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OBJECTIVE: This study aims to investigate the neuroprotective effects of cannabidiol (CBD) on neurodevelopmental impairments in rats subjected to neonatal hypoxia, specifically examining its potential to mitigate motor and sensory deficits without the confounding effects of ischemia. METHODS: Neonatal Sprague-Dawley rats were allocated to one of four groups: Control, Control-CBD, Hypoxia, and Hypoxia-CBD. Hypoxia was induced on postnatal days 0 and 1. CBD (50 mg/kg) was administered orally for 14 days starting at postnatal day 0. Neurodevelopmental outcomes were assessed using the Neurodevelopmental Reflex Testing in Neonatal Rat Pups scale and the Revised Neurobehavioral Severity Scale for rodents. Statistical analyses were conducted using two-way and one-way ANOVA, with Tukey's post-hoc tests for group comparisons. RESULTS: Pup weights were recorded on specified postnatal days, with no significant differences observed across the groups (p = 0.1834). Significant neurological impairments due to hypoxia were noted in the Control group compared to the Hypoxia group, particularly in hindlimb grasping on postnatal day 3 (p = 0.0025), posture on postnatal day 12 (p = 0.0073), and in general balance and sound reflex on postnatal day 20 (p = 0.0016 and p = 0.0068, respectively). Additionally, a statistically significant improvement in posture was observed in the Hypoxia-CBD group compared to the Hypoxia group alone (p = 0.0024). CONCLUSION: Our findings indicate that CBD possesses neuroprotective properties that significantly counteract the neurodevelopmental impairments induced by neonatal hypoxia in rats. This study not only supports the therapeutic potential of CBD in managing conditions characterized by neurodevelopmental challenges due to hypoxia but also underscores the necessity for further investigation into the specific molecular mechanisms driving CBD's neuroprotective effects. Further research is essential to explore CBD's clinical applications and its potential role in treating human neurodevelopmental disorders.

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INTRODUCTION: Surgery is the standard treatment for pancreatic neuroendocrine tumors (pNETs), obtaining favorable results but associating high morbidity and mortality rates. This study assesses stereotactic body radiation therapy (SBRT) as a radical approach for small (< 2 cm) nonfunctioning pNETs. MATERIALS AND METHODS: From January 2017 to June 2023, 20 patients with small pNETs underwent SBRT in an IRB-approved study. Endpoints included local control, tolerance, progression-free survival, and overall survival (OS). Diagnostic assessments comprised endoscopy, CT scans, OctreScan or PET-Dotatoc, abdominal MRI, and histological confirmatory samples. RESULTS: In a 30-month follow-up of 20 patients (median age 55.5 years), SBRT was well-tolerated with no grade > 2 toxicity. 40% showed morphological response, 55% remained stable. Metabolically, 50% achieved significant improvement. With a median OS of 41.5 months, all patients were alive without local or distant progression or need for surgical resection. CONCLUSION: SBRT is a feasible and well-tolerated approach for small neuroendocrine pancreatic tumors, demonstrating effective local control. Further investigations are vital for validation and extension of these findings.

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BACKGROUND: Preoperative radiation therapy following by limb-sparing or conservative surgery is a standard approach for limb and trunk STS. Data supporting hypofractionated radiotherapy schedules are scarce albeit biological sensitivity of STS to radiation would justify it. We sought to evaluate the impact of moderate hypofractionation on pathologic response and its influence on oncologic outcomes. MATERIAL AND METHODS: From October 2018 to January 2023, 18 patients with limb or trunk STS underwent preoperative radiotherapy at a median dose of 52.5 Gy (range 49.5-60 Gy) in 15 fractions of 3.5 Gy (3.3-4 Gy) with or without neoadjuvant chemotherapy. A favorable pathologic response (fPR) was considered as ≥ 90% tumor necrosis on specimen examination. RESULTS: All patients completed planned preoperative radiotherapy. Eleven patients (61.1%) achieved a fPR, and 7 patients (36.8%) a complete pathologic response with total disappearance of tumor cells. Nine patients (47%) developed grade 1-2 acute skin toxicity, and 7 patients (38.8%) had wound complications on follow-up. With a median follow-up of 14 months (range 1-40), no cases of local relapse were observed, and actuarial 3-year overall survival (OS) and distant metastases-free survival (DMFS) are 87% and 76.4%, respectively. In the univariate analysis, the presence of a favorable pathologic response (fPR) was associated with improved 3-year OS (100% vs. 56.03%, p = 0.058) and 3-year DMFS (86.91% vs. 31.46%, p = 0.002). Moreover, both complete or partial RECIST response and radiological stabilization of the tumor lesion showed a significant association with higher rates of 3-year distant metastasis-free survival (DMFS) (83% vs. 83% vs. 56%, p < 0.001) and 3-year overall survival (OS) (100% vs. 80% vs. 0, p = 0.002). CONCLUSIONS: Preoperative moderate hypofractionated radiation treatment for STS is feasible and well tolerated and associates encouraging rates of pathologic response that could have a favorable impact on final outcomes.

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The Enteric Nervous System (ENS) is described as a division of the Peripheral Nervous System (PNS), located within the gut wall and it is formed by two main plexuses: the myenteric plexus (Auerbach's) and the submucosal plexus (Meissner's). The contribution of the ENS to the pathophysiology of various neurological diseases such as Parkinson's or Alzheimer's disease has been described in the literature, while some other studies have found a connection between epilepsy and the gastrointestinal tract. The above could be explained by cholinergic neurons and neurotransmission systems in the myenteric and submucosal plexuses, regulating the vagal excitability effect. It is also understandable, as the discharges arising in the amygdala are transmitted to the intestine through projections the dorsal motor nucleus of the vagus, giving rise to efferent fibers that stimulate the gastrointestinal tract and consequently the symptoms at this level. Therefore, this review's main objective is to argue in favor of the existing relationship of the ENS with the Central Nervous System (CNS) as a facilitator of epileptogenic or ictogenic mechanisms. The gut microbiota also participates in this interaction; however, it depends on many individual factors of each human being. The link between the ENS and the CNS is a poorly studied epileptogenic site with a big impact on one of the most prevalent neurological conditions such as epilepsy.

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Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and immune activation in the nigro-striatal pathway. Simvastatin regulates cholesterol metabolism and protects from atherosclerosis disease. Simvastatin-tween 80 was administered 7 days before sterotaxic intrastriatal administration of MPP+ (1-methyl-4-phenylpyridine) in rats. Fluorescent lipidic product formation, dopamine levels, and circling behavior were considered damage markers. Twenty-four hours and six days after, the animal group lesioned with MPP+ showed significant damage in relation to the control group. Animals pretreated with simvastatin significantly reduced the MPP+-induced damage compared to the MPP+ treated group. As apoptosis promotes neuroinflammation and neuronal degeneration in Parkinson's disease, and since there is not currently a proteomic map of the nigro-striatum of rats and assuming a high homology among the identified proteins in other rat tissues, we based the search for rat protein homologs related to the establishment of inflammation response. We demonstrate that most proteins related to inflammation decreased in the simvastatin-treated rats. Furthermore, differential expression of antioxidant enzymes in striated tissue of rat brains was found in response to simvastatin. These results suggest that simvastatin could prevent striatal MPP+-induced damage and, for the first time, suggest that the molecular mechanisms involved in this have a protective effect.

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Introduction: Uniform chromosome abnormalities are commonly seen in early pregnancy loss, with analyses of the product of conception suggesting the presence of mosaic autosomal trisomy in ∼10% of cases. Although chromosomal mosaicism occurs in a minority of embryos, their relative commonality and uncertainty regarding associated transfer outcomes have created discussion at both the clinical and research levels, highlighting the need to understand the clinical conditions associated with the incidence of embryo mosaicism. Methods: We took advantage of a preimplantation genetic testing for aneuploidy (PGT-A) database created from 2019 to 2022 in more than 160 in vitro fertilization (IVF) clinics in Brazil, the second-largest world market for IVF. We carried out descriptive statistical and associative analyses to assess the proportions of mosaicism associated with clinical conditions and reported incidence by chromosome, clinic origin, and biopsy operator. Results: Chromosomal analysis revealed that most mosaic aneuploidies occurred in the last three chromosomes, with 78.06% of cases having only one chromosome affected. Low mosaicism in trisomy represented the most ordinary form, followed by low mosaicism in monosomy. We identified associations between low (negatively-associated) and high mosaicism (positively-associated) and maternal age, indication (male factor and uterus/ovarian factor negatively associated with low and high mosaic, respectively), day of blastocyst development (day five has an overall better outcome), morphology grade (lower quality increased the chances of low and high mosaicism), origin (vitrified oocyte and embryo increased the rates of low and high mosaicism, respectively), and embryo sex (male embryos negatively associated with low mosaic). Discussion: With these results, we hope to foster an improved understanding of the chromosomal mosaicism linked with distinct clinical conditions and their associations in Brazil.

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OBJECTIVE: To assess the clinical outcomes of patients with spine metastases treated with SBRT at our institution. MATERIALS AND METHODS: Patients with spine metastases treated with SBRT (1 fraction/18 Gy or 5 fractions/7 Gy) during the last 12 years have been analyzed. All patients were simulated supine in a vacuum cushion or with a shoulder mask. CT scans and MRI image registration were performed. Contouring was based on International Spine-Radiosurgery-Consortium-Consensus-Guidelines. Highly conformal-techniques (IMRT/VMAT) were used for treatment planning. Intra and interfraction (CBCT or X-Ray-ExacTrac) verification were mandatory. RESULTS: From February 2010 to January 2022, 129 patients with spinal metastases were treated with SBRT [1 fraction/18 Gy (75%) or 5 fractions/7 Gy] (25%). For patients with painful metastases (74/129:57%), 100% experienced an improvement in pain after SBRT. With a median follow-up of 14.2 months (average 22.9; range 0.5-140) 6 patients (4.6%) experienced local relapse. Local progression-free survival was different, considering metastases's location (p < 0.04). The 1, 2 and 3 years overall survival (OS) were 91.2%, 85.1% and 83.2%, respectively. Overall survival was significantly better for patients with spine metastases of breast and prostate cancers compared to other tumors (p < 0.05) and significantly worse when visceral metastases were present (p < 0.05), when patients were metastatic de novo (p < 0.05), and in those patients receiving single fraction SBRT (p: 0.01). CONCLUSIONS: According to our experience, SBRT for patients with spinal metastases was effective in terms of local control and useful to reach pain relief. Regarding the intent of the treatment, an adequate selection of patients is essential to propose this ablative approach.

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Abstract: Epilepsy is a multifactorial pathology that has allowed the development of various drugs aiming to combat it. This effort was formally initiated in the 1940s when phenytoin began to be used. It eventually turned out to be a drug with great anticonvulsant efficacy. At present, several potentially good new generation anti-seizure medications (ASMs) have been developed. Most of them present more tolerability and less toxic effects. However, they continue to have adverse effects at different levels. In addition, some seizures are difficult to treat with ASMs, representing 30% of the total cases of people who suffer from epilepsy. This review aims to explore the genetic and molecular mechanisms of ASMs neurotoxicity, proposing the study of damage caused by epileptic seizures, in addition to the deterioration generated by anti-seizure drug administration within the central nervous system. It is beyond question that there is a need to develop drugs that lower the lower the risk of secondary and toxic effects of ASMs. Simultaneously, we must find strategies that produce fewer harmful interactions and more health benefits when taking anti-seizure drugs.

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ABSTRACT Epilepsy is a multifactorial pathology that has allowed the development of various drugs aiming to combat it. This effort was formally initiated in the 1940s when phenytoin began to be used. It eventually turned out to be a drug with great anticonvulsant efficacy. At present, several potentially good new generation anti-seizure medications (ASMs) have been developed. Most of them present more tolerability and less toxic effects. However, they continue to have adverse effects at different levels. In addition, some seizures are difficult to treat with ASMs, representing 30% of the total cases of people who suffer from epilepsy. This review aims to explore the genetic and molecular mechanisms of ASMs neurotoxicity, proposing the study of damage caused by epileptic seizures, in addition to the deterioration generated by anti-seizure drug administration within the central nervous system. It is beyond question that there is a need to develop drugs that lower the lower the risk of secondary and toxic effects of ASMs. Simultaneously, we must find strategies that produce fewer harmful interactions and more health benefits when taking anti-seizure drugs.

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Caloric restriction (CR) possesses different cellular mechanisms. Though there are still gaps in the literature regarding its plausible beneficial effects, the suggestion that this alternative therapy can improve the inflammatory and antioxidant response to control epileptic seizures is explored throughout this study. Epilepsy is the second most prevalent neurodegenerative disease in the world. However, the appropriate mechanisms for it to be fully controlled are still unknown. Neuroinflammation and oxidative stress promote epileptic seizures' appearance and might even aggravate them. There is growing evidence that caloric restriction has extensive anti-inflammatory and antioxidant properties. For instance, nuclear factor erythroid 2-related factor 2 (Nrf2) and all-trans retinoic acid (ATRA) have been proposed to induce antioxidant processes and ulteriorly improve the disease progression. Caloric restriction can be an option for those patients with refractory epilepsy since it allows for anti-inflammatory and antioxidant properties to evolve within the brain areas involved.

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Fluoride concentrations of 0.5 mg/L in drinking water are considered useful for dental caries prevention. However, fluoride concentrations higher than 1.2 mg/L in water can pose a risk of dental fluorosis due to high exposure to fluoride. The objective is to determine the fluoride concentration in water from aqueducts of different Colombian municipalities of Cauca (Popayán, Coconuco, and Puracé) to assess the fluoride dietary intake from the consumption of this water. A total of 66 water samples have been taken from Popayán, Coconuco, and Puracé. Fluoride content was determined by fluoride ion-selective electrode (ISE) potentiometry. The fluoride concentrations recorded in Coconuco and Puracé water were ≤ 0.002 mg/L. The mean fluoride content recorded in the Popayán water was 0.42 mg/L, with its highest concentration in Cauca River water (0.83 mg/L). Considering the admissible intake values, the water from Popayán confers remarkable fluoride intakes, especially in children with high percentages of contribution to the admissible daily intake (46.7% to 7- to 12-month children and 41.5% to 1- to 3-year children). The fluoride content in the water of Coconuco and Puracé does not reach an optimal value (< 0.5 mg/L) for the protective effect against dental caries, while the water of the main Cauca River basin does reach the optimal value. Likewise, the intake of fluoride from the consumption of the analyzed water does not confer any health risk. However, the implementation of monitoring systems for fluoride levels is recommended in order to safeguard the consumer's health.

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Neonicotinoids are pesticides that act as agonists of nicotinic receptors for acetylcholine in insects' central nervous system (CNS). Chronic exposure to neonicotinoids in humans is related to autism, memory loss, and finger tremor. In this article, we evaluate the effect of subchronic oral administration of two neonicotinoids in the same mixture: clothianidin and thiacloprid. Decreasing doses of both pesticides were administered to rats starting from the lethal dose 50 (LD50) reported by the manufacturer. Our results indicate that the administration of three doses of decreasing amounts of LD50 (5/10, 4/10, and 3/10 LD50) resulted in 100% death in all cases. Ten administration times of 2/10 LD50 of the mixture caused only 20% of death cases after twenty-seven days, which was determined as a subchronic administration scheme. The animals administered 2/10 LD50 showed behavioral alterations after the first and second administration. Electrographic studies showed abnormal discharge patterns in the CNS. 72 h after the tenth dose, learning and memory tests were performed in the Morris water maze. Our results revealed significant decreases in permanence at the quadrant and the number of crosses (P=0.0447, P=0.0193, respectively), which represent alterations in the short-term memory test, but there were no significant changes in a long-term memory test. Likewise, the brains of these animals showed tissue architecture loss, nucleosomal retraction, and a significant increase in the pycnosis of the granular neurons of the dentate gyrus analyzed at 72 h after the last dose (P=0.0125). Toxic effects and cognitive deterioration that have been found in communities living near contaminated areas are probably related to the agricultural use of neonicotinoids.

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Metal pollution in the marine environment can damage places with exceptional biodiversity such as the Galapagos Islands. For this reason, it is important to evaluate the toxic risk from metals derived from fish consumption and to perform a nutritional assessment. We sampled 20 individuals of demersal (Caulolatilus princeps and Mycteroperca olfax) and pelagic (Thunnus albacares and Seriolella violacea) species. The levels of the toxic elements (Al, B, Ba, Cd, Ni, Pb and Sr), and the macroelements, microelements and trace elements (Ca, Cr, Fe, K, Li, Mn, Mo, Mg, Na, V and Zn) of species muscle tissue were analyzed by Inductively Coupled Plasma Optical Spectrometry (ICP-OES). Demersal species have higher concentrations of Cr, K, Mg and Mo; while pelagic species have higher levels of Zn. M. olfax could potentially cause Cd toxicity so it is recommended not to ingest more than 86 and 73 g of this species (i.e. roughly, one serving) per week for men and women, respectively. None of the species could be marketed in Europe and the USA due to Cd level exceed the allowed limits by EFSA and FAO. Furthermore, the dietary intake of C. princeps is recommended due to its high concentration of Ca, Na, K, Mg and Cr, while T. albacares is recommended for people with Zn deficiency. However, due to the Cd level in C. princeps it is not recommended to ingest more than five servings per week. We attribute the source of metals in the studied fish from the volcanic origin of the islands rather than from human pollution. This is the first study that thoroughly estimate concentration of metals in commercial fish species and its contribution to food security in the Galapagos.

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Water for human consumption is the main source of fluoride exposure. The concentration in water should not exceed 1 mg/L of fluoride since, at higher levels; it increases the risk of dental fluorosis, among other adverse effects. The fluoride content of 149 water samples from different aqueducts in Cauca (Colombia) has been determined by ion exchange chromatography with the aim of fluoride risk assessment. The rural area of the Municipality of Santander de Quilichao registered fluoride concentrations between 0.012 and 0.150 mg/L. The urban area of Santander de Quilichao recorded lower fluoride levels than the rural area (0.027-0.068 mg/L). The urban area of the Municipality of Cajibío registered fluoride levels of 0.082-0.186 mg/L. The highest levels of fluoride were found in Timbío (0.121-0.210 mg/L). The fluoride levels recorded in this study are not considered sufficient to trigger dental fluorosis. Likewise, optimal levels are not considered to protect the child population against dental caries. However, a monitoring plan of fluoride concentrations in water should be implemented to assure the quality and safe of the water.

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Retinoic acid, a metabolite of vitamin A, acts through either genomic or nongenomic actions. The genomic action of retinoids exerts effects on gene transcription through interaction with retinoid receptors such as retinoic acid receptors (RARα, ß, and γ) and retinoid X receptors (RXRα, ß, and γ) that are primarily concentrated in the amygdala, pre-frontal cortex, and hippocampal areas in the brain. In response to retinoid binding, RAR/RXR heterodimers undergo major conformational changes and orchestrate the transcription of specific gene networks. Previous experimental studies have reported that retinoic acid exerts an antiepileptogenic effect through diverse mechanisms, including the modulation of gap junctions, neurotransmitters, long-term potentiation, calcium channels and some genes. To our knowledge, there are no previous or current clinical trials evaluating the use of retinoic acid for seizure control.

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Fluoride has been considered as the single factor most frequently responsible for causing enamel mottling. However, in humans, either endogenous and/or exogenous factors not related to fluoride exposure may also cause enamel mottling. In this sense, various studies in the international literature have reported severe mottling of the teeth that could not be attributed to fluoride exposure. Thus, misdiagnosis of non-fluoride-induced enamel defects may occur frequently. Reports of unexpectedly high population prevalence and individual cases of fluorosis, where such diagnoses are irreconcilable with the identified fluoride history, highlight the necessity for a more precise definition and diagnosis of dental fluorosis. Also, a more discriminating diagnostic procedure is suggested. Particularly, positive identification of environmental fluoride levels to which the communities and individuals are exposed shall be developed before the confirmation of a diagnosis of fluorosis. It is considered that a more critical methodology for the diagnosis of fluorosis will be helpful in the rational use and control of fluorides for dental health, and in the identification of factors that may induce enamel defects.

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The Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez" (INNN) is one of the main institutions in Latin America treating epilepsy; and bibliometric analysis has an increasing role in analyzing the literature, acting as a Google Maps of medical research. We tracked the scientific output in Scopus and the impact of the institution from its foundation to July 2020 in the field of epilepsy. We roughly separated this group by clinical and experimental approach, identifying core journals, type of article, increase with time, and number of citations. A total of 228 papers, from a total of 3,034 produced by the INNN in that period, were found. Additionally, we identified that neurocysticercosis, pharmacology, genetics, and proteins involved in epilepsy were the most investigated topics. Also, there is a sustained growth in the number of papers per year since 1985. The number of authors per paper ranges from one to 15, and neuroscience journals are the preferred target of researchers, with a predilection for "Epilepsy and Behavior".

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Epilepsy is a neurological disorder in which, in many cases, there is poor pharmacological control of seizures. Nevertheless, it may respond beneficially to alternative treatments such as dietary therapy, like the ketogenic diet or caloric restriction. One of the mechanisms of these diets is to produce a hyperpolarization mediated by the adenosine triphosphate (ATP)-sensitive potassium (KATP) channels (KATP channels). An extracellular increase of K+ prevents the release of Ca2+ by inhibiting the signaling of the Wnt pathway and the translocation of ß-catenin to the cell nucleus. Wnt ligands hyperpolarize the cells by activating K+ current by Ca2+. Each of the diets described in this paper has in common a lower use of carbohydrates, which leads to biochemical, genetic processes presumed to be involved in the reduction of epileptic seizures. Currently, there is not much information about the genetic processes implicated as well as the possible beneficial effects of diet therapy on epilepsy. In this review, we aim to describe some of the possible genes involved in Wnt pathways, their regulation through the KATP channels which are implicated in each one of the diets, and how they can reduce epileptic seizures at the molecular level.

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Epilepsy is a neurological disorder that involves abnormal and recurrent neuronal discharges, producing epileptic seizures. Recently, it has been proposed that the Wnt signaling pathway is essential for the central nervous system development and function because it modulates important processes such as hippocampal neurogenesis, synaptic clefting, and mitochondrial regulation. Wnt/ß- catenin signaling regulates changes induced by epileptic seizures, including neuronal death. Several genetic studies associate Wnt/ß-catenin signaling with neuronal excitability and epileptic activity. Mutations and chromosomal defects underlying syndromic or inherited epileptic seizures have been identified. However, genetic factors underlying the susceptibility of an individual to develop epileptic seizures have not been fully studied yet. In this review, we describe the genes involved in neuronal excitability in epileptogenic zones dependent on the Wnt/ß-catenin pathway.

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