascularization . Many paQ waves on the ECG were originally thought to indicate full-thickness myocardial infarction (MI), but in fact, there is no relationship between the presence and extent of Q waves after MI and infarct size assessed by myocardial perfusion imaging, and up to 60% of regions with Q waves have viable myocardium detected by imaging techniques . Fragmennuclear imaging by Positron Emission Tomography (PET) ,nuclear imaging by Single-photon emission-computed tomography (SPECT) ,echocardiography with dobutamine (to assess contractile reserve),echocardiography with intravenous contrast agents (to assess perfusion),in addition, MRI with dobutamine (to assess contractile reserve), and MRI or CT with intravenous contrast agents (to assess scar tissue) are emerging as promising techniques.Ventriculography is the oldest imaging technique and is rarely used clinically today , 35. OthIt is obvious that each of these techniques can detect viability by assessing different factors of the myocardial tissue. The strength of PET as an imaging technique relies on the versatility of positron emitting radionuclides that can be integrated into important biochemical molecules. Not only can the distribution of these molecules be imaged, but their uptake can be quantified. In this way, it is possible to assess myocardial perfusion, glucose utilization, fatty acid uptake and oxidation, oxygen consumption, contractile function, and presynaptic and postsynaptic neuronal activity .Angiotensin converting enzyme (ACE) inhibitors have been radiolabeled and used in experimental systems to study the tissue ACE receptor system directly. Preliminary observations in explanted hearts from patients who had heart failure showed a relationship between binding of [18F]fluorobenzoyl-linsinopril and collagen replacement; ACE was absent in the collagen-stained areas and was increased in the juxtaposed areas of replacement fibrosis . The incSPECT imaging identifies viable and infarcted myocardium based on regional differences in radiotracer uptake, with segments classified as viable as a consequence of preserved mitochondrial function (technetium SPECT) or preserved membrane integrity  .Technetium-labelled tracers have advantages over thallium, such as a shorter half-life with lower radiation exposure to the patient, a higher energy gamma emission that reduces soft-tissue attenuation, more flexibility in imaging times after stress, and the potential for ECG-gated acquisition. However, unlike thallium, technetium tracers have significant redistribution, which necessitates 2 inject ions of the tracer (exercise and rest) for typical stress-rest protocols either on the same day or in two different days . This maTo enhance the ability of technetium SPECT imaging to detect viability, several methods have been used; some are technical  and other included pharmaceutical additives .Recently, Spadafora et al.  proposedThe VIA and REC maps were also represented as 3-D images. On the VIA map, segments with counts <20% of the peak activity were represented in black or dark blue indicating nonviable segments, whereas segments with counts ≥20% were considered hibernated. Similarly, on the REC map, segments with counts <20% of peak activity were represented in black or dark blue indicating regions without functional recovery, and segments with counts ≥20% of the peak were considered as showing functional recovery. The proposed polar map of myocardial viability obtained by gated SPECT imaging accurately predicts functional recovery after coronary revascularization .Bisi et al.  proposedβ-methyl-iodo-pentadecanoic acid (BMIPP) labeled with iodine-123, since it is metabolically trapped in the myocardium due to its methyl branching   , 83.Assessment of resting wall thickness and thickening by resting cine-MRI can be used to assess viability. The underlying hypothesis is that regions of myocardial thinning reflect chronic myocardial infarction. The combination of wall thickness and systolic wall thickening tend to improve the sensitivity and specificity of the technique . Cine-MRDE-MRI can concomitantly detect infarcted and normal myocardium within a given myocardial segment and thereby allows extent of viability to be assessed . The conDE-MRI has been found to be comparable to each of DSE, SPECT, and PET in several studies –93. HoweAlthough using contrast-enhanced CT to assess viability is not new, recent advances in its temporal and spatial resolution with multidetector CT (MDCT) technology have gained interest for this application . Recent Electromechanical endocardial mapping using a nonfluoroscopic catheter-based system (NOGA) was first described in 1996 . BecausePrior studies that evaluated the role of noninvasive imaging techniques in the detection of myocardial viability have focused on several clinical endpoints. These endpoints include: improvement in regional LV function (segments), improvement in global LV function (LVEF), improvement in symptoms , improvement in exercise capacity , reverse LV remodeling (LV volumes), prevention of sudden death (ventricular arrhythmias), and long-term prognosis . Improvement in function after revascularization is still considered the final proof of viability . From thThe proportions of viable segments needed for improvement in the LV EF differed among the studies. The available evidence (mainly using DSE) suggests that 20%–30% of the left ventricle needs to be viable to result in improvement in the LV EF . It is a99 m sestamibi SPECT before OAT randomization, with repeat imaging at 1 year. There were no significant differences in 1-year end-diastolic or end-systolic volume change between those with severely reduced versus moderately retained viability, or when compared by treatment assignment . In multivariable models, increasing baseline viability independently predicted improvement in LV EF (P = .005) but there was no interaction between viability and treatment assignment for any measure of LV remodeling [Another important endpoint in viability assessment is the prediction of LV remodeling, by comparing LV volumes before and after revascularization. Large trials with ACE inhibitors have shown that reverse LV remodeling is associated with improved survival. On the other hand, patients with predominantly scar tissue exhibited adverse LV remodeling, shown as an increase in both LV end-systolic and end-diastolic volumes. Therefore, surgery for patients with predominantly scar tissue did not result in reverse LV remodeling during followup . Udelsonmodeling .In the viability cascade, the areas with preserved response to dobutamine indicate a mild level of damage, which will usually allow adequate restoration of function following revascularization. For presumably more severe levels of damage, myocardial segments may be unresponsive to inotropic stress by dobutamine, but still can take up a significant amount of thallium. This is likely corresponding to a more advanced form of cellular damage, so that only those cellular functions that are strictly essential to cell survival (membrane integrity) are preserved .In a recent meta-analysis, all available studies of regional left ventricular function in patients with ischemic left ventricular dysfunction before and after revascularization were pooled . This anGenerally, the final endpoint in viability studies is the long-term prognosis. Several studies have evaluated the prognostic value of viability in relation to therapy. These studies consistently showed better prognosis in patients who had viable myocardium and were revascularized, suggesting that revascularization stabilizes the unstable substrate of dysfunctional but viable myocardium . Allman It should be noted, however, that medical therapy was not standardized in the studies analyzed by Allman and colleagues  and the Consequently, Camici and coworkers  pooled tIn a prospective study of 167 patients studied with FDG-PET, Desideri et al.  reportedThe Heart failure Revascularization trial (HEART) is a multicenter study of 800 patients with heart failure, LV EF <35% and evidence of CAD who are receiving optimal medical treatment followed for 5 years. The main aim was to determine whether surgical revascularization improves the survival of patients who have evidence of dysfunctional but viable myocardium . Only 13P = 0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P = 0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P = 0.53). The study concluded that although the presence of viable myocardium was associated with a greater probability of survival in patients with CAD and LV dysfunction, however the assessment of myocardial viability did not recognize patients who can benefit from CABG, as compared with medical therapy alone. This finding may reflect the low rates of death among patients with viable myocardium who received medical therapy alone in STICH study (~7% per year), as compared with previously reported rates [In a substudy from STICH trial  601 patied rates .Recently, Gerber et al. studied 144 patients with coronary artery disease and myocardial dysfunction and concluded that detection of functional viable myocardium by DE-CMR is an independent predictor of mortality in patients with ischemic LV dysfunction before revascularization. This observation may be useful for preoperative selection of patients for revascularization .In many of patients with CAD, the extent of remaining viable tissue is of clinical and prognostic significance. It can help to decide between revascularization and cardiac transplantation. Many subjects with heart failure and underlying coronary artery disease have an important amount of viable but dysfunctional myocardium, where myocardium keeps the ability to contract if perfusion improves. The dysfunctional viable myocardium has unique characteristics which form the basis for the different imaging modalities that are currently available for the assessment of myocardial viability. These modalities include different scintigraphic techniques, DSE, and recently MRI and CT modalities. Recent studies showed that the presence of viable myocardium was associated with a greater likelihood of survival in patients with CAD and LV dysfunction, but the assessment of myocardial viability did not identify patients with survival benefit from CABG, as compared with medical therapy alone. Assessment of myocardial viability alone should not be the deciding factor in selecting the best therapy. Whether the method of viability assessment or the underlying myocardial pathology and response, the determinant of optimal and appropriate mode of treatment is still debatable and needs more evidence.


The evolutionary theories of aging are useful for gaining insights into the complex mechanisms underlying senescence. Classical theories argue that high levels of extrinsic mortality should select for the evolution of shorter lifespans and earlier peak fertility. Non-classical theories, in contrast, posit that an increase in extrinsic mortality could select for the evolution of longer lifespans. Although numerous studies support the classical paradigm, recent data challenge classical predictions, finding that high extrinsic mortality can select for the evolution of longer lifespans. To further elucidate the role of extrinsic mortality in the evolution of aging, we implemented a stochastic, agent-based, computational model. We used a simulated annealing optimization approach to predict which model parameters predispose populations to evolve longer or shorter lifespans in response to increased levels of predation. We report that longer lifespans evolved in the presence of rising predation if the cost of mating is relatively high and if energy is available in excess. Conversely, we found that dramatically shorter lifespans evolved when mating costs were relatively low and food was relatively scarce. We also analyzed the effects of increased predation on various parameters related to density dependence and energy allocation. Longer and shorter lifespans were accompanied by increased and decreased investments of energy into somatic maintenance, respectively. Similarly, earlier and later maturation ages were accompanied by increased and decreased energetic investments into early fecundity, respectively. Higher predation significantly decreased the total population size, enlarged the shared resource pool, and redistributed energy reserves for mature individuals. These results both corroborate and refine classical predictions, demonstrating a population-level trade-off between longevity and fecundity and identifying conditions that produce both classical and non-classical lifespan effects. The evolutionary theories of aging attempt to explain why natural selection would favor the almost ubiquitous evolution of senescence, a process which markedly decreases Darwinian fitness. Classical theory can be subdivided into three distinct yet analogous perspectives – Medawar's “mutation accumulation,” Williams's “antagonistic pleiotropy,” and Kirkwood's “disposable soma” theories Drosophila melanogaster, a decrease in longevity and earlier peak fecundity can be directly selected for by increasing extrinsic mortality levels Nothobranchius from a dry region exhibited shorter captive lifespans than those from a humid region These three classical theories all predict that extrinsic mortality levels should be inversely correlated with evolved lifespan. Non-classical theories, in contrast, predict that increased extrinsic mortality could select for the evolution of longer lifespans. Field observations have shown that opossums from an insular, low-predation population exhibit reduced litter sizes and delayed senescence compared to a mainland, high predation population Caenorhabditis remanei, increasing random versus condition-dependent extrinsic mortality had differential effects on evolved lifespan: High random mortality selected for a shorter lifespan while high condition-dependent mortality (induced by heat stress) engendered nematodes that were longer lived. No obvious effects on reproduction were observed for nematodes subjected to either type of mortality Although corroborative of a role for extrinsic mortality in driving the evolution of aging, other studies challenge the classical predictions. In guppies derived from natural populations, fish from high predation localities exhibited earlier maturation ages, enhanced swimming performance, and delayed senescence compared to fish from low predation sites Both modeling and empirical data show that extrinsic mortality can lead to the evolution of either increased or decreased intrinsic mortality. Outside of age-class specificity To test which (if any) conditions can lead to the evolution of an increase or decrease in average longevity, we used simulated annealing optimization We studied the evolution of aging in populations using a stochastic agent-based iterative computational model subject to randomness associated with foraging, mate selection, mating success, predation, inheritance of intrinsic longevity and maturation times, and starvation. In addition to inherent random fluctuations, populations were allowed to evolve over time as individuals with more favorable energy allocation mechanisms were more likely to pass on their intrinsic longevity and maturation times to their offspring . We derii, keeps track of energy level  or decreased lifespans , we derived a stochastic agent-based computational model starting from energy allocation assumptions. To start, we assumed that each individual, i, calculates energy costs  we calculated the fractional size of an individual at any point in time, By assuming that the energy required to grow at each iteration is proportional to the current size, and allowing for an energy conversion modifier  and females were required to be non-gestating (not currently mated). Mating resulted in the expenditure of energy, i becomes pregnant was defined to decrease linearly as a function of age after maturation according to:After accounting for intrinsic energy costs and death effect, surviving, mature females were mated with surviving mature males. Since we assumed that the total lifespan of individuals in the model is relatively short (on the order of 100 iteration rounds), we assumed for simplicity that all eligible individuals have sufficient time to find suitable mates during each iteration round. We imposed energy requirement for individuals to engage in mating behavior: both females and males were required to be non-starving  were discarded without temperature changes. At the end of the simulated annealing procedure, the set of parameters that resulted in the highest recorded score were selected for more detailed simulations and analysis. For a set of simulation-invariant parameters and their allowed ranges see To explore which conditions can lead to a non-classical or classical response to increased extrinsic mortality, we implemented a computational model of an evolving population of individuals subject to shared resources, sexual reproduction, extrinsic density-dependent death from predation, extrinsic death from starvation, and intrinsic inheritable somatic repair rates . AdoptinmateThreshold) is energy needed to eligible for mating, growth efficiency .Specifically, lower average intrinsic death times evolved when energy (food) turnover was relatively low (mateThreshold = 4.70) and mating cost , which was allowed to vary freely between six different types  during tAfter identifying unique conditions impacting the evolution of aging, we analyzed how various statistics were affected by different levels of predation. We refer to classical conditions as conditions which favor a decrease in lifespan in response to higher predation. Conversely, we refer to non-classical conditions as conditions which result in the evolution of an increase in lifespan in response to higher predation. Under classical conditions, rising levels of predation selected for the evolution of shorter mean lifespans  to evolve longer lifespans if food is plentiful and the environment is relatively stable. While controlling food availability is relatively straight forward, various strategies could be employed to adjust the costs associated with mating. Mutations known to enhance or impede reproduction could be introduced or, alternatively, populations could be grown in such a way that the probability of male and female interaction is greatly reduced and/or requires higher energetic costs . Organisms with different mating efficiencies could also be collated in response to increased extrinsic mortality.Aging is a multifarious process marked by epigenetic alterations, telomere shortening, genomic instability, exhaustion of stem cells, defective proteostasis, and other complex and interacting factors. It is also believed to underlie a plethora of age-related ailments such as cancer, Alzheimer's disease, and diabetes Figure S1Graphical depictions of various repair cost functions over time. The shape of the repair function was allowed to change during the simulated annealing optimization. The repair function determines the per-iteration energy cost for maintaining a specific (TIF)Click here for additional data file.Figure S2Different values of predation modifier more commonly caused population extinction then others. The probability of survival, as a function of time, is shown for differently predated populations under classical (A) and non-classical (B) conditions (n = 400). Under classical conditions, a value of 0.02 for predation modifier, A). Under non-classical conditions, a predation modifier of 0.04, followed by 0.02, was most commonly associated with population extinction.(TIF)Click here for additional data file.Figure S3Classical and non-classical effects were qualitatively unchanged when fertility increased with age. To test if an increasing fertility with age could lead to the evolution of increased lifespans, simulations were carried out where individual probability of successful mating was age-independent, but the number of offspring increased linearly with age post-maturation. Average (n = 400) final population average Tmat and Tdie values are shown assuming classical , and non-classical  conditions.(TIF)Click here for additional data file.Figure S4Changes in evolved lifespan and maturation age are accompanied by corresponding shifts in post-juvenile (mature) energetic investments. Under classical (A and B) and non-classical conditions (C and D), the amount of energy devoted to somatic maintenance and reproduction by mature individuals is shown. Under classical conditions, rising levels of predation caused individuals to invest less in somatic maintenance (A) and more into reproduction (B). Under non-classical conditions, larger values of predation modifier, C). Investments in reproduction decreased with increasing values of predation modifier, D).(TIF)Click here for additional data file.Figure S5Per-iteration predation rates evolved under classical and non-classical conditions. Populations subjected to increased extrinsic mortality evolved increasing (A) or decreasing (B) per-iteration probability of death by predation under classical or non-classical conditions, respectively. Graphs show the per-iteration probability of predation as a function of predation modifier, x, and is normalized for population density.(TIF)Click here for additional data file.


Recognizing objects despite infinite variations in their appearance is a highly challenging computational task the visual system performs in a remarkably fast, accurate, and robust fashion. The complexity of the underlying mechanisms is reflected in the large proportion of cortical real-estate dedicated to visual processing, as well as in the difficulties encountered when trying to build models whose performance matches human proficiency.The articles in this Research Topic provide an overview of recent advances in our understanding of the neural mechanisms underlying visual object perception, focusing on integrative approaches which encompass both computational and empirical work. Given the vast expanse of topics covered in the discipline of computational visual neuroscience, it is impossible to provide a comprehensive overview of the field's status-quo. Instead, the presented papers highlight interesting extensions to existing models and novel insights into computational principles and their neural underpinnings. Contributions could be coarsely subdivided into three different sections: Two papers focused on implementing biologically-valid learning rules and heuristics in well-established neural models of the visual pathway  to improve flexible object recognition. Three other studies investigated the role of sparseness, selectivity, and correlation in optimizing neural coding of object features. Finally, another set of contributions focused on integrating computational vision models and human brain responses to gain more insights in the computational mechanisms underlying neural object representations.A key challenge our visual system faces is a trade-off between discrimination and generalization. It should be able to discriminate an encountered object from a myriad of possible alternatives. Yet, it has to generalize across different instances of the same object, or, in other words, be invariant to so-called “identity-preserving transformations”  model “VisNet”  can simultaneously arise as properties of modeled V1 receptive fields by reinforcing diversity  during the training of a restricted Boltzmann machine . Relatedly, Gladilin and Eils discuss the behavioral and neural importance of (phase) correlation in visual input.Interestingly, the findings presented by Human neuropsychological and neuroimaging studies have consistently identified brain regions involved in object recognition. Nevertheless, our current understanding of ongoing computations and feature representations within these areas is rather limited.Aminoff et al. demonstrate that fMRI activation-patterns within scene-selective brain regions, such as the parahippocampal (PPA) and occipital place area (OPA), correlated most strongly with computer-vision models incorporating semantic features. In comparison, correlations were lower for models representing low-level features and for behavioral similarity scores. Conversely, the activation-pattern observed in the retrosplenial complex (RSC) was more in line with one of the low-level models and did correlate with subjective similarity ratings. Although encouraging, the results also clearly indicated that the overall correspondence between empirical and modeled responses was weak, suggesting that we still lack a clear grasp on cortical feature representation. One such feature, visual texture, is further explored in the contribution by Liu et al. using behavioral methods and modeling.One way forward to unravel the identified regions' inner workings is to compare the similarity across neural response patterns elicited by a given stimulus set to the similarity in output of a range of computer-vision models (with different feature extractions) when presented with the same stimulus set. Using this exploratory strategy, Lescroart et al. They compared how well three encoding models, based on different scene-defining feature classes, could voxel-wise predict neural representations in scene-selective brain regions. The encoding models mapped a diverse set of natural images to three qualitatively different feature spaces: 2D-features related to Fourier-power, the subjective 3D—distance to salient objects in the scene, and a more abstract, semantic scene description (“object-categorization”). In line with Aminoff et al. the object-category model provided a better prediction of PPA and OPA activity compared to the other two encoding models which did not include semantic features. In addition, RSC activity was more accurately predicted by the object-category model than the Fourier-power model, but the object-category model and the 3D-distance model performed equally well. Although, results of both studies suggest a different feature representation for scenes in RSC compared to PPA and OPA, it should be noted that feature representations in all areas are more complex than captured by the applied computer-vision and encoding models. Response variance explained by the models was largely shared in the fMRI data of Lescroart et al. To which extent this reflects an actual combined representation of the model's different feature classes, or alternatively the high correlation between these feature spaces in natural images, could be further explored by follow-up studies using stimulus sets with reduced feature covariance . Furthermore, such studies might attempt to establish new encoding models based on feature spaces inspired by feature representations in high-level computer-vision models  or deep neural nets , but also non-spatial attention contributes to an efficient read-out of neural representations by altering the corresponding feature space. In particular, during visual search for objects in a movie, fronto-parietal and occipito-temporal activations become tuned toward the attended object-category, expanding representations of this and semantically related categories, at the cost of unattended categories  predicts human visual search efficiency: targets were more easily identified when subjects were previously adapted to surrounding distractors containing contrastive features represented in neighboring cortical columns. This relates to neural simulations in the contribution of Borji and Itti, suggesting that feature similarity between target and distractors affects whether attention modulates (combinations of) neural gain, shifts in tunings, or sharpening of tunings, to allow for the most informative representations of important stimulus features. Moreover, the employed attentional mechanisms were influenced by task requirements , providing a further demonstration of the adaptive nature of feature representations optimized for fast and efficient read-out by higher-level areas. Adding such cognitive top-down influences that warp feature spaces according to salience and relevance, employing vision models with recurrent connections, and defining specific encoding models for each processing stage remains challenging, yet appears necessary for a profound understanding of object representations in the primate brain.However, even the most optimal feature representations based on such approaches currently miss an important ingredient that might be essential for our fast and efficient object recognition: feature representations in the brain are dynamically influenced by task demands. We actively engage in a dynamical world, intentionally searching for and interacting with objects, rather than passively observing static sceneries. Several aforementioned contributions highlight specific aspects of such active perception, and more aspects can be distinguished. For example, to selectively process objects of interest over distracting information, we can use (c)overt spatial attention to constrain computations  or features can be compared to activation patterns in pre-localized brain regions using similarity estimates . Recently, Khaligh-Razavi et al. (Combining computational and empirical efforts to reveal the neural mechanisms underlying visual object recognition has recently gained momentum. There has been a vast increase in studies employing encoding models to understand how input, transformed to an abstract feature space, predicts measured neural activity. The variety of models under investigation has expanded, ranging from low-level visual descriptors to models that incorporate high-level semantic features. Moreover, advances in high performance computing made it possible to move beyond predefined sets of features, to feature spaces learned from huge and diverse sets of natural world images using deep-learning techniques. Comparing different feature spaces to neural activity can be performed for each measure unit separately (e.g., for each fMRI voxel, see i et al.  showed ti et al. .The advent of ultra-high field fMRI imaging, large-scale electrocorticographic grids, and dense electrode arrays will provide increasingly rich datasets to study neural activity-patterns with unprecedented detail, yet with sufficient coverage to track reformatting of feature representations from low- to mid- to high-level areas along the VVS. By capitalizing on these increasing opportunities to integrate advanced computer-vision models and large-scale, high-resolution neural datasets, future research can rely on an ever-expanding data mining toolbox to probe neural feature and object representations to uncover the underlying neural “vocabularies.”JP wrote the paper with assistance and approval from HO and RG.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Coordinated cell interactions are required to accomplish diverse complex and dynamic tasks of several tissues in vertebrates and invertebrates. Cell functions, such as intercellular propagation of calcium waves and spread of electrotonic potentials, are coordinated by cell-to-cell communication through gap junction channels (GJCs). These channels are formed by the serial docking of two hemichannels (HCs), which in vertebrates are formed by six protein subunits called connexins (Cxs). In humans, a gene family encodes 21 different proteins with a highly variable C-terminal where most posttranslational modifications occur. Among them protein phosphorylation and/or oxidation  induces functional changes.+, adenosine, and cyclic nucleotides) and uptake of metabolically relevant molecules . Additionally, a growing body of evidences shows that HCs are involved in important and diverse processes, such PGE2 release from osteocytes, glucose detection in tanicytes, T cell infection with AIDS virus, memory consolidation in the basolateral amygdala and release of nitric oxide from endothelial cells, among others. However, HCs can also play an important role in the homeostatic imbalance observed in diverse diseases. In fact, enhanced HCs opening induces or accelerates cell death in several pathological conditions. Hemichannel-mediated cell death is due mainly to Ca+2 influx and cellular overload. The latter activates proteases, nucleases and lipases, causing irreversible cell damage. Accordingly, blockade of HCs reduces the cellular damage observed in several animal models of human diseases. Additionally, another family of proteins called pannexins (Panxs) also forms channels at the plasma membrane and some of their functional and pharmacological sensitivities overlap with those of Cx HCs. Recently, Panx channels have been involved in both pathological and physiological processes. Therefore, Cx HCs and Panx channels appear as promising drug targets for clinical treatment of several inherited and acquired human diseases.Currently, it is believed that undocked HCs may have functional relevance in cell physiology allowing diffusional exchange of ions and small molecules between intra- and extra-cellular compartments. In support to this new concept, it has been shown that controlled HC opening allows the release of small signaling molecules (e.g., ATP, glutamate, NADThis research topic gathers 11 articles that give a broad view about the role of Cx- and Panx–based channels from purified molecules reconstituted in a lipid environment and posttranslational regulation, to physiological and pathological implications. In addition, it proposes a putative molecular explanation of HC malfunctioning in specific diseases.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ovarian cancer remains the most common cause of gynecologic cancer-related death among women in developed countries. Nevertheless, subgroups of ovarian cancer patients experience relatively longer survival. Efforts to identify prognostic factors that characterize such patients are ongoing, with investigational areas including tumor characteristics, surgical management, inheritance patterns, immunologic factors, and genomic patterns. This review discusses various demographic, clinical, and molecular factors implicating longevity and ovarian cancer survival. Continued efforts at identifying these prognosticators may result in invaluable adjuncts to the treatment of ovarian cancer, with the ultimate goal of advancing patient care. There has been significant progress in the management of ovarian cancer, yet the disease still has the highest mortality of all pelvic malignancies combined. In the United States, in 2013, approximately 22,000 new cases of ovarian cancer will be diagnosed and over 14,000 women will die due to the disease .The disparity in prognosis is largely a function of disease stage, which is the most important prognostic variable for ovarian cancer survival. However, a subgroup of patients is seemingly cured after standard therapy. Studies have also concentrated on the prognostic importance of tumor characteristics, surgical conditions, and demographic factors. More recently, attention has focused on the significance of molecular features, which are considered a reflection of tumor biology and might thus be utilized to predict response to various therapeutic modalities and determine the long term survival.Age is a widely accepted prognostic factor of ovarian cancer , 7. GeneThe Gynecologic Oncology Group adopted the Eastern Cooperative Oncology Group/World Health Organization scoring criteria for quantitative assessment of a patient's general health at the time of cancer diagnosis and prior to the start of treatment. Based on this system, the following performance status scores are given : 0 is asA better performance status generally confers a greater tolerance to various therapeutic modalities, from surgery to chemotherapy, and perhaps motivates the adoption of a more aggressive treatment plan by clinicians. Several studies support this rationale and confirm the independent prognostic significance of performance status , 13–15.Staging systems describe the severity of a patient's cancer in a terminology that is shared across medical disciplines. While staging was originally developed to optimize treatment planning, a lower stage at diagnosis generally translates into a superior clinical outcome and improved survival , 16. TheFrom a clinical perspective, a higher stage signifies more extensive disease that is less likely to be optimally debulked, compared to a tumor that is confined to the pelvis. The radical surgeries needed to achieve optimal surgical debulking in extra-pelvic (stage III) and extra-abdominal (stage IV) disease also correlate with a higher incidence of perioperative morbidities. Additionally, the presence of a malignant pleural effusion, in the absence of any other criteria for stage IV disease, indicates a significantly poorer prognosis compared to stage III disease ; this fiAscites distinguishes a poorer prognosis in early-stage disease, contributes to the morbidity associated with advanced disease and is thus an important component of the FIGO staging system. Stage I and II diseases are upstaged to subclass C when there are malignant cells detected in ascitic fluid. In terms of management, patients with early-stage disease and ascites cannot be surgically cured. Ascites is thus considered a marker of unfavorable prognosis in early-stage disease and studies suggest that these patients should receive adjuvant chemotherapy following surgical debulking. However, optimal treatment for early-stage disease remains to be determined –27. ConsThe degree of cellular differentiation, or tumor grade, has long been considered a factor influencing tumor behavior and affecting survival. This understanding derives from the fact that poorly differentiated cells represent a higher degree of aberrant mitoses, which equates with a more aggressive cancer cell behavior. However, studies conflict over the association between tumor grade and clinical outcome , 33, 34.A paradigm shift has recently occurred in the classification of ovarian cancer. Based on morphologic and molecular features, epithelial ovarian cancer is recognized as a diverse group of tumors, amenable to a dualistic classification model. Type I tumors include low-grade serous, low-grade endometrioid, clear-cell, mucinous, and transitional cancers. Type II tumors include high-grade serous, undifferentiated, and malignant mixed mesodermal cancers. Type I tumors generally demonstrate slower growth and a lower stage at diagnosis; these tumors also tend to lack mutations involving TP53 and are generally not sensitive to platinum-based chemotherapy. Cell types reflect differences in underlying molecular profile and thus in sensitivity to current chemotherapy. Type II tumors display an aggressive nature and are usually advanced in stage at diagnosis; the majority of these tumors harbor TP53 mutations and are initially sensitive to platinum-based chemotherapy. Platinum sensitivity is pivotal to the treatment of advanced ovarian cancer, for which platinum-taxane combination chemotherapy remains the standard of care following surgical debulking. Tumor-cell type is shown to be the most relevant histologic prognostic factor in advanced ovarian cancer treated with platinum/paclitaxel .Recent studies indicate that low-grade serous carcinoma has a significantly better prognosis than high-grade serous carcinoma , 42. In An extensive United States population-based study demonstrated an association between increased body mass index (BMI) and increased risk of death from all cancers. This study further reported a direct relationship between increasing BMI and increasing risk of mortality from ovarian cancer; women with a BMI of 35 and above had a relative risk of death of 1.51 compared to women with a normal BMI . HoweverIn accordance with a Gompertzian model of general tumor kinetics, a greater initial surgical reduction of tumor burden results in improved 5-year survival with adjuvant chemotherapeutic regimens. This understanding is based on the concept that the growth fraction of a tumor decreases with time; hence, chemotherapy destroys tumor cells based on where a tumor is on its growth curve. Smaller tumor volumes are more readily destroyed than larger volumes because the growth fraction of the smaller volume is higher and thus the fractional cell kill by a chemotherapeutic agent is also higher , 58. TheA recent Cochrane Database Review evaluated the effectiveness of optimal primary cytoreductive surgery for women with advanced epithelial ovarian cancer and assessed the impact of various residual tumors sizes on overall survival . AnalyseIndeed, it has recently been shown that innate tumor features determine cytoreductibility of women with ovarian carcinoma; preoperative CA-125 and P53 can determine if the tumor would be cytoreductible or not. According to a multivariate analysis, patients with tumors that strongly express p53 are significantly less likely to achieve complete cytoreduction than the patients whose tumors had mild or moderate p53 expression .Surgeon subspecialization also impacts the success of initial cytoreductive surgery and survival. Patients with early and advanced-stage disease are both more likely to receive optimal cytoreduction and more likely to experience improved median and overall survivals when operated on by a gynecologic oncologist .The success of neoadjuvant chemotherapy is also an important prognostic factor for patients with ovarian cancer who are not candidates for primary surgical debulking due to the extent of their disease. Unfortunately, some of these patients are refractory to initial treatment and therefore incur a poor prognosis. A recent retrospective study was published that evaluated actionable targets in patients who received neoadjuvant chemotherapy prior to surgical debulking. Of note, hepatocyte growth factor (HGF) and its receptor c-MET were enhanced in those with aggressive ovarian cancer and were associated with refractory disease . The HGFPrognostic factors in recurrent ovarian cancer slightly differ from the primary tumors of the same type. Several studies using multivariate analysis with age, histology, grade, and residual tumor after first-look surgery have demonstrated that residual disease after initial surgery is the main factor significantly related to survival in patients treated with second look laparotomy. Accordingly, cytoreduction at second look laparoscopy will benefit survival only if microscopic residuals remained and this effect is only seen in those patients who start with less than 1 cm of disease. Also tumor grade was associated with survival in recurrent ovarian cancer –72. In rAdditionally, several molecular studies have shown differential expression of few genes in long-term survivors. In this regard, the MAL (myelin and lymphocyte protein) gene, implicated in conferring resistance to cancer therapy, is differentially upregulated in short-term survivors (three-fold increase compared with long-term survivors and 29-fold increase compared with early-stage patients) . SimilarApproximately 5% to 10% of epithelial ovarian cancers are associated with an inherited genetic predisposition, of which there are two recognized syndromes, inherited in an autosomal dominant pattern: the breast and ovarian cancer syndrome, linked to mutations in the BRCA1 and BRCA2 genes and accounting for approximately 90% of hereditary ovarian cancer cases, and the hereditary nonpolyposis colorectal cancer syndrome, accounting for approximately 5% of hereditary ovarian cancer cases , 77. TheSeveral mechanisms can account for this seemingly paradoxical observation that harboring BRCA1 mutations leads to a better prognosis. Ovarian cancers associated with BRCA mutations, particularly BRCA1, present at a younger age compared to sporadic cases , 81. Whi+ cell counts, as well as those with higher CD8+ to CD4+ cell ratios [+ CD25+ T-cells, known as regulatory T-cells—a subset of T-cells with potent immunosuppressor activity, may predict poor clinical outcome [In the case of ovarian cancer, the protective role of the immune system has been demonstrated as a survival benefit conferred by tumor infiltrating lymphocytes , 95. Thil ratios . Notably outcome .+ T-cells. Although this downregulation of HLA class I has been correlated with higher tumor stage [Likewise, overexpression of certain human leukocyte antigens (HLAs) and underexpression of other HLAs have been implicated in the interaction of the host immune response and ovarian cancer cells. Overexpression of human leukocyte antigen-G (HLA-G) may serve as one of the mechanisms by which ovarian cancer cells evade immune surveillance , 98. HLAor stage , there ior stage , 100.The most frequently studied putative molecular biological prognostic factors in ovarian cancer are the tumor suppressor protein 53 (p53), the oncogenes epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2/neu). Results of a recent meta-analysis show that p53, EGFR, and HER-2/neu immunostainings do not have a strong direct relationship with survival, although likely their respective pathways do influence patient prognosis .α and their relation to patient survival and response to treatment. Both EGFR and P-pg enhancements were prognostic factors for poor overall survival (OS) and poor progression free survival (PFS). Of additional utility, LRP, P-pg, and TNF were shown to be possible targets that are associated with response to platinum-based chemotherapy [Additional biomarkers have also been previously identified as potential targets to identify prognosis and appropriate adjuvant chemotherapy after surgical debulking; however, the results have been inconclusive. It seems that, due to these conflicting results, meta-analysis studies are very helpful. For example, a recent meta-analysis evaluated Bcl-2, EGFR, GST, LRP, p16, p21, P-pg, and TNF-otherapy .  Table otherapy .The application of novel approaches based on genomic and proteomic studies has made it possible to obtain a vast amount of data about the molecular platform on which tumors arise and grow. A better understanding of these mechanisms could prove to be invaluable in sketching a roadmap towards the individualization of cancer treatment, with the ultimate goal of developing the least toxic treatment regimens to improve survival. Recently, The Cancer Genome Atlas (TCGA) project completed the first comprehensive genomic analysis of high grade serous ovarian cancer (HGS-OvCa), which accounts for the most ovarian cancer patient deaths. Using approximately 1500 intrinsically variable genes, The Cancer Genome Atlas Research Network found four clusters using unsupervised nonnegative matrix factorization that were termed “Differentiated,” “Immunoreactive,” “Mesechymal,” and “Proliferative.” These four clusters were not different regarding survival .Nevertheless, in accordance with previous studies, TCGA found that almost all HGS-OvCa tumors are characterized by mutations in the tumor suppressor gene TP53 –107. IntFurthermore, the development of novel agents based on actionable targets is dependent on their reproducibility. It has been reported that pathways and pathway-based genes are more reliable biomarkers compared to single gene markers as they are more stable and are better at identifying the subtype of cancer across data sets . AdditioAs a sight for the future, in order to standardize diagnosis and prognosis regimens, we see that there is a strong relation between future improvements and canonical biomarkers. Using well-recognized quantitative features to encode cancer and other phenotypes based on canonical biomarkers will connect different laboratories and give such ability to record marker-based data interchangeably among them. As a result, this relation, outcomes, and information will incorporate genomic cancer information as a matter of course, augmenting current cancer classification protocols and specifying the treatments protocols .This review covered various demographic, clinical, and molecular factors that influence the survival of patients with ovarian cancer. There is a concerted effort to better understand the basis of factors implicating the longevity with this disease at the clinical and molecular levels. Currently known factors affecting patient's outcome include age, performance status, and histopathologic subtype; however, new information regarding the patient's biomarkers is likely to generate the greatest predictor of patient outcome. Therefore, continued efforts at identifying prognosticators of survival may result in invaluable adjuncts to the treatment of ovarian cancer, with the ultimate goal of advancing patient care and survival.