Effect of Neonatal Treatment With the NMDA Receptor Antagonist, MK-801, During Different Temporal Windows of Postnatal Period in Adult Prefrontal Cortical and Hippocampal Function

The neonatal MK-801 model of schizophrenia has been developed based on the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia. This animal model is generated with the use of the NMDA receptor antagonist, MK-801, during different temporal windows of postnatal life of rodents leading to behavioral defects in adulthood. However, no studies have examined the role of specific postnatal time periods in the neonatal MK-801 (nMK-801) rodent model and the resulting behavioral and neurobiological effects. Thus, the goal of this study is to systematically investigate the role of NMDA hypofunction, during specific temporal windows in postnatal life on different cognitive and social behavioral paradigms, as well as various neurobiological effects during adulthood. Both female and male mice were injected intraperitoneally (i.p.) with MK-801 during postnatal days 7–14 (p7–14) or 11–15 (p11–15). Control mice were injected with saline during the respective time period. In adulthood, mice were tested in various cognitive and social behavioral tasks. Mice nMK-801-treated on p7–14 show impaired performance in the novel object, object-to-place, and temporal order object recognition (TOR) tasks, the sociability test, and contextual fear extinction. Mice nMK-801-treated on p11–15 only affects performance in the TOR task, the social memory test, and contextual fear extinction. No differences were identified in the expression of NMDA receptor subunits, the synapsin or PSD-95 proteins, either in the prefrontal cortex (PFC) or the hippocampus (HPC), brain regions significantly affected in schizophrenia. The number of parvalbumin (PV)-expressing cells is significantly reduced in the PFC, but not in the HPC, of nMK-801-treated mice on p7–14 compared to their controls. No differences in PV-expressing cells (PFC or HPC) were identified in nMK-801-treated mice on p11–15. We further examined PFC function by recording spontaneous activity in a solution that allows up state generation. We find that the frequency of up states is significantly reduced in both nMK-801-treated mice on p7–14 and p11–15 compared to saline-treated mice. Furthermore, we find adaptations in the gamma and high gamma activity in nMK-801-treated mice. In conclusion, our results show that MK-801 treatment during specific postnatal temporal windows has differential effects on cognitive and social behaviors, as well as on underlying neurobiological substrates

Effects of antifibrotic agents on TGF-β1, CTGF and IFN-γ expression in patients with idiopathic pulmonary fibrosis

SummaryIdiopathic pulmonary fibrosis (IPF) is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of IFN-γ-1b and colchicine, on biomarkers expression associated with fibrosis (TGF-β, CTGF) and immunomodulatory/antimicrobial activity (IFN-γ), in the lungs of patients with IPF.Fourteen (14) patients with an established diagnosis of IPF received either 200μg of IFN-γ-1b subcutaneously three times per week, or 1mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor β1 (TGF-β1), connective-tissue growth factor (CTGF), and interferon-γ (IFN-γ) genes in lung tissue before and after treatment with IFN-γ-1b or colchicine.Marked mRNA expression of TGF-β1 and CTGF, but complete lack of interferon-γ was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of IFN-γ gene at 6 months that was sustained at 24 months. The expression of CTGF and TGF-β1 remained almost stable before and after treatment, in the IFN-γ-1b group, while TGF-β1 was statistically decreased after therapy, in the colchicine group (p=0.0002). Significant difference in DLCO (% pred), was found between the two treatment groups in favor of IFN-γ-1b group (p=0.04). In addition, the IFN-γ-1b group showed stability in arterial PO2 while the colchicine group significantly deteriorated (p=0.02).In conclusion, we report the effect of antifibrotic agents (IFN-γ-1b and colchicine) in TGF-β, CTGF, and endogenous IFN-γ gene expression, in human fibrosis. However, extended studies are needed to verify the pathophysiological consequences of these findings

Severe airway stenosis associated with Crohn's disease: Case report

BACKGROUND: Symptomatic respiratory tract involvement is not common in Crohn's disease. Upper-airway obstruction has been reported before in Crohn's disease and usually responds well to steroid treatment. CASE PRESENTATION: We report a case of a 32-year old patient with Crohn's disease who presented with progressively worsening dyspnea on exertion. Magnetic Resonance Imaging of the chest and bronchoscopy revealed severe tracheal stenosis and marked inflammation of tracheal mucosa. Histopathology of the lesion showed acute and chronic inflammation and extended ulceration of bronchial mucosa, without granulomas. Tracheal stenosis was attributed to Crohn's disease after exclusion of other possible causes and oral and inhaled steroids were administered. Despite steroid treatment, tracheal stenosis persisted and only mild symptomatic improvement was noted after 8 months of therapy. The patient subsequently underwent rigid bronchoscopy with successful dilatation and ablation of the stenosed areas and remission of her symptoms. CONCLUSION: Respiratory involvement in Crohn's disease might be more common than appreciated. Interventional pulmonology techniques should be considered in cases of tracheal stenosis due to Crohn's disease refractory to steroid treatment

Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD

20 p.-7 fig.Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid–containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.This work was supported by the National Natural Science Foundation of China (81925001 to JFX and 81800063 to LCF) and by the NIH grant P01 HL114501 (AMKC). SMC is supported by Science Foundation Ireland (Future Research Leaders Grant FRL4862). MP is supported by NIH grant K08 HL157728.Peer reviewe

Investigation of NMDA-dependant critical periods in the postnatal period that affect prefrontal cortical and hippocampal function

A critical period is defined as a very specific period of time during which environmental stimuli regulate the development of the neural networks of the brain and result in permanent changes. The critical period for visual system development, which has been extensively studied, is during postnatal days (p)19 to 32. During that developmental window, exogenous visual stimuli are necessary to generate the ocular dominance columns in the visual cortex. To date, however, no studies have examined specific postnatal periods of development that influence different cognitive functions in adulthood. The aim of this study is to investigate the existence of critical periods for the development of different cognitive functions that depend on proper functioning of the prefrontal cortex and hippocampus. The study focuses on the second postnatal week, during which profound changes occur in both the prefrontal cortex and the hippocampus, including changes in the expression levels of NMDA-receptor subunits known to support plasticity mechanisms in the brain. The neonatal MK-801 administration model was used to inhibit NMDA-receptor function at distinct time periods during the second postnatal week: a) at the end of the 2nd postnatal week (p11-p15), b) throughout the 2nd postnatal week (p7-p14), and c) at the beginning of the 2nd postnatal week (p7-p11). Neonatal MK-801 administration towards the end of the second postnatal week (p11-p15) results in deficits in the temporal order object recognition test, the fear extinction test, the sociability test and the sociability memory test. No differences were observed in performance of novel object recognition, object-to-place recognition and contextual fear memory tests. At the same time, this model is characterized by reduced spontaneous activity in the prefrontal cortex and hippocampus. In terms of the synchronization of neuronal circuits, there is a decrease in high gamma oscillations in the prefrontal cortex and an increase in gamma oscillations in the hippocampus. No changes in NMDA receptor subunit or synaptic protein expression were observed in adulthood. Therefore, blockade of NMDA-receptors at the end of the 2nd postnatal week mainly affects the cognitive functions that are mainly based on the function of the prefrontal cortex, although neuronal activity changes are observed both the in the prefrontal cortex and the hippocampus.The neonatal model of MK-801 administration throughout the second postnatal week (p7-p14) shows impairments in the temporal order, novel object, and to place object recognition tests. He also shows deficits in the fear memory extinction test and the sociability test. In the sociability memory test only the female muscles show a deficit. The above deficits are accompanied by a reduced number of parvalbumin-expressing cells in the prefrontal cortex, but not in the hippocampus, while this model is characterized by reduced spontaneous activity in the prefrontal cortex and hippocampus. Regarding neuronal synchronization, an increase in theta, delta and gamma rhythms while a decrease in high gamma rhythms is observed in the prefrontal cortex. On the contrary, an increase is observed in all rhythms in the hippocampus. Therefore, blockade of NMDA-receptors throughout the 2nd postnatal week seems to affect cognitive functions that depend on proper functioning of both the prefrontal cortex and the hippocampus. Finally, the neonatal MK-801 model in which NMDA-receptors are blocked at the beginning of the second postnatal week (p7-p11) is characterized by deficits in the temporal order object and novel object recognition test as well as in the sociability test. In the novel object recognition test, only male mice show a deficit. Spontaneous activity in this model is reduced only in the prefrontal cortex, where the synchronization of neuronal circuits is also affected, as a reduction in gamma and high gamma rates is observed. Therefore, blocking NMDA-receptors at this time appears to affect cognitive functions and neurophysiological mechanisms primarily of the prefrontal cortex. The above results lead to the conclusion that there are different critical periods of development for the prefrontal cortex and the hippocampus, which may even overlap, as intervention in limited time windows during the second postnatal week leads to the appearance of dysfunctions of the prefrontal cortex and the hippocampus in a way depending on the time period of exposure. Future elucidation of the mechanism will lead to potential effective therapeutic targets for neurodevelopmental disorders such as Schizophrenia.Ως κρίσιμη περίοδο ορίζουμε μια πολύ συγκεκριμένη χρονική περίοδο κατά την οποία ερεθίσματα από το περιβάλλον ρυθμίζουν την ανάπτυξη των νευρωνικών δικτύων του εγκεφάλου και δημιουργούν μόνιμες αλλαγές. Μια κρίσιμη περίοδος στο οπτικό σύστημα που έχει μελετηθεί εκτενώς αφορά στις μεταγεννητικές ημέρες 19 έως 32 κατά τις οποίες εξωγενή οπτικά ερεθίσματα είναι απαραίτητα για τη δημιουργία οφθαλμικών στηλών στο φλοιό για τον κάθε οφθαλμό. Έως τώρα όμως, καμία μελέτη δεν έχει εξετάσει συγκεκριμένες μεταγεννητικές περιόδους ανάπτυξης που να επηρεάζουν συγκεκριμένες γνωστικές λειτουργίες κατά την ενηλικίωση. Στόχος αυτής της μελέτης είναι να διερευνηθεί η ύπαρξη κρίσιμων περιόδων για την ανάπτυξη διαφορετικών γνωστικών λειτουργιών οι οποίες βασίζονται στη λειτουργία του προμετωπιαίου φλοιού και του ιπποκάμπου. Η μελέτη εστιάζει στη δεύτερη μεταγεννητική εβδομάδα, κατά τη διάρκεια της οποίας συμβαίνουν έντονες αλλαγές τόσο στον προμετωπιαίο φλοιό όσο και στον ιππόκαμπο, συμπεριλαμβανομένων και αλλαγών στα επίπεδα έκφρασης των υπομονάδων των NMDA-υποδοχέων του γλουταμινικού οξέος που υποστηρίζουν μηχανισμούς πλαστικότητας στον εγκέφαλο. Χρησιμοποιήθηκε το μοντέλο νεογνικής χορήγησης MK-801 ώστε να προκληθεί αναστολή της λειτουργίας των NMDA-υποδοχέων σε διακριτές χρονικές περιόδους κατά τη διάρκεια της δεύτερης μεταγεννητικής εβδομάδας: α) στο τέλος της 2ης μεταγεννητικής εβδομάδας, β) σε όλη τη διάρκεια της 2ης μεταγεννητικής εβδομάδας και γ) στην αρχή 2ης μεταγεννητικής εβδομάδας. Το νεογνικό μοντέλο ΜΚ-801 όπου αποκλείονται οι NMDA-υποδοχείς προς το τέλος της δεύτερης μεταγεννητικής εβδομάδας (p11-p15) παρουσιάζει ελλείμματα στη δοκιμασία αναγνώρισης χρονικής σειράς αντικειμένου, στη δοκιμασία απόσβεσης μνήμης φόβου, στη δοκιμασία κοινωνικότητας και στη δοκιμασία μνήμης κοινωνικότητας. Παράλληλα αυτό το μοντέλο χαρακτηρίζεται από μειωμένη αυθόρμητη δραστηριότητα σε προμετωπιαίο φλοιό και ιππόκαμπο. Ως προς το συγχρονισμό των νευρωνικών κυκλωμάτων, παρουσιάζεται μείωση των υψηλών γάμμα ταλαντώσεων στον προμετωπιαίο φλοιό και αύξηση των γάμμα ταλαντώσεων στον ιππόκαμπο. Ο αποκλεισμός των NMDA-υποδοχέων λοιπόν στο τέλος της 2ης μεταγεννητικής εβδομάδας επηρεάζει κατά κύριο λόγο τις γνωστικές λειτουργίες που βασίζονται κυρίως στη λειτουργία του προμετωπιαίου φλοιού. Όσον αφορά στο νεογνικό μοντέλο χορήγησης ΜΚ-801 σε όλη τη δεύτερη μεταγεννητική εβδομάδα (p7-p14), αυτό παρουσιάζει ελλείμματα στις δοκιμασίες αναγνώρισης χρονικής σειράς αντικειμένου, νέας θέσης αντικειμένου και νέου αντικειμένου. Επίσης παρουσιάζει ελλείμματα στη δοκιμασία απόσβεσης μνήμης φόβου και στη δοκιμασία κοινωνικότητας. Στη δοκιμασία μνήμης κοινωνικότητας έλλειμμα παρουσιάζουν μόνο οι θηλυκοί μύες. Τα παραπάνω ελλείμματα συνοδεύονται από μειωμένο αριθμό κυττάρων που εκφράζουν παρβαλβουμίνη στον προμετωπιαίο φλοιό, αλλά όχι στον ιππόκαμπο, ενώ παράλληλα το εν λόγω μοντέλο χαρακτηρίζεται από μειωμένη αυθόρμητη δραστηριότητα στον προμετωπιαίο φλοιό και στον ιππόκαμπο. Στο συγχρονισμό των νευρωνικών κυκλωμάτων στον προμετωπιαίο φλοιό παρουσιάζεται αύξηση των ρυθμών θήτα, δέλτα και γάμμα ενώ παρατηρείται μείωση των υψηλών γάμμα ρυθμών. Αντιθέτως στον ιππόκαμπο παρατηρείται αύξηση σε όλους τους ρυθμούς. Ο αποκλεισμός των NMDA-υποδοχέων λοιπόν καθ’όλη τη διάρκεια της 2ης μεταγεννητικής εβδομάδας φαίνεται να επηρεάζει περισσότερο τις γνωστικές λειτουργίες που βασίζονται στη λειτουργία του προμετωπιαίου φλοιού και του ιπποκάμπου. Τέλος, το νεογνικό μοντέλο ΜΚ-801 στο οποίο γίνεται αποκλεισμός των NMDA-υποδοχέων στην αρχή της δεύτερης μεταγεννητικής εβδομάδας (p7-p11) χαρακτηρίζεται από ελλείματα στη δοκιμασία αναγνώρισης χρονικής σειράς αντικειμένου και νέου αντικειμένου καθώς και στη δοκιμασία κοινωνικότητας. Στη δοκιμασία αναγνώρισης νέας θέσης αντικειμένου, μόνο οι αρσενικοί μύες της ομάδας p7-p11 ΜΚ-801 παρουσιάζουν έλλειμμα. Επομένως, ο αποκλεισμός των NMDA-υποδοχέων αυτήν την περίοδο φαίνεται να επηρεάζει γνωστικές λειτουργίες που βασίζονται στη λειτουργία τόσο του προμετωπιαίου φλοιού όσο και του ιπποκάμπου. Η αυθόρμητη δραστηριότητα σε αυτό το μοντέλο μειώνεται μόνο στον προμετωπιαίο φλοιό, όπου φαίνεται να επηρεάζεται και ο συγχρονισμός των νευρωνικών κυκλωμάτων καθώς παρατηρείται μείωση των γάμμα και των υψηλών γαμμα ρυθμών. Τα παραπάνω αποτελέσματα οδηγούν στο συμπέρασμα πως υπάρχουν διαφορετικές κρίσιμες περίοδοι ανάπτυξης για τον προμετωπιαίο φλοιό και τον ιππόκαμπο, οι οποίες πιθανόν και να αλληλεπικαλύπτονται, καθώς επέμβαση σε περιορισμένα χρονικά παράθυρα κατά τη δεύτερη μεταγεννητική εβδομάδα οδηγεί στην εμφάνιση δυσλειτουργιών του προμετωπιαίου φλοιού και του ιπποκάμπου με τρόπο εξαρτώμενο από τη χρονική περίοδο της έκθεσης. Μελλοντική διαλεύκανση του μηχανισμού θα οδηγήσει σε πιθανούς αποτελεσματικούς θεραπευτικούς στόχους νευροαναπτυξιακών διαταραχών όπως η Σχιζοφρένεια

Risk Factors for Development of Acute Kidney Injury in Critically Ill Patients: A Systematic Review and Meta-Analysis of Observational Studies

Background. Acute kidney injury (AKI) is a frequent complication of critically ill patients. The impact of different risk factors associated with this entity in the ICU setting is unknown. Objectives. The purpose of this research was to assess the risk factors associated with the development of AKI in critically ill patients by meta-analyses of observational studies. Data Extraction. Two reviewers independently and in duplicate used a standardized form to collect data from published reports. Authors were contacted for missing data. The Newcastle-Ottawa scale assessed study quality. Data Synthesis. Data from 31 diverse studies that enrolled 504,535 critically ill individuals from a wide variety of ICUs were included. Separate random-effects meta-analyses demonstrated a significantly increased risk of AKI with older age, diabetes, hypertension, higher baseline creatinine, heart failure, sepsis/systemic inflammatory response syndrome, use of nephrotoxic drugs, higher severity of disease scores, use of vasopressors/inotropes, high risk surgery, emergency surgery, use of intra-aortic balloon pump, and longer time in cardiopulmonary bypass pump. Conclusion. The best available evidence suggests an association of AKI with 13 different risk factors in subjects admitted to the ICU. Predictive models for identification of high risk individuals for developing AKI in all types of ICU are required