Extracellular Vesicles in Gastrointestinal Cancers’. Functional macromolecules, including lipids, proteins and RNA species, are packaged in naturally nano-to-micro-sized extracellular vesicles (EVs). Interestingly, they have been found in a wide range of biofluids, including plasma, saliva, gastric acid, bile acid, amniotic fluid and urine, and are released by many different cell types . The authors analysed the protein content of EVs derived from the NOZ and OCUG-1 cell lines using liquid chromatography coupled to tandem mass spectrometry. The authors identified a total of 110 abundantly expressed proteins in both cell lines. The bioinformatics analysis of these proteins using the STRING tool revealed that ‘cell adhesion molecule binding’, ‘integrin binding’ and ‘cadherin binding’ are among the top molecular functions while ‘focal adhesion’ is among the top pathways associated with the EV proteins. The authors found the differential abundance of 42 proteins, including haptoglobin (HP), in GBC tissue. They reported that HP, as a representative example, was elevated in GBC patient plasma. Analysis of the receiver operating characteristic (ROC) curve for GBC versus controls revealed an area under the ROC curve (AUC) of 0.8265 for HP. This study raised the prospect that HP and other candidate proteins could be explored for potential clinical use in GBC diagnosis.This Research Topic aims to highlight the roles, mechanisms of action and potential applications of EVs in GI cancers. Ge et al. reviewed the recent findings regarding the role of bacteria-derived EVs in the pathogenesis and treatment of GI cancers. Outer membrane vesicles (OMVs) are a subtype of EVs produced by gram-negative bacteria. They are exosome-like particles that burst from the outer membrane and have been found to play crucial roles in a variety of bacterial life processes, including regulation of microbial interactions, promotion of pathogenesis, stress responses and biofilm formation. The authors summarised EVs of digestive tract microorganisms and their application in the treatment of digestive tract diseases. Bacterial EVs are highly immunogenic due to the presence of pathogen-associated molecular patterns (PAMPs) in bacteria, which allows them to recruit and activate immune cells at tumour locations. The anti-tumour efficacy of immunotherapy can be improved synergistically by the addition of EVs. This combination dramatically inhibits tumour development compared with monotherapy.Besides, Cao et al. introduced tumour-derived exosomes (TDEs) and their function in various tumour immune microenvironments (TIME)-with a focus on GI cancers-and described the therapeutic strategies of exosomes in cancer immune-related therapy. Cancer cells and the immune microenvironment interact with one another. TDEs are crucial components of this equilibrium because they transport cargo from the original cancer cells and express complexes of MHC class I/II epitopes and costimulatory molecules. By analysing the specific expression and mechanism of exosomes derived from cancer cells, exosome-based targets represent a potential strategy for cancer immunotherapy. Improved strategies are needed to sort exosomes conveying genetic material. Meanwhile, enhanced extraction and detection techniques and more precise and stable strategies for modifying drugs delivered via exosomes are needed before exosome-based cancer immunotherapy could be used to treat patients.Xie et al. reviewed the function of exosomes in GI cancers as potential drug delivery systems. Exosomes can be used as drug delivery systems and have the potential to enhance the therapeutic efficacy of cancer treatments. Exosomes as nanocarriers have the advantages of small size, negative charge, immune evasion and deep tissue penetration, making them ideal natural nanocarriers for drug delivery. Exosome-based drug delivery systems inhibit tumour proliferation and metastasis in GI cancers, have the potential to surmount drug resistance and are advantageous for immunotherapy.Overall, this Research Topic has provided some updates on how EV-mediated intercellular communication can control the development of GI cancers or serve as a useful diagnostic biomarker. In addition, the potential of these EVs as drug delivery vehicles for the treatment of GI cancers has been highlighted, opening the door to a promising therapeutic alternative in the near future. EVs are quickly becoming an appealing tool that could eventually be used in individualised cancer diagnosis and therapy.Article writing and draft manuscript preparation: LL, YL, WC. Article modification: LL, WC, ZC, NH. All authors contributed to the article and approved the submitted version.


Morbidity and mortality from skin cancer continue to rise domestically and globally, and melanoma and non-melanoma skin cancers are a topic of interest in the dermatology and oncology communities. In this review, we summarize the stimulator of interferon genes (STING) pathway, its specific role in the pathogenesis of DNA damage and skin cancer, and STING-specific therapies that may fight both melanoma and non-melanoma skin (NMSC) cancers. Furthermore, we discuss specific portions of the STING pathway that may be used in addition to previously used therapies to provide a synergistic effect in future oncology treatments and discuss the limitations of current STING-based therapies. The multi-factorial burden of skin cancer continues to rise rapidly on both a domestic and international scale. Roughly 20 percent of United States citizens will have some form of skin cancer by age 70, and it is predicted that by the year 2030, the United States will have over 112,000 new cases of melanoma . EffortsAlthough multiple types of skin cancers exist, they can broadly be classified into two major categories: non-melanoma skin cancer (NMSC) and melanoma cancer (MC). Examples of non-melanoma skin cancer include basal cell (BCC) and squamous cell (SCC) carcinomas. NMSC has an estimated incidence of 18–20 times higher than melanoma; BCC and SCC make up 99% of NMSCs ,6. AlthoRecent advances in immunotherapy have brought forth new signaling pathways that are hypothesized to be directly linked to the pathogenesis of skin cancer. These have the potential to revolutionize oncological treatments of skin cancers and are gaining traction in both the dermatology and oncology communities. The stimulator of interferon genes (STING) pathway is a promising anti-tumor adapter protein with the potential to oppose tumor growth ,8. SeverMore in-depth studies are required to fully understand how STING therapy may be best utilized in both the oncology and dermatology fields. Furthermore, novel therapies utilizing STING technology may have the ability to target solid tumors within multiple organ systems. This review will provide a greater understanding of how STING works on a molecular signaling level and a summary as to how it may be used in future oncologic therapies.Extensive exposure to sunlight and ultraviolet (UV) radiation is the most important external risk factor for developing malignancy involving the skin . UV radiNormal human skin comprises both the superficial epidermis and the deep dermis, as well as a neighboring hypodermis; these layers serve as part of the innate immune system to aid in host defense. The epidermis has five layers: the stratum corneum , stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale (most deep). Specialized cells make up the epidermis, including melanocytes, keratinocytes, Merkel cells, and Langerhans cells; each of these has a distinct role vital for the normal mechanical and immune function of the skin . When deThe detection of skin cancer is multi-factorial and includes both patients and healthcare providers. Individual cancers may be detected macroscopically or microscopically, and annual skin checks are crucial in identifying early-stage skin cancers before they can metastasize. In terms of simplicity, skin checks can be conducted without the need for extensive equipment apart from a dermatoscope. These examinations are efficient as well, taking only minutes out of a patient’s daily schedule. To ensure comprehensive care, clinicians must obtain a detailed clinical history, perform thorough physical exams and self-examinations, and ensure the patient’s adherence to future appointments.In terms of prevalence, BCC is the most observed subtype of skin cancer overall. These malignancies have a low metastasis rate and have an age-adjusted mortality rate of 0.12 per 100,000 person-years . BCCs arConversely, SCC is the second most observed subtype of NMSC. Compared to BCC, these have a higher rate of metastasis, which occurs at a rate of 3–9%, as shown by previous studies . The ageAlthough less common than NMSC, melanomas are one of the deadliest skin malignancies. These cancers comprise 1% of total cancers but account for 80% of total deaths . MelanomNew technological capabilities have brought the STING signaling pathway to the forefront of the oncology world. The pathway was first described in 2008 as a eukaryotic defense mechanism against viruses ,20.The human immune system’s normal response to foreign antigens is accomplished by two distinct parts of the immune system. Physical barriers, including skin and mucosal membranes, comprise the innate immune system, providing physical and molecular protection defenses against invading organisms and molecules. Conversely, the adaptive immune system comprises cells with specialized functions that interact in order to produce antibodies, activate complement, and activate memory responses in order to identify and eliminate pathogens. Antigens from foreign molecules are ingested and processed by antigen-processing cells, which present these molecules to specialized T-cells via major histocompatibility complexes. Once presented, the antigens can then go on to activate other cells, molecular cascades, signaling pathways, and cytotoxic host responses. The immune system produces various inflammatory cytokines and IFNS in response to acute pathogenic invasion. Of note, there are currently three major IFN classes. Although each family exhibits differences in potency, receptor type, and specific downstream messengers, the STING pathway is most closely intertwined with type 1 IFNs.Type 1 IFNs allow host cells to defend themselves against foreign viruses, bacteria, and fungi and can activate other downstream inflammatory pathways . This clIf non-native double-stranded DNA is detected within the cytoplasm of a host cell, the cGAS-STING pathway is initiated . Once thThe previously mentioned innate immune system reacts to foreign nucleic acids via RNA and DNA sensing receptors to mount a host immune response . DNA infMitochondrial DNA damage also activates this pathway, and degradation has been shown in malignancies to trigger cGAS-STING. Cytosolic mitochondrial DNA release acts as a ligand for pathway potentiation, causing IFN-mediated cell death that may be a target for future therapies ,27. ThisCancers evade the cGAS-STING-mediated signaling once DNA is sensed via targeting gene expression or suppressing their function. Suppression of cGAS-STING signaling downregulates apoptotic and senescence pathways, increasing the protection of malignant cells from host tumor surveillance ,31. UndeGiven the exhibited anti-oncogenic properties of STING, it is no surprise that new advances in oncology have investigated this pathway to target skin cancer tumorigenesis. Several studies have explored how STING responds to damaged DNA released from lysed tumor cells . In addiAlthough checkpoint inhibitor therapies currently exist to target skin cancer, their primary mechanisms do not primarily rely on inducing damage to dsDNA in tumor cells. Therapies for malignant skin cancer, such as radiotherapy and chemotherapy, rely on the STING pathway for regulating type 1 IFN production. Other documented mechanisms such as inducing DNA damage and forming micronuclei, inducing apoptosis, and exposing the damaged DNA to PPRs on the cell surface have been described . Tumor cDrugs that target, the DNA repair enzymes or replication interfere with producing dsDNA recognizable to the host cell, thus activating the STING pathway ,39. TopoSTING agonists are another type of immunotherapy currently being studied for their efficacy on the tumor microenvironment of the integumentary system. In one study, when STING agonists were injected intratumorally into subcutaneous melanomas, the pathway increased the production of local anti-angiogenic factors, chemokines, and LTbR agonists, ultimately aiding in the restoration of the normal vasculature and promotion of local tertiary lymphoid structures resulting in the slow growth of the tumor microenvironment . AlthougRecent studies exploring injection techniques in intertumoral drug delivery, drug formulation, and tumor stroma on the efficacy of the STING agonist on tumor cells have found that STING agonists are significantly more effective in soft tumors such as melanoma than firm tumors such as colorectal cancer . AdditioSTING agonists, combined with drugs that target downstream mechanisms within the STING pathway, have been found to induce significant anti-tumor responses . ResearcThere are limited non-surgical options for treating SCCs, with radiation therapy being a popular treatment for this cancer . SimilarLike SCC, radiation and topical chemotherapy are amongst the more popular non-surgical options for BCC. There are currently no FDA immunotherapy approvals for advanced or metastatic BCCs . Due to STING is vital in prohibiting tumor growth, but to adapt to this, tumor cells have evolved to inhibit aspects of the STING pathway. Research has found that CD8+ T-cells in cancer patients have decreased expression of the STING pathway and are less successful in promoting an anti-oncogenic response. Therefore, when the pathway in CD8+ T-cells that have decreased expression of the pathway was stimulated, the cells were more successful in promoting an anti-tumor response by increasing differentiation of stem-cell CD8+ cells . Tumor cFurther potential therapies include the injection of mRNA-lipid nanoparticles of constitutively active STING mutants into the cancer cells, which have been found to reactivate STING anti-tumor immunity and promote apoptosis of tumor cells . This meTo date, several clinical trials have been initiated for treating head and neck squamous cell carcinoma (HNSCC) with STING agonists including ADU-S100, SB-11285, and MK-1454 ,67,68. TIn the Phase 2 clinical trial that utilized ADU-S100 (a STING-agonist that functions as a synthetic cyclic dinucleotide) co-administered to patients with PD-L1 positive recurrent or metastatic HNSCC, the endpoints of the study were patient safety, preliminary anti-tumor activity, pharmacokinetics, and immunomodulation ,69. SixtThe cGAS-STING signaling pathway has gained significant attention regarding its anti-tumor properties in certain malignancies, especially skin cancer. As demonstrated in STING’s effects on immune modulation pose benefits in both monotherapies and heightened efficacy in combination with other existing forms of both NMSC and melanoma skin cancers. While this pathway has been extensively studied in vitro, further animal and human studies and trials are needed to investigate further the safety and reliability of cutaneous cancer treatment optimization. Furthermore, although clinical trials are currently underway, more data and trials are needed to draw definitive conclusions about the efficacy of the STING pathway in oncology therapy. Collaboration between researchers and clinicians within the oncology and dermatology fields is necessary to push forward the next generation of STING treatments.


Posterior blepharitis and dry eye are common disorders with meibomian gland dysfunction (MGD), a principal driver of their pathophysiology. Meibomian gland dysfunction is increasingly prevalent in older populations with contributory hormonal imbalances. The abnormal meibum in MGD has been documented to have an excess of cholesterol with a resultant disruption of the lipid layer of the tear film. This leads to tear film instability due to the inadequate trapping of the aqueous portion of the tear film with resultant evaporative dry eye. Significant morbidity may follow MGD with ocular surface inflammation disrupting both social and work function. Rosacea is a common chronic inflammatory condition of the central face but can have ocular and systemic inflammatory associations. It is especially prevalent in North European populations and can have onset at any age, but commonly presents between thirty and fifty years of age. In ocular rosacea, MGD is a recognised manifestation as is dyslipidaemia. Ocular rosacea can predate cutaneous disease. As yet, there is no directly reported evidence of the efficacy of the early identification and treatment of ocular rosacea with associated dyslipidaemia and systemic inflammation. We posit that MGD in ocular rosacea sufferers may be a marker for dysregulated cholesterol synthesis and inflammation, and that statins maybe a potential therapy. This article introduces potential strategies to utilise ocular rosacea MGD as a possible marker for ophthalmologists, cardiologists, and primary healthcare physicians to treat rosacea-associated dyslipidaemia and systemic inflammation. This could aid in overall cardiovascular morbidity and mortality control for rosacea sufferers, potentially at an earlier age, while also addressing their tear film de-stabilisation through cholesterol lowering and inflammation reduction. Dry eye, the most common eye disorder , is freqRosacea is a chronic inflammatory dermatosis mainly affecting the cheeks, nose, chin, and forehead. It is characterised by recurrent episodes of transient erythema and/or persistent erythema, phymatous changes, papules, pustules, and telangiectasia. Due to facial involvement, it can have a profound impact on quality of life . Men andCurrently, pathophysiologic modelling suggests a genetic susceptibility and an upregulated and dysregulated innate immune system prone to excessive inflammation and vasodilation, coupled with neurogenic dysregulation from extrinsic triggers . This chDuman et al. reported high total cholesterol, low-density lipoproteins (LDLs) and CRP levels, and a family history of premature cardiovascular disease as being significantly more common in their cohort of rosacea patients than controls . SimilarOcular rosacea is usually mild, although corneal involvement may occur in 41% of cases. Ocular manifestations are usually seen in both eyes, but unilateral or sequential changes can occur . The eyeChronic inflammation associated with rosacea can lead to a non-specific, chronic conjunctivitis, as well as inferior conjunctival scarring and cicatrisation, granulomas, and phlyctenulosis. Corneal changes can vary from mild inferior dryness to marginal keratitis, corneal vascularisation, lipid keratopathy, scarring, ulceration, and corneal perforation in extreme cases ,8. OtherMeibomian gland dysfunction is a chronic diffuse abnormality of the MG, commonly characterised by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretions . The obsIncreased free cholesterol as well as cholesterol esters in the MG may play a role in the pathogenesis of MGD. A higher cholesterol concentration may increase the melting point of meibum, thereby potentially increasing its viscosity with resultant gland orifice plugging ,20. Indep < 0.001). Patients who used statins had a lower risk of developing blepharitis  than those who did not. Moreover, the use of a higher intensity statin has been associated with a lower MGD in 535 patients with moderate-to-severe dry eye disease [The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) enzyme has been found in the MG as well as the pilosebaceous units and glands of Zeis of human eyelids . Oral st disease . Topical disease . This ma disease ,29. ThisWe hypothesise that in rosacea posterior blepharitis, specifically meibomian gland dysfunction, may be a marker for dyslipidaemia and possibly systemic inflammation. Further treatment with statins may not only reduce cardiovascular morbidity and mortality, but also reduce the symptoms and signs of ocular rosacea.Previous studies have suggested that MGD could be utilised for hypercholesterolaemia screening and that rosacea patients should also be investigated for hypercholesterolaemia . The litTo test this hypothesis firstly with respect to topical statins, a fully funded, ethics-approved, prospective, interventional, blinded pilot study would be planned, for which participants with clinically diagnosed rosacea could possibly be randomised to either receive conventional lid hygiene with placebo, such as topical preservative free lubricants, or conventional lid hygiene with topical Atorvastatin 50 μM, as per Ooi et al. . TreatmeWith respect to oral statin usage, a prospective randomised clinical trial (RCT) to investigate the potential for reduction in blepharitis and hypercholesterolaemia in ocular patients with both MGD and dyslipidaemia could be conducted with high dose versus conventionally dosed oral statins. Similarly, funding would also be required and ethics clearance achieved across multiple interested centres. The statins of choice would be atorvastatin and rosuvastatin, given that they are the most effective at LDL-cholesterol lowering and also the safest in terms of renal function being the least likely to result in new onset microalbuminuria . EvaluatIn the longer-term, prospective studies could be conducted to evaluate the efficacy of oral statins in reducing the risk of developing hypercholesterolaemia in those patients with ocular rosacea who seemingly have cholesterol values within the normal range at the time of treatment. These patients may indeed be present with values already above that which could have been considered healthier for them in terms of their tear film stabilisation as well as cardiovascular status. Prophylactic high-dose rosuvastatin, used for its pleiotropic anti-inflammatory effects in patients with low LDL-cholesterol and elevated high-sensitivity CRP, has been shown to significantly reduce first major cardiovascular events compared to placebo over a median of 1.9 years follow-up . Ocular Rosacea is a common inflammatory skin disorder, but its ocular and systemic manifestations are often under-recognised and undertreated. Ocular rosacea-associated MGD may alert clinicians to the presence of and need for the treatment of associated dyslipidaemia and underlying systemic inflammation with statins. If our hypothesis is correct, then the early institution of both topical and oral statins may reduce the burden of ocular rosacea through not only an earlier local ocular surface inflammation control, but indeed a longer-term MG conservation. More importantly, significant cardiovascular morbidity and mortality reduction may follow the earlier introduction of oral statins.The authors have a patent on topical atorvastatin as a novel tear film stabiliser.


Living organisms show seasonality in a wide array of functions such as reproduction, fattening, hibernation, and migration. At temperate latitudes, changes in photoperiod maintain the alignment of annual rhythms with predictable changes in the environment. The appropriate physiological response to changing photoperiod in mammals requires retinal detection of light and pineal secretion of melatonin, but extraretinal detection of light occurs in birds. A common mechanism across all vertebrates is that these photoperiod-regulated systems alter hypothalamic thyroid hormone (TH) conversion. Here, we review the evidence that a circadian clock within the pars tuberalis of the adenohypophysis links photoperiod decoding to local changes of TH signaling within the medio-basal hypothalamus (MBH) through a conserved thyrotropin/deiodinase axis. We also focus on recent findings which indicate that, beyond the photoperiodic control of its conversion, TH might also be involved in longer-term timing processes of seasonal programs. Finally, we examine the potential implication of kisspeptin and RFRP3, two RF-amide peptides expressed within the MBH, in seasonal rhythmicity. Seasonality is a critical property of most organisms. At temperate latitudes, photoperiod is the main synchronizer of seasonal functions. Photoperiodism defines the use of the annual cycle of day and night length to coordinate functions such as reproduction, fattening, hibernation, and migration with predictable changes in the environment, for example in food availability or climatic conditions. Seasonal changes in physiology and behavior typically are innately timed long-term processes, requiring weeks or months to wax and wane. Therefore, additional to photoperiodic readout mechanisms, living creatures have evolved endogenous long-term timing devices, which allow them to anticipate forthcoming seasonal changes. In the most extreme cases, cycles of about 365 days recur for years in animals kept under constant photoperiods; such so-called circannual rhythms exist in a variety of birds and longer-lived mammals.Species with relatively short life spans such as voles and hamsters usually do not display circannual rhythms, but their seasonal cycles also comprise an endogenously generated part, which corresponds to the overwintering period and allows timely emergence from the burrow and reproductive recrudescence in early spring. Endogenous long-term timing is commonplace in vertebrates but its mechanistic basis remains mysterious . Herepars tuberalis (PT), a region of the pituitary stalk apposed to the median eminence. The suprachiasmatic nuclei (SCN) also showed moderate labeling in most species while many brain nuclei showed weak to moderate labeling, with very little species overlap  but inh unclear , 171. Thin birds . Interess2) gene , which is2) gene  does notKiss1 and Rfrp expression display marked photoperiodic, melatonin-dependent, changes in mammals (Kiss1 and Rfrp is indirect . Ive, Ref.  showed tn et al.  showed tTherefore, even though a theoretical possibility exists that another TSH-dependent – but T3-independent pathway – leads to seasonal changes of the reproductive axis, the most parsimonious model is one in which T3 action on RF-amide neurons link the photoperiodic production of TSH within the PT to the seasonal control of GnRH secretion.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.


Background: Social anxiety disorder (SAD) is characterized by abnormal fear and anxiety in social situations. Functional magnetic resonance imaging (fMRI) is a brain imaging technique that can be used to demonstrate neural activation to emotionally salient stimuli. However, no attempt has yet been made to statistically collate fMRI studies of brain activation, using the activation likelihood-estimate (ALE) technique, in response to emotion recognition tasks in individuals with SAD. Methods: A systematic search of fMRI studies of neural responses to socially emotive cues in SAD was undertaken. ALE meta-analysis, a voxel-based meta-analytic technique, was used to estimate the most significant activations during emotional recognition. Results: Seven studies were eligible for inclusion in the meta-analysis, constituting a total of 91 subjects with SAD, and 93 healthy controls. The most significant areas of activation during emotional vs. neutral stimuli in individuals with SAD compared to controls were: bilateral amygdala, left medial temporal lobe encompassing the entorhinal cortex, left medial aspect of the inferior temporal lobe encompassing perirhinal cortex and parahippocampus, right anterior cingulate, right globus pallidus, and distal tip of right postcentral gyrus. Conclusion: The results are consistent with neuroanatomic models of the role of the amygdala in fear conditioning, and the importance of the limbic circuitry in mediating anxiety symptoms. Social anxiety disorder (SAD), or generalized social phobia (GSP), the more pervasive and severe subtype of SAD, are characterized by fear and anxiety in social situations, with individuals experiencing significant concerns about feeling embarrassed or publicly humiliated , a voxel-based meta-analytic technique that allows one to generate parametric maps of consistent activation across different imaging studies . Both encompass symptoms of being negatively evaluated in social situations, particularly in relation to self-performance  fMRI studies of emotion recognition in which healthy controls were compared with participants diagnosed with SAD or GSP according to standardized diagnostic criteria as described above.The selection process took place in three stages. Two independent reviewers firstly assessed the titles and retrieved articles for relevance. Second, the articles that remained eligible were assessed based on the abstract to determine whether any inclusion criteria were not met. The full text of all remaining articles was then assessed using with a data extraction template, constructed for the purpose of organizing and extracting information from included articles. Following this procedure, 244 initial publications were found, which were reduced to 44 after examining the title and abstract. A total of 7 out of 44 studies fulfilled all inclusion criteria, resulting in a combined sample of 91 subjects with SAD and 93 healthy controls.http://www.brainmap.org/ale/), a contemporary method to analyse brain imaging data. MRICron (REF) was used to illustrate the results. Data from studies reporting Talairach stereotactic  coordinates were extracted and subsequently referred to as foci. We used foci from all studies representing greater activation in cases (vs. controls) to emotional  stimuli. Studies reporting foci in other atlases  were converted using the GingerALE convert foci tool. ALE involves the generation of a statistical parametric map (SPM) of brain activation, in this case, in response to a task (emotion recognition), through the quantitative synthesis of whole-brain coordinate data across multiple studies. The likelihood that activation in particular voxels occurs by chance is determined through reference to an empirically derived probabilistic map of brain activity  would receive more weight with regard to their contribution to the meta-analysis. The latest version of GingerALE (version 2.1.1), on the other hand, identifies each reported coordinate within the study that generated it, by obtaining a single modeled activation (MA) map for each study. The probability that a particular voxel is activated is then calculated as the union of the probabilities for that voxel across studies. This revised algorithm allows weighting for the precision location of the foci reported by each study, based on its sample size  value which determines how widely-dispersed or “blurred” that activation is). The algorithm assumes that larger studies provide more reliable estimates of activation. The lastest version of GingerALE also restricts voxels of interest to those areas of the brain which have a greater than 10% probability of containing gray matter, as no BOLD signal will typically be observed in white matter.For this ALE, the latest version of the ALE software  and MRICron (http://www.mccauslandcenter.sc.edu/mricro/mricron/).The data extracted included; (a) author names, (b) date of publication, (c) journal name, (d) digital object identifier, (e) type of emotion recognition task, (f) subject group numbers, (g) comorbidities and medication, (h) mean age with standard deviation, (i) ratio of gender, and (j) neural activation coordinates. All data included in this meta-analysis are derived from between-subject activation to emotion recognition tasks. In other words, the neutral condition  is first subtracted by the authors' from the emotion condition , and the residual activation is compared between cases and controls. The case vs. control comparison is reported as between subject foci in each paper included in this meta-analysis. We illustrate the results using Mango , left amygdala , left medial temporal lobe encompassing amygdala and entorhinal cortex , left medial aspect of the inferior temporal lobe encompassing perirhinal cortex and parahippocampus , right anterior cingulate , right globus pallidus  and distal tip of right postcentral gyrus   in those with SAD, consistent with the involvement of this structure in Pavlovian contextual fear conditioning in both animals and humans  contribute to the brain activation we observe. Nevertheless, this study is the first to conduct an activation-likelihood meta-analysis of fMRI studies examining neural correlates of emotion recognition in SAD. Our findings support a growing body of work on development of a neurocircuitry model of SAD. Future work on larger samples, including perhaps collaborations across different sites, is needed to address more comprehensively some of the likely sources of inter-individual variance (Furmark et al., In conclusion, our meta-analysis confirms that increased activation of the bilateral amygdala is a prominent feature in those with SAD, particularly in response to socially emotive stimuli. The contribution of other brain regions implicated in neurobiological models of SAD, such as parahippocampus and anterior cingulate, are also highlighted (Morgan et al., 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.


Neuronal excitability of the brain and ongoing homeostasis depend not only on intrinsic neuronal properties, but also on external environmental factors; together these determine the functionality of neuronal networks. Homeostatic factors become critically important during epileptogenesis, a process that involves complex disruption of self-regulatory mechanisms. Here we focus on the bioenergetic homeostatic network regulator adenosine, a purine nucleoside whose availability is largely regulated by astrocytes. Endogenous adenosine modulates complex network function through multiple mechanisms including adenosine receptor-mediated pathways, mitochondrial bioenergetics, and adenosine receptor-independent changes to the epigenome. Accumulating evidence from our laboratories shows that disruption of adenosine homeostasis plays a major role in epileptogenesis. Conversely, we have found that reconstruction of adenosine’s homeostatic functions provides new hope for the prevention of epileptogenesis. We will discuss how adenosine-based therapeutic approaches may interfere with epileptogenesis on an epigenetic level, and how dietary interventions can be used to restore network homeostasis in the brain. We conclude that reconstruction of homeostatic functions in the brain offers a new conceptual advance for the treatment of neurological conditions which goes far beyond current target-centric treatment approaches. Epileptogenesis is a complex process that not only involves changes in neuronal excitability and circuitry, but also changes in glial physiology and in the homeostatic environment in which neurons need to survive and to function properly . CharactUnfortunately, the pursuit of neurocentric therapeutic targets did not yield any antiepileptogenic therapies to date . In contGlial cells play a major role in the homeostatic state of the brain by regulating the ambient concentration of synaptic neurotransmitters; modulating the permeability of the blood brain barrier (BBB) through astrocyte–endothelial interactions; regulating cerebral blood flow; and microglial control of brain immunity. Thereby, glial cells directly influence brain function on multiple levels including neuronal excitability and synaptic transmission; delivering energy substrates from the periphery; and recovery from injury or infection . As a coWithin human epileptic foci the most prominent pathological finding is gliosis, with reports of reactive astrocytes, microglia, glial scars, and/or gliomas being present . PatholoATP channels. These findings highlight the potential for altered metabolism restoring and maintaining homeostasis in the central nervous system (CNS), and have implications for exploring the prevention and treatment of neurological disorders using strategies other that traditional neurocentric approaches.Alongside gliosis, it is increasingly appreciated that epilepsy is a global dysregulation involving metabolic dysfunction , and, fuHere we outline homeostatic therapeutic strategies with a focus on adenosine, an endogenous bioenergetic homeostatic regulator; multiple lines of evidence suggest that adenosine homeostasis is a key factor in preventing and stopping seizures. This review will first discuss glial mechanisms of epileptogenesis with emphasis on disruptions of adenosine homeostasis. Based on these mechanisms, we identify glia-centric therapeutic strategies that treat epilepsy through restoring normal brain homeostasis. We then highlight recent evidence regarding the role of adenosine in the process of epileptogenesis and describe metabolic therapy via a ketogenic diet, which may restore adenosine homeostasis.Figure 1). Astrocytes regulate or modulate a number of neuronal functions including excitability, synaptic transmission, and plasticity. As a consequence, the presence of reactive astrocytes, as found in patients with mTLE, FCD, and TSC, disrupts normal neuronal activity that either promotes epileptogenesis or decreases seizure threshold  modulation of synaptic transmission through glutamate, adenosine triphosphate (ATP), adenosine, gamma-aminobutyric acid (GABA), or D-serine from astrocytes  can induce a wide range of growth factors, neurotrophins, and transcription factors . Increas NMDARs; . In astrARs; 2AR . Whereas+ . The adenosine-AMP cycle is linked to ADP and ATP with adenylate kinase. Thus, adenosine is linked tightly to energy metabolism. Whereas mitochondrial uncouplers decrease ATP and increase adenosine (via net dephosphorylation of ATP), mitochondrial enhancers, or other strategies, which enhance ATP also appear to increase adenosine. Therefore, improving mitochondrial bioenergetics has the potential to offer dual benefits of improving metabolic dysfunction and restoring adenosine homeostasis.Adenosine triphosphate is released from various pathways including vesicular release , gap junTaken together, adenosine’s role in maintaining homeostasis interacts directly with mitochondrial bioenergetics and energy metabolism . The intModifications to the epigenome that include changes in DNA methylation, histone tail modifications, and incorporation of histone variants are mechanisms by which network homeostasis can be dramatically altered and consequently change the entire gene expression profile of a tissue. There are a number of epilepsy-associated neurological diseases that are directly attributed to primary genetic mutations and result in secondary deregulation of the epigenome . Gene prS-adenosylmethionine (SAM)-dependent transmethylation reactions . SAM donates a methyl group to unmethylated cytosines in DNA. Following methyl group donation, SAM is converted to S-adenosylhomocysteine (SAH). SAH is further hydrolyzed to adenosine and homocysteine (HCY). Adenosine is cleared by ADK-mediated phosphorylation to AMP, and HCY is converted to methionine in a folate-dependent manner. Importantly, DNA methylation is dependent on the continuous removal and subsequent equilibrium constants of SAH, adenosine and HCY .As outlined above, glial pathologies play important roles in epileptogenesis. Astrocytes form the major metabolic reuptake route for synaptic adenosine and control the availability of extracellular adenosine via expression changes of the astrocyte-based enzyme ADK, which phosphorylates adenosine to AMP and thereby drives the influx of adenosine into the astrocyte through equilibrative transporters . Using t2AR expression in glial cells appears to play a prominent role. In primary cultures of glial cells lipopolysaccharide (LPS) was found to induce A2AR mRNA and protein expression with a peak at 48 h after treatment  and the release of prostaglandin E2 (PGE2) were shown to mediate additional pro-inflammatory effects of adenosine  phenotype  responded to adenosine therapy with a decrease in the DNA methylation status of their respective promoters. Consequently, these targets are poised as likely candidates to mediate adenosine-dependent changes in major homeostatic functions  simultaneously. It becomes clear that conventional drugs with a mode of action that is restricted to only one target or pathway might be sufficient to block a symptom , but are unlikely to affect a neurological condition on the network level. Novel therapeutic interventions based on adenosine, epigenetic mechanisms, or dietary interventions might hold promise to affect network homeostasis as a novel conceptual strategy to treat and prevent epilepsy on the network level. For future therapy development it is important to note that adenosine augmentation has no known adverse effects. In preclinical toxicity studies of intrathecal adenosine in dogs, no side effects were observed with intrathecal adenosine infused chronically for 26 days  or its adaptive response to its environment (transcription and translation) results in a loss of CNS homeostasis and pathological dysfunction. It becomes clear that complex neurological syndromes, such as epilepsy, which are not only defined by a dominant symptom , but also by a growing number of associated comorbidities, can best be explained by the disruption of network homeostasis. Disruption of network homeostasis will lead to the dysregulation of several molecular pathways (e.g., those dependent on K 26 days . Likewis 26 days ,b. Impor 26 days , suggestThe 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.


Although there is increasing evidence for the positive effects of a healthy lifestyle on mental health, most studies only take into account a single lifestyle factor, ignore the possibility of bidirectional causality, and focus on average group results.In the present single-subject study, we used multivariate time-series analysis (Vector Auto Regressive modeling) to unravel the dynamic interplay between symptom and treatment variables in a multi-component treatment of anxiety disorder. Main treatment variables were two lifestyle factors .The patient in this study recovered completely. Time-series analysis revealed an intricate pattern of dynamic relationships between symptom and treatment variables. Relaxation was predictive of symptom reduction but physical activity surprisingly worsened the symptoms. Changes in energy predicted changes in anxiety. Evidence for bidirectional causality was present as well, with changes in relaxation predicting changes in energy and vice versa, indicating a positive feedback loop.This study aimed to unravel the dynamic relationships between psychological symptoms and the health-related behaviors intended to improve these symptoms. These relationships turned out to be characterized by bidirectionality, lagged influences, indirect effects, and feedback loops, both between symptoms and behaviors as well as among them. This patient’s symptoms and behavior were interrelated in an intricate way. This type of research seems useful for gaining insight into the causal mechanisms underlying the effects of a healthy lifestyle on mental health.


Stegastes partitus, sampled on reefs of the upper Florida Keys, USA over 6 years. Otolith analysis of settlers and juveniles coupled with environmental data revealed that mean near-reef water temperature explained a significant proportion of variation in pelagic larval duration (PLD), early larval growth, size-at-settlement, and growth during early juvenile life. Among all cohorts, surviving juveniles were consistently larger at settlement, but grew more slowly during the first 6 d post-settlement. For the other ELHTs, selective mortality varied seasonally: during winter and spring months, survivors exhibited faster larval growth and shorter PLDs, whereas during warmer summer months, selection on PLD reversed and selection on larval growth became non-linear. Our results demonstrate that temperature not only shapes growth-related traits, but can also influence the direction and intensity of selective mortality.For organisms with complex life cycles, processes occurring at the interface between life stages can disproportionately impact survival and population dynamics. Temperature is an important factor influencing growth in poikilotherms, and growth-related processes are frequently correlated with survival. We examined the influence of water temperature on growth-related early life history traits (ELHTs) and differential mortality during the transition from larval to early juvenile stage in sixteen monthly cohorts of bicolor damselfish  Most animals have complex life cycles with multiple ontogenetic shifts, characterized by changes in morphology, physiology, behavior, and/or habitat Temperature is well recognized in influencing metabolism and growth in poikilotherms Thalassoma bifasciatum) The growth-mortality hypothesis (GMH) Where environments are heterogeneous and variable, not only will the range of traits exhibited by poikilotherms vary, but the nature of their contributions to survival may change After removing fish that were too old or did not settle during the appropriate 14 d settlement windows, 1357 of 1682 aged fish were used in the analysis . SixteenThe CCA for six environmental variables and four ELHTs yielded a significant biplot based on a global permutation test , there was a significant positive relationship between early mean larval growth and mean water temperature , likely due to the strong negative relationship between PLD and temperature , since size-at-settlement is a function of growth rate and the number of days spent in the plankton. Larvae grew rapidly in warmer water, but settled sooner, resulting in smaller sizes-at-settlement. Mean near-reef water temperature explained 38% of the variation in mean juvenile growth over days 1–6 (p<0.05). Seasonal larval growth trajectories demonstrated that summer S. partitus cohorts grew consistently faster than winter cohorts until day 27 of the larval period when most of the warmer-water fish were nearing settlement and either feeding less or devoting more energy to locating suitable settlement habitat, while cooler-water fish maintained more constant growth possibly because they were not competent to settle  regardless of temperature , thus fib-spline, points to the existence of disruptive selection . Relationships between temperature and ELHTs in only larvae were similar, but more significant , suggesting that selective mortality tended to dampen temperature-trait relationships (unpubl. data). Recruitment magnitude varied seasonally, but was unrelated to any of the ELHTs examined. Although recruitment of reef fishes to other locations, such as Panama, is known to be significantly related to larval growth or size-at-settlement ELHTs varied among the 16 damselfish cohorts we examined and a significant portion of the variation could be explained by temperature. Mean near-reef water temperature explained 62% of variation in PLD: larvae in warmer water spent less time in the plankton. Additionally, warmer water fish settled at smaller sizes, largely because they experienced a shorter larval duration. While there was no significant relationship between overall larval growth and water temperature, early juvenile growth (averaged over the first 6 d) was faster during the summer compared to the winter .Contrary to what is predicted by the GMH, S. partitus illustrates how events occurring in one stage can carry over to influence survival during subsequent stages. The extents to which these carry-over effects continue to influence fitness in the adults that survive to contribute to the population are unknown, but could have important consequences for population dynamics.The consistent importance of size-at-settlement  to survival of juvenile Patterns in selective mortality acting on larval growth and PLD changed with seasonal water temperature. In the cooler winter and spring months, individuals with slower larval growth rates and longer PLDs were selectively removed from the population, in accordance with the GMH. However, during the summer months, there was a reversal in selection to that against individuals that spent shorter periods in the plankton. There was no significant directional selective mortality acting on larval growth during the warmest months, and evidence of disruptive selection . Overall growth during the warmest months was faster . This situation is further complicated by the fact that PLD was negatively correlated with temperature. Under warmer conditions, PLD should be shorter, but selective mortality against short PLDs could result in lower fitness of a large portion of the settling cohort. The larger implications are that adaptive trends could change with increasing global temperatures, leading to the evolution of new early life strategies.Taking into account ongoing global climate change, our results suggest that patterns in selective mortality may diverge from what currently exists. For instance, for Population replenishment of organisms to the Florida Keys reef tract (FKRT) is influenced by the dominant Florida Current (FC) and the formation and propagation of mesoscale eddies along the FC front Stegastes partitus is a zooplanktivorous fish common to the FKRT and greater Caribbean. Adults maintain benthic territories in which they spawn demersal eggs on a monthly basis, throughout the year Stegastes partitus is an ideal model species for studying processes affecting the early life history because they are common throughout their range, are integral to the trophic dynamics of the reef community, are easy to observe and collect at all life stages, and have otoliths (ear stones) that provide a daily record of events occurring during early life.The bicolor damselfish S. partitus larvae as they settled to the reef, light traps were deployed intermittently from June 2001 until January 2004 in conjunction with two other studies S. partitus juveniles were censused and collected 3–5 d later at the same sites, with the exception of FR and MO, which are protected areas where benthic sampling was not permitted. Instead, recruits were collected just north of FR . Recruit density was estimated by counting the number of newly recruited juveniles within ∼20 haphazardly placed 5×1 m transects. Approximately 30 recruits were collected by divers using hand nets and the anesthetic Quinaldine. Subsequent collections were made every 3–5 d thereafter for approximately two weeks, resulting in a total of three or four collections for each cohort . All collected juveniles were immediately stored in 95% EtOH following collection to preserve their otoliths.To capture settlement-stage sensu Sponaugle and Pinkard) Standard procedures were used to digitally measure the standard length (SL) of each fish, dissect out and clear (in immersion oil) their otoliths, read and innumerate increments (at 400×) along the longest axis of the clearest lapilli, and validate readings (unpubl. data), enabling inter-cohort comparisons. We used back-calculated dates of settlement to select only fish that settled within 14 d of each other for the analyses, resulting in 16 distinct cohorts. Utilizing the earliest hatch date and the earliest and latest settlement dates for each cohort, near-reef water temperature, chlorophyll a concentration, wind speed, alongshore and cross-shelf current velocity data, and all otolith-derived ELHTs  were averaged over the larval and juvenile periods separately.Standard length-otolith radius relationships  was utilized to distinguish the relative importance of the various environmental factors in influencing ELHTs. Because of the known importance of temperature in influencing growth, the relationships among ELHTs and water temperature were further examined by comparing mean cohort-specific water temperature with mean cohort-specific larval growth over the entire larval period and during separate 5 d intervals, PLD, size-at-age, and size-at-settlement using least-squares regression techniques (SYSTAT version 11.0). Likewise, mean cohort-specific juvenile growth over the first 6 d post-settlement was regressed against the cohort-specific water temperature averaged over the juvenile period.Because ELHTs have been demonstrated to influence recruitment magnitude Each cohort was further divided into four age groups: larvae, newly settled recruits (1–7 d post-settlement), intermediate juveniles (8–14 d post-settlement), and survivors (15–21 d post-settlement), which provided realistic timescales over which selective mortality could occur and resulted in sufficient sample sizes within the most age groups for each cohort. To determine whether mortality was selective with regard to any of the ELHTs, we compared the distribution of traits among age groups: A shift in the distribution of a trait between age groups would indicate directional selection. We used analysis of covariance (ANCOVA) to examine ELHTs among age groups with temperature as a covariate. For traits that could not be evaluated using ANCOVA (i.e. due to significant interactions between temperature and age group), monthly cohorts were divided into three seasonal groups by temperature  and the traits were compared among age groups using general linear model (GLM) techniques. When significant differences were detected, Tukey's post-hoc test was used to identify significant pair-wise differences.b-spline approach originated by Schluter h(t) is the probability that a fish with a particular value of trait t at an initial age was caught in a sample of survivors, given that it was collected in one of the two samples. As per Sinclair et al. h(t) estimated using a generalized additive model assuming a binomial error distribution and a logit link:b-spline smooth function of t, with a smoothing parameter λ chosen by generalized cross-validation.To determine whether growth trajectories of the different seasonal groups diverged through time, we examined daily growth by effect-coded season using repeated measures general linear model techniques (RM-GLM). To depict both linear and nonlinear forms of selective mortality, we estimated fitness functions using the cubic


Cytomegalovirus (CMV) retinitis may occur in profoundly immunocompromised patients and be the initial AIDS-defining infection. The incidence and prevalence of CMV retinitis has declined substantially in the era of highly active antiretroviral therapy (HAART); nevertheless, it remains a leading cause of ocular morbility. We report the case of a 40-year-old man with blurred vision and pain in the right eye, three weeks after the initiation of effective HAART treatment. Ocular examination revealed a panuveitis causing an anterior chamber reaction with hypopyon and a dense vitreous haze. An endogenous endophthalmitis was suspected and treatment was ensued, without improvement. A vitreous tap was performed, and a positive polymerase chain reaction for CMV was found. A diagnosis of immune recovery uveitis (IRU) was made, and the patient responded to treatment with valganciclovir and dexamethasone. IRU is an intraocular inflammation that develops in patients with HAART-induced immune recovery and inactive CMV retinitis, although cases of active CMV retinitis have been described. Presentation with panuveitis and hypopion is rare and may be misleading regarding diagnosis and management. Cytomegalovirus (CMV) retinitis is a common opportunistic disease among patients with acquired immunodeficiency syndrome (AIDS) and typically manifests itself as progressive necrotizing retinitis with little or no intraocular inflammation –4. Vitri Due to the advent of highly active antiretroviral therapy (HAART), many patients may experience an immune reconstitution syndrome that can manifest itself as an ocular inflammatory response, termed immune recovery uveitis (IRU). This inflammatory response to CMV retinitis is a significant cause of visual morbidity in patients with AIDS –9.We herein report a case of severe IRU with active CMV retinitis in a 40-year-old male infected with human immunodeficiency virus (HIV) and no known previous ophthalmological examination. When HAART was initiated, he developed signs of severe intraocular inflammation with panuveitis and hypopyon. A 40-year-old male presented with progressive visual loss, floaters, pain, and redness in the right eye for a week, with no other systemic complaints. He had been diagnosed with HIV-1 infection in 2010 and was being treated with abacavir, lamivudine, and efavirenz for six months (from March until August of 2012), but, due to low therapy adherence, he developed drug resistance. + T-lymphocyte count of 16 cells/μL  and an HIV viral load of 216000 copies/mL. He then had a CD4A new HAART scheme with zidovudine, tenofovir, and atazanavir was implemented, together with cotrimoxazole and azithromycin prophylaxis. Ocular symptoms and complaints started 3 weeks after initiating the new HAART scheme. He had no known history of opportunistic infections.On examination, his best corrected visual acuity was hand movements in the right eye (OD) and 10/10 in the left eye (OS). On slit-lamp examination, OS was normal and OD showed marked circumcilliary congestion, corneal edema, aqueous cell and flare grade 3, and a 2 mm mobile hypopyon. Intraocular pressure (IOP) with applanation tonometry was 8 mmHg OD and 14 mmHg OS. The ocular fundus examination of OD showed severe vitritis obscuring retinal details, and OS was normal. The systemic examination was unremarkable  was negative for bacteria, fungi, and viruses. Hemocultures and urocultures were also negative. Blood count, erythrocyte sedimentation rate, interferon-pars plana vitrectomy. The surgery consisted of a pars plana vitrectomy (as complete as possible) together with complete lensectomy  and no intraocular lens (IOL) implant. During surgery, scattered, granular, yellow-white areas of retinal necrosis with patchy haemorrhages typical of active CMV retinitis were visible in the superior periphery. The superior peripheral retina broke due to severe necrosis originating a giant retinal tear which was treated with laser photocoagulation  and a decrease in viral load (from 216000 copies/mL to 650 copies/mL). The patient probably has achieved only limited CMV immunity: enough to mount an inflammatory response against CMV, but insufficient to prevent its reproduction in the retina.In our case, the patient had an active CMV retinitis and severe ocular inflammation, indicating an immune reconstitution. This was evidenced by an increase in levels of CD4Other ocular pathogens and mechanisms can cause similar intraocular inflammation such as endogenous endophthalmitis, the use of cidofovir, and IRU in patients with tuberculosis and toxoplasmosis. In our case, we attribute the hypopyon and posterior segment inflammatory response to increased immune function as a result of HAART because no other ocular pathogens besides CMV were found, the lesions in retina were suggestive of CMV retinitis, and the patient had not undergone treatment with cidofovir.Initiation of HAART should be delayed until after the induction phase of anti-CMV therapy, as the reduction of antigen load with anti-CMV agents may reduce potential risk of IRU .There are several anti-CMV drugs available including ganciclovir and its prodrug valganciclovir, foscarnet, cidofovir, and fomivirsen. The most commonly used are the ganciclovir intraocular implant and oral valganciclovir. The implant has the advantage of not causing systemic toxicity, but it does not protect against systemic CMV or contralateral CMV retinitis.Treatment starts with high-dose induction therapy. Maintenance treatment should be continued until immune recovery is achieved because none of the anti-CMV drugs available eradicate ocular and systemic CMV antigens in the immunocompromised patient. Anti-CMV therapy is important during immune recovery because it has been proved to be protective against the development of IRU by reducing the amount of CMV antigens in the retina, although it is has not shown a favorable cost-effectiveness ratio where there are no signs of CMV retinitis .+ T-lymphocyte count inferior to 50 cells/μL because 15% of patients with active CMV retinitis are asymptomatic.CMV retinitis screening is recommended at 3-month intervals in patients with a CD4Our patient did not undergo any ophthalmological examination before starting HAART. If so, he could have been diagnosed with active CMV retinitis and HAART would have been delayed until after the induction phase and he could have had a less severe inflammatory reaction.Although the incidence of CMV retinitis has markedly decreased with the improved immune function that has resulted from the institution of HAART, it remains an important problem in the HAART era; new cases continue to be seen, not only among those for whom this therapy is not available, but also in patients who develop resistance to it.The prevalence of IRU is substantial among eyes of patients with immune recovery, and it is an important cause of visual morbidity.IRU usually develops in patients with inactive CMV retinitis; however, it can rarely occur in eyes with active CMV retinitis (as seen in our case).Our case demonstrates the importance of ophthalmological screening in all patients before the initiation of antiretroviral therapy, reducing the probability of a prominent inflammatory response in the presence of an active infection.


Meta-analyses show collaborative care models (CCMs) with nurse care management are effective for improving primary care for depression. This study aimed to develop CCM approaches that could be sustained and spread within Veterans Affairs (VA). Evidence-based quality improvement (EBQI) uses QI approaches within a research/clinical partnership to redesign care. The study used EBQI methods for CCM redesign, tested the effectiveness of the locally adapted model as implemented, and assessed the contextual factors shaping intervention effectiveness.The study intervention is EBQI as applied to CCM implementation. The study uses a cluster randomized design as a formative evaluation tool to test and improve the effectiveness of the redesign process, with seven intervention and three non-intervention VA primary care practices in five different states. The primary study outcome is patient antidepressant use. The context evaluation is descriptive and uses subgroup analysis. The primary context evaluation measure is naturalistic primary care clinician (PCC) predilection to adopt CCM.For the randomized evaluation, trained telephone research interviewers enrolled consecutive primary care patients with major depression in the evaluation, referred enrolled patients in intervention practices to the implemented CCM, and re-surveyed at seven months.Interviewers enrolled 288 CCM site and 258 non-CCM site patients. Enrolled intervention site patients were more likely to receive appropriate antidepressant care , but showed no significant difference in symptom improvement compared to usual care. In terms of context, only 40% of enrolled patients received complete care management per protocol. PCC predilection to adopt CCM had substantial effects on patient participation, with patients belonging to early adopter clinicians completing adequate care manager follow-up significantly more often than patients of clinicians with low predilection to adopt CCM .Depression CCM designed and implemented by primary care practices using EBQI improved antidepressant initiation. Combining QI methods with a randomized evaluation proved challenging, but enabled new insights into the process of translating research-based CCM into practice. Future research on the effects of PCC attitudes and skills on CCM results, as well as on enhancing the link between improved antidepressant use and symptom outcomes, is needed.NCT00105820ClinicalTrials.gov:  Despite efficacious therapies, depression remains a leading cause of disability -3. Most Implementation of CCM as part of routine primary care requires system redesign. EBQI is a redesign method that supports clinical managers in making use of prior evidence on effective care models while taking account of local context -10. For Theory suggests that durable organizational change of the kind required by CCM is most likely when stakeholders are involved in design and implementation ,13. Yet CCM can be considered a practice innovation. Research shows that early adopters of innovations may be different from those who lag in using the innovation . We hypoIn this paper, we evaluate implementation by asking the intent to treat question: did depressed EBQI-CCM practice patients enrolled in the randomized evaluation and referred to CCM have better care than depressed patients at practices not implementing CCM? We also asked the contextual subgroup question: do EBQI-CCM site patients of early adopter clinicians experience different CCM participation outcomes than those of clinicians with a low predilection to adopt CCM? Because our purpose was to study and formatively evaluate the implementation of a well-researched technology , our graThis study evaluated EBQI-CCM implementation through a cluster-randomized trial. The EBQI process occurred in seven randomly allocated group practices in three VA multi-state administrative regions; three additional practices (one in each region) were simultaneously selected to serve as comparison sites in the subsequent cluster randomized evaluation reported here. Primary care providers began referring their patients to EBQI-CCM through VA's usual computer-based consult system a year prior to any patient enrollment in the randomized evaluation as part of the ongoing TIDES (Translating Initiatives in Depression into Effective Solutions) QI program . AdditioResearchers formed partnerships with three volunteer Veterans Health Administration regions between 2001 and 2002 to foster a CCM implementation QI project (TIDES). Participating regions spanned 19 states in the Midwest and South. Regional directors agreed to engage their mental health, primary care, QI, and nursing leadership in EBQI teams for improving depression care, and to provide release time to enable team members to participate. Each region agreed to hire a care manager for depression. Researchers provided dollars totaling the equivalent of one halftime nurse care manager for 21 months to each region.Prior to initiation of EBQI, each regional administrator agreed to identify three primary care practices of similar size, availability of mental health personnel, and patient population profiles for participation in the study. Study practices mirrored staffing characteristics of small to medium-sized non-academic practices nationally in VA. As described elsewhere, however, baseline levels of participation in care for depression in primary care varied .In 2002, the study statistician randomly assigned one practice per region as control practices, and the remaining two practices per region to EBQI-CCM. One of the six EBQI-CCM sites selected by regional administrators was a single administrative entity but composed of two geographically separated practices with different staffing. We therefore analyzed it as two separate practices for a total of seven EBQI-CCM sites.All study procedures for the QI process and for the randomized evaluation were approved by Institutional Review Boards (IRBs) at each participating site and at each site housing investigators .We described the steps, or phases, in the TIDES EBQI process and their cost in prior publications . These iDuring preparation (approximately 2001 and 2002), each region learned about the project and identified its regional leadership team. During the design phase, the regional leadership team and representatives from some local sites carried out a modified Delphi panel ,22 to see.g., 10 to 15 patients) care managers began engaging additional clinicians and patients through academic detailing and local seminars [The implementation phase began with enrollment of the first patient in a PDSA cycle. After the depression care manager (DCM) was designated or hired, she and a single PCC initially worked together to plan and implement rapid enlarging PDSA cycles that aimed to test the referral process, safety, process of depression care, and outcomes. Cycles began with one patient and one clinician in each participating practice. After several cycles  and keep registries of patient process and outcomes. Registry data provided measures for overarching quarterly PDSA cycles focused on patient enrollment , patient process of care , and patient symptom outcomes.In terms of measures, we rigorously trained DCMs to administer instruments  levels. Quarterly reports were formatted like laboratory tests, with a graph of patient outcome results; an example report is included in a previous publication .Researchers created a database of potential patient evaluation participants from CCM and non-CCM practices using VA electronic medical records. Inclusion criteria were having at least one primary care appointment in the preceding 12 months in a participating practice, and having one pending appointment scheduled within the three months post-selection . Exclusion criteria were having conditions that required urgent care , inability to communicate over the telephone, or prior naturalistic referral by the patient's PCC to the DCM.Trained interviewers from California Survey Research Services Inc. (CSRS) screened eligible patients for depression or dysthymia symptoms between June 2003 and June 2004 using the first two questions of the PHQ-9  by telepBoth patients naturalistically referred to CCM prior to and during the study and patients referred to CCM as part of the randomized evaluation were followed by DCMs according to the TIDES care manager protocol. The protocol, developed by participating experts and sites, defined patients who had probable major depression  as eligible for six months of DCM panel management. Patients with subthreshold depression  who also had a) a prior history of depression, or b) dysthymia were also eligible. Patients who entered into mental health specialty care could be discharged from the panel after the initial assessment and any needed follow-up to ensure successful referral. All others were to receive at least four care manager follow-up calls that included patient self-management support and PHQ-9 measurement. All panel-eligible patients were to be called and re-assessed by the DCM at six months. The protocol specified that any patient not eligible for or who discontinued care management be referred back to the primary care provider with individualized resource and management suggestions.Design power calculations indicated that to detect a 50% improvement in anti-depressant prescribing assuming an intra-class correlation coefficient (ICC) of 0.01, and nine sites, with 46 patients per site, the study would have about 81% power using a two-sided 5% significance level. To allow for 20% attrition, 56 patients needed to be enrolled from each site. During data collection, new studies indicated the assumed ICC might have been too small, so within budgetary limitations, the sampling from CCM practices was increased to 386 and non-CCM practices to 375. Post-power calculations showed that the actual ICC was 0.028 and the within-group standard deviation 6.25, suggesting there was adequate power (0.96) to detect a 20% difference in anti-depressant prescribing between the two study arms, but not enough power (0.45) to detect a 10% difference. Power calculations for detecting a difference in depression symptom improvement across the two study arms show a posteriori power to detect a 20% difference between the two study arms of between 0.21 and 0.29.Our primary study outcome measure, and the basis for our power calculations, was receipt of appropriate treatment, a process of care goal that requires less power than that required to demonstrate symptom outcome improvement. Previous studies  had demoOur covariate measures included baseline measures of depression symptoms, functioning, satisfaction, and adherence as described above, as well as other variables hypothesized to affect outcomes. These included dysthymia , historyWe trained DCMs to collect registry information on all patients referred to them and used it to prepare quarterly reports to regional and site managers. DCMs entered data, including PHQ-9 results, on each patient referred to them (including those referred by research interviewers) into a Microsoft Excel-based depression registry. Care managers recorded, de-identified, and then transmitted registry data. DCMs transmitted data on 974 patients between the date of the first PDSA cycle and the end date of the randomized evaluation. Recorded data included whether the patient had been naturalistically referred or referred as part of the randomized evaluation, and indicated the patient's PCC, but no patient personal health information identifiers such as age. The project statistician replaced clinician names with assigned study codes that linked clinicians to practice site only, without additional information.i.e., those carried out as part of routine care outside of the randomized evaluation) recorded in the registry for each PCC to characterize PCC adopter status [We used the number of naturalistic referrals  to assess the impact of CCM intervention at seven months after the baseline with repeated measures at the patient level, two records per person (pre- and post-intervention periods) . The effWe used chi-square to assess the relationships between provider referral type and adequate care manager follow-up. We used one-way ANOVA to assess PHQ-9 difference scores with Scheffe post-hoc comparisons to show which level of follow-up by DCMs had the strongest relationships with PHQ-9 outcomes.Figure Table Table Evaluation of adherence to CCM protocols showed delays in contacting and initiating treatment among patients referred by the study. Care managers initiated patient contact an average of 47 days after referral among randomized evaluation patients, and initiated treatment an average of 16 days after first contact (not shown).Figure All regions and target practices carried out priority setting followed by PDSA cycles and design and implementation of CCM. CCM as implemented included all aspects of the Chronic Illness Care model , includiTable Among the 241, 71% (41 of 58) of patients of CCM habitual users , 78% (42 of 54) of patients of CCM early adopters , 64% (36 of 56) of patients of CCM slow adopters, and 48% (35 of 73) of patients of clinicians with a low predilection to adopt CCM, received adequate care manager follow-up (p = 0.003). Results were similar if we conducted the analyses on the full population of 386 randomized evaluation patients referred to care management, and assigned those not reached by DCMs as not receiving adequate follow-up , or if we restricted the analyses to the 230 of 241 randomized evaluation patients who were eligible for panel management based on a baseline PHQ-9 by the DCM that showed probable major depression (p = 0.01).Figure We found that CCM offered as a voluntary referral service to PCCs was heavily used by some clinicians and rarely used by others (not shown). Naturalistically referred patients came predominantly from early adopters and habitual users, while research-referred, randomized evaluation-enrolled patients reflected the full distribution of clinician adopter levels. For example, among the 386 randomized evaluation-enrolled patients referred for care management, 27.2% came from clinicians who had referred 10 or more patients to CCM . Among 590 naturalistically referred patients, 72.5% came from clinicians who were habitual users of CCM (p < 0.001).Finally, we assessed the relationship between depression symptom outcomes and adequate depression care manager follow-up. We found that 24-week PHQ-9 outcomes were significantly better among patients in EBQI-CCM practices  who received adequate care manager follow-up than among those who did not based on bivariate regression analysis with PHQ-9 change as the dependent variable (p = 0.001). As shown in Table i.e., patient self-management support, decision support, delivery system design, and clinical information systems) [This study aimed to determine whether healthcare organizations could improve depression care quality using EBQI for adapting CCM to local and organizational context -11. Thissystems) . ResearcUnlike our answer regarding the effectiveness of EBQI-CCM, our answer regarding the usefulness of randomized trials for formative evaluation is strongly positive. The trial was relatively inexpensive  relative to system costs for fully implementing CCM nationally; identified the need to improve the EBQI-CCM model; and provided critical information on how to improve it. Information on issues raised by this trial, such as care manager workload, follow-up, access, and clinician effects on patient outcomes, is essential if the results of over 35 CCM randomized trials are to be replicated in routine care.To understand study results, we evaluated adherence to the study intervention plans. In this study, the investigators implemented EBQI, rather than CCM itself; engaged sites implemented CCM. In terms of overall adherence to EBQI methods, our approach engaged regional and local leaders effectively in guiding local QI teams through PDSA cycles for designing and implementing CCM. All participating practices implemented and maintained EBQI-CCM throughout the study. In terms of adherence to CCM, as implemented by regional and local leaders with EBQI support, QI data  showed tDespite the identified problems with completion of assessments, the EBQI-CCM site patients were prescribed antidepressants at appropriate doses significantly more often than those in non EBQI-CCM practices (a 23% difference). EBQI-CCM site patients similarly had significantly more prescriptions actually filled (a 22% difference). Prior studies of CQI or lower-intensity EBQI for depression in primary care have not shown improved prescribing ,14,15. IBecause we aimed for the most efficient use of study resources for evaluating the process and effectiveness of an implementation method, rather than the effectiveness of CCM, we predicated our design on the lower sample size required for assessing a key process of care (antidepressant use) rather than the more demanding sample size needed for assessing effects on patient symptom outcomes. Our power to detect a 20% difference in depression symptoms was only between 0.21 and 0.29, based on the obtained sample size and ICC. We thus cannot definitively say that depression symptom outcomes did not improve within the timeframe studied. We were, however, disappointed in the lack of robust symptom impacts, and sought to determine more explicitly what lessons readers should take away from our work.To place our findings in context, we first asked: Do our randomized evaluation results test the effectiveness of CCM as a model? We conclude they do not. Other CCM studies have tested the CCM model as implemented using designs with higher researcher control, and shown effectiveness in diverse healthcare sites -7. TheseOur goal of combing a randomized evaluation with QI methods resulted in challenges related to timing. Our fixed windows for baseline and follow-up surveys meant that delays in initiation of care management for study patients, followed by lags in PCC ordering of treatments, were not accommodated in assessing outcomes. Thus, for many patients, antidepressant treatment or psychotherapy began only a short time before the seven-month follow-up survey. Furthermore, while 81% of randomized evaluation patients eligible for panel management completed the six month DCM assessment, many fewer had completed the designated number of follow-up contacts by that time. These results highlight the challenges for researchers in timing outcome measures relative to patient access to CCM in a study with a rigorous randomized design but low researcher control of the intervention.Excessive demand for care management proved to be another challenge, and one that is potentially relevant to CCM program managers. While we did not intend to overload care managers, we inadvertently did. As originally envisioned, the randomized evaluation would have begun after EBQI-CCM practices had completed a small number of PDSA cycles of the CCM intervention involving as few as ten and no more than fifty total patients. Under this scenario, care managers could have covered both naturalistic referrals and randomized evaluation referrals, given typical care manger caseloads . In realOur study mimicked a potential organizational policy such that patients screening positive for depression would be automatically referred to CCM, along with patients referred by their PCCs. This scenario represents a potentially realistic policy in VA in particular, because routine depression screening is already mandated. Our results show that implementing effective follow-up of primary care-detected depression for all eligible patients will be challenging.Few previous studies of CCM have tested reach  or the dLooking within the randomized evaluation and its patients, we found unanticipated associations between patient outcomes and whether the PCC they belonged to was an early adopter of CCM. Patients referred to CCM by the study team, but whose PCC was an early CCM adopter , were siWe think the clinician effects we observed are likely to substantially affect CCM models under naturalistic conditions. Clinician effects did not influence patient enrollment in the study. No clinicians in these practices refused to have their patients referred to CCM by study personnel, and the proportions of randomized evaluation patients belonging to early adopter clinicians versus those with a low predilection to adopt the model mirrored the proportions of clinicians who fell into these categories in the study practices.Clinician predisposition to adopt CCM affects use of the model under naturalistic conditions in another way as well. In essence, patients of early adopter clinicians tend to monopolize the DCM resource. For example, 73% of naturalistically referred patients belonged to clinicians who habitually used CCM , while only 27% of randomized evaluation patients belonged to this type of clinician. Registry data on patients naturalistically referred to CCM shows the same pattern we saw in data from the randomized evaluation; the quality of CCM care is better among patients of early adopter clinicians . DiffereTheories of social justice and mental health parity would argue that patient need, rather than clinician characteristics, should govern access to clinical resources. Our results emphasize the importance of active PCC engagement in CCM, a topic not addressed in most prior CCM research, though identified as issue by prior qualitative work on the TIDES program . CliniciThere are reasons to collect program evaluation data other than testing program efficacy or effectiveness. We think CCM programs should monitor patient outcomes using a registry, as was done in this study, for purposes of monitoring program utility and safety. Unlike our randomized evaluation results, our pre-post care manager registry data reflects how the program functions naturalistically. These naturalistic data, while not testing model effectiveness, show that CCM as implemented in these VA sites performed safely, and with outcomes that met or exceeded CCM targets for patients whose clinicians chose to refer them.We used our registry data as well as our randomized trial data to shape and improve EBQI-CCM. As reported elsewhere ,19, regiOur comparison of registry data with rigorous study data is encouraging regarding the validity of registry data for depression program monitoring purposes. Although we would not have discovered the effects of clinician adopter status based on registry data, because of the few included patients belonging to low adopter clinicians, we can replicate this clinician effect in retrospect through the registry. Other major context effects demonstrated by the randomized experiment, including effects of patient complexity, can also be observed through the registry data, supporting its validity. Per protocol analysis (looking only at patients who received full CCM) of symptom and functional status outcomes for randomized evaluation patients was consistent with registry results in terms of the level of outcome improvement observed, providing qualitative triangulation on the importance of ensuring patient completion of CCM as a critical target for improvement. We conclude that registry data on patient care and symptom outcomes can be accurate enough for program monitoring, with appropriate attention to selection bias and care manager training on data collection.Registry data has limitations in addition to its inability to provide fully representative data. We know that registry patients were selected and not representative of all eligible patients. In addition, care managers, though extensively trained, may have been less objective or consistent in their administration of the PHQ-9 than were external data collectors.One of the explicit goals of the TIDES program was to develop a CCM model that could be spread nationally in VA . In termThis study has limitations. The study focused on a single healthcare system (the VA), and on non-academic, small to medium-sized practices, almost a third of which were rural . ResultsIn summary, this study showed that CCM, as implemented using EBQI, improved antidepressant prescribing across a representative sample of patients attending study practices. While this randomized evaluation does not test the effectiveness of CCM as an ideal model, it does test the effectiveness of CCM as designed and implemented in VA using QI methods, albeit early in the program's lifespan. The study encountered a number of difficulties likely to apply to other healthcare organizations implementing CCM as routine care, including the consequences of care manager overload and of differential PCC adoption of CCM. The lack of robust patient symptom improvement for the experimental group compared to usual care points to the importance of continuously monitoring and improving CCM programs during and after implementation. Otherwise, the cost-effectiveness benefits promised by CCM studies will not be achieved in reality.The authors declare that they have no competing interests.EC, LR, CL, EY, BS, and BF substantially contributed to the conception and design. CB, ML, AL, and JU contributed to the analysis and interpretation of the data. All authors were involved in drafting the manuscript and/or critically revising it. All authors read and approved the final manuscript.


Severe acute respiratory syndrome (SARS) was first described during a 2002–2003 global outbreak of severe pneumonia associated with human deaths and person-to-person disease transmission. The etiologic agent was initially identified as a coronavirus by thin-section electron microscopic examination of a virus isolate. Virions were spherical, 78 nm in mean diameter, and composed of a helical nucleocapsid within an envelope with surface projections. Herein, we show that infection with the SARS-associated coronavirus resulted in distinct ultrastructural features: double-membrane vesicles, nucleocapsid inclusions, and large granular areas of cytoplasm. These three structures and the coronavirus particles were shown to be positive for viral proteins and RNA by using ultrastructural immunogold and in situ hybridization assays. In addition, ultrastructural examination of a bronchiolar lavage specimen from a SARS patient showed numerous coronavirus-infected cells with features similar to those in infected culture cells. Electron microscopic studies were critical in identifying the etiologic agent of the SARS outbreak and in guiding subsequent laboratory and epidemiologic investigations. A large outbreak of severe pneumonia associated with human deaths occurred in late 2002 in Guangdong Province, China. Beginning in late February 2003, a similar illness was reported concurrently in Vietnam, Hong Kong, Canada, Singapore, and other countries  specimen. Viral immunogold labeling and ultrastructural in situ hybridization (ISH) were used to further analyze the morphogenesis of this newly emergent virus.6 rad), and processed for standard, immunolabeling electron microscopy (IEM) or ISH EM as previously described  or occasionally on the membranes of the rough endoplasmic reticulum that form the outer layer of the nuclear membrane. Virions acquired an envelope by budding into the cisternae and formed mostly spherical, sometimes pleomorphic, particles that averaged 78 nm in diameter . ChaThe SARS outbreak is a prime example of an emerging infectious disease that can rapidly and easily spread, reaching global proportions. With SARS, as with previous investigations of outbreaks involving such viruses as Ebola (


Glioneuronal tumors are an increasingly recognized cause of partial seizures that occur primarily in children and young adults. Focal epilepsy associated with glioneuronal tumors is often resistant to pharmacological treatment. The cellular mechanisms underlying the epileptogenicity of glioneuronal tumors remain largely unknown. The involved mechanisms are certain to be multifactorial and depend on specific tumor histology, integrity of the blood-brain barrier, characteristics of the peritumoral environment, circuit abnormalities, or cellular and molecular defects. Glioneuronal tumors presenting with epilepsy were observed to have relatively benign biological behavior. The completeness of the tumor resection is of paramount importance in avoiding tumor progression and malignant transformation, which are rare in cases of epileptogenic glioneuronal tumors. An evolving understanding of the various mechanisms of tumor-related epileptogenicity may also lead to a more defined surgical objective and effective therapeutic strategies, including antiepileptogenic treatments, to prevent epilepsy in at-risk patients. Glioneuronal tumors are an increasingly recognized cause of partial seizures that occur primarily in children and young adults , 2.These are tumors with an admixture of glial and neuronal components. Both cell types are thought to be part of the same neoplastic process. Entrapment of preexisting neurons by an infiltrating glioma therefore has to be distinguished from glioneuronal tumors. More well-established examples of glioneuronal tumors include dysembryoplastic neuroepithelial tumors (DNTs) ganglioglioma and desmoplastic infantile ganglioglioma. More recently recognized entities partly included in the latest version of the WHO classification include the rosette-forming tumor of the fourth ventricle the papillary glioneuronal tumor and rosetted glioneuronal tumor/glioneuronal tumor with neuropil-like islands. The glial component in these tumors varies but often resembles either a pilocytic astrocytoma or an infiltrating glioma with astrocytic or oligodendroglial features .Gangliogliomas and DNTs arise most commonly in the temporal lobe and appear to be associated with an increased incidence of cortical dysplasia or neuronal migration abnormalities , 4, 5. Focal epilepsy that is often resistant to pharmacological treatment is a common presenting symptom of glioneuronal tumors , 2. EvenWhile a subset of epilepsy patients with glioneuronal tumors may be candidates for epilepsy surgery, a better understanding of underlying mechanisms of epileptogenesis in this group of developmental brain disorders could lead to more effective therapeutic strategies, including antiepileptogenic treatments to prevent epilepsy in at-risk patients.The cellular mechanism(s) underlying the epileptogenicity of glioneuronal tumors remain largely unknown. The high success rate of “lesionectomy” during epilepsy surgery, with many studies reporting over a 60–75% seizure-free rate, also supports the idea that the lesions directly produce seizures –10. HoweA growing intracranial lesion can both structurally and functionally alter the surrounding brain tissue with edema, vascular insufficiency, inflammation, and release of metabolically active molecules, hence also promoting seizure activity. The involved mechanisms are certain to be multifactorial and depend on specific tumor histology, integrity of the blood-brain barrier, and characteristics of the peritumoral environment .Seizures clearly consist of synchronous electrical activity reverberating through complex neuronal networks and thus ultimately must always include abnormalities on the circuit level. Ultimately, both network and cellular/molecular abnormalities will stimulate epileptogenesis by upsetting the normal physiological balance between excitation and inhibition in the brain .β- (IL-1β-) activated pathways in ictogenesis. Intracerebral application of IL-1β in rodents prolongs seizure activity [β using blockers of interleukin-converting enzyme, also named caspase-1, significantly reduces seizures in rodents [β produced in the brain in pathological conditions, such as during seizures or as a consequence of underlying inflammatory processes [β gene, which is associated with therapy-resistant temporal lobe epilepsy and in children with febrile seizures [An important role in hyperexcitability has been attributed to the neuronal component of these lesions, consisting of highly differentiated cells containing, for example, neuropeptides, neurotrophins, gap junctions, and receptors for different neurotransmitters , 13–15. activity . Accordiactivity . Inhibit rodents . These orocesses , 21. It rocesses , 23. Finseizures . Ravizzaseizures  demonstrParticular attention has been focused on the neuronal glutamatergic population, consisting of highly differentiated cells expressing different glutamate receptor subtypes . HoweverThe stem cell epitope CD34 is highly expressed in gangliogliomas. The presence of a prominent CD34-immunoreactive cell element in glioneuronal lesions associated with focal epilepsies points towards an origin from dysplastic and/or neoplastically transformed precursor cells . SeveralSome studies point to a role of genes and pathways in epilepsy-associated glioneuronal lesions , 40, othTyrosine kinase receptors trkA, -B, and -C were observed to be strongly expressed in neuronal components of gangliogliomas, focal cortical dysplasia and DNET . FassunkThe plasminogen (fibrinolytic) system comprises the inactive proenzyme, plasminogen, that can be converted to the active enzyme plasmin by two serine proteases, the tissue-type plasminogen activator (tPA) and the urokinase-type plasminog activator (uPA) . In the The resistance to the pharmacological treatment with a broad range of antiepileptic drugs (AEDs) is characteristic of these developmental lesions , 55. TheEpilepsy that is often resistant to pharmacological treatment is a common presenting symptom of glioneuronal tumors (in 75% of cases), and the temporal lobe is the most frequent location (in 60% of cases). The best approach to management of epilepsies related to benign tumours is controversial. Several studies have suggested a very benign clinical course in most patients with gangliogliomas. However, tumor recurrence, malignant progression, and secondary glioblastoma multiforme are observed in some patients , 5, 59. Epilepsy control represents the main therapeutic goal , 2, 5. FControversy exists regarding the most appropriate surgical treatment for children suffering from epilepsy associated with brain tumors. Some investigators consider complete tumor excision sufficient –64 whereFew studies, however, have specifically focused on the long-term seizure outcome after lesionectomy in selected series of children harboring glioneuronal tumors. Other authors have investigated seizure outcome after lesionectomy in groups in which glioneuronal tumors occurred together with other different epileptogenic types of tumor , 63.Giulioni et al.  demonstrRecently Yang et al.  reviewedFurthermore, glioneuronal tumors presenting with epilepsy were observed to have relatively benign biological behavior. The seizure outcomes do not appear to be related to the duration of epilepsy, seizure type, and frequency or completeness of tumor removal. The completeness of the tumor resection is of paramount importance in avoiding tumor progression and malignant transformation, which are rare in cases of epileptogenic glioneuronal tumors .Finally, despite the probable developmental defects in glioneuronal proliferation in the relevant malformations of cortical development, classes of drugs are already available that can inhibit cell proliferation. In particular, the recent discovery of mTOR pathway dysregulation in TSC, as well as focal cortical dysplasia and gangliogliomas, offers a remarkably direct “bench-to-bedside” strategy for treating these malformations of cortical development. Rapamycin will specifically inhibit the mTOR pathway, leading to decreased cellular proliferation , and hasPatients with drug-resistant epilepsy associated to glioneuronal tumors should undergo evaluation in dedicated epilepsy surgery programmes. The procedure should include diagnosis of the type of tumour by advanced imaging and radio-nuclear methods followed by rapid determination of intractability to antiepileptic drug treatment. Although many patients become seizure-free with a standard “lesionectomy,” a significant proportion of patients continue to have seizures despite lesionectomy and might benefit from a more extensive surgical resection involving broader perilesional regions. A large-scale screening of currently available drugs have identified a number of drugs that can upregulate astrocyte glutamate transporters, which may counteract the detrimental effects of impaired astrocyte glutamate transport seen in epilepsy and other neurological disorders . Glial-sFuture advances in imaging techniques and molecular markers might be able to more accurately identify the true extent of the epileptogenic zone that needs to be resected to achieve seizure freedom. Further advances into the distinct pathophysiologies of epilepsy associated with different tumor histologies will promote an even more rational choice of medical therapy. An evolving understanding of the various mechanisms of tumor-related epileptogenicity and the role of the perilesional tissue may also lead to a more defined surgical objective for the patient presenting with tumor-related epilepsy. In addition to pharmacological interventions, future therapeutic gene replacement or gene manipulation approaches may eventually allow a more definitive correction of the molecular genetic defects in these diseases.