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Low-valent cobalt complexes can promote intramolecular (3 + 2) cycloadditions of alkyne-tethered cyclopropenes to provide bicyclic systems containing highly substituted cyclopentadienyl moieties with electronically diverse functional groups. The adducts can be easily transformed into new types of CpRh(III) and CpIr(III) complexes, which show catalytic activity in several relevant transformations. Preliminary computational (DFT) and experimental studies provide relevant information on the mechanistic peculiarities of the cobalt-catalyzed process and allow us to rationalize its advantages over the homologous rhodium-promoted reaction.
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Rationale Evaluating approaches to reduce treatment burden is a research priority among people with CF (pwCF) on highly effective modulators including elexacaftor/tezacaftor/ivacaftor (ETI). Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods SIMPLIFY participants ≥12 years old on ETI and comprising a subgroup using both HS and DA at study entry were randomized to the HS or DA trial, and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY versus a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth and percent predicted forced expiratory volume in one second (ppFEV1) at study entry. Results There were 43 participants who discontinued both therapies by the end of SIMPLIFY and 63 who remained on both, with overall average ppFEV1 at study entry 96.7% and average duration of follow up from beginning of the first trial to completion of the second trial 3.9 months, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued versus remained on both therapies (difference: 0.22% Off-On, 95% CI: -1.60,2.03). Changes in LCI2.5, patient reported, and safety outcomes were also comparable. Patient reported treatment burden, as measured by a CFQ-R subscale, significantly decreased in those discontinuing both therapies. Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.
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BACKGROUND: A personalized approach to assessing medication knowledge may identify opportunities for education to support self-management of cystic fibrosis (CF). This project describes the development, scoring, and preliminary validity of the Personalized CF Medication Questionnaire (PCF-MQ), designed to assess knowledge of prescribed CF medication purpose, administration, and dose and frequency. METHODS: Participants completed the PCF-MQ, the Knowledge of Disease Management (KDM-CF), and the Cystic Fibrosis-Medication Beliefs Questionnaire (CF-MBQ). Prescribed regimens were abstracted from medical records. Eligibility criteria were age 12 years and older, diagnosed with CF, and prescribed a CF medication. Statistical analyses were conducted using R software. Spearman rho was used to test correlations between measures. RESULTS: Sixty people with CF (pwCF) were enrolled; three people reported a regimen that substantially deviated from the medical record and were excluded from the analyses. The mean (SD) age was 20.2 (7.3) years, 54 % were female, and 74 % had a FEV1pp ≥70 %. The mean (SD) PCF-MQ total score was 77.8 (12.3) and knowledge scores ranged from a low of 58.3 for levalbuterol to 100 for ivacaftor. The PCF-MQ total score correlated with the KDM total score and subscales (Spearman Rho= 0.32-0.59, p < 0.05) and was not correlated with the CF-MBQ subscales (p > 0.05)). CONCLUSIONS: The PCF-MQ was correlated with another measure of general CF knowledge, but not health beliefs; because of the small sample size, this should be considered preliminary evidence of its validity. Advantages over existing CF knowledge measures include its practicality for use to help assess pwCF's knowledge about their prescribed regimen.
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Allylic sulfone-embedded cyclobutenes have been prepared in one pot from alkynes. The carbocycle and the alkenyl sulfone moieties were installed through consecutive bis(triflyl)cyclobutenylation of a triple bond and tetra-n-butylammonium fluoride (TBAF)-assisted hydrodesulfonylation of an allylic bis(sulfone). It is noteworthy that 1,1-bis(triflyl)ethylene acts as a CF3SO2CHâCH2 source for the first time.
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Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of mortality in patients with cystic fibrosis (pwCF), necessitating treatment with antibiotics. Pf is a filamentous bacteriophage produced by Pa and acts as a structural element in Pa biofilms. Pf presence has been associated with antibiotic resistance and poor outcomes in pwCF, although the underlying mechanisms are unclear. We have investigated how Pf and sputum biopolymers impede antibiotic diffusion using pwCF sputum and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf in sputum reduces the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.
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Antibacterianos , Pseudomonas aeruginosa , Esputo , Electricidad Estática , Esputo/microbiología , Antibacterianos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/virología , Humanos , Fibrosis Quística/metabolismo , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Tobramicina/farmacología , Difusión , Biopelículas/efectos de los fármacos , BacteriófagosRESUMEN
Microscopic colitis is a form of chronic and recurrent inflammatory bowel disease characterized by non-bloody, watery diarrhea, macroscopically normal colonic mucosa, and characteristic histopathological findings. Some drugs have been described as triggers of colonic inflammation in predisposed individuals, while others may exacerbate microscopic colitis that evolves on its own. We present the case of a patient diagnosed with active microscopic colitis in relation to taking fluoxetine at high doses.
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Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of morbidity and mortality in patients with cystic fibrosis, necessitating treatment with inhaled antibiotics. Pf phage is a filamentous bacteriophage produced by Pa that has been reported to act as a structural element in Pa biofilms. Pf presence has been associated with resistance to antibiotics and poor outcomes in cystic fibrosis, though the underlying mechanisms are unclear. Here, we have investigated how Pf phages and sputum biopolymers impede antibiotic diffusion using human sputum samples and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf phages and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf phages in sputum reduce the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf phages and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.
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A 68-year-old male presented to the Emergency Department with a one-month history of intermittent epigastrium pain. Laboratory tests revealed leukocytosis and elevated lipase (4129 UI/l), with normal liver function, so he was admitted for its first episode of acute pancreatitis. Abdominal ultrasound showed liver steatosis, without cholelithiasis or bile duct dilatation. A thoraco-abdominal computed tomography was performed, revealing a pedunculated gastric polyp in lesser curvature measuring 64x38mm with no evidence of metastatic disease. Gastroscopy was performed, showing a 7-cm pedunculated gastric polyp prolapsed through the pylorus into the duodenum. The polyp was moved into the stomach, and a fragmented resection of the polyp was carried out with a hot snare. Histopathologic evaluation was compatible with hyperplastic polyp with low-grade dysplasia. The patient had a favourable evolution with no complications after the procedure.
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BACKGROUND: The inovirus Pf4 is a lysogenic bacteriophage of Pseudomonas aeruginosa (Pa). People with Cystic Fibrosis (pwCF) experience chronic airway infection with Pa and a significant proportion have high numbers of Pf4 in their airway secretions. Given the known severe damage in the airways of Pa-infected pwCF, we hypothesized a high Pf4 burden can affect airway healing and inflammatory responses. In the airway, basal epithelial cells (BCs) are a multipotent stem cell population critical to epithelium homeostasis and repair. We sought to investigate the transcriptional responses of BCs under conditions that emulate infection with Pa and exposure to high Pf4 burden. METHODS: Primary BCs isolated from pwCF and wild-type (WT) donors were cultured in vitro and exposed to Pf4 or bacterial Lipopolysaccharide (LPS) followed by transcriptomic and functional assays. RESULTS: We found that BCs internalized Pf4 and this elicits a strong antiviral response as well as neutrophil chemokine production. Further, we found that BCs that take up Pf4 demonstrate defective migration and proliferation. CONCLUSIONS: Our findings are highly suggestive of Pf4 playing a role in the pathogenicity of Pa in the airways. These findings provide additional evidence for the ability of inoviruses to interact with mammalian cells and disrupt cell function.
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Fibrosis Quística , Infecciones por Pseudomonas , Animales , Humanos , Sistema Respiratorio , Células Epiteliales , Epitelio , Proliferación Celular , Antivirales , Pseudomonas aeruginosa/fisiología , Infecciones por Pseudomonas/microbiología , MamíferosRESUMEN
The potential of monitoring biomarkers in sweat for health-related applications has spurred rapid growth in the field of wearable sweat sensors over the past decade. Some of the key challenges have been addressed, including measuring sweat-secretion rate and collecting sufficient sample volumes for real-time, continuous molecular analysis without intense exercise. However, except for assessment of cystic fibrosis and regional nerve function, the ability to accurately measure analytes of interest and their physiological relevance to health metrics remain to be determined. Although sweat is not a crystal ball into every aspect of human health, we expect sweat measurements to continue making inroads into niche applications involving active sweating, such as hydration monitoring for athletes and physical laborers and later for medical and casual health monitoring of relevant drugs and hormones.
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Biomarcadores , Técnicas Biosensibles , Sudor , Dispositivos Electrónicos Vestibles , Humanos , Sudor/química , Técnicas Biosensibles/métodos , Biomarcadores/análisis , Biomarcadores/metabolismo , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/instrumentación , Fibrosis Quística , SudoraciónRESUMEN
ABSTRACT: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.
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Síndromes de Inmunodeficiencia , Síndrome de Deficiencia de Adhesión del Leucocito , Enfermedades de Inmunodeficiencia Primaria , Inmunodeficiencia Combinada Grave , Humanos , Recién Nacido , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/metabolismo , Neutrófilos/metabolismo , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/metabolismo , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Proteína RCA2 de Unión a GTP , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/metabolismo , Superóxidos/metabolismoRESUMEN
BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). RESEARCH QUESTION: Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? STUDY DESIGN AND METHODS: This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. RESULTS: In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P = .03), lower FVC z scores (P = .01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P < .01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. INTERPRETATION: Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www. CLINICALTRIALS: gov.
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Cobalt(I) catalysts equipped with bisphosphine ligands can be used to promote formal (3 + 2 + 2) intramolecular cycloadditions of enynylidenecyclopropanes of type 1. The method provides synthetically appealing 5,7,5-fused tricyclic systems in good yields and with complete diastereo- and chemoselectivity. Interestingly, its scope differs from that of previously reported annulations based on precious metal catalysts, specifically rhodium and palladium. Noticeably, density functional theory calculations confirm that the mechanism of the reaction is also different from those proposed for these other catalysts.
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Elevated alkaline phosphatase (ALP) levels are found in multiple hepatobiliary diseases and in bone diseases. ALP can also originate in the intestine and placenta. Very few cases of persistent elevations of IALP or in the context of benign familial intestinal hyperphosphatasemia (BFIH) without underlying pathology have been reported in the literature. In the evaluation of elevated ALP, most patients will not require determination of its isoenzymes. However, it is important to be aware of this entity to avoid unnecessary additional studies and to establish the diagnosis of a persistent but benign biochemical abnormality.
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Primary ciliary dyskinesia (PCD) is a genetic disorder associated with recurrent and chronic respiratory infections due to functional defects of motile cilia. In this study, we aimed to elucidate inflammatory and proliferative responses in PCD respiratory epithelium and evaluate the effect of Azithromycin (AZT) on these responses. Airway basal cells (BCs) were isolated from nasal samples of Wild-type (WT) epitope of healthy donors and PCD donors with bi-allelic mutations in DNAH5, DNAH11 and CCDC39. Cells were expanded in vitro and stimulated with either Lipopolysaccharide (LPS) or vehicle control. Post stimulation, cells were treated with either Azithromycin (AZT) or vehicle control. Cell proliferation was imaged in real-time. Separately, BCs from the same donors were expanded and grown at an air-liquid interface (ALI) to generate a multi-ciliated epithelium (MCE). Once fully mature, cells were stimulated with LPS, AZT, LPS + AZT or vehicle control. Inflammatory profiling was performed on collected media by cytokine Luminex assay. At baseline, there was a significantly higher mean production of pro-inflammatory cytokines by CCDC39 BCs and MCEs when compared to WT, DNAH11 and DNAH5 cells. AZT inhibited production of cytokines induced by LPS in PCD cells. Differences in cell proliferation were noted in PCD and this was also corrected with AZT treatment.
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Azitromicina , Trastornos de la Motilidad Ciliar , Humanos , Azitromicina/farmacología , Lipopolisacáridos/toxicidad , Células Epiteliales , Inflamación/tratamiento farmacológico , Proliferación Celular , CitocinasRESUMEN
Herein, we report a facile isocoumarin and isoquinolone preparation by taking advantage of an initial bis(triflyl)ethylation [triflyl = (trifluoromethyl)sulfonyl] reaction, followed by heterocyclization, which contrasts with our previous results on cyclobutene formation. The efficiency of the catalyst- and irradiation-free heterocyclization/bis(triflyl)ethylation sequence showed exquisite dependence on the electronic nature of the substituents at the 2-ethynylbenzoate(benzamide) precursors. Molecular docking of model bis(triflyl)ethylated isocoumarins on human acetylcholinesterase (hAChE) revealed promising biological activities through selective coordination on both the catalytic active site and peripheral active site.
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Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases.NEW & NOTEWORTHY Our findings show that low-dose, short-term topical or systemic γ-secretase inhibitor treatment may lead to restoration of multiciliated cells without toxicity and potentially improve epithelial function in a wide range of chronic lung diseases.