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1.
Article in English | MEDLINE | ID: mdl-38959416

ABSTRACT

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI) are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor NDI, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in inter-organ communication in diverse pathological processes. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of alveolar macrophage (AM) markers, CD11b, CD11c, and CD206, and ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction inspired oxygen (FiO2) therapy (HO2, ≥30%) had increased levels of AM-derived EV-ASC compared with infants on lower FiO2 (LO2, <30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain crosstalk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

2.
Angiogenesis ; 2024 May 06.
Article in English | MEDLINE | ID: mdl-38709389

ABSTRACT

BACKGROUND: Retinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and is a leading cause of severe vision impairment in children worldwide. Activations of the inflammasome cascade and microglia have been implicated in playing a role in the development of both ROP and BPD. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly. Utilizing mouse models of both oxygen-induced retinopathy (OIR) and BPD, this study was designed to test the hypothesis that hyperoxia induces ASC speck formation, which leads to microglial activation and retinopathy, and that inhibition of ASC speck formation by a humanized monoclonal antibody, IC100, directed against ASC, will ameliorate microglial activation and abnormal retinal vascular formation. METHODS: We first tested ASC speck formation in the retina of ASC-citrine reporter mice expressing ASC fusion protein with a C-terminal citrine (fluorescent GFP isoform) using a BPD model that causes both lung and eye injury by exposing newborn mice to room air (RA) or 85% O2 from postnatal day (P) 1 to P14. The retinas were dissected on P14 and retinal flat mounts were used to detect vascular endothelium with AF-594-conjugated isolectin B4 (IB4) and citrine-tagged ASC specks. To assess the effects of IC100 on an OIR model, newborn ASC citrine reporter mice and wildtype mice (C57BL/6 J) were exposed to RA from P1 to P6, then 75% O2 from P7 to P11, and then to RA from P12 to P18. At P12 mice were randomized to the following groups: RA with placebo PBS (RA-PBS), O2 with PBS (O2-PBS), O2 + IC100 intravitreal injection (O2-IC100-IVT), and O2 + IC100 intraperitoneal injection (O2-IC100-IP). Retinal vascularization was evaluated by flat mount staining with IB4. Microglial activation was detected by immunofluorescence staining for allograft inflammatory factor 1 (AIF-1) and CD206. Retinal structure was analyzed on H&E-stained sections, and function was analyzed by pattern electroretinography (PERG). RNA-sequencing (RNA-seq) of the retinas was performed to determine the transcriptional effects of IC100 treatment in OIR. RESULTS: ASC specks were significantly increased in the retinas by hyperoxia exposure and colocalized with the abnormal vasculature in both BPD and OIR models, and this was associated with increased microglial activation. Treatment with IC100-IVT or IC100-IP significantly reduced vaso-obliteration and intravitreal neovascularization. IC100-IVT treatment also reduced retinal microglial activation, restored retinal structure, and improved retinal function. RNA-seq showed that IC100 treatment corrected the induction of genes associated with angiogenesis, leukocyte migration, and VEGF signaling caused by O2. IC100 also corrected the suppression of genes associated with cell junction assembly, neuron projection, and neuron recognition caused by O2. CONCLUSION: These data demonstrate the crucial role of ASC in the pathogenesis of OIR and the efficacy of a humanized therapeutic anti-ASC antibody in treating OIR mice. Thus, this anti-ASC antibody may potentially be considered in diseases associated with oxygen stresses and retinopathy, such as ROP.

3.
Int J Med Inform ; 189: 105499, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38815318

ABSTRACT

INTRODUCTION: Chronic kidney disease is a worldwide public health problem, with a high prevalence of patients on dialysis. mHealth technologies can greatly support the treatment and monitoring of these patients. Thus, this study aimed to evaluate the spontaneous use of the application (app) Renal Health, a previously available technology, for patients on hemodialysis and validate content to support patients undergoing peritoneal dialysis. METHODS: The first stage consisted of evaluating the spontaneous use of the app, and the second stage consisted of methodological research for the development, evaluation, and improvement of a technological instrument for use in clinical practice as a support for patients undergoing peritoneal dialysis (PD). The association between categorical variables was performed using the chi-square test, adopting a significance level of 5%. RESULTS: The app was accessed by 753 users and of these, 34 % accessed the hemodialysis section. Most accesses were in the state of São Paulo/Brazil and performed by women. The records of biochemical tests did not vary according to gender and age group (p > 0.05). The developed and validated PD section enables section control, allowing the user to manage their sessions. The analysis of the technology by the specialists showed good results for the global content validity index (CVI) regarding objectives (CVI = 0.95), structure (CVI = 0.97), and relevance (CVI = 1.0). CONCLUSION: It is concluded that the hemodialysis section of the Renal Health app aroused the interest of the population and that the developed peritoneal dialysis section was validated by specialists.

4.
Food Microbiol ; 121: 104531, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38637091

ABSTRACT

The present study aimed to assess the occurrence and counts of Staphylococcus aureus in Brazilian artisanal cheeses (BAC) produced in five regions of Brazil: Coalho and Manteiga (Northeast region); Colonial and Serrano (South); Caipira (Central-West); Marajó (North); and Minas Artisanal cheeses, from Araxá, Campos das Vertentes, Cerrado, Serro and Canastra microregions (Southeast). The resistance to chlorine-based sanitizers, ability to attach to stainless steel surfaces, and antibiogram profile of a large set of S. aureus strains (n = 585) were assessed. Further, a total of 42 isolates were evaluated for the presence of enterotoxigenic genes (sea, seb, sec, sed, see, seg, sei, sej, and ser) and submitted to typing using pulsed-field gel electrophoresis (PFGE). BAC presented high counts of S. aureus (3.4-6.4 log CFU/g), varying from 25 to 62.5%. From the S. aureus strains (n = 585) assessed, 16% could resist 200 ppm of sodium hypochlorite, whereas 87.6% produced strong ability to attach to stainless steel surfaces, corroborating with S. aureus ability to persist and spread in the environment. Furthermore, the relatively high frequency (80.5%) of multidrug-resistant S. aureus and the presence of enterotoxin genes in 92.6% of the strains is of utmost attention. It reveals the lurking threat of SFP that can survive when conditions are favorable. The presence of enterotoxigenic and antimicrobial-resistant strains of S. aureus in cheese constitutes a potential risk to public health. This result calls for better control of cheese contamination sources, and taking hygienic measures is necessary for food safety. More attention should be paid to animal welfare and hygiene practices in some dairy farms during manufacturing to enhance the microbiological quality of traditional cheese products.


Subject(s)
Cheese , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Animals , Staphylococcus aureus/genetics , Cheese/microbiology , Brazil , Food Microbiology , Stainless Steel/analysis , Enterotoxins/genetics , Milk/microbiology
5.
Clin Perinatol ; 51(1): 21-43, 2024 03.
Article in English | MEDLINE | ID: mdl-38325942

ABSTRACT

Neonatal pulmonary hypertension (PH) is a devastating disorder of the pulmonary vasculature characterized by elevated pulmonary vascular resistance and mean pulmonary arterial pressure. Occurring predominantly because of maldevelopment or maladaptation of the pulmonary vasculature, PH in neonates is associated with suboptimal short-term and long-term outcomes because its pathobiology is unclear in most circumstances, and it responds poorly to conventional pulmonary vasodilators. Understanding the pathogenesis and pathophysiology of neonatal PH can lead to novel strategies and precise therapies. The review is designed to achieve this goal by summarizing pulmonary vascular development and the pathogenesis and pathophysiology of PH associated with maladaptation, bronchopulmonary dysplasia, and congenital diaphragmatic hernia based on evidence predominantly from preclinical studies. We also discuss the pros and cons of and provide future directions for preclinical studies in neonatal PH.


Subject(s)
Bronchopulmonary Dysplasia , Hernias, Diaphragmatic, Congenital , Hypertension, Pulmonary , Infant, Newborn , Humans , Lung , Vascular Resistance , Hernias, Diaphragmatic, Congenital/therapy
6.
J Neuroinflammation ; 21(1): 16, 2024 Jan 10.
Article in English | MEDLINE | ID: mdl-38200558

ABSTRACT

BACKGROUND: Preterm birth is often associated with chorioamnionitis and leads to increased risk of neurodevelopmental disorders, such as autism. Preterm birth can lead to cerebellar underdevelopment, but the mechanisms of disrupted cerebellar development in preterm infants are not well understood. The cerebellum is consistently affected in people with autism spectrum disorders, showing reduction of Purkinje cells, decreased cerebellar grey matter, and altered connectivity. METHODS: Preterm rhesus macaque fetuses were exposed to intra-amniotic LPS (1 mg, E. coli O55:B5) at 127 days (80%) gestation and delivered by c-section 5 days after injections. Maternal and fetal plasma were sampled for cytokine measurements. Chorio-decidua was analyzed for immune cell populations by flow cytometry. Fetal cerebellum was sampled for histology and molecular analysis by single-nuclei RNA-sequencing (snRNA-seq) on a 10× chromium platform. snRNA-seq data were analyzed for differences in cell populations, cell-type specific gene expression, and inferred cellular communications. RESULTS: We leveraged snRNA-seq of the cerebellum in a clinically relevant rhesus macaque model of chorioamnionitis and preterm birth, to show that chorioamnionitis leads to Purkinje cell loss and disrupted maturation of granule cells and oligodendrocytes in the fetal cerebellum at late gestation. Purkinje cell loss is accompanied by decreased sonic hedgehog signaling from Purkinje cells to granule cells, which show an accelerated maturation, and to oligodendrocytes, which show accelerated maturation from pre-oligodendrocytes into myelinating oligodendrocytes. CONCLUSION: These findings suggest a role of chorioamnionitis on disrupted cerebellar maturation associated with preterm birth and on the pathogenesis of neurodevelopmental disorders among preterm infants.


Subject(s)
Chorioamnionitis , Premature Birth , Infant, Newborn , Female , Infant , Animals , Humans , Pregnancy , Hedgehog Proteins , Macaca mulatta , Escherichia coli , Infant, Premature , Cerebellum , RNA, Small Nuclear
7.
Sci Rep ; 13(1): 19538, 2023 11 09.
Article in English | MEDLINE | ID: mdl-37945645

ABSTRACT

Neonatal hyperoxia induces long-term systemic vascular stiffness and cardiovascular remodeling, but the mechanisms are unclear. Chemokine receptor 7 (CXCR7) represents a key regulator of vascular homeostasis and repair by modulating TGF-ß1 signaling. This study investigated whether pharmacological CXCR7 agonism prevents neonatal hyperoxia-induced systemic vascular stiffness and cardiac dysfunction in juvenile rats. Newborn Sprague Dawley rat pups assigned to room air or hyperoxia (85% oxygen), received CXCR7 agonist, TC14012 or placebo for 3 weeks. These rat pups were maintained in room air until 6 weeks when aortic pulse wave velocity doppler, cardiac echocardiography, aortic and left ventricular (LV) fibrosis were assessed. Neonatal hyperoxia induced systemic vascular stiffness and cardiac dysfunction in 6-week-old rats. This was associated with decreased aortic and LV CXCR7 expression. Early treatment with TC14012, partially protected against neonatal hyperoxia-induced systemic vascular stiffness and improved LV dysfunction and fibrosis in juvenile rats by decreasing TGF-ß1 expression. In vitro, hyperoxia-exposed human umbilical arterial endothelial cells and coronary artery endothelial cells had increased TGF-ß1 levels. However, treatment with TC14012 significantly reduced the TGF-ß1 levels. These results suggest that dysregulation of endothelial CXCR7 signaling may contribute to neonatal hyperoxia-induced systemic vascular stiffness and cardiac dysfunction.


Subject(s)
Hyperoxia , Ventricular Dysfunction, Left , Animals , Humans , Rats , Animals, Newborn , Endothelial Cells , Fibrosis , Hyperoxia/complications , Pulse Wave Analysis , Rats, Sprague-Dawley , Transforming Growth Factor beta1 , Vascular Remodeling
8.
J Neuroinflammation ; 20(1): 205, 2023 Sep 07.
Article in English | MEDLINE | ID: mdl-37679766

ABSTRACT

BACKGROUND: Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury. METHODS: Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes. RESULTS: Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO. CONCLUSIONS: GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.


Subject(s)
Brain Injuries , Hyperoxia , Animals , Humans , Infant, Newborn , Mice , Animals, Newborn , Gene Knockout Techniques , Hippocampus , Hyperoxia/complications , Infant, Premature , Mice, Knockout , Phosphate-Binding Proteins , Pore Forming Cytotoxic Proteins
9.
Res Sq ; 2023 Jun 15.
Article in English | MEDLINE | ID: mdl-37398125

ABSTRACT

Background: Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found inhibition of GSDMD activation attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury. Methods: Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal day 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1), a marker of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes. Results: Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure failed to increase either AIF1+ or TUNEL+ cell numbers, nor decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air- exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, and core development pathways hypoxia-induced factor 1, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO. Conclusion: GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

10.
Bioinformatics ; 39(7)2023 07 01.
Article in English | MEDLINE | ID: mdl-37471595

ABSTRACT

MOTIVATION: The resemble between relatives computed from pedigree and genomic data is an important resource for geneticists and ecologists, who are interested in understanding how genes influence phenotypic variation, fitness adaptation, and population dynamics. RESULTS: The AGHmatrix software is an R package focused on the construction of pedigree (A matrix) and/or molecular markers (G matrix), with the possibility of building a combined matrix of pedigree corrected by molecular markers (H matrix). Designed to estimate the relationships for any ploidy level, the software also includes auxiliary functions related to filtering molecular markers, and checks pedigree errors in large data sets. After computing the relationship matrices, results from the AGHmatrix can be used in different contexts, including on prediction of (genomic) estimated breeding values and genome-wide association studies. AVAILABILITY AND IMPLEMENTATION: AGHmatrix v2.1.0 is available under GPL-3 license in CRAN at https://cran.r-project.org/web/packages/AGHmatrix/index.html and also in GitHub at https://github.com/rramadeu/AGHmatrix. It has a comprehensive tutorial, and it follows with real data examples.


Subject(s)
Genome-Wide Association Study , Software , Genomics , Ploidies , Pedigree
11.
J Cardiothorac Vasc Anesth ; 37(10): 1938-1945, 2023 10.
Article in English | MEDLINE | ID: mdl-37453808

ABSTRACT

OBJECTIVES: The aim of this analysis was to compare the effect of extubating in the operating room (OR) versus and the intensive care unit (ICU) among patients undergoing coronary artery bypass grafting (CABG). DESIGN: A retrospective cohort analysis. SETTING: Ten cardiac referral hospitals in Latin America; participants of the São Paulo Registry of Cardiovascular Surgery II (REPLICCAR II). PARTICIPANTS: The database included a total of 4,015 patients who underwent primary and isolated CABG surgery and were ≥18 years old, of whom 205 patients were extubated in the OR. INTERVENTIONS: The analysis was made after a propensity score matching (PSM) adjustment in the population sample of patients extubated in the OR and ICU by the following variables: sex, age, body mass index, smoking, type of surgery, chronic obstructive pulmonary disease, preoperative atrial fibrillation, cardiopulmonary bypass time, preoperative creatinine, and preoperative left ventricular ejection fraction. MEASUREMENTS AND MAIN RESULTS: This study focused on the analysis of the ICU and hospital length of stay, need for reintubation, morbidity, and mortality. After PSM, 402 patients were analyzed. Both groups had similar baseline characteristics, such as age (p = 0.132), sex (p = 1.00), and estimated risk of prolonged ventilation (>24 hours, p = 0.168); however, the median ventilation time was significantly shorter in the group extubated in the OR compared to the ICU group (5.67 hours v 17.55 hours, p < 0.001). The group of patients extubated in the ICU had a longer postoperative stay (7.54 ± 3.40 days v 6.41 ± 2.91 days, p < 0.001) and longer total hospitalization time (11.49 ± 5.70 days v 10.36 ± 5.72, p = 0.013) compared to those extubated in the OR. The authors did not observe a significant difference in the need for reintubation, morbidity, or mortality rates among the evaluated groups. CONCLUSIONS: In the REPLICCAR II database, extubation performed in the OR was associated with a reduced length of postoperative and total hospital stays compared to extubation in the ICU.


Subject(s)
Airway Extubation , Operating Rooms , Humans , Adolescent , Length of Stay , Retrospective Studies , Stroke Volume , Brazil , Ventricular Function, Left , Coronary Artery Bypass/adverse effects
12.
Front Pediatr ; 11: 1144230, 2023.
Article in English | MEDLINE | ID: mdl-37287630

ABSTRACT

Vertical transmission of SARS-CoV-2 from mother to fetus is widely accepted. Whereas most infected neonates present with mild symptoms or are asymptomatic, respiratory distress syndrome (RDS) and abnormal lung images are significantly more frequent in COVID-19 positive neonates than in non-infected newborns. Fatality is rare and discordant meta-analyses of case reports and series relating perinatal maternal COVID-19 status to neonatal disease severity complicate their extrapolation as prognostic indicators. A larger database of detailed case reports from more extreme cases will be required to establish therapeutic guidelines and allow informed decision making. Here we report an unusual case of a 28 weeks' gestation infant with perinatally acquired SARS-CoV-2, who developed severe protracted respiratory failure. Despite intensive care from birth with first line anti-viral and anti-inflammatory therapy, respiratory failure persisted, and death ensued at 5 months. Lung histopathology showed severe diffuse bronchopneumonia, and heart and lung immunohistochemistry confirmed macrophage infiltration, platelet activation and neutrophil extracellular trap formation consistent with late multisystem inflammation. To our knowledge, this is the first report of SARS CoV-2 pulmonary hyperinflammation in a preterm newborn with fatal outcome.

13.
Reprod Sci ; 30(11): 3222-3234, 2023 11.
Article in English | MEDLINE | ID: mdl-37264260

ABSTRACT

Despite widespread use, dosing regimens for antenatal corticosteroid (ACS) therapy are poorly unoptimized. ACS therapy exerts a programming effect on fetal development, which may be associated with an increased risk of cardiovascular disease. Having demonstrated that low-dose steroid therapy is an efficacious means of maturing the preterm lung, we hypothesized that a low-dose steroid exposure would exert fewer adverse functional and transcriptional changes on the fetal heart. We tested this hypothesis using low-dose steroid therapy (10 mg delivered to the ewe over 36 h via constant infusion) and compared cardiac effects with those of a higher dose treatment (30 mg delivered to the ewe over 24 h by intramuscular injection; simulating currently employed clinical ACS regimens). Fetal cardiac function was assessed by ultrasound on the day of ACS treatment initiation. Transcriptomic analyses were performed on fetal myocardial tissue. Relative to saline control, fetuses in the higher-dose clinical treatment group had significantly lower ratios between early diastolic ventricular filling and ventricular filling during atrial systole, and showed the differential expression of myocardial hypertrophy-associated transcripts including ßMHC, GADD45γ, and PPARγ. The long-term implications of these changes remain unstudied. Irrespective, optimizing ACS dosing regimens to maximize respiratory benefit while minimizing adverse effects on key organ systems, such as the heart, offers a means of improving the acute and long-term outcomes associated with this important obstetric therapy.


Subject(s)
Betamethasone , Heart Diseases , Sheep , Female , Pregnancy , Animals , Fetal Organ Maturity , Adrenal Cortex Hormones , Steroids , Fetal Heart/diagnostic imaging , Heart Diseases/drug therapy
14.
J Pediatr Orthop ; 43(7): e583-e590, 2023 Aug 01.
Article in English | MEDLINE | ID: mdl-37254037

ABSTRACT

PURPOSE: The aim of this study was to analyze the results of single-event multilevel surgery (SEMLS) in cerebral palsy (CP) based on objective gait outcomes and self-reported evaluations. METHODS: In total, 258 patients with spastic diplegic CP, GMFCS I-III, who underwent SEMLS and with preoperative and postoperative gait analyses, were included in the SEMLS group (SG). The same database was used to compose the control group (CG) formed of 88 subjects who had performed at least 2 gait analyses and did not undergo surgical intervention between tests. Demographic data, Gait Deviation Index (GDI), and a self-reported questionnaire were analyzed, and results were compared between groups. RESULTS: The GDI decreased from 59.6 to 57.9 in the CG and increased from 51.3 to 58.4 in the SG ( P <0.001). There was no change in patients' walking ability in the CG. The number of patients who walk community distances increased after SEMLS in the group that had a GDI improvement >5 points (from 12.3% to 24.7%, P =0.008) and in patients GMFCS I and II (from 9.2% to 20.4%, P =0.028). According to patient and parental responses on satisfaction, the most significant improvements were reported in self-esteem, mobility, body image, and independence. In total, 51.1% of the patients were extremely satisfied or satisfied, while 3.9% were unsatisfied or extremely unsatisfied with the treatment results. Of the parents surveyed, 60.1% were extremely satisfied or satisfied, whereas just 5.0% were unsatisfied or extremely unsatisfied. CONCLUSIONS: In the studied group, an improvement in outdoor walking for community distances after SEMLS, as reported in questionnaires, was observed only when GDI increase was >5 points and in GMFCS I and II. LEVEL OF EVIDENCE: Level III.


Subject(s)
Cerebral Palsy , Humans , Self Report , Cerebral Palsy/surgery , Patient Satisfaction , Treatment Outcome , Gait/physiology , Retrospective Studies
15.
J Phys Chem C Nanomater Interfaces ; 127(16): 7674-7682, 2023 Apr 27.
Article in English | MEDLINE | ID: mdl-37144042

ABSTRACT

The pertechnetate ion TcVIIO4 - is a nuclear fission product whose major issue is the high mobility in the environment. Experimentally, it is well known that Fe3O4 can reduce TcVIIO4 - to TcIV species and retain such products quickly and completely, but the exact nature of the redox process and products is not completely understood. Therefore, we investigated the chemistry of TcVIIO4 - and TcIV species at the Fe3O4(001) surface through a hybrid DFT functional (HSE06) method. We studied a possible initiation step of the TcVII reduction process. The interaction of the TcVIIO4 - ion with the magnetite surface leads to the formation of a reduced TcVI species without any change in the Tc coordination sphere through an electron transfer that is favored by the magnetite surfaces with a higher FeII content. Furthermore, we explored various model structures for the immobilized TcIV final products. TcIV can be incorporated into a subsurface octahedral site or adsorbed on the surface in the form of TcIVO2·xH2O chains. We propose and discuss three model structures for the adsorbed TcIVO2·2H2O chains in terms of relative energies and simulated EXAFS spectra. Our results suggest that the periodicity of the Fe3O4(001) surface matches that of the TcO2·2H2O chains. The EXAFS analysis suggests that, in experiments, TcO2·xH2O chains were probably not formed as an inner-shell adsorption complex with the Fe3O4(001) surface.

16.
Sci Rep ; 13(1): 143, 2023 01 04.
Article in English | MEDLINE | ID: mdl-36599874

ABSTRACT

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants.


Subject(s)
Bronchopulmonary Dysplasia , Gasdermins , Retinopathy of Prematurity , Animals , Mice , Animals, Newborn , Bronchopulmonary Dysplasia/genetics , Bronchopulmonary Dysplasia/metabolism , Disease Models, Animal , Hyperoxia/complications , Hyperoxia/metabolism , Hypertension, Pulmonary/pathology , Lung/pathology , Phosphate-Binding Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism , Retinopathy of Prematurity/genetics , Retinopathy of Prematurity/complications , Gasdermins/genetics , Gasdermins/metabolism
17.
Front Cell Dev Biol ; 11: 1245747, 2023.
Article in English | MEDLINE | ID: mdl-38481391

ABSTRACT

Background: Intra-amniotic inflammation (IAI) is associated with increased risk of preterm birth and bronchopulmonary dysplasia (BPD), but the mechanisms by which IAI leads to preterm birth and BPD are poorly understood, and there are no effective therapies for preterm birth and BPD. The transcription factor c-Myc regulates various biological processes like cell growth, apoptosis, and inflammation. We hypothesized that c-Myc modulates inflammation at the maternal-fetal interface, and neonatal lung remodeling. The objectives of our study were 1) to determine the kinetics of c-Myc in the placenta, fetal membranes and neonatal lungs exposed to IAI, and 2) to determine the role of c-Myc in modulating inflammation at the maternal-fetal interface, and neonatal lung remodeling induced by IAI. Methods: Pregnant Sprague-Dawley rats were randomized into three groups: 1) Intra-amniotic saline injections only (control), 2) Intra-amniotic lipopolysaccharide (LPS) injections only, and 3) Intra-amniotic LPS injections with c-Myc inhibitor 10058-F4. c-Myc expression, markers of inflammation, angiogenesis, immunohistochemistry, and transcriptomic analyses were performed on placenta and fetal membranes, and neonatal lungs to determine kinetics of c-Myc expression in response to IAI, and effects of prenatal systemic c-Myc inhibition on lung remodeling at postnatal day 14. Results: c-Myc was upregulated in the placenta, fetal membranes, and neonatal lungs exposed to IAI. IAI caused neutrophil infiltration and neutrophil extracellular trap (NET) formation in the placenta and fetal membranes, and neonatal lung remodeling with pulmonary hypertension consistent with a BPD phenotype. Prenatal inhibition of c-Myc with 10058-F4 in IAI decreased neutrophil infiltration and NET formation, and improved neonatal lung remodeling induced by LPS, with improved alveolarization, increased angiogenesis, and decreased pulmonary vascular remodeling. Discussion: In a rat model of IAI, c-Myc regulates neutrophil recruitment and NET formation in the placenta and fetal membranes. c-Myc also participates in neonatal lung remodeling induced by IAI. Further studies are needed to investigate c-Myc as a potential therapeutic target for IAI and IAI-associated BPD.

18.
An Acad Bras Cienc ; 94(4): e20211080, 2022.
Article in English | MEDLINE | ID: mdl-36287484

ABSTRACT

Slope stability is one of the biggest concerns for mining practices and to consider the rock mass response over blasting is fundamental to achieve pit geometry. This study consists in developing a methodology which connects the dynamic behavior of one lithological domain to blast designs applied at a copper mine. The central element of this study was the construction of vibration attenuation and seed wave model which, in conjunction with geomechanical properties, has allowed the characterization of this particular rock mass and the vibration attenuation phenomena. The new blast design was developed from the model simulations, once it was possible to recognize which parameters of the blast design affect most of the damage induced by blasting. To guarantee model representativeness, two blast tests were conducted: one with the usual blast design and another using the new one. Furthermore, holes were drilled behind the blasts, which were inspected before and after each blast to compare the produced fracturing with the fracturing expected by the model. The results obtained in these blast tests show a strong correlation between the modeled and the real. The modeling proved to be a useful tool providing manners to stablish a blast design, which generates stable walls.


Subject(s)
Copper , Vibration , Explosions , Mining
19.
Rev. Fac. Med. Hum ; 22(4): 669-681, octubre-diciembre 2022.
Article in English, Spanish | LILACS-Express | LILACS | ID: biblio-1401380

ABSTRACT

Las intoxicaciones en la población pediátrica son una gran parte de las causas de atención en los servicios de urgencias, pero así mismo representan en muchos casos eventos fatídicos, en nuestro país. La exposición a un tóxico o veneno y sus efectos adversos se pueden convertir en emergencias médicas de gran magnitud, por lo que muchos autores las consideran como: "Trauma múltiple de origen químico". Es por esto que el manejo de un paciente pediátrico intoxicado tiene un enfoque único debido al desafío diagnóstico que representa. La atención oportuna y sistematizada de un paciente pediátrico en el contexto de una intoxicación puede representar el éxito de la atención oportuna, valoración correcta y de un adecuado proceso de atención. El objetivo de este trabajo es presentar un enfoque general para el paciente pediátrico intoxicado en cuanto al manejo inicial, el abordaje, y los datos clínicos que nos puedan orientar en el servicio de urgencias ante un paciente pediátrico intoxicado.


Intoxications in the pediatric population account for a significant portion of the causes of care in emergency services, but they are also fatal in many cases in our country. Exposure to a toxic or poison and its adverse effects can become medical emergencies of great magnitude, which is why many authors consider them "multiple traumas of chemical origin." This is why the management of an intoxicated pediatric patient has a unique approach due to the diagnostic challenge that it represents. Timely and systematized care of a pediatric patient in the context of poisoning can represent the success of timely care, correct assessment, and an adequate care process. The objective of this work is to present a general approach for the intoxicated pediatric patient regarding the initial management, the approach, and the clinical data that can guide us in the emergency department when faced with an intoxicated pediatric patient.

20.
J Card Surg ; 37(11): 3492-3506, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36116058

ABSTRACT

OBJECTIVE: The objective of this study is to evaluate protamine sulfate effects on graft's blood flow by comparing transit-time flow measurement (TTFM) values before and after protamine administration. METHODS: This is an observational study with data collected between years 2018 and 2020. Immediate graft patency was evaluated using TTFM. Only patients with TTFM parameters registered before and after protamine infusion were included. The main three parameters studied were:  mean graft flow  (MGF),  pulsatility index (PI), and  diastolic flow (DF). In the first analysis, all conduits were evaluated regardless of the surgical technique used. In a second analysis, on-pump and off-pump groups were compared. Evaluated grafts were left internal thoracic artery, saphenous vein graft (SVG), radial artery, and right internal thoracic artery. Since SVG was numerically the most used graft, an exclusive analysis was created. RESULTS: Our study included 575 patients, resulting in a total of 1686 grafts, mean 2.93 grafts/patient. Off-pump surgery was performed in 158 patients. Before protamine infusion, inadequate TTFM parameters were observed in 3.8% of grafts. Overall, after protamine administration, MGF decreased in all grafts, but its reduction was not statistically significant. PI values increased in the SVG and DF values reduced in LIMA grafts. SVG group analysis showed that after protamine PI values were higher in OM1 and RCA. DF values increased in RCA. The comparison between off and on-pump surgeries, showed that in off-pump cases TTFM measures did not present statistically significant differences. CONCLUSION: Significant variations were observed in TTFM values before and after protamine administration. Although different, those values remained within the normal reference ranges. We recommend that flow measurement should be performed before protamine infusion.


Subject(s)
Coronary Artery Bypass , Mammary Arteries , Blood Flow Velocity , Coronary Artery Bypass/methods , Coronary Circulation/physiology , Humans , Mammary Arteries/transplantation , Protamines , Vascular Patency
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