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BACKGROUND AND AIMS: Predicting personalized risk for adverse events following percutaneous coronary intervention (PCI) remains critical in weighing treatment options, employing risk mitigation strategies, and enhancing shared decision-making. This study aimed to employ machine learning models using pre-procedural variables to accurately predict common post-PCI complications. METHODS: A group of 66 adults underwent a semiquantitative survey assessing a preferred list of outcomes and model display. The machine learning cohort included 107 793 patients undergoing PCI procedures performed at 48 hospitals in Michigan between 1 April 2018 and 31 December 2021 in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) registry separated into training and validation cohorts. External validation was conducted in the Cardiac Care Outcomes Assessment Program database of 56 583 procedures in 33 hospitals in Washington. RESULTS: Overall rate of in-hospital mortality was 1.85% (n = 1999), acute kidney injury 2.51% (n = 2519), new-onset dialysis 0.44% (n = 462), stroke 0.41% (n = 447), major bleeding 0.89% (n = 942), and transfusion 2.41% (n = 2592). The model demonstrated robust discrimination and calibration for mortality {area under the receiver-operating characteristic curve [AUC]: 0.930 [95% confidence interval (CI) 0.920-0.940]}, acute kidney injury [AUC: 0.893 (95% CI 0.883-0.903)], dialysis [AUC: 0.951 (95% CI 0.939-0.964)], stroke [AUC: 0.751 (95%CI 0.714-0.787)], transfusion [AUC: 0.917 (95% CI 0.907-0.925)], and major bleeding [AUC: 0.887 (95% CI 0.870-0.905)]. Similar discrimination was noted in the external validation population. Survey subjects preferred a comprehensive list of individually reported post-procedure outcomes. CONCLUSIONS: Using common pre-procedural risk factors, the BMC2 machine learning models accurately predict post-PCI outcomes. Utilizing patient feedback, the BMC2 models employ a patient-centred tool to clearly display risks to patients and providers (https://shiny.bmc2.org/pci-prediction/). Enhanced risk prediction prior to PCI could help inform treatment selection and shared decision-making discussions.
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Injúria Renal Aguda , Intervenção Coronária Percutânea , Acidente Vascular Cerebral , Humanos , Intervenção Coronária Percutânea/métodos , Preferência do Paciente , Resultado do Tratamento , Diálise Renal , Fatores de Risco , Hemorragia/etiologia , Aprendizado de Máquina , Acidente Vascular Cerebral/etiologia , Injúria Renal Aguda/etiologia , Medição de Risco/métodosRESUMO
Postnatal lung development results in an increasingly functional organ prepared for gas exchange and pathogenic challenges. It is achieved through cellular differentiation and migration. Changes in the tissue architecture during this development process are well-documented and increasing cellular diversity associated with it are reported in recent years. Despite recent progress, transcriptomic and molecular pathways associated with human postnatal lung development are yet to be fully understood. In this study, we investigated gene expression patterns associated with healthy pediatric lung development in four major enriched cell populations (epithelial, endothelial, and nonendothelial mesenchymal cells, along with lung leukocytes) from 1-day-old to 8-yr-old organ donors with no known lung disease. For analysis, we considered the donors in four age groups [less than 30 days old neonates, 30 days to < 1 yr old infants, toddlers (1 to < 2 yr), and children 2 yr and older] and assessed differentially expressed genes (DEG). We found increasing age-associated transcriptional changes in all four major cell types in pediatric lung. Transition from neonate to infant stage showed highest number of DEG compared with the number of DEG found during infant to toddler- or toddler to older children-transitions. Profiles of differential gene expression and further pathway enrichment analyses indicate functional epithelial cell maturation and increased capability of antigen presentation and chemokine-mediated communication. Our study provides a comprehensive reference of gene expression patterns during healthy pediatric lung development that will be useful in identifying and understanding aberrant gene expression patterns associated with early life respiratory diseases.NEW & NOTEWORTHY This study presents postnatal transcriptomic changes in major cell populations in human lung, namely endothelial, epithelial, mesenchymal cells, and leukocytes. Although human postnatal lung development continues through early adulthood, our results demonstrate that greatest transcriptional changes occur in first few months of life during neonate to infant transition. These early transcriptional changes in lung parenchyma are particularly notable for functional maturation and activation of alveolar type II cell genes.
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Pulmão , Transcriptoma , Humanos , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Recém-Nascido , Lactente , Criança , Pré-Escolar , Masculino , Feminino , Análise de Sequência de RNA/métodos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Perfilação da Expressão GênicaRESUMO
INTRODUCTION: Following ileocolic resection (ICR), the clinical importance and prognostic implications of histologic activity on biopsies in Crohn's disease (CD) patients with endoscopic remission are not well defined. The aim of this study was to determine if histologic activity in patients with endoscopic remission is associated with future risk of endoscopic and/or radiologic postoperative recurrence (POR). METHODS: In this multicenter retrospective cohort study, adult patients with CD who underwent ICR between 2009 and 2020 with endoscopic biopsies of ileal mucosa from Rutgeerts i0 on index colonoscopy were included. The composite rate of endoscopic (Rutgeerts score ≥i2b) and radiologic (active inflammation on imaging) recurrence was compared in patients with and without histologic activity using a Kaplan-Meier survival analysis. A multivariable Cox proportional hazard regression model including clinically relevant risk factors of POR, postoperative biologic prophylaxis, and histology activity was designed. RESULTS: A total of 113 patients with i0 disease on index colonoscopy after ICR were included. Of these, 42% had histologic activity. Time to POR was significantly earlier in the histologically active versus normal group ( P = 0.04). After adjusting for clinical risk factors of POR, histologic activity (HR 2.37, 95% CI 1.17-4.79; P = 0.02) and active smoking (HR 2.54, 95% CI 1.02-6.33; P = 0.05) were independently associated with subsequent composite POR risk. DISCUSSION: In patients with postoperative CD, histologic activity despite complete endoscopic remission is associated with composite, endoscopic, and radiographic recurrence. Further understanding of the role of histologic activity in patients with Rutgeerts i0 disease may provide a novel target to reduce disease recurrence in this population.
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Throughout evolution, plants have developed strategies to confront and alleviate the detrimental impacts of abiotic stresses on their growth and development. The combat strategies involve intricate molecular networks and a spectrum of early and late stress-responsive pathways. Plant peptides, consisting of fewer than 100 amino acid residues, are at the forefront of these responses, serving as pivotal signalling molecules. These peptides, with roles similar to phytohormones, intricately regulate plant growth, development and facilitate essential cell-to-cell communications. Numerous studies underscore the significant role of these small peptides in coordinating diverse signalling events triggered by environmental challenges. Originating from the proteolytic processing of larger protein precursors or directly translated from small open reading frames, including microRNA (miRNA) encoded peptides from primary miRNA, these peptides exert their biological functions through binding with membrane-embedded receptor-like kinases. This interaction initiates downstream cellular signalling cascades, often involving major phytohormones or reactive oxygen species-mediated mechanisms. Despite these advances, the precise modes of action for numerous other small peptides remain to be fully elucidated. In this review, we delve into the dynamics of stress physiology, mainly focusing on the roles of major small signalling peptides, shedding light on their significance in the face of changing environmental conditions.
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Reguladores de Crescimento de Plantas , Plantas , Reguladores de Crescimento de Plantas/metabolismo , Plantas/metabolismo , Desenvolvimento Vegetal , Peptídeos/metabolismo , Estresse Fisiológico/genéticaRESUMO
A full-field swept-source optical coherence tomography (FF-SS-OCT) for in vivo murine retinal imaging is demonstrated. The on-axis FF-SS-OCT system was built in a Mach-Zehnder interferometer configuration employing a tunable laser source with an adjustable sweep rate and sweep range in conjunction with a fast 2D-CMOS camera. A large field retinal (coherent) illumination was accomplished using an imaging interface comprised of a short-focal length imaging lens and a contact lens. The magnification between the camera and retina (spatial sampling) was appropriately chosen to record the microscopic structural features of the retina in the image. A pupil stop was employed in the detection path to reject unwanted backscattering from the mouse eye and other sources and limit aberrations distorting the retinal images. In vivo mouse retinal imaging was performed at a sweep rate of 150â Hz to acquire volumes unaffected by the system vibrations, which predominated at lower frequencies. Operating the FF-SS-OCT at this speed yielded an effective axial scan rate of 20â million A-scans/s and a field of view of 820 × 410â µm (24.12° × 12.06°). High-quality retinal B-scans and enface images of the retina were obtained with the SS-FF-OCT, revealing all major retinal layers and vascular plexuses.
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Retina , Tomografia de Coerência Óptica , Tomografia de Coerência Óptica/métodos , Animais , Camundongos , Retina/diagnóstico por imagemRESUMO
INTRODUCTION: Texas consistently accounts for approximately 10% of annual national births, the second highest of all US states. This temporal study aimed to evaluate incidences of neonatal surgical conditions across Texas and to delineate regional pediatric surgeon accessibility. METHODS: The Texas Birth Defects Registry was queried from 1999 to 2018, based on 11 well-established regions. Nine disorders (30,476 patients) were identified as being within the operative scope of pediatric surgeons: biliary atresia (BA), pyloric stenosis (PS), Hirschsprung's disease, stenosis/atresia of large intestine/rectum/anus, stenosis/atresia of small intestine, tracheoesophageal fistula/esophageal atresia, gastroschisis, omphalocele, and congenital diaphragmatic hernia. Annual and regional incidences were compared (/10,000 births). Statewide pediatric surgeons were identified through the American Pediatric Surgical Association directory. Regional incidences of neonatal disorder per surgeon were evaluated from 2010 to 2018 as a surrogate for provider disparity. RESULTS: PS demonstrated the highest incidence (14.405/10,000), while BA had the lowest (0.707/10,000). Overall, incidences of PS and BA decreased significantly, while incidences of Hirschsprung's disease and small intestine increased. Other diagnoses remained stable. Regions 2 (48.24/10,000) and 11 (47.79/10,000) had the highest incidence of neonatal conditions; Region 6 had the lowest (34.68/10,000). Three rural regions (#2, 4, 9) lacked pediatric surgeons from 2010 to 2018. Of regions with at least one surgeon, historically underserved regions (#10, 11) along the Texas-Mexico border consistently had the highest defect per surgeon rates. CONCLUSIONS: There are temporal and regional differences in incidences of neonatal conditions treated by pediatric surgeons across Texas. Improving access to neonatal care is a complex issue that necessitates collaborative efforts between state legislatures, health systems, and providers.
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Atresia Biliar , Atresia Esofágica , Gastrosquise , Doença de Hirschsprung , Estenose Pilórica Hipertrófica , Recém-Nascido , Criança , Humanos , Texas/epidemiologia , Constrição Patológica , Atresia Esofágica/cirurgiaRESUMO
INTRODUCTION: Activated hepatic stellate cells (HSCs) are the primary effector cells in hepatic fibrosis, over depositing extracellular matrix (ECM) proteins. Our previous work found oridonin analog CYD0682 attenuates proliferation, Transforming Growth Factor ß (TGFß)-induced signaling, and ECM production in immortalized HSCs. The underlying mechanism behind these reductions is unclear. The Signal Transduction and Activator of Transcription 3 (STAT3) pathway plays a central role in HSC activation and has been found to be overexpressed in models of hepatic injury. In this study, we will examine the effect of CYD0682 on STAT3 signaling. METHODS: Immortalized human (LX-2) and rat (HSC-T6) HSC lines were treated with CYD0682 or Tanespimycin (17-AAG) with or without TGF-ß. Nuclear and cytosolic proteins were extracted. Protein expression was analyzed with Western blot. DNA binding activity was assessed with STAT3 DNA Binding ELISA. Cell viability was assessed with Alamar blue assay. RESULTS: CYD0682 treatment inhibited STAT3 phosphorylation at tyrosine 705 in a dose-dependent manner in LX-2 and HSC-T6 cells. STAT3 DNA binding activity and STAT3 regulated protein c-myc were significantly decreased by CYD0682. Notably, TGFß-induced STAT3 phosphorylation and ECM protein expression were inhibited by CYD0682. STAT3 is reported to be a Heat Shock Protein 90 (HSP90) client protein. Notably, CYD0682 attenuated the expression of endogenous STAT3 and other HSP90 client proteins FAK, IKKα, AKT and CDK9. HSP90 specific inhibitor 17-AAG suppressed endogenous and TGFß-induced STAT3 phosphorylation and ECM protein production. CONCLUSIONS: CYD0682 attenuates endogenous and TGFß-induced STAT3 activation and ECM production via an HSP90 dependent pathway in HSCs. Further study of this pathway may present new targets for therapeutic intervention in hepatic fibrosis.
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Benzoquinonas , Diterpenos do Tipo Caurano , Proteínas de Choque Térmico HSP90 , Células Estreladas do Fígado , Fator de Transcrição STAT3 , Transdução de Sinais , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fator de Transcrição STAT3/metabolismo , Humanos , Ratos , Animais , Diterpenos do Tipo Caurano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Benzoquinonas/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular , Fosforilação/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologiaRESUMO
INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation. METHODS: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age. RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD. HIGHLIGHTS: This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex-specific metabolic differences, similar to human study cohorts. The early-onset 5XFAD mouse model primarily alters brain metabolites while the late-onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum.
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Doença de Alzheimer , Encéfalo , Modelos Animais de Doenças , Metabolômica , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Encéfalo/metabolismo , Camundongos , Masculino , Feminino , Metaboloma , Caracteres Sexuais , Humanos , Apolipoproteína E4/genéticaRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. HIGHLIGHTS: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.
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Apolipoproteína E4 , Apolipoproteínas E , Acoplamento Neurovascular , Tomografia por Emissão de Pósitrons , Animais , Feminino , Masculino , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Glucose/metabolismo , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
INTRODUCTION: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. RESULTS: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DISCUSSION: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. HIGHLIGHTS: A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.
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Doença de Alzheimer , Modelos Animais de Doenças , Predisposição Genética para Doença , Camundongos Transgênicos , Doença de Alzheimer/genética , Animais , Camundongos , Humanos , Fatores de Risco , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Masculino , Encéfalo/patologia , Encéfalo/metabolismo , FemininoRESUMO
INTRODUCTION: MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer's disease (LOAD) more accurately. METHODS: We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aß). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD). We assessed disease-relevant outcome measures in plasma and brain including neuroinflammation, Aß, neurodegeneration, neuroimaging, and multi-omics. RESULTS: By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain Aß42, increased plasma neurofilament light chain (NfL), and altered gene/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen-based cognitive tasks were observed. DISCUSSION: The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles. HIGHLIGHTS: By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease-relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age-dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen-based cognitive tasks.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Proteínas tau , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Camundongos , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Camundongos Transgênicos , Encéfalo/patologia , Encéfalo/metabolismo , Sinapses/patologia , Sinapses/metabolismo , Masculino , Feminino , HumanosRESUMO
BACKGROUND: In recent years, there have anecdotal reports of intra-arterial thrombolysis (IAT) for the treatment of spinal cord ischemia (SCI) with encouraging results. We describe a patient with acute cervical SCI who underwent IAT with Tenecteplase at our institution. CASE PRESENTATION: A 20-year-old man presented to the emergency department with a 12-hour history of progressive onset upper and lower extremity numbness, weakness, and urinary incontinence after sustaining a fall. MRI of cervical spine demonstrated T2 and STIR hyperintensity in the ventral aspect of the spinal cord spanning the C3, C4, and C5 levels suggestive of SCI. He demonstrated progression of neurologic deficits to C4 ASIA B spinal cord injury with complete loss of motor function, diminished sensation, and absent rectal tone. Emergent angiography was performed with prominent anterior spinal supply via the left ascending cervical artery. A total of 30 mg of Tenecteplase was administered intra-arterially in the bilateral vertebral arteries, bilateral ascending cervical arteries, and bilateral inferior thyroid arteries. Two-week post-intervention neurologic examination demonstrated improvement in injury level and severity. The patient was C6 ASIA C SCI, with 2/5 strength in the distal upper and lower extremities and improved sensation. CONCLUSION: IAT with Tenecteplase may be a feasible option for the treatment of acute spinal cord ischemia in carefully selected patients.
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Medula Cervical , Isquemia do Cordão Espinal , Masculino , Humanos , Adulto Jovem , Adulto , Tenecteplase , Medula Espinal , Isquemia do Cordão Espinal/diagnóstico por imagem , Isquemia do Cordão Espinal/tratamento farmacológico , Isquemia do Cordão Espinal/etiologia , Vértebras Cervicais/diagnóstico por imagem , Isquemia , Terapia TrombolíticaRESUMO
Tryptophan indole lyase (TIL; [E.C. 4.1.99.1]) is a bacterial pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes reversible ß-elimination of indole from L-tryptophan. The mechanism of elimination of indole from L-tryptophan starts with the formation of an external aldimine of the substrate and PLP, followed by deprotonation of the α-CH of the substrate, forming a resonance-stabilized quinonoid intermediate. Proton transfer to C3 of the indole ring and carbon-carbon bond cleavage of the quinonoid intermediate provide indole and aminoacrylate bound to PLP, which then releases indole, followed by iminopyruvate. We have now determined the X-ray crystal structures of TIL complexes with (3S)-dioxindolyl-l-alanine, an inhibitor, and with substrates L-tryptophan, 7-aza-L-tryptophan, and S-ethyl-l-cysteine (SEC) in the presence of benzimidazole (BZI), an isostere of the product indole. These structures show a mixture of gem-diamine, external aldimine, quinonoid, and aminoacrylate intermediates, in both open and closed active site conformations. In the closed conformations of L-tryptophan, (3S)-dioxindolyl-l-alanine, and 7-aza-L-tryptophan complexes, hydrogen bonds form between Asp-133 with N1 of the ligand heterocyclic ring and NE2 of His-458 in the small domain of TIL. This hydrogen bond also forms in the BZI complex with the aminoacrylate intermediates formed from both L-tryptophan and SEC. The closed quinonoid complex of 7-aza-L-tryptophan shows that the azaindole ring in the closed conformation is bent out of plane of the Cß-C3 bond by about 40°, putting it in a geometry that leads toward the transition-state geometry. Thus, both conformational dynamics and substrate activation play critical roles in the reaction mechanism of the TIL.
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Peracetylation of the methanolic extract of Benincasa hispida led to the isolation of a compound with a peracetylated hex-4-en-3-one backbone. Mechanistic insights revealed that the isolated compound is an outcome of the chemical transformation of a α-dicarbonyl compound.
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Cerebrospinal fluid (CSF) leak can cause spontaneous intracranial hypotension (SIH) which can lead to neurologic symptoms, such as orthostatic headache. Over time, imaging techniques for detecting and localizing CSF leaks have improved. These techniques include computed tomography (CT) myelography, dynamic CT myelography, cone-beam CT, MRI, MR myelography, and digital subtraction myelography (DSM). DSM provides the highest sensitivity for identifying leak sites and has comparable radiation exposure to CT myelography. The introduction of the lateral decubitus DSM has proven invaluable in localizing leaks when other imaging tests have been inconclusive.
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Vazamento de Líquido Cefalorraquidiano , Hipotensão Intracraniana , Humanos , Vazamento de Líquido Cefalorraquidiano/diagnóstico por imagem , Vazamento de Líquido Cefalorraquidiano/complicações , Hipotensão Intracraniana/diagnóstico por imagem , Mielografia/métodos , Tomografia Computadorizada por Raios X/métodos , Imageamento por Ressonância Magnética/métodosRESUMO
The methanolic extract of Amorphophallus paeoniifolius was peracetylated to obtain an unusual peracetylated γ-lactone backbone. Structure elucidation revealed that this compound is an outcome of the chemical transformation of heptonic acid γ-lactone.
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Parsonage-Turner Syndrome, or neuralgic amyotrophy, is an acute-onset upper limb and shoulder girdle palsy that can occur in a post-viral, post-surgical or idiopathic setting. There have also been some reported cases of the syndrome occurring following vaccinations. The pathophysiology of neuralgic amyotrophy is not completely understood and many of the commonly used diagnostic imaging modalities we use to try and diagnose this syndrome are inaccurate and misleading. We present the case of a 40-year-old gentleman who presented with acute onset burning pain and fasciculations in his right upper extremity following vaccination with the second dose of the Pfizer-BioNTech COVID-19 vaccine. His symptoms progressed to weakness in isolated muscle groups with electromyographic evidence of decreased nerve conduction. MRI of the cervical spine demonstrated multilevel central and foraminal stenosis, suggesting a diagnosis of cervical radiculopathy. The patient underwent a C4-5/C5-6 and C6-7 laminoforaminotomy and tolerated the procedure well. Post-operatively, the patient has experienced gradual symptom improvement with residual right triceps and pectoralis muscle weakness as well as paresthesias of the right elbow and forearm. Parsonage-Turner Syndrome is a brachial plexus palsy that can affect one or multiple branches of the brachial plexus. It causes acute-onset pain and weakness, and the diagnosis can be difficult to make with the commonly used diagnostic imaging methods. We reviewed other case reports about neuralgic amyotrophy following vaccinations as well as the current literature on more accurate diagnostic imaging modalities that may help our diagnosis and understanding of the pathophysiology of this condition.
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Neurite do Plexo Braquial , COVID-19 , Radiculopatia , Masculino , Humanos , Adulto , Neurite do Plexo Braquial/diagnóstico por imagem , Neurite do Plexo Braquial/etiologia , Radiculopatia/diagnóstico por imagem , Radiculopatia/etiologia , Vacinas contra COVID-19/efeitos adversos , Vacina BNT162 , ParalisiaRESUMO
BACKGROUND: Incidence of sternal dehiscence, wound infection, and mortality are prevalent following sternotomy. Bone wax is widely used over the sternal edges for augmenting hemostasis. This study evaluated the clinical equivalence of Truwax® (Healthium Medtech Limited, Bengaluru, India) with Ethicon® (Johnson & Johnson, New Brunswick, New Jersey, United States) bone wax for sternal wound hemostasis in subjects undergoing surgical procedures by sternotomy. METHODS: The primary endpoint of this prospective (May 2022-April 2023), parallel-group, two-arm, randomized, single-blind, multicenter study was to evaluate the proportion of subjects having sternal dehiscence within 26 weeks of median sternotomy closure. Secondary endpoints assessed the average time to hemostasis on sternum sides, bone wax properties, number of dressing changes, sternal bone instability (clinically/chest radiography), pain, perioperative/postoperative complications, blood and blood products used, duration of intensive care unit (ICU)/hospital stay, reoperations, time taken to return back to work and normal day-to-day activities, subject satisfaction and quality of life (QoL), and adverse events. A probability of <0.05 was considered significant. RESULTS: No incidence of sternal dehiscence or postoperative complications was witnessed. Time to hemostasis, bone wax properties, number of dressing changes, sternal stability, pain, blood and blood products used, duration of ICU/hospital stay, reoperations, time taken to return back to normal day-to-day activities and to work, and subject satisfaction and QoL were comparable between Truwax® and Ethicon® bone wax groups. CONCLUSION: Truwax® and Ethicon® bone waxes are safe and effective and provide sternal wound hemostasis in people undergoing sternotomy.
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Artonin E (AA2) and artobiloxanthone (AA3) were extracted and purified from the acetone extract of the stem bark of Artocarpus altilis (Parkinson) Fosberg. Preliminary investigations of both candidates revealed promising cytotoxic effects in oral cancer cells. Moreover, these candidates modulated the expression of pivotal proteins linked to oral cancer progression, eliciting apoptosis through caspase-3 and caspase-9 activation. Additionally, our results showed that AA2 and AA3 suppressed several proteins linked with oral cancer, such as Bcl-2, COX-2, VEGF, and MMP-9, and modulated the cell signaling pathways, such as Akt/mTOR and STAT-3, offering valuable insights into the underlying mechanism of action of these compounds. These findings were robustly validated in silico using molecular docking and molecular dynamic simulations. To our knowledge, these findings have not been previously reported, and the continued exploration and development of these natural products may offer a potential avenue for the effective management of this malignancy.