Efficacy and Safety of Intravitreal Aflibercept Treat and Extend for Polypoidal Choroidal Vasculopathy in the ATLANTIC Study: A Randomized Clinical Trial.

IMPORTANCE: Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed. METHODS: A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin. The main outcome measures were changes in best-corrected visual acuity (BCVA) from baseline to 52 weeks and polyp occlusion at week 52. Data are presented as median (interquartile range [IQR]) for BCVA, number of IVAI, and change in central retinal thickness (CRT). RESULTS: Of the 50 patients included in the study, 48 patients completed the 52 weeks of follow-up. During this period, a significant median (IQR) BCVA gain of 6 [2-12] Early Treatment Diabetic Retinopathy Study letters was observed for all patients (p < 0.001), after 8 (7-9) injections, with a significant reduction of -93.0 [-154.0, -44.0] µm in central macular thickness (p < 0.001). Using indocyanine green angiography, a complete occlusion of polypoidal lesions was documented in 72% of the cases. Still, no significant difference was detected between the sham PDT and the aflibercept PDT arms, at week 52, for BCVA change (6.5 [2-11] vs. 5 [2-13] letters (p = 0.98)), number of IVAIs (8.5 [7-9] vs. 8 [7-9] (p = 0.21)), change in CRT (-143 [-184; -47] vs. -89 [-123; -41.5] µm [p = 0.23]), and rates of complete polyp occlusion: 77 versus 68% (p = 0.53) or presence of fluid: 68 versus 57% (p = 0.56). No serious ocular adverse events were registered in the 2 arms. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first RCT to compare aflibercept T&E monotherapy with aflibercept T&E plus verteporfin PDT in a Caucasian population with PCV. Aflibercept monotherapy in a T&E showed to be effective and safe with a significant median BCVA improvement of 6 letters and a complete occlusion of polypoidal lesions in near 3 quarters of the eyes, at 1 year. As only 22% of the eyes underwent PDT treatment, the benefit of combined treatment for PCV in Caucasian patients could not be definitively elucidated from this study. TRIAL REGISTRATION: The clinical trial was registered in ClinicalTrials.gov Identifier NCT02495181 and the European Union Drug Regulating Authorities Clinical Trials Database EudraCT No. 2015-001368-20.

A Resting-State Functional MR Imaging and Spectroscopy Study of the Dorsal Hippocampus in the Chronic Unpredictable Stress Rat Model.

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.

Bioorthogonal Labeling Reveals Different Expression of Glycans in Mouse Hippocampal Neuron Cultures during Their Development.

The expression of different glycans at the cell surface dictates cell interactions with their environment and other cells, being crucial for the cell fate. The development of the central nervous system is associated with tremendous changes in the cell glycome that is tightly regulated. Herein, we have employed biorthogonal Cu-free click chemistry to image temporal distribution of different glycans in live mouse hippocampal neurons during their maturation in vitro. We show development-dependent glycan patterns with increased fucose and decreased mannose expression at the end of the maturation process. We also demonstrate that this approach is biocompatible and does not affect glycan transport although it relies on an administration of modified glycans. The applicability of this strategy to tissue sections unlocks new opportunities to study the glycan dynamics under more complex physiological conditions.

The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a marked decline in cognition and memory function. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, including those produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (Aß) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways of relevance for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive Aß accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3months, which became lower than WT at 5-6 and 11-12months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3months. Altogether, these findings provide new insights on a possible interplay between type I and II IFN responses in AD and point to IFNs as targets for modulation in cognitive decline.

Pattern recognition of hematological profiles of tumors of the digestive tract: an exploratory study.

Aims: In this study, we aimed to apply laboratory blood analysis to identify the hematological (based on hemoglobin concentration, erythrocytes, hematocrit, and RDW count) profiles associated with the most prevalent forms of digestive tract malignancies. Furthermore, we aimed to evaluate how these profiles contributed to distinguishing these tumors at diagnosis. Methods: We collected data from the date of ICD-10 diagnostic coding for C15 esophagus, C16 stomach, C18 colon, and C19 rectum tumors of 184 individuals. The statistical analysis and data visualization approaches, notably the heat map and principal component analysis (PCA), allowed for creating a summary hematological profile and identifying the most associated parameters for each pathologic state. Univariate and multivariate data modeling and ROC analysis were performed in both SPSS and Python. Results: Our data reveal unique patterns based on tumor development anatomical location, clustering the C18 colon and C19 rectum from the C15 esophagus and C16 stomach. We found a significant difference between C16 stomach carcinoma and the other tumors, which substantially correlated with raised RDW in conjunction with low hemoglobin concentration, erythrocytes, and hematocrit counts. In contrast, C18 colon carcinoma had the higher red blood cell count, allowing for the best classification metrics in the test set of the binary logistic regression (LR) model, accounting for an AUC of 0.77 with 94% sensitivity and 52% specificity. Conclusion: This study emphasizes the significance of adding hematological patterns in diagnosing these malignancies, which could path further investigations regarding profiling and monitoring at the point of care.

Stress shifts the response of the bed nucleus of the stria terminalis to an anxiogenic mode.

The bed nucleus of the stria terminalis (BNST) is critically implicated in anxiety behavior and control of the hypothalamus-pituitary-adrenal axis. Having previously shown that chronic stress triggers dendritic/synaptic remodeling in specific nuclei of the BNST, we characterised the pattern of activation of neurons within different regions of the BNST under basal conditions and after an anxiogenic stimulus in control and stressed rats. Under basal conditions, stressed, but not control, animals displayed increased cFOS expression in the dorsomedial nucleus and decreased activation of the principal nucleus. This pattern resembled that observed in controls that had been exposed to the anxiogenic stimulus. Subsequent analysis of various BNST subnuclei revealed differential patterns of gene expression in controls and stressed animals. We found decreased levels of corticotropin-releasing hormone 1 receptor mRNA expression in the dorsomedial and fusiform nuclei, and a global increase in the levels of corticotropin-releasing hormone 2 receptor in the principal nucleus. In addition, we found subnuclei-specific increases in GABA(A) and NR2B receptors in stressed animals, which suggest changes in the GABAergic and glutamergic innervation of the BNST. Importantly, these findings were associated with increased anxiety-like behavior and impaired control of the hypothalamus-pituitary-adrenal axis in stressed animals. In summary, these data reveal that chronic stress shifts the pattern of response of the BNST to an anxiogenic mode and provide new information on the underlying mechanisms of the stress-induced hypercorticalism and hyperanxious status.

Lipocalin-2 does not influence EAE clinical score but it increases inflammation in central nervous system.

The contribution of lipocalin-2 (LCN2) to multiple sclerosis (MS) is controversial. Herein, we induced experimental autoimmune encephalomyelitis (EAE) in LCN2-null and wild-type (Wt) mice. While we did not find differences between genotypes regarding clinical score, LCN2-null EAE mice presented decreased expression of interferon gamma and diminished demyelination in the cerebellum. Both genotypes presented similar alterations in the thymocyte and splenocyte populations. In MS patients, higher LCN2 CSF levels at diagnosis could be associated with faster disease progression, however further studies are needed to confirm these results, since this association was lost after controlling for the patients age, presence of oligoclonal bands and gender. Overall, our results support a harmful role for LCN2 in the disease context.

Lenstar LS 900 versus Pentacam-AXL: analysis of refractive outcomes and predicted refraction.

Analysis of refractive outcomes, using biometry data collected with a new biometer (Pentacam-AXL, OCULUS, Germany) and a reference biometer (Lenstar LS 900, HAAG-STREIT AG, Switzerland), in order to assess differences in the predicted and actual refraction using different formulas. Prospective, institutional study, in which intraocular lens (IOL) calculation was performed using the Haigis, SRK/T and Hoffer Q formulas with the two systems in patients undergoing cataract surgery between November 2016 and August 2017. Four to 6 weeks after surgery, the spherical equivalent (SE) was derived from objective refraction. Mean prediction error (PE), mean absolute error (MAE) and the median absolute error (MedAE) were calculated. The percentage of eyes within ± 0.25, ± 0.50, ± 1.00, and ± 2.00 D of MAE was determined. 104 eyes from 76 patients, 35 males (46.1%), underwent uneventful phacoemulsification with IOL implantation. Mean SE after surgery was - 0.29 ± 0.46 D. Mean prediction error (PE) using the SRK/T, Haigis and Hoffer Q formulas with the Lenstar was significantly different (p > 0.0001) from PE calculated with the Pentacam in all three formulas. Percentage of eyes within ± 0.25 D MAE were larger with the Lenstar device, using all three formulas. The difference between the actual refractive error and the predicted refractive error is consistently lower when using Lenstar. The Pentacam-AXL user should be alert to the critical necessity of constant optimization in order to obtain optimal refractive results.

Distribution of micropollutants in estuarine and sea water along the Portuguese coast.

This work provides the first spatial distribution report of micropollutants (MPs) in the entire Portuguese coast, comprising the ocean shore (sea water, SW) and whenever possible the nearest river discharging on it (estuarine water, EW). This surface water monitoring programme aimed to assess the spatial distribution of 37 MPs with a wide chemical nature, including some substances prioritized by the European Union Directive 39/2013/EU and contaminants of emerging concern targeted in the Watch List of Decisions 495/2015/EU and 840/2018/EU. The risk quotients were estimated in each sampling point for the detected MPs. High concentrations of diclofenac, tramadol and carbamazepine were determined, the latter with medium to high risk for algae. Some pharmaceuticals and perfluorooctanesulfonic acid (PFOS) were broadly distributed, maybe due to the direct discharge into the sea. Atrazine and alachlor were found in the majority of the samples, with alachlor levels often considered as medium to high risk.

The choroid plexus response to a repeated peripheral inflammatory stimulus.

BACKGROUND: Chronic systemic inflammation triggers alterations in the central nervous system that may relate to the underlying inflammatory component reported in neurodegenerative disorders such as multiple sclerosis and Alzheimer's disease. However, it is far from being understood whether and how peripheral inflammation contributes to induce brain inflammatory response in such illnesses. As part of the barriers that separate the blood from the brain, the choroid plexus conveys inflammatory immune signals into the brain, largely through alterations in the composition of the cerebrospinal fluid. RESULTS: In the present study we investigated the mouse choroid plexus gene expression profile, using microarray analyses, in response to a repeated inflammatory stimulus induced by the intraperitoneal administration of lipopolysaccharide every two weeks for a period of three months; mice were sacrificed 3 and 15 days after the last lipopolysaccharide injection. The data show that the choroid plexus displays a sustained response to the repeated inflammatory stimuli by altering the expression profile of several genes. From a total of 24,000 probes, 369 are up-regulated and 167 are down-regulated 3 days after the last lipopolysaccharide injection, while at 15 days the number decreases to 98 and 128, respectively. The pathways displaying the most significant changes include those facilitating entry of cells into the cerebrospinal fluid, and those participating in the innate immune response to infection. CONCLUSION: These observations contribute to a better understanding of the brain response to peripheral inflammation and pave the way to study their impact on the progression of several disorders of the central nervous system in which inflammation is known to be implicated.

Dual enantioselective LC-MS/MS method to analyse chiral drugs in surface water: Monitoring in Douro River estuary.

This work presents the development of an enantioselective method to quantify chiral drugs (CDs) in surface water and its application in the Douro River estuary monitoring. Different classes of CDs were targeted, including 23 compounds, namely beta-blockers, antidepressants, one beta2-adrenergic agonist, non-steroidal anti-inflammatory drugs, stimulants, and some illicit drugs as cocaine (COC) and its metabolites, and amphetamines. The analytical method was based on an innovative application of solid phase extraction (SPE), followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a triple quadrupole analyzer. The ground-breaking approach of SPE consists in the use of Oasis® MCX cartridges to pre-concentrate 500 mL of water samples, allowing the simultaneous extraction of acidic, basic and neutral analytes, rather than the conventional recovery of basic compounds only. Two chiral columns were used for enantiomeric separation in reverse elution mode, a Chirobiotic™V and a Pirkle type Whelk-O®1, for basic and acidic compounds, respectively. The method validation demonstrated good linearity (r2 > 0.99), selectivity and sensitivity, with method detection limits between 0.01 and 2.66 ng L-1 and method quantification limits between 0.02 and 5.71 ng L-1. The developed method was successfully applied to monitor daily variations along one week in surface waters collected in 5 locations of the Douro River estuary. Tramadol (TRM) and its metabolite N-desmethyltramadol (NDT), presented high concentrations near the affluent of a tributary river, while the second eluted enantiomer of O-desmethyltramadol (ODT) was found at high concentrations at the mouth of the Douro River. The metabolite NDT was quantified at higher concentrations than TRM. Venlafaxine (VNF) was found at high concentrations near the affluent of the same tributary river, but its metabolite, O-desmethylvenlafaxine (ODV), was found at concentrations 3 times higher. COC was found every day at all sampling points along the estuary, with slight variations.

Monitoring of the 17 EU Watch List contaminants of emerging concern in the Ave and the Sousa Rivers.

The occurrence of micropollutants in the environment is a matter of high concern. Some regulations have been published in the last years and a Watch List of contaminants of emerging concern (CECs) for European Union monitoring of surface water was launched in the Decision 2015/495, including three estrogens (estrone, E1; 17-ß-estradiol, E2; and 17-α-ethinylestradiol, EE2), four pharmaceuticals (diclofenac and the macrolide antibiotics azithromycin, clarithromycin and erythromycin), an anti-oxidant (2,6-ditert-butyl-4-methylphenol, BHT), an UV filter (2-ethylhexyl 4-methoxycinnamate, EHMC), some pesticides (methiocarb and the neonicotinoids imidacloprid, thiacloprid, thiamethoxam, clothianidin and acetamiprid) and two herbicides (oxadiazon and triallate). This study provides the first spatial and seasonal monitoring campaign in the Ave and the Sousa Rivers for the all set of the 17 Watch List CECs (not reported yet for any country), in order to assess their occurrence, distribution, frequency and risk assessment. It also highlights the need of extend the study to other regions and environmental matrices to investigate the occurrence and possible sources of contamination of CECs, aiming to give insights for decision makers to define mitigation strategies for a more sustainable water policy.

Lipocalin 2 is a choroid plexus acute-phase protein.

Lipocalin 2 (LCN2) is able to sequester iron-loaded bacterial siderophores and, therefore, is known to participate in the mammalian innate immune response. Of notice, LCN2 was shown to display bacteriostatic effects both in in vitro and in vivo. To reach the brain, bacteria must cross the blood-brain or the choroid plexus (CP)/cerebrospinal fluid (CSF) barriers. Additionally, as the CP is responsible for the production of most of the CSF, responses of the CP mediate signaling into the brain. We show here that in conditions of peripheral inflammation, LCN2 behaves as an acute phase protein in the CP. As early as 1 h after lipopolysaccharide peripheral administration, Lcn2 mRNA levels are upregulated, returning to basal levels after 72 h. Increased LCN2 protein is observed in choroidal epithelia and in endothelial cells of blood vessels in the brain parenchyma. Higher levels of LCN2 are also present in the CSF. These observations suggest that expression of LCN2 at the CP/CSF barrier might be bacteriostatic in the brain, avoiding bacteria dissemination within the CSF into the brain parenchyma. This study shows that the LCN2 is produced by the CP as a component of the innate immune response that protects the central nervous system from infection.

A review on environmental monitoring of water organic pollutants identified by EU guidelines.

The contamination of fresh water is a global concern. The huge impact of natural and anthropogenic organic substances that are constantly released into the environment, demands a better knowledge of the chemical status of Earth's surface water. Water quality monitoring studies have been performed targeting different substances and/or classes of substances, in different regions of the world, using different types of sampling strategies and campaigns. This review article aims to gather the available dispersed information regarding the occurrence of priority substances (PSs) and contaminants of emerging concern (CECs) that must be monitored in Europe in surface water, according to the European Union Directive 2013/39/EU and the Watch List of Decision 2015/495/EU, respectively. Other specific organic pollutants not considered in these EU documents as substances of high concern, but with reported elevated frequency of detection at high concentrations, are also discussed. The search comprised worldwide publications from 2012, considering at least one of the following criteria: 4 sampling campaigns per year, wet and dry seasons, temporal and/or spatial monitoring of surface (river, estuarine, lake and/or coastal waters) and ground waters. The highest concentrations were found for: (i) the PSs atrazine, alachlor, trifluralin, heptachlor, hexachlorocyclohexane, polycyclic aromatic hydrocarbons and di(2-ethylhexyl)phthalate; (ii) the CECs azithromycin, clarithromycin, erythromycin, diclofenac, 17α-ethinylestradiol, imidacloprid and 2-ethylhexyl 4-methoxycinnamate; and (iii) other unregulated organic compounds (caffeine, naproxen, metolachlor, estriol, dimethoate, terbuthylazine, acetaminophen, ibuprofen, trimethoprim, ciprofloxacin, ketoprofen, atenolol, Bisphenol A, metoprolol, carbofuran, malathion, sulfamethoxazole, carbamazepine and ofloxacin). Most frequent substances as well as those found at highest concentrations in different seasons and regions, together with available risk assessment data, may be useful to identify possible future PS candidates.

Lenstar® LS 900 vs Pentacam®-AXL: Comparative study of ocular biometric measurements and intraocular lens power calculation.

PURPOSE:: Comparison of biometric measurements and calculation of intraocular lens with a new biometer (Pentacam®-AXL, Oculus, Germany) and a reference biometer (Lenstar LS 900®, Haag-Streit AG, Switzerland), in order to assess the agreement between these two devices. SETTING:: Centro Hospitalar de Leiria, Portugal. MATERIALS AND METHODS:: Prospective, institutional study, in which measurements of axial length, anterior chamber depth from the corneal epithelium and endothelium to the anterior surface of the lens (anterior chamber depth ext and anterior chamber depth int), central corneal thickness and keratometry readings of the flattest and steepest meridians (K1 and K2) were obtained with the two systems. Intraocular lens calculation was also performed, using the Haigis, SRK/T and HofferQ formulas. RESULTS:: The study sample included 136 eyes of 79 patients. Of these, 42 were women and 37 were men. Statistically significant differences were found (p < 0.05, paired T test) in K1, K2 and central corneal thickness between the 2 biometers. Intraocular lens calculation with the Lenstar® and the Pentacam® with Haigis, SRK/T and HofferQ formulas showed statistically significant differences (p < 0.05 Paired T test). CONCLUSION:: Axial length measurements obtained with the Pentacam® and Lenstar® appear to be interchangeable, while measurements of anterior chamber depth, K1 and K2, and central corneal thickness do not appear to be interchangeable between different devices. Statistically significant differences were found in the calculation of intraocular lenses in all formulas used.

Descriptive Analysis of LAP1 Distribution and That of Associated Proteins throughout Spermatogenesis.

Spermatogenesis comprises highly complex differentiation processes. Nuclear envelope (NE) proteins have been associated with these processes, including lamins, lamina-associated polypeptide (LAP) 2 and the lamin B-receptor. LAP1 is an important NE protein whose function has not been fully elucidated, but several binding partners allow predicting putative LAP1 functions. To date, LAP1 had not been associated with spermatogenesis. In this study, LAP1 expression and cellular/subcellular localization during spermatogenesis in human and mouse testes is established for the first time. The fact that LAP1 is expressed during nuclear elongation in spermiogenesis and is located at the spermatids' centriolar pole is singularly important. LAP1 binds to members of the protein phosphatase 1 (PP1) family. Similar localization of LAP1 and PP1γ2, a testis-specific PP1 isoform, suggests a shared function for both proteins during spermiogenesis. Furthermore, this study suggests an involvement of LAP1 in manchette development and chromatin regulation possibly via interaction with acetylated α-tubulin and lamins, respectively. Taken together, the present results indicate that, by moving to the posterior pole in spermatids, LAP1 can contribute to the achievement of non-random, sperm-specific chromatin distribution, as well as modulate cellular remodeling during spermiogenesis. In addition, LAP1 seems to be associated with dynamic microtubule changes related to manchette formation and flagella development.

Bioengineered cell culture systems of central nervous system injury and disease.

Cell culture systems, either 2D or explant based, have been pivotal to better understand the pathophysiology of several central nervous system (CNS) disorders. Recently, bioengineered cell culture systems have been proposed as an alternative to the traditional setups. These innovative systems often combine different cell populations in 3D environments that more closely recapitulate the different niches that exist within the developing or adult CNS. Given the importance of such systems for the future of CNS-related research, we discuss here the most recent advances in the field, particularly those dealing with neurodegeneration, neurodevelopmental disorders, and trauma.

The choroid plexus is modulated by various peripheral stimuli: implications to diseases of the central nervous system.

The blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB) form the barriers of the brain. These barriers are essential not only for the protection of the brain, but also in regulating the exchange of cells and molecules in and out of the brain. The choroid plexus (CP) epithelial cells and the arachnoid membrane form the BCSFB. The CP is structurally divided into two independent compartments: one formed by a unique and continuous line of epithelial cells that rest upon a basal lamina; and, a second consisting of a central core formed by connective and highly vascularized tissue populated by diverse cell types (fibroblasts, macrophages and dendritic cells). Here, we review how the CP transcriptome and secretome vary depending on the nature and duration of the stimuli to which the CP is exposed. Specifically, when the peripheral stimulation is acute the CP response is rapid, strong and transient, whereas if the stimulation is sustained in time the CP response persists but it is weaker. Furthermore, not all of the epithelium responds at the same time to peripheral stimulation, suggesting the existence of a synchrony system between individual CP epithelial cells.

Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities.

Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) share few characteristics apart from self-renewal and multipotency. In fact, the neurogenic and osteogenic stem cell niches derive from two distinct embryonary structures; while the later originates from the mesoderm, as all the connective tissues do, the first derives from the ectoderm. Therefore, it is highly unlikely that stem cells isolated from one niche could form terminally differentiated cells from the other. Additionally, these two niches are associated to tissues/systems (e.g., bone and central nervous system) that have markedly different needs and display diverse functions within the human body. Nevertheless they do share common features. For instance, the differentiation of both NSCs and MSCs is intimately associated with the bone morphogenetic protein family. Moreover, both NSCs and MSCs secrete a panel of common growth factors, such as nerve growth factor (NGF), glial derived neurotrophic factor (GDNF), and brain derived neurotrophic factor (BDNF), among others. But it is not the features they share but the interaction between them that seem most important, and worth exploring; namely, it has already been shown that there are mutually beneficially effects when these cell types are co-cultured in vitro. In fact the use of MSCs, and their secretome, become a strong candidate to be used as a therapeutic tool for CNS applications, namely by triggering the endogenous proliferation and differentiation of neural progenitors, among other mechanisms. Quite interestingly it was recently revealed that MSCs could be found in the human brain, in the vicinity of capillaries. In the present review we highlight how MSCs and NSCs in the neurogenic niches interact. Furthermore, we propose directions on this field and explore the future therapeutic possibilities that may arise from the combination/interaction of MSCs and NSCs.

From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.