Detecting image manipulation with ELA-CNN integration: a powerful framework for authenticity verification.

The exponential progress of image editing software has contributed to a rapid rise in the production of fake images. Consequently, various techniques and approaches have been developed to detect manipulated images. These methods aim to discern between genuine and altered images, effectively combating the proliferation of deceptive visual content. However, additional advancements are necessary to enhance their accuracy and precision. Therefore, this research proposes an image forgery algorithm that integrates error level analysis (ELA) and a convolutional neural network (CNN) to detect the manipulation. The system primarily focuses on detecting copy-move and splicing forgeries in images. The input image is fed to the ELA algorithm to identify regions within the image that have different compression levels. Afterward, the created ELA images are used as input to train the proposed CNN model. The CNN model is constructed from two consecutive convolution layers, followed by one max pooling layer and two dense layers. Two dropout layers are inserted between the layers to improve model generalization. The experiments are applied to the CASIA 2 dataset, and the simulation results show that the proposed algorithm demonstrates remarkable performance metrics, including a training accuracy of 99.05%, testing accuracy of 94.14%, precision of 94.1%, and recall of 94.07%. Notably, it outperforms state-of-the-art techniques in both accuracy and precision.

DNA Methylation of PXDN Is Associated with Early-Life Adversity in Adult Mental Disorders.

Early-life adversity (ELA) is characterized by exposure to traumatic events during early periods of life, particularly involving emotional, sexual and/or physical adversities during childhood. Mental disorders are strongly influenced by environmental and lifestyle-related risk factors including ELA. However, the molecular link between ELA and the risk of an adult mental disorder is still not fully understood. Evidence is emerging that long-lasting changes in the epigenetic processes regulating gene expression, such as DNA methylation, play an important role in the biological mechanisms linking ELA and mental disorders. Based on a recent study, we analyzed the DNA methylation of a specific CpG site within the gene PXDN-cg10888111-in blood in the context of ELA across a set of psychiatric disorders, namely Borderline Personality Disorder (BPD), Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), and its potential contribution to their pathogenesis. We found significant hypermethylation in mentally ill patients with high levels of ELA compared to patients with low levels of ELA, whereas cg10888111 methylation in healthy control individuals was not affected by ELA. Further investigations revealed that this effect was driven by the MDD cohort. Providing a direct comparison of cg10888111 DNA methylation in blood in the context of ELA across three mental disorders, our results indicate the role of PXDN regulation in the response to ELA in the pathogenesis of mental disorders, especially MDD. Further studies will be needed to validate these results and decipher the corresponding biological network that is involved in the transmission of ELA to an adult mental disorder in general.

The lateral habenula integrates age and experience to promote social transitions in developing rats.

Early caregiving adversity (ECA) is associated with social behavior deficits and later development of psychopathology. However, the infant neural substrates of ECA are poorly understood. The lateral habenula (LHb), a highly conserved brain region with consistent links to adult psychopathology, is understudied in development, when the brain is most vulnerable to environmental impacts. Here, we describe the structural and functional ontogeny of the LHb and its behavioral role in infant and juvenile rat pups. We show that the LHb promotes a developmental transition in social approach behavior under threat as typically reared infants mature. By contrast, we show that ECA disrupts habenular ontogeny, including volume, protein expression, firing properties, and corticohabenular connectivity. Furthermore, inhibiting a specific corticohabenular projection rescues infant social approach deficits following ECA. Together, these results identify immediate biomarkers of ECA in the LHb and highlight this region as a site of early social processing and behavior control.

ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways. / ELABELA衍生肽ELA13通过抑制Smad和ERK信号通路减轻肾纤维化.

Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently, there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however, its biological activity has been very little studied. In the present study, we evaluated the therapeutic effect of ELA13 on transforming growth factor-ß1 (TGF-ß1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum, and reduce the expression of fibrosis biomarkers confirmed by Masson staining, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore, we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion, ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

Influence of heavy Canadian crude oil on pristine freshwater boreal lake ecosystems in an experimental oil spill.

The overall impact of a crude oil spill into a pristine freshwater environment in Canada is largely unknown. To evaluate the impact on the native microbial community, a large-scale in situ model experimental spill was conducted to assess the potential role of the natural community to attenuate hydrocarbons. A small volume of conventional heavy crude oil (CHV) was introduced within contained mesocosm enclosures deployed on the shoreline of a freshwater lake. The oil was left to interact with the shoreline for 72 h and then free-floating oil was recovered using common oil spill response methods (i.e. freshwater flushing and capture on oleophilic absorptive media). Residual polycyclic aromatic hydrocarbon (PAH) concentrations returned to near preoiling concentrations within 2 months, while the microbial community composition across the water, soil, and sediment matrices of the enclosed oligotrophic freshwater ecosystems did not shift significantly over this period. Metagenomic analysis revealed key polycyclic aromatic and alkane degradation mechanisms also did not change in their relative abundance over the monitoring period. These trends suggest that for small spills (<2 l of oil per 15 m2 of surface freshwater), physical oil recovery reduces polycyclic aromatic hydrocarbon concentrations to levels tolerated by the native microbial community. Additionally, the native microbial community present in the monitored pristine freshwater ecosystem possesses the appropriate hydrocarbon degradation mechanisms without prior challenge by hydrocarbon substrates. This study corroborated trends found previously (Kharey et al. 2024) toward freshwater hydrocarbon degradation in an environmentally relevant scale and conditions on the tolerance of residual hydrocarbons in situ.

Association Between Epidural Labor Analgesia and Autism Spectrum Disorder in Offspring: A Systematic Review and Meta-Analysis.

Purpose: Many studies have focused on the association between Autism spectrum disorder (ASD) and epidural labor analgesia (ELA), which is the most effective way to manage labor pain. The purpose of this meta-analysis was to summarize the current state of the association between ELA and ASD. Methods: A search of the literature yielded 201 relevant studies, of which 7 cohort studies met our inclusion criteria. Two independent reviewers screened the inclusion results, extracted data, and assessed the risk of bias and quality of evidence. Results: Compared to parturient who did not receive ELA, parturient who received ELA had a slightly increased risk of ASD (adjusted hazard ratio [aHR], 1.12; 95% confidence interval [CI], 1.06-1.17; I2, 69%; P < 0.001; seven studies). After excluding one literature (aHR, 1.09; 95% CI, 1.06-1.12; I2, 4%; P < 0.001; six studies). The sensitivity analyses had consistent outcomes with the main analyses involving siblings (aHR 1.11; 95% CI 1.03-1.19), cesarean section and instrumental deliveries (aHR 1.07; 95% CI 1.03-1.10), non-overlapping populations (aHR 1.09; 95% CI 1.05-1.12), full-term birth populations (aHR 1.10; 95% CI 1.06-1.14), and studies assessed to have moderate risk of bias (aHR 1.09; 95% CI 1.02-1.16). Conclusion: This meta-analysis revealed a modest positive association between ELA and ASD, acknowledging a slight potential risk. However, it is important to note that this risk cannot be completely dismissed due to the possibility of bias and this association is based on low-quality evidence. Future studies are required to assess and mitigate different confounding biases and investigate the time-dose-response relationship.

Detection of AI-Created Images Using Pixel-Wise Feature Extraction and Convolutional Neural Networks.

Generative AI has gained enormous interest nowadays due to new applications like ChatGPT, DALL E, Stable Diffusion, and Deepfake. In particular, DALL E, Stable Diffusion, and others (Adobe Firefly, ImagineArt, etc.) can create images from a text prompt and are even able to create photorealistic images. Due to this fact, intense research has been performed to create new image forensics applications able to distinguish between real captured images and videos and artificial ones. Detecting forgeries made with Deepfake is one of the most researched issues. This paper is about another kind of forgery detection. The purpose of this research is to detect photorealistic AI-created images versus real photos coming from a physical camera. Id est, making a binary decision over an image, asking whether it is artificially or naturally created. Artificial images do not need to try to represent any real object, person, or place. For this purpose, techniques that perform a pixel-level feature extraction are used. The first one is Photo Response Non-Uniformity (PRNU). PRNU is a special noise due to imperfections on the camera sensor that is used for source camera identification. The underlying idea is that AI images will have a different PRNU pattern. The second one is error level analysis (ELA). This is another type of feature extraction traditionally used for detecting image editing. ELA is being used nowadays by photographers for the manual detection of AI-created images. Both kinds of features are used to train convolutional neural networks to differentiate between AI images and real photographs. Good results are obtained, achieving accuracy rates of over 95%. Both extraction methods are carefully assessed by computing precision/recall and F1-score measurements.

Genetic Tagging Uncovers a Robust, Selective Activation of the Thalamic Paraventricular Nucleus by Adverse Experiences Early in Life.

Background: Early-life adversity (ELA) is associated with increased risk for mood disorders, including depression and substance use disorders. These disorders are characterized by impaired reward-related behaviors, suggesting compromised operations of reward-related brain circuits. However, the brain regions engaged by ELA that mediate these enduring consequences of ELA remain largely unknown. In an animal model of ELA, we identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits. Methods: Employing TRAP2 (targeted recombination in active populations) male and female mice, in which neurons activated within a defined time frame are permanently tagged, we compared ELA- and control-reared mice, assessing the quantity and distribution of ELA-related neuronal activation. After validating the TRAP2 results using native c-Fos labeling, we defined the molecular identity of this population of activated neurons. Results: We uniquely demonstrated that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus was robustly and almost exclusively activated by ELA and was the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated paraventricular nucleus of the thalamus neurons expressed CRF1, the receptor for the stress-related peptide, corticotropin-releasing hormone, but these neurons did not express corticotropin-releasing hormone itself. Conclusions: The paraventricular nucleus of the thalamus, an important component of reward circuits that is known to encode remote, emotionally salient experiences to influence future motivated behaviors, encodes adverse experiences as remote as those occurring during the early postnatal period and is thus poised to contribute to the enduring deficits in reward-related behaviors consequent to ELA.

Subcutaneous Mycobacterium vaccae ameliorates the effects of early life adversity alone or in combination with chronic stress during adulthood in male and female mice.

Chronic psychosocial stress is a burden of modern society and poses a clear risk factor for a plethora of somatic and affective disorders, of which most are associated with an activated immune status and chronic low-grade inflammation. Preclinical and clinical studies further suggest that a failure in immunoregulation promotes an over-reaction of the inflammatory stress response and, thus, predisposes an individual to the development of stress-related disorders. Therefore, all genetic (i.e., sex) and environmental (i.e., early life adversity; ELA) factors facilitating an adult's inflammatory stress response are likely to increase their stress vulnerability. In the present study we investigated whether repeated subcutaneous (s.c.) administrations with a heat-killed preparation of Mycobacterium vaccae (M. vaccae; National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, are protective against negative behavioral, immunological and physiological consequences of ELA alone or of ELA followed by chronic psychosocial stress during adulthood (CAS) in male and female mice. ELA was induced by the maternal separation (MS) paradigm, CAS was induced by 19 days of chronic subordinate colony housing (CSC) in males and by a 7-week exposure to the social instability paradigm (SIP) in females. Our data indicate that ELA effects in both sexes, although relatively mild, were to a great extent prevented by subsequent s.c. M. vaccae administrations. Moreover, although the use of different paradigms for males and females impedes a direct comparison, male mice seemed to be more susceptible to CAS than females, with only females benefitting slightly from the stress protective effects of s.c. M. vaccae administrations when given prior to CAS alone. Finally, our data support the hypothesis that female mice are more vulnerable to the additive effects of ELA and CAS than male mice and that s.c. M. vaccae administrations subsequent to ELA but prior to CAS are protective in both sexes. Taken together and considering the limitation that CAS in males and females was induced by different paradigms, our findings are consistent with the hypotheses that murine stress vulnerability during different phases of life is strongly sex dependent and that developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of stress-related disorders.

Mass balance of Nehnar glacier from 2000 to 2020, using temperature indexed-IAAR approach.

Glacier mass balance is inextricably linked to annual meteorological conditions and is a key indicator for assessing the ice reserves of a glacier. As a result, a number of studies have estimated glacier mass balance using different methods. Here, we have used the improved accumulation area-ratio (IAAR) method to study the mass balance of the Nehnar glacier from 2000 to 2020. This study also aims to study the spatiotemporal behavior and other dynamics of the glacier. Results have shown that the glacier has continuously lost its ice reserves throughout the studied period though at a lower rate since 2010. Its annual specific mass balance has changed from - 50.10 ± 3 cm w.e in 2000 to - 59.46 ± 3 cm w.e. in 2020. The equilibrium line altitude (ELA) of the glacier rose by 90 m and has shifted from 4260 masl in 2000 to 4350 masl in 2020. The glacier has shrunk from an area of 1.64 km2 in 2000 to 1.38 km2 in 2020 losing nearly 16% of its area. The study highlights the need for continued monitoring of glacier mass balance to better understand and predict the effects of climate change. These findings have important implications for the future of glacier retreat and water reserves of the Jhelum basin.

Sensitive response of glaciers to changing climate in the Yankti Kuti valley, Kumaon Himalaya, India, between 1990 and 2021.

This study provides the first comprehensive account of the glaciation of the Yankti Kuti valley of the upper Kali Ganga catchment of the Kumaon Himalaya, Uttarakhand. Employing multi-year satellite images from 1990 to 2021, the study investigated the loss of glacial area, ice volume, snout recession, and the changes in the equilibrium line altitude (ELA) in the Yankti Kuti Valley. The investigation showed an overall reduction of ~ 21 km2 (~ 21%) of the total glacier area of the basin. The basin witnesses an ice volume loss of ~ 23% and ~ 41 m upward shifting of the equilibrium line altitude (ELA) between 1990 and 2021. The retreat rate of the four studied glaciers shows ranges from ~ 18 to 41 m/year. The glaciers in the valley are melting at a significant rate due to global warming, giving rise to the increasing number of pro-glacial lakes in the study area from 04 in 1990 to 10 in 2021 and making them vulnerable to glacial lake outburst floods (GLOFs) in the future. The study, therefore, calls for continued glacier monitoring in the upper Kali Ganga catchment in order to assess the future response of the Himalayan cryosphere and to make robust quantitative assessments about the sustainable mitigation and adaptation strategies in the lower valleys.

ELABELA/APJ Axis Prevents Diabetic Glomerular Endothelial Injury by Regulating AMPK/NLRP3 Pathway.

ELABELA (ELA), a recently discovered peptide, is highly expressed in adult kidneys and the endothelium system. It has been identified as a novel endogenous ligand for the apelin receptor (APJ). This study aims to investigate the role of ELA in diabetic glomerular endothelial pyroptosis and its underlying mechanism. Initially, a significant decrease in ELA mRNA levels was observed in the renal cortex of db/db mice and high glucose-treated glomerular endothelial cells (GECs). It was also found that ELA deficiency in ELA+/- mice significantly accelerated diabetic glomerular injury, as shown by exacerbated glomerular morphological damage, increased serum creatine and blood urea nitrogen, and elevated 24-h urinary albumin excretion. In addition, in vivo overexpression of ELA prevented diabetic glomerular injury, reduced von Willebrand factor expression, restored endothelial marker CD31 expression, and attenuated the production of adhesive molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Furthermore, in vitro studies confirmed that treatment with ELA inhibited GEC injury by regulating the NOD-like receptor protein 3 (NLRP3) inflammasome, as indicated by blocking NLRP3 inflammasome formation, decreasing cleaved Caspase-1 production, and inhibiting interleukin-1ß and interleukin-18 production. Moreover, in vitro experiments demonstrated that the protective effects of ELA in GECs during hyperglycemia were diminished by inhibiting adenosine monophosphate-activated protein kinase (AMPK) using Compound C or by APJ deficiency. Taken together, this study provides the first evidence that ELA treatment could prevent diabetic glomerular endothelial injury, which is partly mediated by the regulation of the AMPK/NLRP3 signaling pathway. Therefore, pharmacologically targeting ELA may serve as a novel therapeutic strategy for diabetic kidney disease.

A Case Series of Parturients With Mechanical Mitral Valves: Anticoagulation Management During Labor and Delivery.

More women with mechanical mitral valves (MMVs) are pursuing pregnancy. Guidelines exist for pregnancy anticoagulation, but they do not address individualized anticoagulation during delivery-a period of risk for bleeding, thrombosis, and anesthetic complications. This case series of parturients with MMVs highlights the challenges in, and the evidence and strategies for, treating these patients. (Level of Difficulty: Advanced.).

Photobiomodulation attenuates oligodendrocyte dysfunction and prevents adverse neurological consequences in a rat model of early life adversity.

Rationale: Adverse experiences in early life including abuse, trauma and neglect, have been linked to poor physical and mental health outcomes. Emerging evidence implies that those who experienced early life adversity (ELA) are more likely to develop cognitive dysfunction and depressive-like symptoms in adulthood. The molecular mechanisms responsible for the negative consequences of ELA, however, remain unclear. In the absence of effective management options, anticipatory guidance is the mainstay of ELA prevention. Furthermore, there is no available treatment that prevents or alleviates the neurologic sequelae of ELA, especially traumatic stress. Hence, the present study aims to investigate the mechanisms for these associations and evaluate whether photobiomodulation (PBM), a non-invasive therapeutic procedure, can prevent the negative cognitive and behavioral manifestations of ELA in later life. Methods: ELA was induced by repeated inescapable electric foot shock of rats from postnatal day 21 to 26. On the day immediately following the last foot shock, 2-min daily PBM treatment was applied transcranially for 7 consecutive days. Cognitive dysfunction and depression-like behaviors were measured by a battery of behavioral tests in adulthood. Subsequently, oligodendrocyte progenitor cells (OPCs) differentiation, the proliferation and apoptosis of oligodendrocyte lineage cells (OLs), mature oligodendrocyte, myelinating oligodendrocyte, the level of oxidative damage, reactive oxygen species (ROS) and total antioxidant capacity were measured and analyzed using immunofluorescence staining, capillary-based immunoassay (ProteinSimple®) and antioxidant assay kit. Results: The rats exposed to ELA exhibited obvious oligodendrocyte dysfunction, including a reduction in OPCs differentiation, diminished generation and survival of OLs, decreased OLs, and decreased matured oligodendrocyte. Furthermore, a deficit in myelinating oligodendrocytes was observed, in conjunction with an imbalance in redox homeostasis and accumulated oxidative damage. These alternations were concomitant with cognitive dysfunction and depression-like behaviors. Importantly, we found that early PBM treatment largely prevented these pathologies and reversed the neurologic sequelae resulting from ELA. Conclusions: Collectively, these findings provide new insights into the mechanism by which ELA affects neurological outcomes. Moreover, our findings support that PBM may be a promising strategy to prevent ELA-induced neurologic sequelae that develops later in life.

Age- and sex-specific effects of maternal separation on the acoustic startle reflex in rats: early baseline enhancement in females and blunted response to ambiguous threat.

Early life adversity (ELA) increases the incidence of later-life anxiety disorders. Dysregulated threat processing, including responsivity to ambiguous threats, is an indicator of anxiety disorders and can be influenced by childhood experiences. The acoustic startle response is a defensive reflex displayed by mammals when exposed to sudden intense stimuli reflecting individual variations in vigilance. These measures can be altered by previous experience and experimental modifications, including the introduction of unconditioned aversive stimuli. Rats emit ultrasonic vocalizations (USVs) in the 22 KHz range in negative contexts. As such, 22 KHz USVs are an ethologically relevant social cue of environmental threat shown to induce anxiety-like behavior in recipient rats. Because the timing of symptom manifestation after early life adversity can differ between sexes, the current study sought to identify the age- and sex-specific effects of daily maternal separation (MS) on responsivity to ambiguous threat in rats. In Experiment 1, rat pups underwent MS or control rearing from postnatal day (P) 2-20, then underwent behavioral testing beginning on P24, 34, or 54 to determine whether MS modified the baseline startle response or the modulation of startle by 22 KHz USVs. In Experiment 2, rats were tested in a light-enhanced startle paradigm at P54 after MS or control rearing to determine whether MS influenced light-enhanced startle. Results show an enhancement of the baseline startle magnitude by MS in females at P34. At P54, MS reduced the modulation of the startle response by 22 KHz USVs and prevented light-enhanced startle, indicating an MS-induced deficit in defensive responsivity when exposed to potential threat.

Epigenetic Effects in HPA Axis Genes Associated with Cortical Thickness, ERP Components and SUD Outcome.

Association between familial loading for alcohol use disorders (AUD) and event-related potentials (ERPs) suggests a genetic basis for these oscillations though much less is known about epigenetic pathways influenced by environmental variation. Early life adversity (ELA) influences negative outcomes much later in life. The stress-activated neuropeptide corticotropin-releasing hormone (CRH) contributes to the deleterious effects of ELA on brain structure and function in animals. Accordingly, we hypothesized that ELA would be related to cortical thickness and electrophysiological characteristics through an epigenetic effect on CRH receptor type-1 (CRHR1) methylation. A total of 217 adolescent and young adult participants from either multiplex alcohol dependence or control families were scanned using magnetic resonance imaging (MRI) at 3T and cortical thickness was determined. Longitudinal follow-up across childhood, adolescence, and young adulthood provided developmental ERP data and measures of adversity. Blood samples for genetic and epigenetic analyses were obtained in childhood. Cortical thickness and visual ERP components were analyzed for their association and tested for familial risk group differences. Visual P300 amplitude at Pz and cortical thickness of the left lateral orbitofrontal region (LOFC), were significantly related to risk group status. LOFC cortical thickness showed a negative correlation with CRHR1 methylation status and with childhood total stress scores from the Life Stressors and Social Resources Inventory (LISRES). Stress scores were also significantly related to P300 amplitude recorded in childhood. The present results suggest that early life adversity reflected in greater total LISRES stress scores in childhood can impact the methylation of the CRHR1 gene with implications for brain development as seen in cortical thickness and electrophysiological signals emanating from particular brain regions.

ELA-11 protects the heart against oxidative stress injury induced apoptosis through ERK/MAPK and PI3K/AKT signaling pathways.

Increasing evidence revealed that apoptosis and oxidative stress injury were associated with the pathophysiology of doxorubicin (DOX)-induced myocardial injury. ELABELA (ELA) is a newly identified peptide with 32 amino acids, can reduce hypertension with exogenous infusion. However, the effect of 11-residue furn-cleaved fragment (ELA-11) is still unclear. We first administrated ELA-11 in DOX-injured mice and measured the cardiac function and investigated the effect of ELA-11 in vivo. We found that ELA-11 alleviated heart injury induced by DOX and inhibited cardiac tissues from apoptosis. In vitro, ELA-11 regulated the sensitivity towards apoptosis induced by oxidative stress with DOX treatment through PI3K/AKT and ERK/MAPK signaling pathway. Similarly, ELA-11 inhibited oxidative stress-induced apoptosis in cobalt chloride (CoCl2)-injured cardiomyocytes. Moreover, ELA-11 protected cardiomyocyte by interacting with Apelin receptor (APJ) by using 4-oxo-6-((pyrimidin-2-ylthio) methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221). Hence, our results indicated a protective role of ELA-11 in oxidative stress-induced apoptosis in DOX-induced myocardial injury.

Evolución de pacientes con ELA bajo seguimiento neumológico y comparación de dos áreas asistenciales en una provincia española / Evolution under respiratory follow-up of patients with ALS and comparison of two healthcare areas in a Spanish province

Introducción: Describir las características de pacientes con Esclerosis Lateral Amiotrófica (ELA) remitidos para valoración respiratoria, determinando si existen factores diferenciales en el manejo clínico y su evolución en dos áreas asistenciales. Métodos: Análisis retrospectivo (seguimiento de 16 años) de pacientes con ELA atendidos en dos Servicios de Neumología en la misma provincia. Se analizan características demográficas, tipo de ELA, clase de adaptación a la ventilación domiciliaria (VMD), modalidad ventilatoria, uso de asistencia mecánica para la tos e indicación de gastrostomía, comparando supervivencia. El Área Sanitaria de Talavera de la Reina cuenta con acreditación de Unidad de Ventilación Domiciliaria Especializada, siendo de Unidad Básica en el Área de Toledo. Resultados: Se analizaron 97 pacientes (60 en Toledo). La edad media fue de 63,3 años y el 60,8% varones. Inicio espinal en el 55,7% y bulbar 35,1%. Se inició VMD en el 88% de los pacientes, siendo programada en el 80%. Indicación de tos asistida mecánica en un 35,1% y en el 51,5% de los pacientes se realizó gastrostomía. La supervivencia media global fue de 32,3 meses, desde el inicio de la VMD de 26,2 meses y 17,1 meses desde la realización de gastrostomía. Los datos de supervivencia fueron similares comparando ambas áreas asistenciales. Conclusiones: Los pacientes con ELA atendidos en dos áreas asistenciales, con criterios clínicos similares, pero con estrategias diferenciadas según los recursos disponibles, presentaron una supervivencia global similar, así como tras el inicio de la VMD y la realización de gastrostomía y con un resultado equiparable al de centros de referencia.(AU)

Background: We aim to describe the characteristics of patients with Amyotrophic Lateral Sclerosis (ALS) referred for respiratory assessment, and whether there are differential factors in the evolution of patients according to two different healthcare areas. Methods: Retrospective analysis of patients with ALS in two Pulmonology services at the same province in Spain (16-year follow-up). We analysed demographic variables, ALS subtype, Home Mechanical Ventilation (HMV) modality and way of adaptation, use of mechanical assisted cough and gastrostomy indication, comparing survival. In the Health Area of Talavera there is a Specialized Unit of HMV according to accreditation by Spanish Respiratory Society, with a Basic Unit in the Toledo Area. Results: A total of 97 patients were analysed (60 in Toledo). The mean age was 63,3 years and 60,8% were male. The form of onset was spinal: 55,7% and bulbar: 35,1%. HMV was started in 88% of the patients, programmed in 80% of them. The use of mechanical assisted cough reached 35,1% of the patients and up to 51,5% of them underwent gastrostomy. Median survival was 32,3 months, being 26,2 months from the start of HMV and 17,1 months after gastrostomy. When comparing the two areas survival data were similar. Conclusions: Patients with ALS assisted in two healthcare areas at the same province, with similar clinical criteria, but with differentiated strategies according to the available resources, present a similar overall survival, as well as after the start of HMV and the performance of gastrostomy and with a similar outcome compared with reference units.(AU)

Effects of Early Life Adversity on Tooth Enamel Formation.

In a systemic effort to survive environmental stress, organ systems fluctuate and adapt to overcome external pressures. The evolutionary drive back toward homeostasis makes it difficult to determine if an organism experienced a toxic exposure to stress, especially in early prenatal and neonatal periods of development. Previous studies indicate that primary human teeth may provide historical records of experiences related to stressors during that early time window. To assess the molecular effects of early life adversity on enamel formation, we used a limited bedding and nesting (LBN) mouse model of early life adversity (ELA) to assess changes in the enamel organ gene expression and enamel matrix mineralization. On average, postnatal day 12 (P12) ELA mice weighed significantly less than the controls. When adjusted for animal weight, ELA molar enamel volume was reduced as compared with the controls, and the relative mineral density of molar enamel was significantly increased. There were no obvious changes in enamel matrix crystal morphology or structure in ELA as compared with the control mouse enamel. RNAseq showed extracellular matrix organization to be the most significantly affected GO and reactome pathways, whereas butanote metabolism was the most significantly altered KEGG pathway. Transcripts expressing the enamel matrix proteins amelogenin (Amelx) and enamelin (Enam) were among the top 4 most differentially expressed genes. When evaluating molecular mechanisms for the changes in gene expression in ELA enamel organs, we found significantly increased expression of Dlx3, while transcripts for clock genes Per1 and Nrd1 were downregulated. These findings support the possibility that the developing enamel organ is sensitive to the pressures of early life adversity and produces molecular and structural biomarkers reflecting these challenges.

Effect of Fc-Elabela-21 on renal ischemia/reperfusion injury in mice: Mediation of anti-apoptotic effect via Akt phosphorylation.

INTRODUCTION: Renal ischemia/reperfusion injury (IRI) is the most common cause of acute kidney injury (AKI), and patients with AKI have a high rate of mortality. Apelin is a therapeutic candidate for treatment of IRI and Elabela (ELA) is a recently discovered hormone that also activates the apelin receptor (APJ). We examined the use of ELA as a preventive treatment for IRI using in vitro and in vivo models. METHODS: Male mice were subjected to renal IRI, with or without administration of a stabilized form of ELA (Fc-ELA-21) for 4 days. Renal tubular lesions were measured using H&E staining, reactive oxygen species (ROS) were measured using a dihydroethidium stain assay, and renal cell apoptosis was measured using the TUNEL assay and flow cytometry. Immortalized human proximal tubular epithelial (HK-2) cells were pretreated with or without LY294002 and/or ELA-32, maintained at normoxic or hypoxic conditions, and then returned to normal culture conditions to mimic IRI. Cell apoptosis was determined using the TUNEL assay and cell proliferation was determined using the MTT assay. The levels of Akt, p-Akt, ERK1/2, p- ERK1/2, Bcl-2, Bax, caspase-3 and cleaved caspase-3 were measured using western blotting. RESULTS: Fc-ELA-21 administration reduced renal tissue damage, ROS production, and apoptosis in mice that had renal IRI. ELA-32 reduced HK-2 cell apoptosis and restored the proliferation of cells subjected to IRI. Akt phosphorylation had a role in the anti-apoptotic effect of ELA. CONCLUSION: This study of in vitro and in vivo models of IRI indicated that the preventive and anti-apoptotic effects of ELA were mediated via the PI3K/Akt signaling pathway.