Effects of Cryolipolysis on the Conversion of White Adipose Tissue: Pilot Study.

INTRODUCTION: Cryolipolysis (CLL) is a widely employed noninvasive procedure for body fat reduction. It operates by inducing cooling, leading to the crystallization of cytoplasmic lipids, loss of cellular integrity, and apoptosis/necrosis of adipocytes, accompanied by local inflammation. Ongoing discussions revolve around CLL's potential to transform white adipocytes into brown adipocytes, potentially yielding more significant effects compared to alternative procedures. OBJECTIVE: Thus, this randomized, blinded clinical study aimed to investigate the effects of CLL on adipose tissue and elucidate the mechanisms involved in its application and capacity for adipocyte conversion. METHODOLOGY: Tissue samples from six patients were assessed at intervals of 45, 60, and 90 days following the application of the CLL protocol during abdominoplasty surgeries. RESULTS: The samples underwent immunohistochemical analyses targeting various markers, revealing higher expression of PPAR-gamma, PPAR-alpha, and UCP-1 markers in CLL-treated samples. CONCLUSION: Therefore, the present study suggests that CLL has the ability to intervene in adipocyte conversion.

The angiotensin-(1-7)/MasR axis improves pneumonia caused by Pseudomonas aeruginosa: Extending the therapeutic window for antibiotic therapy.

Pseudomonas aeruginosa is a frequent cause of antimicrobial-resistant hospital-acquired pneumonia, especially in critically ill patients. Inflammation triggered by P. aeruginosa infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data have shed light on the pro-resolving actions of angiotensin-(1-7) [Ang-(1-7)] signaling through the G protein-coupled receptor Mas (MasR) during infections. Herein, we investigated the role of the Ang-(1-7)/Mas axis in pneumonia caused by P. aeruginosa by using genetic and pharmacological approach and found that Mas receptor-deficient animals developed a more severe form of pneumonia showing higher neutrophilic infiltration into the airways, bacterial load, cytokines, and chemokines production and more severe pulmonary damage. Conversely, treatment of pseudomonas-infected mice with Ang-(1-7) was able to decrease neutrophilic infiltration in airways and lungs, local and systemic levels of pro-inflammatory cytokines and chemokines, and increase the efferocytosis rates, mitigating lung damage/dysfunction caused by infection. Notably, the therapeutic association of Ang-(1-7) with antibiotics improved the survival rates of mice subjected to lethal inoculum of P. aeruginosa, extending the therapeutic window for imipenem. Mechanistically, Ang-(1-7) increased phagocytosis of bacteria by neutrophils and macrophages to accelerate pathogen clearance. Altogether, harnessing the Ang-(1-7) pathway during infection is a potential strategy for the development of host-directed therapies to promote mechanisms of resistance and resilience to pneumonia.

Genetic polymorphisms in external apical root resorption and orthodontic tooth movements: A systematic review.

Objective: External apical root resorption (EARR) is characterized by permanent loss of dental structure at the root apex. This study aimed to systematically review gene polymorphisms associated with EARR in orthodontic patients. Methods: Electronic database searches were performed across several databases. Results: This systematic review included 21 studies. Outcome measures were based on tooth dimensions observed on radiographs obtained before and after treatment. Polymorphisms in the following genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis: purinergic-receptor-P2X, ligand-gated ion channel 7 (P2RX7), caspase-1/interleukin-converting enzyme (CASP1/ICE), caspase-5 (CASP5), IL-1beta (IL1B), IL-1alpha (IL1A), interleukin-1 receptor antagonist gene (IL1RN), tissue non-specific alkaline phosphatase (TNSALP), tumor necrosis factor-alpha (TNFα), tumor necrosis factor receptor superfamily gene member 11a (TNFRSF11A), secreted phosphoprotein 1 (SPP1), tumor necrosis factor receptor superfamily gene member 11b (TNFRSF11B), interleukin 17A (IL17), interleukin 6 (IL6), receptor activator of nuclear factor-kappa B (RANK), osteoprotegerin (OPG), stromal antigen 2 (STAG2), vitamin D receptor (VDR), cytochrome P450 family 24 subfamily A member 1 (CYP24A1), cytochrome P450 family 27 subfamily B (CYP27B1), group-specific component (GC), and interleukin-1 receptor-associated kinases 1 (IRAK1). Conclusions: Almost all studies suggested that IL1 gene is associated with EARR. Additionally, P2RX7 may be an important factor contributing to the etiopathogenesis of EARR. TNFRSF11A, SPP1, IL1RN, IL6, TNFRSF11B, STAG2, VDR, IRAK1, IL-17, CASP1/ICE and CASP5 have been identified in isolated studies. Further observational studies are needed to better explain the association between these genes and EARR.

Abnormal neurovascular control during central and peripheral chemoreceptors stimulation in heart failure patients with preserved ejection fraction.

PURPOSE: Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF. METHODS: Patients aged 55-80 years with symptoms of heart failure, body mass index ≤ 35 kg/m2, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m2, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e' index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF, n = 9). Patients without heart failure with preserved ejection fraction (non-HFpEF, n = 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O2 and 90% N2, with CO2 titrated) and central chemoreceptors stimulation (7% CO2 and 93% O2) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography. RESULTS: During hypoxia, MSNA responses were greater (p < 0.001) and FBF responses were lower in patients with HFpEF (p = 0.006). Likewise, MSNA responses during hypercapnia were higher (p < 0.001) and forearm vascular conductance (FVC) levels were lower (p = 0.030) in patients with HFpEF. CONCLUSIONS: Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction.

ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review.

Ramon syndrome (OMIM #266270) was first described in a patient with cherubism, gingival fibromatosis, epilepsy, intellectual disability, hypertrichosis, and stunted growth. In 2018, Mehawej et al. described a patient with Ramon syndrome in whom a homozygous variant in ELMO2 was identified, suggesting that this gene may be the causative for this syndrome. ELMO2 biallelic pathogenic variants were also described in patients with a primary intraosseous vascular malformation (PIVM; OMIM #606893). These patients presented gingival bleeding and cherubism phenotype. Herein, a patient with gingival hypertrophy, neurodevelopmental delay, and cherubism phenotype with a novel homozygous predicted loss-of-function (LOF) variant in the ELMO2 gene and family recurrence was reported. A surgical approach to treat gingival bleeding and mandible vascular malformation was also described. Furthermore, this study includes a comprehensive literature review of molecular data regarding the ELMO2 gene. All the variants, except one described in the ELMO2, were predicted as LOF, including our patient's variant. There is an overlapping between PIVM, also caused by LOF biallelic variants in the ELMO2 gene, and Ramon syndrome, which can suggest that they are not different entities. However, due to a limited number of cases described with molecular evaluation, it is hard to establish a genotype-phenotype correlation. Our study supports that LOF pathogenic biallelic variants in the ELMO2 gene cause a phenotype that has cherubism and gingival hypertrophy as main characteristics.

Anti-migratory and cytotoxic effect of indole derivative in C6 glioma cells.

Gliomas are among the most common primary malignant brain tumors. Despite advances in cancer treatment, survival is very low, so the discovery of new therapeutic agents is essential. In this context, indole is an important source for the development of new bioactive molecules. A pharmacological screening of ten indole derivatives was carried out to evaluate the cytotoxic capacity against three tumor cell lines. After pharmacological screening, three compounds were selected, based on their high capacity to reduce cell proliferation, and their IC50 values were determined. Compound 9 exhibited the highest cytotoxic activity (IC50 = 0.4 µg/mL) in gliomas (C6 cell line), and were selected for further experiments. C6 cells were treated with compound 9 to evaluate cellular mechanisms such as colony formation and cell migration capacity and morphological alterations. Compound 9 decreased clone formation (0.4 and 0.8 µg/mL), and inhibited migration (0.2-0.8 µg/mL) in C6 cells. Morphological changes in cells treated with the compound 9 were also observed, such as chromatin condensation, and disorganization in cellular stress beams. Indole derivatives had a cytotoxic effect on tumor cells, and compound 9 showed the best anti-proliferative and anti-migratory activity in glioma cells.

Innovation of the protocol for the application of cryolipolysis: Effects and mechanisms of action.

BACKGROUND: In recent years, aesthetic procedures aiming at body remodeling and have grown exponentially. Cryolipolysis (CLL) has stood out as a noninvasive resource that acts directly on the subcutaneous adipose tissue promoting a significant reduction of adipose tissue through of cooling that could lead to the crystallization cytoplasmic lipids, loss of cellular integrity, apoptosis/necrosis of adipocytes, and local inflammation, producing selective loss of adipose tissue. Thus, the objective of the present study was to evaluate the effects of a specific technique of CLL application on the inflammatory reactions of the target tissue in different post-application times. METHODS: This is a randomized, blind clinical study that evaluated the tissue sample of six patients after 45, 60, and 90 days of an innovative protocol for the application of CLL, with samples collected through abdominoplasty surgeries. The samples were evaluated by immunohistochemical analyses of several markers. RESULTS: A significantly greater increase in fibroblasts was observed at 45 days and greater phagocytic action at 60 days. Regarding the apoptosis process, the expression of caspase 3 and cleaved caspase 3 markers varied at different times, with cleaved caspase 3 being higher at 45 and 90 days after CLL application. CONCLUSION: The protocol of the CLL presented in this study was able to induce inflammatory responses in addition to confirming the selective apoptotic action at the different times studied.

In vitro susceptibility to fosfomycin in clinical and environmental extended-spectrum beta-lactamase producing and/or ciprofloxacin-non-susceptible Escherichia coli isolates

ABSTRACT Extended-spectrum beta-lactamase producing and ciprofloxacin-non-susceptible Escherichia coli are clinical and environmental issues. We evaluated the susceptibility profile of fosfomycin in non-susceptible E. coli isolated from urine and the environment. We measured the activity of fosfomycin against 319 and 36 E. coli strains from urine and environmental isolates, respectively, collected from rivers. Fosfomycin resistance profiles were investigated using the minimal inhibitory concentration (MIC), according to the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) guidelines. Antibiotic susceptibility testing revealed that 5% and 6.6% of urine samples were non-susceptible to fosfomycin according to CLSI and EUCAST guidelines, respectively. The fosfomycin MIC50/90 was 0.5/4 mg/L. Of the 36 E. coli isolates from river water, 11.1% and 13,8% were non-susceptible to fosfomycin according to CLSI and EUCAST, respectively (range ≤0.25 ≥512 mg/L). All the isolates with MIC ≥512 mg/L for fosfomycin showed the fosA3 gene. Fosfomycin resistance was more frequent in the environment than in clinical samples.

Outcomes and factors associated with tolerance in infants with non-IgE-mediated cow's milk allergy with gastrointestinal manifestations

Abstract Objectives To evaluate outcomes of oral food challenge (OFC) test to assess tolerance in infants with non-IgE-mediated cow's milk allergy (CMA) with gastrointestinal manifestations and explore clinical data predictive of these outcomes. Methods Single-center retrospective study including infants (age < 12 months) who were referred for CMA between 2000 and 2018 and underwent OFC on follow-up. A univariate logistic regression test was performed to evaluate variables associated with the outcomes of the follow-up OFC test. Results Eighty-two patients were included, 50% were male. Eighteen patients had a positive OFC test (22%). Most patients had presented with hematochezia (77%). The median age of symptom onset was 30 days. Two-thirds of the patients were on appropriate infant formula (extensively hydrolyzed or amino acid-based formula), exclusively or in association with breastfeeding. The median time on an elimination diet before the OFC test was 8 months (Q1 6 - Q3 11 months). All cases with positive follow-up OFC tests (n= 18) had been exposed to cow's milk-based formula before the first clinical manifestation of CMA. Five out of eight cases with Food Protein-Induced Enterocolitis Syndrome (FPIES) had positive OFC tests. Exposure to cow's milk-based formula before diagnosis, a history of other food allergies, hematochezia and diarrhea were predictors of a positive OFC test. Conclusions In infants with non-IgE-mediated CMPA with gastrointestinal manifestations, the use of cow's milk-based formula, a history of other food allergies, and hematochezia and diarrhea upon initial presentation were associated factors for the later achievement of tolerance.

Resources for health literacy among caregivers of prematurely born children: a scoping review / Recursos para el alfabetismo en salud de cuidadores de niños nacidos prematuramente: revisión de alcance / Recursos para o letramento em saúde de cuidadores de crianças nascidas prematuras: revisão de escopo

ABSTRACT Objectives: to map the available evidence on resources used to promote health literacy among caregivers of prematurely born children during outpatient follow-up. Methods: the Joanna Briggs Institute's scope review protocol was utilized. The search encompassed six databases, incorporating studies from 2012 to 2022. Results: the three included publications revealed that the resources employed are: mobile applications, phone calls, individual counseling, videos, educational pamphlets, and group discussions. Implementing an education protocol during the transition home enhances scientifically grounded health promotion rates. Conclusions: there is limited literature addressing the health literacy of these caregivers. The nursing team plays a crucial role in health education and in developing resources applicable to these families.

RESUMEN Objetivos: mapear las evidencias disponibles sobre los recursos utilizados para la promoción del alfabetismo en salud de cuidadores de niños nacidos prematuramente en el seguimiento ambulatorio. Métodos: se utilizó el protocolo de revisión de alcance del Joanna Briggs Institute. La búsqueda se realizó en seis bases de datos, incluyendo estudios entre 2012 y 2022. Resultados: las tres publicaciones incluidas evidenciaron que los recursos utilizados son: aplicaciones para teléfonos móviles, llamadas telefónicas, asesoramiento individual, videos y folletos educativos, y discusiones en grupos. Implementar un protocolo educativo en la transición al hogar aumenta los índices de promoción de la salud respaldada científicamente. Conclusiones: hay poca información en la literatura sobre el alfabetismo en salud de estos cuidadores. El equipo de enfermería juega un papel fundamental en la educación en salud y en la creación de recursos que pueden aplicarse a estas familias.

RESUMO Objetivos: mapear as evidências disponíveis sobre os recursos utilizados para a promoção do letramento em saúde de cuidadores de crianças nascidas prematuras no seguimento ambulatorial. Métodos: utilizou-se o protocolo de revisão de escopo do Joanna Briggs Institute. A busca foi realizada em seis bases de dados, incluindo estudos entre 2012 e 2022. Resultados: as três publicações incluídas evidenciaram que os recursos utilizados são: aplicativos para celulares, ligações telefônicas, aconselhamento individual, vídeos e folhetos educativos e discussões em grupos. Efetivar um protocolo de educação na transição para casa aumenta os índices de promoção da saúde cientificamente embasada. Conclusões: pouco se aborda na literatura sobre o letramento em saúde desses cuidadores. A equipe de enfermagem desempenha um papel fundamental na educação em saúde e na construção de recursos que podem ser aplicados a essas famílias.

Color and surface roughness alterations of bulk-fill resin composites submitted to simulated toothbrushing with whitening dentifrices

Aim: To evaluate the surface roughness and color stability of bulk-fill resin composites after simulated toothbrushing with whitening dentifrices. The radioactive/relative dentin abrasion (RDA) and radioactive/relative enamel abrasion (REA) of dentifrices were also assessed. Methods: Specimens (n=10) of Tetric N Ceram Bulk Fill (TNCB), Filtek One Bulk Fill (FOB) resin composites, and Z100(Control) were prepared using a cylindrical Teflon matrix. Surface roughness (Ra, µm) was assessed by a roughness meter and the color evaluations (ΔEab , ΔE00 , WID ) were performed using a digital spectrophotometer based on the CIELAB system. Three measurements were performed per sample, before and after simulated toothbrushing with 3D Oral-B White Perfection (3DW) and Black is White (BW) dentifrices. The abrasivity (REA and RDA values) of the used dentifrices was also determined by the Hefferren abrasivity test. Results: The Ra values increased significantly in all resin composites after 3DW and BW toothbrushing. The acceptable threshold color varied among resin composites, and TNCB and Z100 presented the highest ΔEab and ΔE00 for BW dentifrice. The 3DW dentifrice was significantly more abrasive than BW dentifrice on enamel and dentin. Conclusions: simulated toothbrushing with tested whitening dentifrices increased the surface roughness at acceptable levels. The Tetric N Ceram Bulk-fill and Z100 composite showed the highest color alteration in BW. 3D White Perfection dentifrice was more abrasive on dentin and enamel than Black is White.

Relationship between permanent upper anterior teeth and anthropometric facial measures in different populations: a narrative review

Aim: The main purpose of this study was to conduct a narrative review investigating the possible relationship between permanent maxillary anterior teeth and anthropometric facial parameters in different populations. Methods: Searches were performed in the PubMed, BVS (Biblioteca Virtual em Saúde) and SciELO databases to identify relevant scientific articles using the following search terms: "maxillary anterior teeth", "facial measurements" and "anthropometry", in such a way that 218 publications were found. After application of inclusion and exclusion criteria, 13 publications remained for full-text reading. Results: All studies involved male and female samples and it was notorious that male measurements were unanimously higher than those obtained in the opposite sex. The age of the analyzed participants ranged from 17 to 60 years; however, a mean age of 18 to 25 years was the most investigated in literature. In addition, facial measurements including the bizygomatic width, interpupillary distance, intercanthal distance, interalar width and intercommissural width have been proposed to help determine the correct size of anterior teeth. Conclusion: It was concluded that despite the limited number of studies, some factors that influence dental and facial dimensions, such as sex and age, can be identified. However, there is no standardization of the facial or dental parameters used in the studies, a fact that makes it difficult to establish a universal ratio for clinical dental practice

Association between childhood trauma and postpartum depression among Brazilian puerperal women / Asociación entre traumas en la infancia y depresión posparto en puérperas brasileñas / Associação entre trauma na infância e depressão pós-parto em puérperas brasileiras

Objective: to evaluate the association between different forms of childhood trauma and postpartum depression in Brazilian puerperal women. Method: this cross-sectional survey included 253 puerperal women who were evaluated using the Edinburgh Postnatal Depression Scale and the Childhood Trauma Questionnaire. Multivariate logistic regression analyses were performed to verify the association of different types of trauma and the co-occurrence of forms of abuse and neglect with postpartum depression. Results: postpartum depression was identified in 93 women (36.8%; 95% Confidence Interval: 30.8-42.7). All forms of childhood trauma assessed (emotional abuse, emotional neglect, physical abuse, physical neglect and sexual abuse) were independently associated with postpartum depression after adjusting for confounding variables. Emotional abuse remained associated with postpartum depression when the co-occurrence of all forms of childhood trauma was analyzed. Conclusion: the results suggest an association between the different forms of childhood trauma and postpartum depression. In this sense, childhood trauma is an indicator for Nursing professionals to screen for risk factors of postpartum depression during obstetric_follow-up.

Objetivo: evaluar la asociación entre diferentes formas de traumas en la infancia y depresión posparto en puérperas brasileñas. Método: en este estudio transversal se incluyó a 253 puérperas que fueron evaluadas con la Edinburgh Postnatal Depression Scale y el Childhood Trauma Questionnaire . Se realizaron análisis de regresión logística multivariados para verificar la asociación de diferentes tipos de trauma y la coocurrencia de formas de abuso y negligencia con la depresión posparto. Resultados: se identificó depresión posparto en 93 mujeres (36,8%; intervalo de confianza del 95%: 30,8-42,7). Todas las formas de traumas en la infancia que se evaluaron (abuso emocional, negligencia emocional, abuso físico, negligencia física y abuso sexual) estuvieron asociadas de manera independiente con la depresión posparto después de ajustar por variables de confusión. El abuso emocional siguió estando asociado con la depresión posparto cuando se analizó la coocurrencia de todas las formas de traumas en la infancia. Conclusión: los resultados sugieren una asociación entre las diferentes formas de traumas en la infancia y la depresión posparto. En este sentido, los traumas en la infancia son un indicador para que los profesionales de Enfermería detecten factores de riesgo para la depresión posparto en los controles obstétricos.

Objetivo: avaliar a associação entre diferentes formas de trauma na infância e depressão pós-parto em puérperas brasileiras. Método: estudo transversal incluiu 253 puérperas que foram avaliadas pela Edinburgh Postnatal Depression Scale e pelo Childhood Trauma Questionnaire . Análises multivariadas de regressão logística foram realizadas para verificar a associação entre diferentes tipos de trauma e a coocorrência de formas de abuso e negligência com depressão pós-parto. Resultados: a depressão pós-parto foi identificada em 93 mulheres (36,8%; Intervalo de Confiança de 95%: 30,8-42,7). Todas as formas de trauma na infância avaliadas (abuso emocional, negligência emocional, abuso físico, negligência física e abuso sexual) foram independentemente associadas à depressão pós-parto após ajuste para variáveis de confusão. O abuso emocional permaneceu associado à depressão pós-parto quando foi analisada a coocorrência de todas as formas de trauma na infância. Conclusão: os resultados sugerem associação entre as diferentes formas de trauma na infância e depressão pós-parto. Nesse sentido, o trauma na infância é um indicador para os profissionais de Enfermagem rastrearem fatores de risco de depressão pós-parto durante o acompanhamento obstétrico.

AI-Driven Colon Cleansing Evaluation in Capsule Endoscopy: A Deep Learning Approach.

Gastroenterology is increasingly moving towards minimally invasive diagnostic modalities. The diagnostic exploration of the colon via capsule endoscopy, both in specific protocols for colon capsule endoscopy and during panendoscopic evaluations, is increasingly regarded as an appropriate first-line diagnostic approach. Adequate colonic preparation is essential for conclusive examinations as, contrary to a conventional colonoscopy, the capsule moves passively in the colon and does not have the capacity to clean debris. Several scales have been developed for the classification of bowel preparation for colon capsule endoscopy. Nevertheless, their applications are limited by suboptimal interobserver agreement. Our group developed a deep learning algorithm for the automatic classification of colonic bowel preparation, according to an easily applicable classification. Our neural network achieved high performance levels, with a sensitivity of 91%, a specificity of 97% and an overall accuracy of 95%. The algorithm achieved a good discriminating capacity, with areas under the curve ranging between 0.92 and 0.97. The development of these algorithms is essential for the widespread adoption of capsule endoscopy for the exploration of the colon, as well as for the adoption of minimally invasive panendoscopy.

Management of Buerger's disease during pregnancy.

Buerger's disease (BD), also known as thromboangiitis obliterans, is a non-atherosclerotic inflammatory disorder of unknown aetiology that affects small-sized and medium-sized vessels of the extremities. It is usually observed in middle-aged adults, especially those who smoke or use tobacco products. This condition is more frequently observed in men, although recent findings indicate an increasing prevalence among women, potentially due to increased cigarette use. The association between pregnancy and BD is rare, with only a few published cases. Previous reports have indicated that BD may worsen during gestation due to the characteristic hypercoagulable state of pregnancy. In addition, it seems to be associated with intrauterine growth restriction secondary to infarction of placental vessels. Careful obstetric management of maternal and fetal status is mandatory in pregnancies complicated with BD. We report a successful case of a pregnancy in a patient with BD treated with low-molecular-weight heparin.

Mosaic trisomy 5 in amniotic fluid in a live fetus with Ebstein anomaly and complete trisomy 5 in chorionic villus sampling.

Complete trisomy 5 is a rare and lethal abnormality. Mosaic trisomy 5 presents in various phenotypes, ranging from a clinically normal fetus to fetuses presenting uterine growth restriction, congenital heart anomalies, multiple dysmorphic features and psychomotor development abnormalities. Although rare, there are cases of a normal psychomotor development regardless of the associated low fetal growth frequently associated with mosaic trisomy 5. This is the first case report to date of a live fetus with complete trisomy 5 reported in chorionic villus sampling and mosaic trisomy 5 in amniotic fluid with a concomitant Ebstein anomaly. Diagnosis of mosaic trisomy 5 represents a challenge for the clinical team and patients, as the information regarding this syndrome is scarce and based mostly on case reports of liveborns, which may introduce a selection bias when counselling the parents.

A 5-Lipoxygenase Inhibitor, Zileuton, Modulates Host Immune Responses and Improves Lung Function in a Model of Severe Acute Respiratory Syndrome (SARS) Induced by Betacoronavirus.

Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4+-, and Treg CD8+-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host's capacity to deal with infection.

Effect of photobiomodulation on the behaviour of mesenchymal stem cells in three-dimensional cultures.

Photobiomodulation (PBM) has been proposed as a strategy to improve the regenerative capacity of human adipose-derived stem cells (hASCs). Yet, this effect has been proved in 2D culture conditions. To analyze the effect of different doses of laser irradiation (660 nm) with different levels of energy (1 J, 2 J and 6 J) on hASCs cultured at 2D and 3D conditions. We used gellan gum spongy-like hydrogels as a biomaterial to 3D culture hASCs. Different doses (1-7 daily irradiations) and energy levels (1-6 J) of PBM were applied, and the metabolic activity, viability, proliferation, and release of ROS and IL-8 was evaluated up to 7 days. In 3D, cell proliferation increased at high energy (6 J) and after a single dose of irradiation, while in 2D, metabolic activity and proliferation was enhanced only after 3 doses and independently of the energy. More than 1 dose was needed to promote ROS secretion both in 2D and 3D culture conditions. Interestingly, a decrease of IL-8 secretion was detected only in 3D after 3-7 daily irradiations. Overall, hASCs response to PBM was not only dependent on the energy level and the number of applied stimuli, but also on the in vitro culture conditions.

GILZ Modulates the Recruitment of Monocytes/Macrophages Endowed with a Resolving Phenotype and Favors Resolution of Escherichia coli Infection.

Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on the migration of mononuclear cells under nonphlogistic conditions and Escherichia coli-evoked peritonitis. TAT-GILZ (a cell-permeable GILZ-fusion protein) injection into the pleural cavity of mice induced monocyte/macrophage influx alongside increased CCL2, IL-10 and TGF-ß levels. TAT-GILZ-recruited macrophages showed a regulatory phenotype, exhibiting increased expression of CD206 and YM1. During the resolving phase of E. coli-induced peritonitis, marked by an increased recruitment of mononuclear cells, lower numbers of these cells and CCL2 levels were found in the peritoneal cavity of GILZ-deficient mice (GILZ-/-) when compared to WT. In addition, GILZ-/- showed higher bacterial loads, lower apoptosis/efferocytosis counts and a lower number of macrophages with pro-resolving phenotypes. TAT-GILZ accelerated resolution of E. coli-evoked neutrophilic inflammation, which was associated with increased peritoneal numbers of monocytes/macrophages, enhanced apoptosis/efferocytosis counts and bacterial clearance through phagocytosis. Taken together, we provided evidence that GILZ modulates macrophage migration with a regulatory phenotype, inducing bacterial clearance and accelerating the resolution of peritonitis induced by E. coli.

TNF/iNOS/NO pathway mediates host susceptibility to endothelial-dependent circulatory failure and death induced by betacoronavirus infection.

Poor disease outcomes and lethality are directly related to endothelial dysfunction in betacoronavirus infections. Here, we investigated the mechanisms underlying the vascular dysfunction caused by the betacoronaviruses MHV-3 and SARS-CoV-2. Wild-type C57BL/6 (WT) and knockout mice for inducible nitric oxide synthase (iNOS-/-) or TNF receptor 1 (TNFR1-/-) were infected with MHV-3, and K18-hACE2 transgenic mice expressing human ACE2 were infected with SARS-CoV-2. Isometric tension was used to evaluate vascular function. Protein expression was determined by immunofluorescence. Tail-cuff plethysmography and Doppler were used to assess blood pressure and flow, respectively. Nitric oxide (NO) was quantified with the DAF probe. ELISA was used to assess cytokine production. Survival curves were estimated using Kaplan-Meier. MHV-3 infection reduced aortic and vena cava contractility, arterial blood pressure, and blood flow, resulting in death. Resistance mesenteric arteries showed increased contractility. The contractility of the aorta was normalized by removing the endothelium, inhibiting iNOS, genetically deleting iNOS, or scavenging NO. In the aorta, iNOS and phospho-NF-kB p65 subunit expression was enhanced, along with basal NO production. TNF production was increased in plasma and vascular tissue. Genetic deletion of TNFR1 prevented vascular changes triggered by MHV-3, and death. Basal NO production and iNOS expression were also increased by SARS-CoV-2. In conclusion, betacoronavirus induces an endothelium-dependent decrease in contractility in macro-arteries and veins, leading to circulatory failure and death via TNF/iNOS/NO. These data highlight the key role of the vascular endothelium and TNF in the pathogenesis and lethality of coronaviruses.