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MGMT promoter methylation status can change in response to several factors, treatment with alkylating therapy being the mechanism more commonly cited in the literature. Some authors have attempted to quantify these alterations, with inconsistent results. This study aims to determine changes in MGMT promoter methylation status by pyrosequencing, which quantitatively yields results, in a cohort of patients reoperated for recurrent glioblastoma and having previously completed the Stupp protocol. Methylation status of the MGMT promoter gene of a total of 24 pairs of glioblastoma preselected tumor samples was retrospectively analyzed using pyrosequencing and depicted as percentages or categories (hypermethylated, intermediate methylation, unmethylated). Matched samples were compared using Wilcoxon signed-rank test, and log-rank test was used to establish a correlation with survival data. The median value of MGMT promoter methylation status declined after adjuvant treatment from 20.35% to 14.25% (p = 0.346). A significant correlation between methylation in primary samples and overall survival (p = 0.05) and progression-free survival (p = 0.024) was found. Intermediate methylation status at recurrence was linked to greater survival after progression, without reaching statistical significance (post-progression survival [PPS]) (p = 0.217). Although treatment with alkylating chemotherapy was a common feature in all patients of our cohort, switching in both directions was observed when MGMT promoter methylation status was analyzed as a continuous variable. These data suggest that the dynamics of epigenetics may be very complex and not entirely explained by clonal selection influenced by temozolomide.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Estudos Retrospectivos , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Metilação de DNA , Antineoplásicos Alquilantes/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Prognóstico , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
This research communication describes the reproductive and productive parameters and somatic cell count (SCC) of primiparous and multiparous cows from specialized dairy Holstein herds in South region of Brazil, and correlates these parameters using test-day records. A total of 24 011 records of animals from 75 producers obtained between 2017 and 2018 were used. The variables analyzed included milk production, SCC, milk fat, protein and urea nitrogen contents and reproductive characteristics (number of services per conception, service period and percentage of pregnant cows). Data were analyzed using multivariate logistic regression and the statistical differentiation between the classes of SCC and milk production. Milk production, SCC, number of services per conception and service period were all higher in multiparous cows. The percentage of pregnant cows was higher when the SCC was less than 200 000 cells/ml and was higher in primiparous cows. There was no adverse effect of milk production on reproductive parameters in high producing cows (>40 kg milk/d), however, the percentage of pregnant cows with this production level was significantly higher in multiparous cows. In conclusion, the milk production level need not affect the reproduction of specialized dairy cows if the animals are kept under adequate environmental conditions.
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Lactação , Leite , Gravidez , Feminino , Bovinos , Animais , Reprodução , Paridade , Contagem de Células/veterináriaRESUMO
The participation of the tether moiety in fullerene recognition of corannulene-based molecular tweezers is known to be an important factor. In the present work, we describe the synthesis of a set of fullerene receptors bearing two corannulene units located at a suitable distance to effectively interact with C60 and C70. The tether comprises a fluorene-like scaffold where an assortment of different groups with variable electronic properties has been grafted. The photophysical and electrochemical properties of all final compounds have been unveiled and correlated to the donor/acceptor (DA) nature of the tether. Despite these strong variations, their affinity toward fullerenes cannot be correlated in any way to simple DA behavior as the main contribution to the interaction correspond to London dispersion forces. We found, however, that the sulfur-derived subfamily is able to adapt better to the fullerene outer surface slightly increasing the charge transfer and electrostatic attractive interactions being the most outstanding example the case of thiophene 4-S with C70 as it is capable of forming a ternary 2:1 inclusion complex in solution with an electronic binding energy that offsets entropy and desolvation penalties typically associated with higher-order inclusion complexes.
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BACKGROUND: Two-thirds of the US population is considered obese and about 8% morbidly obese. Obese patients may present a unique challenge to anesthesia clinicians in airway management. Videolaryngoscopes may provide better airway visualization, which theoretically improves intubation success. However, previous work in morbidly obese patients was limited. We therefore tested the primary hypothesis that the use of McGrath video laryngoscope improves visualization of the vocal cords versus Macintosh direct laryngoscopy (Teleflex, Morrisville, NC) in morbidly obese patients. METHODS: We enrolled 130 surgical patients, aged 18-99 years, with a body mass index ≥40 kg/m and American Society of Anaesthesiologists (ASA) physical status I-III. Patients were randomly allocated 1:1-stratified for patient's body mass index ≥50 kg/m-to McGrath video laryngoscope versus direct laryngoscopy with a Macintosh blade. The study groups were compared on glottis visualization, defined as improved Cormack and Lehane classification, with proportional odds logistic regression model. RESULTS: McGrath video laryngoscope provided significantly better glottis visualization than Macintosh direct laryngoscopy with an estimated odds ratio of 4.6 (95% confidence interval [CI], 2.2-9.8; P < .01). We did not observe any evidence that number of intubation attempts and failed intubations increased or decreased. CONCLUSIONS: McGrath video laryngoscope improves glottis visualization versus Macintosh direct laryngoscopy in morbidly obese patients. Large clinical trials are needed to determine whether improved airway visualization with videolaryngoscopy reduces intubation attempts and failures.
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Manuseio das Vias Aéreas/métodos , Intubação Intratraqueal/métodos , Laringoscópios , Laringoscopia/métodos , Obesidade Mórbida/cirurgia , Cirurgia Vídeoassistida/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Manuseio das Vias Aéreas/instrumentação , Desenho de Equipamento/instrumentação , Desenho de Equipamento/métodos , Feminino , Glote/diagnóstico por imagem , Glote/cirurgia , Humanos , Intubação Intratraqueal/instrumentação , Laringoscopia/instrumentação , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/diagnóstico por imagem , Estudos Prospectivos , Cirurgia Vídeoassistida/instrumentação , Adulto JovemRESUMO
Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.
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Doença de Charcot-Marie-Tooth/patologia , Glicina-tRNA Ligase/fisiologia , Mutação , Receptor trkA/metabolismo , Células Receptoras Sensoriais/patologia , Animais , Células Cultivadas , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Receptor trkA/genética , Células Receptoras Sensoriais/metabolismoRESUMO
CuCl2·2H2O and Cu(ClO4)2·6H2O are able to promote aldol addition of pyridine-2-carboxaldehyde (pyca) with acetone, acetophenone, or cyclohexenone under neutral and mild conditions. The general and simple one-pot procedure for the aldol addition to Cu(II) complexes accesses novel Cu complexes with a large variety of different structural motifs, from which the aldol-addition ligand can be liberated by treatment with NH3. Neutral heteroleptic complexes in which the ligand acts as bidentate, or homoleptic cationic complexes in which the ligand acts as tridentate can be obtained depending on the copper salt used. The key step in these reactions is the coordination of pyca to copper, which increases the electrophilic character of the aldehyde, with Cu(ClO4)2 leading to a higher degree of activation than CuCl2, as predicted by DFT calculations. A regio- and stereoselective double aldol addition of pyca in the reaction of Cu(ClO4)2·6H2O with acetone leads to the formation of a dimer copper complex in which the novel double aldol addition product acts as a pentadentate ligand. A possible mechanism is discussed. The work is supported by extensive crystallographic studies.
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BACKGROUND: Inhibition of the renin-angiotensin-aldosterone pathways reduces blood pressure and proliferation of vascular smooth muscles and may therefore reduce the risk of stroke. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for at least 6 months have fewer postoperative strokes after non-neurological, noncarotid, and noncardiac surgeries than those who do not. METHODS: We considered adults who had noncardiac surgery at the Cleveland Clinic between January 2005 and December 2017. After excluding neurological and carotid surgeries, we assessed the confounder-adjusted association between chronic use of ACEIs/ARBs (during 6 preoperative months) and the incidence of postoperative stroke using logistic regression models. RESULTS: Postoperative strokes occurred in 0.26% (27/10,449) of patients who were chronic ACEI/ARBs users and in 0.18% (112/62,771) of those who were not. There was no significant association between ACEI/ARB use and postoperative stroke, with an adjusted odds ratio of 1.15 (95% confidence interval [CI]: 0.91-1.44; P =0.24). Secondarily, there was no association between exposures to ACEIs and postoperative stroke, versus no such exposure (adjusted odds ratio 0.88, 95% CI: 0.65-1.19; P =0.33). Similarly, there was no association between exposure to ARBs and postoperative stroke, versus no such exposure (adjusted odds ratio 1.05, 95% CI: 0.75-1.48; P =0.75). CONCLUSION: We did not detect an effect of chronic ACEI/ARB use on postoperative strokes in patients who had non-neurological, noncarotid and noncardiac surgery; however, power was extremely limited.
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Inibidores da Enzima Conversora de Angiotensina , Acidente Vascular Cerebral , Adulto , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Estudos de Coortes , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/epidemiologiaRESUMO
Addressing control over molecular machines resulting in variable output modulation by mimicking nature mechanisms is a current hot topic. The exploitation of reversibility in thiol/disulfide motifs in chemical systems flanked by nonplanar corannulene moieties capable to recognize fullerenes is presented herein. Two redox-based machines have been conceived for this purpose: an ON/OFF switch that activates its binding properties upon dimerization and a self-resetting (i.e., with an automated backward process) host that substantially modulates its affinity.
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The spindle pole body (SPB) is the sole site of microtubule nucleation in Saccharomyces cerevisiae; yet, details of its assembly are poorly understood. Integral membrane proteins including Mps2 anchor the soluble core SPB in the nuclear envelope. Adjacent to the core SPB is a membrane-associated SPB substructure known as the half-bridge, where SPB duplication and microtubule nucleation during G1 occurs. We found that the half-bridge component Mps3 is the budding yeast member of the SUN protein family (Sad1-UNC-84 homology) and provide evidence that it interacts with the Mps2 C terminus to tether the half-bridge to the core SPB. Mutants in the Mps3 SUN domain or Mps2 C terminus have SPB duplication and karyogamy defects that are consistent with the aberrant half-bridge structures we observe cytologically. The interaction between the Mps3 SUN domain and Mps2 C terminus is the first biochemical link known to connect the half-bridge with the core SPB. Association with Mps3 also defines a novel function for Mps2 during SPB duplication.
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Proteínas de Ciclo Celular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/fisiologia , Fuso Acromático/metabolismo , Sequência de Aminoácidos , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Centrossomo/metabolismo , Quinase do Ponto de Checagem 2 , Segregação de Cromossomos , Proteínas de Membrana/química , Dados de Sequência Molecular , Mutação , Proteínas Nucleares/química , Proteínas Nucleares/genética , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
Herein, we report molecular tweezers for fullerene recognition based on 2,2'-bipyridine-bearing corannulene motifs. The syn or anti confirmation can be selected simply by Cu(I) coordination/decoordination, thus controlling the fullerene recognition capability of the system on demand and leading to the formation of effective metal-triggered ON/OFF molecular tweezers.
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A critical component of tissue engineering is the ability to functionally replace native tissue stroma. Electrospinning is a technique capable of forming fibrous constructs with a high surface area for increased cell-material interaction and enhanced biocompatibility. However, physical and biological properties of electrospun scaffolds are limited by design controllability on a macroscale. We developed a methodology for generating electrospun scaffolds with defined patterns and topographic features to influence physical properties and biological interactions. Five unique design electrospinning target collectors were fabricated to allow for generation of defined polymeric scaffold patterns including lines, sinusoids, squares, zigzags, and solid. Poly(lactic-co-glycolic) acid was electrospun under identical conditions utilizing these varied targets, and constructs generated were examined as to their physical configuration, mechanical and chemical properties, and their ability to foster vascular smooth muscle cell adhesion and retention at 24 h. Modifying collector designs led to significant differences in fiber target coverage ranging from 300 mm2 for solid (100% of the target area) to 217.8 mm2 for lines (72.6% of the target area). Measured fiber excess, residual open area, and contact angle (hydrophobicity) followed the same trend as fiber target coverage with respect to the collector pattern: lines > sinusoids > squares > zigzags > solid. Similarly, the line design allowed for the greatest cell adhesion and retention (258 ± 31 cells), whereas solid exhibited the lowest (150 ± 15 cells); p < 0.05. There was a strong direct correlation of cell adhesion to construct residual open area (R2 = 0.94), normalized fiber excess (R2 = 0.99), and fiber grammage (R2 = 0.72), with an inverse relationship to fiber target coverage (R2 = 0.94). Our results demonstrate the ability to utilize patterned collectors for modifying macroscopic and microscopic electrospun scaffold features, which directly impact cell adhesion and retention, offering translational utility for designing specific tissue constructs.
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Materiais Biocompatíveis/química , Células Endoteliais da Veia Umbilical Humana/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Adesão Celular , Células Cultivadas , Humanos , Teste de Materiais , Tamanho da PartículaRESUMO
Thyroid hormone (TH) action is essential for hepatic lipid synthesis and oxidation. Analysis of hepatocyte-specific thyroid receptor ß1 (TRß1) knockout mice confirmed a role for TH in stimulating de novo lipogenesis and fatty acid oxidation through its nuclear receptor. Specifically, TRß1 and its principal corepressor NCoR1 in hepatocytes repressed de novo lipogenesis, whereas the TH-mediated induction of lipogenic genes depended on the transcription factor ChREBP. Mice with a hepatocyte-specific deficiency in ChREBP lost TH-mediated stimulation of the lipogenic program, which, in turn, impaired the regulation of fatty acid oxidation. TH regulated ChREBP activation and recruitment to DNA, revealing a mechanism by which TH regulates specific signaling pathways. Regulation of the lipogenic pathway by TH through ChREBP was conserved in hepatocytes derived from human induced pluripotent stem cells. These results demonstrate that TH signaling in the liver acts simultaneously to enhance both lipogenesis and fatty acid oxidation.
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Células-Tronco Pluripotentes Induzidas , Lipogênese , Hormônios Tireóideos , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lipogênese/genética , Fígado/metabolismo , Camundongos , Hormônios Tireóideos/metabolismoRESUMO
OBJECTIVE: Deep brain stimulation (DBS) is an effective therapy for different neurological diseases, despite the lack of comprehension of its mechanism of action. The use of nonhuman primates (NHPs) has been historically important in advancing this field and presents a unique opportunity to uncover the therapeutic mechanisms of DBS, opening the way for optimization of current applications and the development of new ones. To be informative, research using NHPs should make use of appropriate electrode implantation tools. In the present work, the authors report on the feasibility and accuracy of targeting different deep brain regions in NHPs using a commercially available frameless stereotactic system (microTargeting platform). METHODS: Seven NHPs were implanted with DBS electrodes, either in the subthalamic nucleus or in the cerebellar dentate nucleus. A microTargeting platform was designed for each animal and used to guide implantation of the electrode. Imaging studies were acquired preoperatively for each animal, and were subsequently analyzed by two independent evaluators to estimate the electrode placement error (EPE). The interobserver variability was assessed as well. RESULTS: The radial and vector components of the EPE were estimated separately. The magnitude of the vector of EPE was 1.29 ± 0.41 mm and the mean radial EPE was 0.96 ± 0.63 mm. The interobserver variability was considered negligible. CONCLUSIONS: These results reveal the suitability of this commercial system to enhance the surgical insertion of DBS leads in the primate brain, in comparison to rigid traditional frames. Furthermore, our results open up the possibility of performing frameless stereotaxy in primates without the necessity of relying on expensive methods based on intraoperative imaging.
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Encéfalo/cirurgia , Neuronavegação , Algoritmos , Animais , Gânglios da Base/anatomia & histologia , Gânglios da Base/cirurgia , Encéfalo/anatomia & histologia , Estimulação Encefálica Profunda/métodos , Eletrodos Implantados , Estudos de Viabilidade , Feminino , Imageamento Tridimensional , Macaca fascicularis , Macaca mulatta , Imageamento por Ressonância Magnética/métodos , Variações Dependentes do Observador , Núcleo Subtalâmico , Tomografia Computadorizada por Raios XRESUMO
Cognitive aids and evidence-based checklists are frequently utilized in complex situations across many disciplines and sectors. The purpose of such aids is not simply to provide instruction so as to fulfill a task, but rather to ensure that all contingencies related to the emergency are considered and accounted for and that the task at hand is completed fully, despite possible distractions. Furthermore, utilization of a checklist enhances communication to all team members by allowing all stakeholders to know and understand exactly what is occurring, what has been accomplished, and what remains to be done. Here we present a set of evidence-based critical event cognitive aids for neuroanesthesia emergencies developed by the Society for Neuroscience in Anesthesiology and Critical Care (SNACC) Education Committee.
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Anestesiologia/métodos , Lista de Checagem/métodos , Técnicas de Apoio para a Decisão , Tratamento de Emergência/métodos , Neurocirurgia , Cognição , Consenso , Cuidados Críticos , Emergências , Humanos , Neurociências , Sociedades MédicasRESUMO
The non-canonical NF-κB signaling (RelB/p52) pathway drives pro-labor genes in the human placenta, including corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), making this a potential therapeutic target to delay onset of labor. Here we sought to identify small molecule compounds from a pre-existing chemical library of orally active drugs that can inhibit this NF-κB signaling, and in turn, human placental CRH and COX-2 production. We used a cell-based assay coupled with a dual-luciferase reporter system to perform an in vitro screening of a small molecule library of 1,120 compounds for inhibition of the non-canonical NF-κB pathway. Cell toxicity studies and drug efflux transport MRP1 assays were used to further characterize the lead compounds. We have found that 14 drugs have selective inhibitory activity against lymphotoxin beta complex-induced activation of RelB/p52 in HEK293T cells, several of which also inhibited expression of CRH and COX-2 in human term trophoblast. We identified sulfapyridine and propranolol with activity against CRH and COX-2 that deserve further study. These drugs could serve as the basis for development of orally active drugs to affect length of gestation, first in an animal model, and then in clinical trials to prevent preterm birth during human pregnancy.
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Avaliação Pré-Clínica de Medicamentos , Propranolol/isolamento & purificação , Inibidores de Proteínas Quinases/isolamento & purificação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas , Sulfapiridina/isolamento & purificação , Tocolíticos/isolamento & purificação , Células Cultivadas , Hormônio Liberador da Corticotropina/biossíntese , Ciclo-Oxigenase 2/biossíntese , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Placenta , Gravidez , Propranolol/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sulfapiridina/farmacologia , Tocolíticos/farmacologia , Trofoblastos/efeitos dos fármacos , Quinase Induzida por NF-kappaBRESUMO
STUDY OBJECTIVE: Studying postoperative in-hospital mortality is crucial to the understanding of the perioperative process failures and to the implementation of strategies to improve patient outcomes. We intend to classify the causes of perioperative deaths up to 30â¯days after procedures requiring anesthesia and to evaluate the risk factors for early (48â¯h) or late (30â¯day) mortality. DESIGN: Retrospective cohort study. SETTING: A quaternary University Hospital from South Brazil. PATIENTS: The information related to the perioperative care was collected from surgeries performed between January 2012 and December 2011. INTERVENTIONS: None (observational study). MEASUREMENTS: Three anesthesiologists classified the causes of deaths according to the ANZCA (Australian and New Zealand College of Anesthetists) classification, used in the report of Anesthesia-Related Mortality in Australia since 1985, which defines eight death categories. The risk factors for early or late death were analyzed in a regression model. MAIN RESULTS: 11.562 surgeries were performed, with a mortality incidence of 2.75% within 30â¯days (319 deaths). Most deaths were inevitable (50.7%), as they were related to advanced illnesses and would occur regardless of anesthetic or surgical procedures. The second most common cause was related to surgical complications (25%). The death rate having anesthesia as a likely contributor was 1.72:10.000 procedures, and as a potential contributor 7.78:10.000. These deaths occurred significantly earlier (<48â¯h) when compared to deaths from other causes. Transoperative vasopressor, extremes of age and out-of-hour surgery were independent variables associated to early deaths. CONCLUSIONS: The study confirms that postoperative mortality in which anesthesia was involved occurred earlier in the perioperative period. In addition, it was revealed that this involvement of anesthesia as a morbidity contributor shows higher frequency when considering the anesthesiologist perioperative role, and when assessing the mortality in the long term (30â¯days).
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Anestesia/efeitos adversos , Mortalidade Hospitalar , Avaliação de Processos e Resultados em Cuidados de Saúde/estatística & dados numéricos , Complicações Pós-Operatórias/mortalidade , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anestesia/métodos , Brasil/epidemiologia , Causas de Morte , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória/efeitos adversos , Assistência Perioperatória/métodos , Assistência Perioperatória/estatística & dados numéricos , Período Perioperatório/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Vasoconstritores/efeitos adversos , Adulto JovemRESUMO
The mechanism by which dominantly inherited mutations in the housekeeping gene GARS, which encodes glycyl-tRNA synthetase (GlyRS), mediate selective peripheral nerve toxicity resulting in Charcot-Marie-Tooth disease type 2D (CMT2D) is still largely unresolved. The transmembrane receptor protein neuropilin 1 (Nrp1) was recently identified as an aberrant extracellular binding partner of mutant GlyRS. Formation of the Nrp1/mutant GlyRS complex antagonises Nrp1 interaction with one of its main natural ligands, vascular endothelial growth factor-A (VEGF-A), contributing to neurodegeneration. However, reduced extracellular binding of VEGF-A to Nrp1 is known to disrupt post-natal blood vessel development and growth. We therefore analysed the vascular system at early and late symptomatic time points in CMT2D mouse muscles, retina, and sciatic nerve, as well as in embryonic hindbrain. Mutant tissues show no difference in blood vessel diameter, density/growth, and branching from embryonic development to three months, spanning the duration over which numerous sensory and neuromuscular phenotypes manifest. Our findings indicate that mutant GlyRS-mediated disruption of Nrp1/VEGF-A signalling is permissive to maturation and maintenance of the vasculature in CMT2D mice.
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Vasos Sanguíneos/metabolismo , Glicina-tRNA Ligase/genética , Homeostase , Mutação , Neuropilina-1/genética , Animais , Expressão Gênica , Glicina-tRNA Ligase/metabolismo , Humanos , Camundongos , Neurônios Motores , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Neuropilina-1/metabolismo , Especificidade de Órgãos/genética , Permeabilidade , Ligação Proteica , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Hypertension is associated with increased cardiovascular deaths in patients with acromegaly. OBJECTIVE: To evaluate the accuracy of blood pressure (BP) by 24-h ambulatory blood pressure monitoring (ABPM) and office BP measurements to represent the real BP status in acromegalic patients and its relationship with acromegalic activity and echocardiogram parameters. PATIENTS AND METHODS: Cohort of 37 patients with acromegaly in a tertiary endocrine outpatient service. RESULTS: Twenty-three percent of the patients were considered hypertensive by ABPM versus 32% by office BP measurements (Pâ=â0.006). BP obtained from the ABPM was associated with growth hormone, insulin-like growth factor type 1 levels and echocardiogram parameters of acromegalic myocardiopathy. Nondipper behavior presented a significant association with the hormonal profile. CONCLUSION: BP levels assessed by ABPM were associated with acromegalic activity and echocardiogram parameters. ABPM can correctly identify BP levels and their repercussion on acromegalic patients.
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Acromegalia/fisiopatologia , Monitorização Ambulatorial da Pressão Arterial , Hipertensão/fisiopatologia , Acromegalia/complicações , Adulto , Idoso , Pressão Sanguínea , Cardiomiopatias/etiologia , Cardiomiopatias/fisiopatologia , Ecocardiografia , Feminino , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/metabolismo , Humanos , Hipertensão/etiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) "stealth lipids" built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials.
RESUMO
Introdução: Os procedimentos de alta complexidade são caracterizados pelo uso da alta tecnologia. A classificação e a escolha dos equipamentos são um desafio para os profissionais envolvidos. Objetivo: Comparar a classificação das cirurgias abdominais de alta complexidade e a escolha dos equipamentos pela equipe multiprofissional entre duas instituições hospitalares. Método: Pesquisa descritiva, quantitativa, transversal e comparativa, com questionários estruturados sobre a opinião dos cirurgiões, anestesiologistas e enfermeiros. Resultado: A classificação dos procedimentos é semelhante quando levados em conta equipamentos (P<1,0) e estrutura física (P=0,172) diferenciados. Discussão: A classificação dos procedimentos mais complexos tem concordância entre os profissionais comparado à legislação, mesmo não englobando o porte anestésico, tipo de procedimento e condições clínicas na sua classificação; a escolha dos equipamentos é do profissional que os utiliza, incluindo amplas salas de operações, sendo a cirurgia robótica dispensável aos cirurgiões. Conclusão: Há diferenças entre instituições de saúde em relação à escolha, à disponibilidade de equipamentos e aos tipos de cirurgias abdominais.
Introduction: High-complexity procedures are characterized by the use of high-technology. The classification and choice of equipment are challenging for the professionals involved. Objective: To compare the classification of high-complexity abdominal surgeries and the choice of equipment by the multi-professional team between two hospital institutions. Method: Descriptive, quantitative, transversal and comparative research, with structured questionnaires on the opinion of surgeons, anesthesiologists and nurses. Results: The classification of procedures is similar when considering differentiated equipment (P<1.0) and physical structure (P=0.172). Discussion: The classification of more complex procedures is in agreement between professionals when compared to the legislation, even if not encompassing anesthetic dimensions, type of procedure or clinical conditions in their classification; the equipment is chosen by the professional who uses them, including operating rooms, with robotic surgeries being expendable to surgeons. Conclusion: There are differences between the choices made by health institutions, the availability of equipment and the types of abdominal surgeries.
Introducción: procedimientos de alta complejidad se caracterizan por el uso de alta tecnología. La clasificación y elección de los equipos son un desafío para los profesionales. Objetivo: comparar la clasificación de cirugías abdominales de alta complejidad y la elección del equipo por parte del equipo multiprofesional entre dos instituciones hospitalarias. Método: investigación descriptiva, cuantitativa, transversal y comparativa, con cuestionarios estructurados sobre la opinión de cirujanos, anestesiólogos y enfermeras. Resultados: la clasificación de los procedimientos es similar cuando se consideran equipos diferenciados (P<1,0) y estructura física (P=0,172). Discusión: la clasificación de procedimientos más complejos está de acuerdo entre los profesionales en comparación con la legislación, incluso si no abarca dimensiones anestésicas, tipo de procedimiento o condiciones clínicas en su clasificación; el equipo es elegido por el profesional que los utiliza, incluidos los quirófanos, y las cirugías robóticas son dispensables para los cirujanos. Conclusión: hay diferencias entre las elecciones realizadas por las instituciones de salud, la disponibilidad de equipos y los tipos de cirugías abdominales.