Dysregulation of mTOR Signaling after Brain Ischemia.

In this review, we provide recent data on the role of mTOR kinase in the brain under physiological conditions and after damage, with a particular focus on cerebral ischemia. We cover the upstream and downstream pathways that regulate the activation state of mTOR complexes. Furthermore, we summarize recent advances in our understanding of mTORC1 and mTORC2 status in ischemia-hypoxia at tissue and cellular levels and analyze the existing evidence related to two types of neural cells, namely glia and neurons. Finally, we discuss the potential use of mTORC1 and mTORC2 as therapeutic targets after stroke.

Artificial Intelligence on FDG PET Images Identifies Mild Cognitive Impairment Patients with Neurodegenerative Disease.

The purpose of this project is to develop and validate a Deep Learning (DL) FDG PET imaging algorithm able to identify patients with any neurodegenerative diseases (Alzheimer's Disease (AD), Frontotemporal Degeneration (FTD) or Dementia with Lewy Bodies (DLB)) among patients with Mild Cognitive Impairment (MCI). A 3D Convolutional neural network was trained using images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The ADNI dataset used for the model training and testing consisted of 822 subjects (472 AD and 350 MCI). The validation was performed on an independent dataset from La Fe University and Polytechnic Hospital. This dataset contained 90 subjects with MCI, 71 of them developed a neurodegenerative disease (64 AD, 4 FTD and 3 DLB) while 19 did not associate any neurodegenerative disease. The model had 79% accuracy, 88% sensitivity and 71% specificity in the identification of patients with neurodegenerative diseases tested on the 10% ADNI dataset, achieving an area under the receiver operating characteristic curve (AUC) of 0.90. On the external validation, the model preserved 80% balanced accuracy, 75% sensitivity, 84% specificity and 0.86 AUC. This binary classifier model based on FDG PET images allows the early prediction of neurodegenerative diseases in MCI patients in standard clinical settings with an overall 80% classification balanced accuracy.

Childhhood Trauma in Schizophrenia Spectrum Disorders: Dissociative, Psychotic Symptoms, and Suicide Behavior.

Current evidence suggests a high prevalence of childhood trauma (CT) among adult patients diagnosed with schizophrenia spectrum disorders. Exposure to CT might lead to clinical differences eventually observed in these patients. We present a cross-sectional study with 54 patients with schizophrenia spectrum disorder (schizophrenia and schizoaffective disorder). We obtained sociodemographic data, as well as data on CT, dissociation, suicide history, and intensity of positive and negative psychotic symptoms. More than 75% of the patients reported a history of CT. We observed a link between CT and suicidal behavior. Patients showed high rates of dissociation. Dissociative experiences were related to CT, both in terms of intensity of trauma and number of traumas experienced. All CT forms except emotional neglect showed direct correlations with dissociative experiences. We found no correlation between intensity of CT and intensity of positive psychotic symptoms, yet we observed a moderate inverse correlation with negative psychotic symptoms.

Simulation Study of a Frame-Based Motion Correction Algorithm for Positron Emission Imaging.

Positron emission tomography (PET) is a functional non-invasive imaging modality that uses radioactive substances (radiotracers) to measure changes in metabolic processes. Advances in scanner technology and data acquisition in the last decade have led to the development of more sophisticated PET devices with good spatial resolution (1-3 mm of full width at half maximum (FWHM)). However, there are involuntary motions produced by the patient inside the scanner that lead to image degradation and potentially to a misdiagnosis. The adverse effect of the motion in the reconstructed image increases as the spatial resolution of the current scanners continues improving. In order to correct this effect, motion correction techniques are becoming increasingly popular and further studied. This work presents a simulation study of an image motion correction using a frame-based algorithm. The method is able to cut the acquired data from the scanner in frames, taking into account the size of the object of study. This approach allows working with low statistical information without losing image quality. The frames are later registered using spatio-temporal registration developed in a multi-level way. To validate these results, several performance tests are applied to a set of simulated moving phantoms. The results obtained show that the method minimizes the intra-frame motion, improves the signal intensity over the background in comparison with other literature methods, produces excellent values of similarity with the ground-truth (static) image and is able to find a limit in the patient-injected dose when some prior knowledge of the lesion is present.

Focal cerebral ischemia induces changes in oligodendrocytic tau isoforms in the damaged area.

Ischemic stroke is a major cause of death and the first leading cause of long-term disability worldwide. The only therapeutic strategy available to date is reperfusion and not all the patients are suitable for this treatment. Blood flow blockage or reduction leads to considerable brain damage, affecting both gray and white matter. The detrimental effects of ischemia have been studied extensively in the former but not in the latter. Previous reports indicate that preservation of white matter integrity reduces deleterious effect of ischemia on the brain. Oligodendrocytes are sensitive to ischemic damage, however, some reports demonstrate that oligodendrogenesis occurs after ischemia. These glial cells have a complex cytoskeletal network, including tau, that plays a key role to proper myelination. 4R-Tau/3R-Tau, which differ in the presence/absence of Exon 10, are found in oligodendrocytes; but the precise role of each isoform is not understood. Using permanent middle cerebral artery occlusion model and immunofluorescence, we demonstrate that cerebral ischemia induces an increase in 3R-Tau versus 4R-Tau in oligodendrocytes in the damaged area. In addition, cellular distribution of Tau undergoes a change after ischemia, with some oligodendrocytic processes showing positive staining for 3R-Tau. This occurs simultaneously with the amelioration of neurological damage in ischemic rats. We propose that ischemia triggers an endogenous mechanism involving 3R-Tau, that induces colonization of the ischemic damaged area by oligodendrocytes in an attempt to myelinate-injured axons. Understanding the molecular mechanism of this phenomenon could pave the way for the design of therapeutic strategies that exploit glial cells for the treatment of ischemia.

Intimate Partner Violence Among Patients Diagnosed With Severe Mental Disorder.

Intimate partner violence (IPV) has a remarkable impact on mental health and is common in people diagnosed with severe mental disorders (SMDs). Data of 102 outpatients were collected from clinical records and the Traumatic Life Events Questionnaire (TLEQ). Global estimation of lifetime IPV exposure was obtained by combining answers to selected TLEQ questions about physical, psychological, and sexual IPV. Overall, 24.5% of the participants reported at least one lifetime episode of IPV victimization. Female gender (odds ratio [OR] = 3.15, p = 0.016) and childhood trauma (OR = 4.7, p = 0.002) significantly increased the likelihood of IPV victimization. Conversely, posttraumatic stress disorder was not significantly increased in IPV victims. These findings are in line with current literature and suggest a remarkable and transdiagnostic prevalence of lifetime IPV victimization in SMD. Gender, childhood trauma, and SMD are relevant factors in IPV analysis and prevention. Diathesis of trauma, psychosocial vulnerability to revictimization and intersectional feminist theory help explain our results.

Effectiveness of the application of massage therapy and kinesitherapy by parents on premature neonates: A research protocol.

AIM: The study aims to analyse the efficacy of massage therapy and kinesitherapy applied by parents of premature infants admitted to hospital. BACKGROUND: Premature newborns suffer early somatic deprivation that has adverse effects on their growth and development and that also has a negative impact on the emotional state of their parents. Massage therapy and kinesitherapy is beneficial in alleviating somatic deficit and facilitates the bond between parents and newborns. DESIGN: A quasi-experimental community intervention trial will be conducted in a neonatology unit. METHODS: This study will compare the benefits of a 15-min massage protocol applied by parents with the usual medical and nursing care given by neonatal units for premature babies. The evaluation of neuromotor development will take place through the Spanish Premie-Neuro scale. The determination of weight, size, and head circumference will be based on the unit's usual procedures. DISCUSSION: If the implementation of a massage therapy and kinesitherapy protocol is effective in promoting the growth and development of hospitalized premature infants, the results of this study could give an impetus for the inclusion of somatic stimulation in the usual nursing care given for preterm infants. IMPACT: Prematurity and its associated morbidity pose a major global public health problem. Somatic and kinaesthetic stimulation has beneficial effects on anthropometric and neuromotor development in preterm infants. The results will have a positive impact on premature neonates and their families, both during the hospitalization, and a positive socio-economic effect throughout their lives (education, work, disability). TRIAL REGISTRATION: NCT03704012.

Effects of Massage Therapy and Kinesitherapy to Develop Hospitalized Preterm Infant's Anthropometry: A Quasi-Experimental Study.

PURPOSE: The aim of this study was to analyze the efficacy of massage therapy and kinesitherapy on the anthropometric development of hospitalized preterm infants applied by parents. DESIGN AND METHODS: A prospective quasi-experimental study was designed. Hospitalized preterm infants received a daily 15-minute session of massage therapy and kinesitherapy. The control group received regular medical and nursing care. RESULTS: The massage therapy and kinesitherapy protocol significantly improved the anthropometric parameters studied: weight (895.7 ±â€¯547.9 vs 541.8 ±â€¯536.2; p < 0.001) size (5.5 ±â€¯4.3 vs. 3.0 ±â€¯3.1; p < 0.001) and head circumference (4.2 ±â€¯3.2 vs 2.4 ±â€¯2.6; p < 0.001). CONCLUSIONS: The implementation of a massage therapy and kinesitherapy protocol is beneficial for the anthropometric development of hospitalized preterm infants. PRACTICE IMPLICATIONS: An easy to administer and cost-effective intervention such as massage therapy and kinesitherapy can improve the anthropometric development of preterm infants and reduce growth-related morbidity in the short, medium, and long term.

Optimization of Antipsychotic and Benzodiazepine Drugs in Patients with Severe Mental Disorders in an Intensive Case Management Program.

The Intensive Case Management (ICM) model is a community-based program for people with severe mental illness that may reduce hospitalization and increase retention in care. The aims of this study were to analyze changes in the antipsychotic and benzodiazepine dosage in 106 patients who participated in an Individualized Service Program based on the ICM model for at least 6 months and to assess the change in the number of patients taking a high or very high dose of an antipsychotic drug and the number receiving antipsychotic polytherapy. Both the average daily dose of antipsychotic and benzodiazepine drugs and the number of patients with high doses of antipsychotic and more than one antipsychotic drug decreased significantly. Implementing the ICM program in patients with severe mental illness could help to decrease adverse drug effects and health care expenditures.

Angiotensin II type-2 receptor stimulation induces neuronal VEGF synthesis after cerebral ischemia.

Intense efforts are being undertaken to understand the pathobiology of ischemia and to develop novel and effective treatments. Angiotensin II type 2 receptor (AT2R) is related with a beneficial role in neurodegenerative disorders, including ischemia. However, the underlying molecular mechanism remains elusive. In this study, we have established that AT2R stimulation by C21 compound, a specific AT2R agonist, caused a VEGF upregulation. Using mouse primary cortical neurons exposed to oxygen-glucose deprivation (OGD), we established that this effect was mediated by a mechanism dependent of mTORC1 signaling since mTOR inhibition abolished the C21-induced VEGF upregulation. Also, we have temporally characterized the changes on VEGF levels after ischemia induction in rats using two different approaches: transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO). VEGF levels were permanently augmented after reperfusion (tMCAO) whereas lower levels of VEGF were found after pMCAO, remarkably at 21days. Therefore, C21 compound accelerated the recovery of the neurological status of pMCAO rats, reduced the ischemic damage area and abolished pMCAO-induced VEGF downregulation at 21days. This effect of C21 compound was mainly observed in neurons of the peri-infarct area. Our results suggest that a C21-induced VEGF upregulation may be crucial after an ischemic neuronal insult in both of our experimental approaches. This upregulation was mediated by a mechanism dependent of Akt/mTOR signaling pathway, since mTOR inhibition abolished the VEGF upregulation induced by C21. Considering that VEGF is involved in regenerative processes, we propose that AT2R activation could be used as a potential pharmacological strategy after ischemic stroke.

ATP-P2X7 Receptor Modulates Axon Initial Segment Composition and Function in Physiological Conditions and Brain Injury.

Axon properties, including action potential initiation and modulation, depend on both AIS integrity and the regulation of ion channel expression in the AIS. Alteration of the axon initial segment (AIS) has been implicated in neurodegenerative, psychiatric, and brain trauma diseases, thus identification of the physiological mechanisms that regulate the AIS is required to understand and circumvent AIS alterations in pathological conditions. Here, we show that the purinergic P2X7 receptor and its agonist, adenosine triphosphate (ATP), modulate both structural proteins and ion channel density at the AIS in cultured neurons and brain slices. In cultured hippocampal neurons, an increment of extracellular ATP concentration or P2X7-green fluorescent protein (GFP) expression reduced the density of ankyrin G and voltage-gated sodium channels at the AIS. This effect is mediated by P2X7-regulated calcium influx and calpain activation, and impaired by P2X7 inhibition with Brilliant Blue G (BBG), or P2X7 suppression. Electrophysiological studies in brain slices showed that P2X7-GFP transfection decreased both sodium current amplitude and intrinsic neuronal excitability, while P2X7 inhibition had the opposite effect. Finally, inhibition of P2X7 with BBG prevented AIS disruption after ischemia/reperfusion in rats. In conclusion, our study demonstrates an involvement of P2X7 receptors in the regulation of AIS mediated neuronal excitability in physiological and pathological conditions.

Changes in use, knowledge, beliefs and attitudes relating to tobacco among nursing and physiotherapy students: a 10-year analysis.

AIM: To analyse changes in prevalence, knowledge, beliefs and attitudes relating to smoking among undergraduate nursing and physiotherapy students over a 10-year period. BACKGROUND: Few studies have been performed to describe changes in the use of tobacco and associated characteristics. DESIGN: This study was a sequential cross-sectional study. METHODS: A self-administered survey was performed during three academic years among nursing and physiotherapy students in a Spanish Faculty of Health Sciences. FINDINGS: The proportion of smokers among nursing and physiotherapy students in 2003, 2008 and 2013 was 29·3%, 24·7% and 18·2% respectively. The ages when participants first smoked did not vary over the years. The Fagerström test showed low nicotine dependence. A significantly high percentage of students stated they were unaware of the link between smoking and bladder cancer and oral leukoplakia. Students declared they were unaware of the association between under-weight new-borns and second-hand smoke. The majority of students recognized that healthcare professionals were role models in society, there being little variation over the years studied. In relation to education and training, the study showed a need to inform students about methods and strategies to help people quit smoking. CONCLUSIONS: The prevalence of smoking among nursing and physiotherapy students decreased over the ten years. Active programmes should be implemented to encourage those university students who smoke to break this habit. The decline over the years in knowledge about smoking provided evidence of a significant deficit in undergraduate training.

Spanish Validation of the Premie-Neuro Scale in Premature Infants.

This study was an observational cross-validation of a Spanish version of the Premie-Neuro, a neurological examination for preterm infants. A cross-cultural translation was used to generate a Spanish version of the scale. The results showed an internal consistency of 0.72 according to Cronbach's alpha coefficient. The intra-class coefficient of correlation for the overall scores was 0.78. Factor analysis provided evidence of construct validity. The Spanish version of the Premie-Neuro was found to be a reliable and valid instrument for evaluating neurological and physical statements for premature infants admitted to a neonatal intensive care unit.

Cumulative effects of childhood traumas: polytraumatization, dissociation, and schizophrenia.

The study objective was to measure and compare the presence of childhood trauma and dissociative symptoms in a convenience sample of healthy controls and a probabilistic sample of outpatients with a diagnosis of schizophrenia. Patients reported more childhood trauma and more polytraumatization than the controls, and had a higher average dissociation score. In both cases and controls, the presence of childhood trauma was related to the intensity of the dissociation observed. Childhood trauma, clinical dissociation and schizophrenia are closely related, particularly when the patient has been the victim of more than one type of abuse.

Predominance of CXCR4 tropism in HIV-1 CRF14_BG strains from newly diagnosed infections.

OBJECTIVES: R5-tropic viruses are associated with HIV-1 transmission and predominate during the early stages of infection. X4-tropic populations have been detected in ~50% of patients with late-stage disease infected with subtype B viruses. In this study, we compared the frequency of X4 tropism in individuals infected with HIV-1 CRF14_BG viruses, which have a V3 loop of subtype B, with a control group of individuals infected with subtype B viruses. METHODS: Sixty-three individuals infected with HIV-1 CRF14_BG (n = 31) or subtype B (n = 32) were studied. Similar proportions of newly diagnosed and chronically infected individuals were included in the subtype B and CRF14_BG groups. V3 sequences were obtained and coreceptor tropism was predicted using the Geno2pheno[coreceptor] algorithm. V3 net charge and 11/25 rules were also used for coreceptor prediction. RESULTS: Overall, X4 tropism was more frequent among individuals infected with CRF14_BG viruses (87.1%) than subtype B viruses (34.3%), a difference that was statistically highly significant (P = 0.00001). Importantly, the frequencies among newly diagnosed individuals were 90% and 13.3%, respectively (P = 0.0007). Characteristic amino acids in the V3 loop (T13, M14, V19 and W20) were identified at higher frequencies in CRF14_BG viruses (54%) than subtype B viruses (0%; P < 0.000001). CONCLUSIONS: CRF14_BG is the genetic form with the highest proportion of X4-tropic viruses reported to date in newly diagnosed and chronic infections. This suggests high pathogenicity for CRF14_BG viruses, potentially leading to rapid disease progression. CCR5 antagonists will be ineffective in most CRF14_BG-infected patients, even at early stages of infection.

Detecting ultrasonographic hollowness in small choroidal melanocytic tumors using 10 MHz and 20 MHz ultrasonography: a comparative study.

BACKGROUND: The purpose of this work was to compare the detection of ultrasonographic hollowness (UH), as a risk sign for evolution from small choroidal melanocytic tumors (SCMT) to uveal melanoma (UM), between conventional ultrasonography (standardized 8 MHz ultrasonography and B-mode 10 MHz ultrasonography) and high-resolution 20 MHz ultrasonography. METHODS: Fifty SCMTs from 50 eyes were included in this work. In all cases, ultrasonographic studies were performed using: 8 MHz standardized A-mode, 10 MHz B-mode, and posterior pole 20 MHz B-mode. Comparison between the presence and the absence of UH were carried out between the ultrasonographic images. RESULTS: There were no statistically significant differences between the SCMT dimensions obtained using the 8-10 and 20 MHz techniques. UH was detected in 12 and 20 cases by means of ten and 20 MHz probes respectively. The difference between these proportions was statistically different from zero (McNemar test, p-value = 0.008). Cases without UH by 20 MHz have lower height values than cases with UH. However, these differences were not found by 10 MHz ultrasonography. By receiver operating characteristic (ROC) study, specificity was better by 20 MHz than 10 MHz ultrasonography when the value of tumor height as marker for UH was studied. CONCLUSIONS: UH is easier to detect by 20 MHz than by 10 MHz ultrasonography. This ultrasonographic sign appears to be correlated with the height of the tumor. Thus, we believe UH estimation by 20 MHz ultrasonography could be used as a significant predictive factor for SCMT growth.

BraNet: a mobil application for breast image classification based on deep learning algorithms.

Mobile health apps are widely used for breast cancer detection using artificial intelligence algorithms, providing radiologists with second opinions and reducing false diagnoses. This study aims to develop an open-source mobile app named "BraNet" for 2D breast imaging segmentation and classification using deep learning algorithms. During the phase off-line, an SNGAN model was previously trained for synthetic image generation, and subsequently, these images were used to pre-trained SAM and ResNet18 segmentation and classification models. During phase online, the BraNet app was developed using the react native framework, offering a modular deep-learning pipeline for mammography (DM) and ultrasound (US) breast imaging classification. This application operates on a client-server architecture and was implemented in Python for iOS and Android devices. Then, two diagnostic radiologists were given a reading test of 290 total original RoI images to assign the perceived breast tissue type. The reader's agreement was assessed using the kappa coefficient. The BraNet App Mobil exhibited the highest accuracy in benign and malignant US images (94.7%/93.6%) classification compared to DM during training I (80.9%/76.9%) and training II (73.7/72.3%). The information contrasts with radiological experts' accuracy, with DM classification being 29%, concerning US 70% for both readers, because they achieved a higher accuracy in US ROI classification than DM images. The kappa value indicates a fair agreement (0.3) for DM images and moderate agreement (0.4) for US images in both readers. It means that not only the amount of data is essential in training deep learning algorithms. Also, it is vital to consider the variety of abnormalities, especially in the mammography data, where several BI-RADS categories are present (microcalcifications, nodules, mass, asymmetry, and dense breasts) and can affect the API accuracy model.

The dynamics of oligodendrocyte populations following permanent ischemia promotes long-term spontaneous remyelination of damaged area.

Stroke is a major public health concern, with limited clinically approved interventions available to enhance sensorimotor recovery beyond reperfusion. Remarkably, spontaneous recovery is observed in certain stroke patients, suggesting the existence of a brain self-repair mechanism not yet fully understood. In a rat model of permanent cerebral ischemia, we described an increase in oligodendrocytes expressing 3RTau in damaged area. Considering that restoration of myelin integrity ameliorates symptoms in many neurodegenerative diseases, here we hypothesize that this cellular response could trigger remyelination. Our results revealed after ischemia an early recruitment of OPCs to damaged area, followed by their differentiation into 3RTau+ pre-myelinating cells and subsequent into remyelinating oligodendrocytes. Using rat brain slices and mouse primary culture we confirmed the presence of 3RTau in pre-myelinating and a subset of mature oligodendrocytes. The myelin status analysis confirmed long-term remyelination in the damaged area. Postmortem samples from stroke subjects showed a reduction in oligodendrocytes, 3RTau+ cells, and myelin complexity in subcortical white matter. In conclusion, the dynamics of oligodendrocyte populations after ischemia reveals a spontaneous brain self-repair mechanism which restores the functionality of neuronal circuits long-term by remyelination of damaged area. This is evidenced by the improvement of sensorimotor functions in ischemic rats. A deep understanding of this mechanism could be valuable in the search for alternative oligodendrocyte-based, therapeutic interventions to reduce the effects of stroke.

Pharmacological inhibition of mTORC1 reduces neural death and damage volume after MCAO by modulating microglial reactivity.

Ischemic stroke is a sudden and acute disease characterized by neuronal death, increment of reactive gliosis (reactive microglia and astrocytes), and a severe inflammatory process. Neuroinflammation is an early event after cerebral ischemia, with microglia playing a leading role. Reactive microglia involve functional and morphological changes that drive a wide variety of phenotypes. In this context, deciphering the molecular mechanisms underlying such reactive microglial is essential to devise strategies to protect neurons and maintain certain brain functions affected by early neuroinflammation after ischemia. Here, we studied the role of mammalian target of rapamycin (mTOR) activity in the microglial response using a murine model of cerebral ischemia in the acute phase. We also determined the therapeutic relevance of the pharmacological administration of rapamycin, a mTOR inhibitor, before and after ischemic injury. Our data show that rapamycin, administered before or after brain ischemia induction, reduced the volume of brain damage and neuronal loss by attenuating the microglial response. Therefore, our findings indicate that the pharmacological inhibition of mTORC1 in the acute phase of ischemia may provide an alternative strategy to reduce neuronal damage through attenuation of the associated neuroinflammation.

Genetic Analysis as a Tool to Improve the Monitoring of Stranded Cetaceans in Chile.

Cetacean strandings are a valuable source of information for several studies from species richness to conservation and management. During the examination of strandings, taxonomic and sex identification might be hindered for several reasons. Molecular techniques are valuable tools to obtain that missing information. This study evaluates how gene fragment amplification protocols can support the records of strandings done in the field in Chile by identifying, corroborating, or correcting the identification of the species and sex of the recorded individuals. Through a collaboration between a scientific laboratory and government institution in Chile, 63 samples were analyzed. Thirty-nine samples were successfully identified to the species level. In total, 17 species of six families were detected, including six species of conservation interest. Of the 39 samples, 29 corresponded to corroborations of field identifications. Seven corresponded to unidentified samples and three to corrected misidentifications, adding up to 28% of the identified samples. Sex was successfully identified for 58 of the 63 individuals. Twenty were corroborations, 34 were previously unidentified, and four were corrections. Applying this method improves the stranding database of Chile and provides new data for future management and conservation tasks.