Infection by zika virus increase angiotensin I-converting enzyme activity in mouse brain.

Congenital zika virus syndrome (CZS) has become a significant worldwide concern since the sudden rise of microcephaly related to zika virus (ZIKV) in Brazil. Primarily transmitted by Aedes mosquitoes, ZIKV shares serologic similarities with dengue virus (DENV), complicating the diagnosis and/or clinical management. The Angiotensin I-Converting Enzyme (ACE) was associated with either neuroprotective or anti-inflammatory properties in the central nervous system (CNS). The possible role(s) of ACE in these two flaviviruses infection remain largely unexplored. In this study, we evaluate ACE activity in the brain of ZIKV- or DENV-infected mice, both compared to MOCK, showing about 30 % increased ACE activity only in ZIKV-infected mice (p = 0.024), while no change was noticed in brain from DENV-infected animals (p = 0.888). In addition, the treatment with interferon beta (IFNß), under conditions previously demonstrated to rescue the normal size of microcephalic brains determined by ZIKV infection, also restored ACE activity in ZIKV-infected animals to levels close to that of the MOCK control group. Although inflammatory responses expected for either ZIKV or DENV infections, only ZIKV was associated with microcephaly, as well as with increased ACE activity and reversion by treatment with IFNß. Furthermore, this increase in ACE activity was observed only after intracerebroventricular (ICV) injection (F (2, 16) = 7.907, p = 0.004), but not for intraperitoneal (IP) administration of ZIKV (F (2, 26) = 1.996, p = 0.156), suggesting that the observed central ACE activity modulation may be associated with the presence of this specific flavivirus in the brain.

Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms.

BACKGROUND: Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with "profound" autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known. METHODS: Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we  tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions. RESULTS: At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences. LIMITATIONS: Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes. CONCLUSIONS: By embryogenesis, the biological bases of two subtypes of ASD social and brain development-profound autism and mild autism-are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler's social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.

Sodium nitroprusside as an adjunctive treatment for schizophrenia reduces the Ndel1 oligopeptidase activity.

OBJECTIVE: Schizophrenia (SCZ) is a disabling disorder that continues to defy clinicians and researchers. We investigated the effects of sodium nitroprusside (sNP) in an animal model of SCZ and as an add-on therapy in patients and the relationship between treatment with sNP and activity of the nDel1 enzyme, whose involvement in the pathophysiology of the disorder has been suggested earlier. METHODS: Ndel1 activity was measured following sNP infusions in spontaneously hypertensive rats (SHR; 2.5 or 5.0 mg/kg) and in a double-blind trial with SCZ patients (0.5 µg/kg/min). RESULTS: Ndel1 activity was significantly reduced after sNP infusion in blood of SHR compared to controls, and in patients receiving sNP (t = 7.756, df = 97, p < 0.0001, dcohen = 1.44) compared to placebo. Reduced Ndel1 activity between baseline and the end of the infusion was only seen in patients after treatment with sNP. CONCLUSION: Our findings suggest that SCZ patients may benefit from adjunctive therapy with sNP and that the Ndel1 enzyme is a candidate biomarker of psychopathology in the disorder. Future research should look into the role of Ndel1 in SCZ and the potential effects of sNP and drugs with similar profiles of action in both animals and patients.

Identification of an ex vivo inhibitor of the schizophrenia biomarker Ndel1 by high throughput screening.

Ndel1 oligopeptidase activity shows promise as a potential biomarker for diagnosing schizophrenia (SCZ) and monitoring early-stage pharmacotherapy. Ndel1 plays a pivotal role in critical aspects of brain development, such as neurite outgrowth, neuronal migration, and embryonic brain formation, making it particularly relevant to neurodevelopmental disorders like SCZ. Currently, the most specific inhibitor for Ndel1 is the polyclonal anti-Ndel1 antibody (NOAb), known for its high specificity and efficient anti-catalytic activity. NOAb has been vital in measuring Ndel1 activity in humans and animal models, enabling the prediction of pharmacological responses to antipsychotics in studies with patients and animals. To advance our understanding of in vivo Ndel1 function and develop drugs for mental disorders, identifying small chemical compounds capable of specifically inhibiting Ndel1 oligopeptidase is crucial, including within living cells. Due to challenges in obtaining Ndel1's three-dimensional structure and its promiscuous substrate recognition, we conducted a high-throughput screening (HTS) of 2,400 small molecules. Nine compounds with IC50-values ranging from 7 to 56 µM were identified as potent Ndel1 inhibitors. Notably, one compound showed similar efficacy to NOAb and inhibited Ndel1 within living cells, although its in vivo use may pose toxicity concerns. Despite this, all identified compounds hold promise as candidates for further refinement through rational drug design, aiming to enhance their inhibitory efficacy, specificity, stability, and biodistribution. Our ultimate goal is to develop druggable Ndel1 inhibitors that can improve the treatment and support the diagnosis of psychiatric disorders like SCZ.

Euthymic and depressed bipolar patients are characterized by different RNA editing patterns in blood.

Bipolar disorder (BD) is a worldwide leading cause of disability. Inflammation roles in this disease is well established. ADAR1-mediated RNA editing is one of the key mechanisms regulating the inflammatory response. We have identified a panel of RNA editing-based blood biomarkers which allowed to discriminate unipolar from BD depression with high accuracy. We confirmed here the diagnostic value of this panel in a new cohort of BD patients recruited in Brazil. We also identified new combinations which allow a clear discrimination of BD from healthy controls and among BD subgroups, confirming that RNA editing is a key mechanism in BD.

Assessing the role of Ndel1 oligopeptidase activity in congenital Zika syndrome: Potential predictor of congenital syndrome endophenotype and treatment response.

Maternal infections are among the main risk factors for cognitive impairments in the offspring. Zika virus (ZIKV) can be transmitted vertically, causing a set of heterogeneous birth defects, such as microcephaly, ventriculomegaly and corpus callosum dysgenesis. Nuclear distribution element like-1 (Ndel1) oligopeptidase controls crucial aspects of cerebral cortex development underlying cortical malformations. Here, we examine Ndel1 activity in an animal model for ZIKV infection, which was associated with deregulated corticogenesis. We observed here a reduction in Ndel1 activity in the forebrain associated with the congenital syndrome induced by ZIKV isolates, in an in utero and postnatal injections of different inoculum doses in mice models. In addition, we observed a strong correlation between Ndel1 activity and brain size of animals infected by ZIKV, suggesting the potential of this measure as a biomarker for microcephaly. More importantly, the increase of interferon (IFN)-beta signaling, which was used to rescue the ZIKV infection outcomes, also recovered Ndel1 activity to levels similar to those of uninfected healthy control mice, but with no influence on Ndel1 activity in uninfected healthy control animals. Taken together, we demonstrate for the first time here an association of corticogenesis impairments determined by ZIKV infection and the modulation of Ndel1 activity. Although further studies are still necessary to clarify the possible role(s) of Ndel1 activity in the molecular mechanism(s) underlying the congenital syndrome induced by ZIKV, we suggest here the potential of monitoring the Ndel1 activity to predict this pathological condition at early stages of embryos or offspring development, during while the currently employed methods are unable to detect impaired corticogenesis leading to microcephaly. Ndel1 activity may also be possibly used to follow up the positive response to the treatment, such as that employing the IFN-beta that is able to rescue the ZIKV-induced brain injury.

Crotamine/siRNA Nanocomplexes for Functional Downregulation of Syndecan-1 in Renal Proximal Tubular Epithelial Cells.

Proteinuria drives progressive tubulointerstitial fibrosis in native and transplanted kidneys, mainly through the activation of proximal tubular epithelial cells (PTECs). During proteinuria, PTEC syndecan-1 functions as a docking platform for properdin-mediated alternative complement activation. Non-viral gene delivery vectors to target PTEC syndecan-1 could be useful to slow down alternative complement activation. In this work, we characterize a PTEC-specific non-viral delivery vector composed of the cell-penetrating peptide crotamine complexed with a syndecan-1 targeting siRNA. Cell biological characterization was performed in the human PTEC HK2 cell line, using confocal microscopy, qRT-PCR, and flow cytometry. PTEC targeting in vivo was carried out in healthy mice. Crotamine/siRNA nanocomplexes are positively charged, about 100 nm in size, resistant to nuclease degradation, and showed in vitro and in vivo specificity and internalization into PTECs. The efficient suppression of syndecan-1 expression in PTECs mediated by these nanocomplexes significantly reduced properdin binding (p < 0.001), as well as the subsequent complement activation by the alternative complement pathway (p < 0.001), as observed in either normal or activated tubular conditions. To conclude, crotamine/siRNA-mediated downregulation of PTEC syndecan-1 reduced the activation of the alternative complement pathway. Therefore, we suggest that the present strategy opens new venues for targeted proximal tubular gene therapy in renal diseases.

Poly(N-vinylcaprolactam)-Gold Nanorods-5 Fluorouracil Hydrogels: In the Quest of a Material for Topical Therapies against Melanoma Skin Cancer.

Chemically crosslinked hydrogels based on poly(N-vinylcaprolactam) (PNVCL) were synthetized by a photoinitiated chemical method. A galactose-based monomer, 2-lactobionamidoethyl methacrylate (LAMA), and N-vinylpyrrolidone (NVP) were added with the aim to improve the physical and chemical properties of hydrogels. The effects of both comonomers on the swelling ratio (Q), volume phase transition temperature (VPTT), glass transition temperature (Tg), and Young's moduli by mechanical compression below and above the VPTT were studied. Gold nanorods (GNRDs) and 5-fluorouracil (5FU) were embedded into the hydrogels, to study the drug release profiles with and without the excitation of GNRDs by irradiation in the near-infrared region (NIR). Results showed that the addition of LAMA and NVP increased the hydrogels' hydrophilicity, elasticity, and VPTT. The loading of GNRDs in the hydrogels changed the release rate of 5FU when irradiated intermittently with an NIR laser. The present study reports on the preparation of a hydrogel-based platform of PNVCL-GNRDs-5FU as a potential hybrid anticancer hydrogel for chemo/photothermal therapy that could be applied against skin cancer for topical 5FU delivery.

Angiotensin-converting enzymes as druggable features of psychiatric and neurodegenerative disorders.

The renin-angiotensin system (RAS) plays essential roles in maintaining peripheral cardiovascular homeostasis, with its potential roles in the brain only being recognized more recently. Angiotensin-I-converting enzyme (ACE) is the main component of the RAS, and it has been implicated in various disorders of the brain. ACE and other RAS components, including the related enzyme ACE2, angiotensin peptides and their respective receptors, can participate in the pathological state, as well as with potential to contribute to neuroprotection and/or to complement existing treatments for psychiatric illness. In this narrative review, we aimed to identify the main studies describing the functions of the RAS and ACEs in the brain and their association with brain disorders. These include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. We also discuss the possible association of a functional polymorphism of the ACE gene with these brain diseases and the relevance of the neuroprotective and anti-inflammatory properties of ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Based on this, we conclude that there is significant potential value to the inclusion of ACEis and/or ARBs as a novel integrated approach for the treatment of various disorders of the brain, and particularly for psychiatric illness.

Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease.

Positively charged repeat peptides are emerging as key players in neurodegenerative diseases. These peptides can perturb diverse cellular pathways but a unifying framework for how such promiscuous toxicity arises has remained elusive. We used mass-spectrometry-based proteomics to define the protein targets of these neurotoxic peptides and found that they all share similar sequence features that drive their aberrant condensation with these positively charged peptides. We trained a machine learning algorithm to detect such sequence features and unexpectedly discovered that this mode of toxicity is not limited to human repeat expansion disorders but has evolved countless times across the tree of life in the form of cationic antimicrobial and venom peptides. We demonstrate that an excess in positive charge is necessary and sufficient for this killer activity, which we name 'polycation poisoning'. These findings reveal an ancient and conserved mechanism and inform ways to leverage its design rules for new generations of bioactive peptides.

1H NMR Metabolomics and Lipidomics To Monitor Positive Responses in Children with Autism Spectrum Disorder Following a Guided Parental Intervention: A Pilot Study.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by patients displaying at least two out of the classical symptoms, such as impaired social communication, impaired interactions, and restricted repetitive behavior. Early parent-mediated interventions, such as video modeling for parental training, were demonstrated to be a successful low-cost way to deliver care for children with ASD. Nuclear magnetic resonance (NMR)-based metabolomics/lipidomics has been successfully employed in several mental disorder studies. Metabolomics and lipidomics of 37 ASD patients (children, aged 3-8 years), who were divided into two groups, one control group with no parental-training intervention (N = 18) and the other in which the parents were trained by a video modeling intervention (ASD parental training, N = 19), were analyzed by proton NMR spectroscopy. Patients in the ASD parental-training group sera were seen to have increased glucose, myo-inositol, malonate, proline, phenylalanine, and gangliosides in their blood serum, while cholesterol, choline, and lipids were decreased, compared to the control group, who received no parental-training. Taken together, we demonstrated here significant changes in serum metabolites and lipids in ASD children, previously demonstrated to show clinical positive effects following a parental training intervention based on video modeling, delivered over 22 weeks. We demonstrate the value of applying metabolomics and lipidomics to identify potential biomarkers for clinical interventions follow-up in ASD.

Doderlin: isolation and characterization of a broad-spectrum antimicrobial peptide from Lactobacillus acidophilus

Lactobacillus acidophilus are Gram-positive bacteria distributed in diverse environments, and as a component of the normal microbiota of gastrointestinal and urogenital tract, they are relevant for human beings. Classified as lactic acid bacteria, due to the production of lactic acid, Lactobacillus can also produce antimicrobial peptides (AMPs), which is a compound synthesized by all forms of life aiming for protecting themselves from threats and to increase their competitivity to survive in a specific environment. AMPs are molecules capable of inhibiting the growth of microorganisms and, due to the indiscriminate use of conventional antibiotics and the emergence of multi-resistant bacteria, they have become an alternative, not only for treating multi-resistant infections, but also for the identification of probiotic products and food conservation. Considering the rampant rise of bacterial resistance to classical antimicrobials, the present study aimed to isolate and characterize AMPs from L. acidophilus extracts. Lactobacillus acid extract was pre-fractionated on disposable cartridges, followed by a high-performance liquid chromatography (HPLC). The collected fractions were evaluated in a liquid growth inhibition assay allowing to identify eight fractions with antimicrobial activity, and one of them showed antimicrobial activity against Candida albicans and, for this reason, was further characterized by mass spectrometry (MS). A peptide with a molecular mass of 1788.01 Da, showing the primary sequence NEPTHLLKAFSKAGFQ, as determined by MS, was named as Doderlin. Interestingly, antimicrobial molecules isolated from L. acidophilus have already been described previously, but few reports describe AMPs effective against C. albicans as the one reported here. We show here that this newly discovered molecule has a biological property with potential to be used in pharmaceutical and food companies, in the fight against contamination and/or for treating infections caused by microorganisms, respectively.

Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells.

Mitochondria have pivotal roles in cellular physiology including energy metabolism, reactive oxygen species production, Ca2+ homeostasis, and apoptosis. Altered mitochondrial morphology and function is a common feature of cancer cells and the regulation of mitochondrial homeostasis has been identified as a key to the response to chemotherapeutic agents in human leukemias. Here, we explore the mechanistic aspects of cytotoxicity produced by thioridazine (TR), an antipsychotic drug that has been investigated for its anticancer potential in human leukemia cellular models. TR exerts selective cytotoxicity against human leukemia cells in vitro. A PCR array provided a general view of the expression of genes involved in cell death pathways. TR immediately produced a pulse of cytosolic Ca2+, followed by mitochondrial uptake, resulting in mitochondrial permeabilization, caspase 9/3 activation, endoplasmic reticulum stress, and apoptosis. Ca2+ chelators, thiol reducer dithiothreitol, or CHOP knockdown prevented TR-induced cell death. TR also exhibited potent cytotoxicity against BCL-2/BCL-xL-overexpressing leukemia cells. Additionally, previous studies have shown that TR exhibits potent antitumor activity in vivo in different solid tumor models. These findings show that TR induces a Ca2+-mediated apoptosis with involvement of mitochondrial permeabilization and ER stress in leukemia and it emphasizes the pharmacological potential of TR as an adjuvant in antitumor chemotherapy.

Unraveiling the correlation among neurodevelopmental and inflammatory biomarkers in patients with chronic schizophrenia.

INTRODUCTION: Nuclear distribution element like-1 (Ndel1) is a cytosolic oligopeptidase, which was suggested as a potential biomarker of aberrant neurodevelopment and early stage of schizophrenia (SCZ). The involvement of Ndel1 in neurite outgrowth, neuronal migration and neurodevelopment was demonstrated. Moreover, Ndel1 cleaves neuropeptides, including the endogenous antipsychotic peptide neurotensin, and lower Ndel1 activity was reported in SCZ patients compared with healthy controls (HCs). Changes in brain-derived neurotrophic factor (BDNF) and inflammatory cytokines levels were also implicated in SCZ. OBJECTIVE: This preliminary study aimed to investigate the interactions between these immune and neurodevelopmental/neurotrophic biomarkers, namely BDNF and the recently identified SCZ biomarker Ndel1. RESULTS: We observed lower Ndel1 activity and IL-4 levels, and higher BDNF levels, in plasma of SCZ (N = 23) compared with HCs (N = 29). Interestingly, significant correlation between Ndel1 activity and IL-4 levels was observed in SCZ, while no correlation with any other evaluated interleukins (namely IL-2, IL-8, IL-10 and IL-17A) or BDNF levels was noticed. CONCLUSION: Although this hypothesis needs to be further explored for a better understanding of the mechanisms by which these altered pathways are associated to each other in SCZ, we suggest that Ndel1 and the inflammatory marker IL-4 are directly correlated.

Development of Rhizophora mangle (Rhizophoraceae) and Avicennia schaueriana (Avicenniaceae) in the presence of a hydrocarbon-degrading bacterial consortium and marine diesel oil.

The development of Rhizophora mangle and Avicennia schaueriana seedlings impacted by marine diesel oil (MDO) was evaluated in the presence or absence of a hydrocarbon-degrading bacterial consortium (HBC). The bioassays were conducted in a greenhouse during 6 months and consisted of three different treatments (control, MDO only and MDO + HBC). The bacterial consortium was mainly composed of Bacillus spp. (73%), but Rhizobium spp., Pseudomonas spp., Ochrobactrum spp., and Brevundimonas spp. were also present. After 6 months, A. schaueriana seedlings showed higher mortality compared to those of R. mangle; R. mangle exhibited 68% (control), 44% (MDO alone) and 50% (MDO + HBC) seedlings survivorship compared to 42% (control), 0% (MDO alone) and 4% (MDO + HBC) for A. schaueriana. This variability may be due to differences in species physiology. Stem growth, diameter and number of leaves remained constant during the 6 months of the experiment with marine diesel oil and hydrocarbon-degrading bacterial consortium (MDO + BBC). For both mangrove species, bacterial enzymatic activity in the sediments was sufficient to maintain cell counts of 107 cells cm-3 in the rhizospheric soil and possibly synthetize the extracellular polymeric substances (EPS) that may emulsify and solubilize oil products.

Rosiglitazone protects INS-1E cells from human islet amyloid polypeptide toxicity.

Human islet amyloid polypeptide (hIAPP or amylin) is a hormone co-secreted with insulin by pancreatic ß-cells, and is the main component of islet amyloid. Islet amyloid is found in the pancreas of patients with type 2 diabetes and may be involved in ß-cell dysfunction and death, observed in this disease. Thus, counteracting islet amyloid toxicity represents a therapeutic approach to preserve ß-cell mass and function. In this sense, thiazolidinediones (TZDs), as rosiglitazone, have shown protective effects against other harmful insults to ß-cells. For this reason, we investigated whether rosiglitazone could protect ß-cells from hIAPP-induced cell death and the underlying mechanisms mediating such effect. Here, we show that rosiglitazone improved the viability of hIAPP-exposed INS-1E cells. This benefit is not dependent on the insulin-degrading enzyme (IDE) since rosiglitazone did not modulate IDE protein content and activity. However, rosiglitazone inhibited hIAPP fibrillation and decreased hIAPP-induced expression of C/EBP homologous protein (CHOP) (CTL 100.0 ± 8.4; hIAPP 182.7 ± 19.1; hIAPP + RGZ 102.8 ± 9.5), activating transcription factor-4 (ATF4) (CTL 100.0 ± 3.1; hIAPP 234.9 ± 19.3; hIAPP + RGZ 129.6 ± 3.0) and phospho-eukaryotic initiation factor 2-alpha (p-eIF2α) (CTL 100.0 ± 31.1; hIAPP 234.1 ± 36.2; hIAPP + RGZ 150.4 ± 18.0). These findings suggest that TZDs treatment may be a promising approach to preserve ß-cell mass and function by inhibiting islet amyloid formation and decreasing endoplasmic reticulum stress hIAPP-induced.

Association between the intensity of obstructive sleep apnea and skeletal alterations in the face and hyoid bone / Relação entre a influência da gravidade da apneia obstrutiva do sono e alterações craniofaciais e do posicionamento do osso hioide

Abstract Introduction The association between the intensity of obstructive sleep apnea and skeletal alterations in the face and hyoid bone is still scarcely addressed in the literature. Objective To evaluate whether the intensity of obstructive sleep apnea is associated with craniofacial alterations and the position of the hyoid bone in children with mixed dentition. Methods 76 children aged 7 to 10 years old were examined by otorhinolaryngological evaluation, polysomnography, and orthodontic assessment, including cephalometry. The participants were divided in 3 groups: primary snoring, mild obstructive sleep apnea and moderate to severe obstructive sleep apnea. Cephalometric measures of the face and hyoid bone were assessed. These measures were compared among the different groups by unpaired Student's t test. Moreover, these measures were correlated with the patient's obstructive apnea and hypopnea index variable using Pearson's correlation test. Results Of the 76 children, 14 belonged to group 1, with primary snoring; 46 to group 2, with mild obstructive sleep apnea; and 16 to group 3, with moderate-severe obstructive sleep apnea. There was no difference between the groups regarding the craniofacial variables. Children with obstructive sleep apnea showed a longer distance from the hyoid bone to the mandibular plane when compared to the primary snoring group (p < 0.05). Between the two obstructive sleep apnea subgroups, patients with moderate or severe disease showed significantly shorter horizontal distance between the hyoid bone and the posterior pharyngeal wall (p < 0.05), when compared to the groups with mild obstructive sleep apnea. We also observed a significant positive correlation between obstructive apnea and hypopnea index and the distance from the hyoid to the mandibular plane (p < 0.05) as well as a significant negative association between obstructive apnea and hypopnea index and the horizontal distance from the hyoid to the posterior pharyngeal wall (p < 0.01). Conclusion We did not observe any association between obstructive sleep apnea and linear lateral alterations of the face. In contrast, there is a direct association between obstructive sleep apnea severity and the inferior and posterior position of the hyoid bone in children aged 7 to 10 years old.

Resumo Introdução A relação entre a intensidade da apneia obstrutiva do sono e alterações esqueléticas da face e do hioide em crianças é pouco explorada na literatura. Objetivo Avaliar se a intensidade da apneia obstrutiva do sono correlaciona-se às alterações craniofaciais e ao posicionamento do osso hioide em crianças em fase de dentição mista. Método Foram submetidas 76 crianças entre 7 e 10 anos à avaliação otorrinolaringológica, polissonografia e avaliação ortodôntica, inclusive cefalometria. Os participantes foram divididos em 3 grupos: grupo 1 com ronco primário, grupo 2 com apneia obstrutiva do sono leve e grupo 3 com apneia obstrutiva do sono moderada/grave. Foram analisadas medidas cefalométricas da face e do osso hioide. Essas medidas foram comparadas entre si dentro dos diferentes grupos por teste t de Student não pareado. Além disso, essas medidas foram correlacionadas com a variável índice de apneias obstrutivas e hipopneias do paciente através do teste de correlação de Pearson. Resultados Das 76 crianças, 14 constituíram o grupo 1, ronco primário; 46 o grupo 2, apneia obstrutiva do sono leve; e 16 o grupo 3, apneia obstrutiva do sono moderada/grave. Não se observou diferença significante entre os grupos para as variáveis craniofaciais. Observou-se maior distância do osso hioide ao plano mandibular nos dois grupos com apneia obstrutiva do sono quando comparado ao ronco primário (p < 0,05). Entre os dois subgrupos da apneia obstrutiva do sono, os pacientes com doença moderada ou grave apresentaram distância horizontal entre o hioide e a parede posterior da faringe significantemente menor (p < 0,05), quando comparados aos grupos com apneia obstrutiva do sono leve. Observamos ainda correlação significantemente positiva entre índice de apneias obstrutivas e hipopneias e a distância do hioide ao plano mandibular (p < 0,05) e significantemente negativa entre índice de apneias obstrutivas e hipopneias e distância horizontal do hioide com a parede posterior da faringe (p < 0,01). Conclusão Não observamos relação da apneia obstrutiva do sono com alterações lineares laterais da face. Em contraste, existe relação direta entre a gravidade da apneia obstrutiva do sono e a posição inferior e posterior do osso hioide em crianças entre 7 e 10 anos.

NVCL-Based Hydrogels and Composites for Biomedical Applications: Progress in the Last Ten Years.

Hydrogels consist of three-dimensionally crosslinked polymeric chains, are hydrophilic, have the ability to absorb other molecules in their structure and are relatively easy to obtain. However, in order to improve some of their properties, usually mechanical, or to provide them with some physical, chemical or biological characteristics, hydrogels have been synthesized combined with other synthetic or natural polymers, filled with inorganic nanoparticles, metals, and even polymeric nanoparticles, giving rise to composite hydrogels. In general, different types of hydrogels have been synthesized; however, in this review, we refer to those obtained from the thermosensitive polymer poly(N-vinylcaprolactam) (PNVCL) and we focus on the definition, properties, synthesis techniques, nanomaterials used as fillers in composites and mainly applications of PNVCL-based hydrogels in the biomedical area. This type of material has great potential in biomedical applications such as drug delivery systems, tissue engineering, as antimicrobials and in diagnostic and bioimaging.

NVCL-Based Galacto-Functionalized and Thermosensitive Nanogels with GNRDs for Chemo/Photothermal-Therapy.

Dual-function nanogels (particle size from 98 to 224 nm) synthesized via surfactant-free emulsion polymerization (SFEP) were tested as smart carriers toward synergistic chemo- and photothermal therapy. Cisplatin (CDDP) or doxorubicin (DOX) and gold nanorods (GNRDs) were loaded into galacto-functionalized PNVCL-based nanogels, where the encapsulation efficiency for CDDP and DOX was around 64 and 52%, respectively. PNVCL-based nanogels were proven to be an efficient delivery vehicle under conditions that mimic the tumor site in vitro. The release of CDDP or DOX was slower at pH 7.4 and 37 °C than at tumor conditions of pH 6 and 40 °C. On the other hand, in the systems with GNRDs at pH 7.4 and 37 °C, the sample was irradiated with a 785 nm laser for 10 min every hour, obtaining that the release profiles were even higher than in the conditions that simulated a cancer tissue (without irradiation). Thus, the present study demonstrates the synergistic effect of chemo- and photothermal therapy as a promising dual function in the potential future use of PNVCL nanogels loaded with GNRDs and CDDP/DOX to achieve an enhanced chemo/phototherapy in vivo.

Revisiting the potential of South American rattlesnake Crotalus durissus terrificus toxins as therapeutic, theranostic and/or biotechnological agents.

The potential biotechnological and biomedical applications of the animal venom components are widely recognized. Indeed, many components have been used either as drugs or as templates/prototypes for the development of innovative pharmaceutical drugs, among which many are still used for the treatment of human diseases. A specific South American rattlesnake, named Crotalus durissus terrificus, shows a venom composition relatively simpler compared to any viper or other snake species belonging to the Crotalus genus, although presenting a set of toxins with high potential for the treatment of several still unmet human therapeutic needs, as reviewed in this work. In addition to the main toxin named crotoxin, which is under clinical trials studies for antitumoral therapy and which has also anti-inflammatory and immunosuppressive activities, other toxins from the C. d. terrificus venom are also being studied, aiming for a wide variety of therapeutic applications, including as antinociceptive, anti-inflammatory, antimicrobial, antifungal, antitumoral or antiparasitic agent, or as modulator of animal metabolism, fibrin sealant (fibrin glue), gene carrier or theranostic agent. Among these rattlesnake toxins, the most relevant, considering the potential clinical applications, are crotamine, crotalphine and gyroxin. In this narrative revision, we propose to organize and present briefly the updates in the accumulated knowledge on potential therapeutic applications of toxins collectively found exclusively in the venom of this specific South American rattlesnake, with the objective of contributing to increase the chances of success in the discovery of drugs based on toxins.