RESUMO
BACKGROUND AND OBJECTIVES: There are limited data on cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS) outcomes beyond infancy. The goal of this study was to analyze outcomes of infants with CRMS up to the age of 9-10 years using the CF Foundation Patient Registry (CFFPR). METHODS: We analyzed data from the CFFPR for individuals with CF and CRMS born between 2010 and 2020. We classified all patients based on the clinical diagnosis reported by the CF care center and the diagnosis using CFF guideline definitions for CF and CRMS, classifying children into groups based on agreement between clinical report and guideline criteria. Descriptive statistics for the cohort were calculated for demographics, nutritional outcomes, and microbiology for the first year of life and lung function and growth outcomes were summarized for ages 6-10 years. RESULTS: From 2010 to 2020, there were 8765 children with diagnosis of CF or CRMS entered into the CFFPR with sufficient diagnostic data for classification, of which 7591 children had a clinical diagnosis of CF and 1174 had a clinical diagnosis of CRMS. CRMS patients exhibited normal nutritional indices and pulmonary function up to age 9-10 years. The presence of respiratory bacteria associated with CF, such as Pseudomonas aeruginosa from CRMS patients ranged from 2.1% to 9.1% after the first year of life. CONCLUSIONS: Children with CRMS demonstrate normal pulmonary and nutritional outcomes into school age. However, a small percentage of children continue to culture CF-associated respiratory pathogens after infancy.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Síndrome Metabólica , Humanos , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Fibrose Cística/complicações , Criança , Masculino , Feminino , Síndrome Metabólica/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Sistema de Registros , Lactente , Testes de Função Respiratória , Pré-EscolarRESUMO
Commercially available hops (Humulus lupulus L.) bitter acid extracts contain a mixture of three major congeners (co-, n-, and ad-) in addition to cis/trans diastereomers for each congener. Individual isomerized α-acids were obtained by the consecutive application of two separate countercurrent chromatography methods. First, individual isomerized α-acid congeners as a mixture of cis/trans diastereomers were obtained using a solvent system consisting of hexane and aqueous buffer. The second purification, capable of separating cis/trans diastereomers, was accomplished using a quaternary solvent system; an alternative procedure using ß-cyclodextrin followed by countercurrent chromatography was also investigated. The NaBH(4) reduction of the purified isomerized α-acid compounds followed by countercurrent chromatography purification resulted in individual ρ iso α-acids (>95%). Similarly, catalytic hydrogenation of the purified isomerized α-acid compounds followed by countercurrent chromatography purification produced individual tetrahydro isomerized α-acids (>95%). Reported herein is a widely applicable approach that focuses on three critical variables--solvent system composition, pH, and buffer-to-sample ratio--that enable the efficient purification of individual bitter acids (≥95%) from commercially available hops extracts.
Assuntos
Ácidos/isolamento & purificação , Distribuição Contracorrente/métodos , Humulus/química , Extratos Vegetais/isolamento & purificação , Ácidos/química , Isomerismo , Extratos Vegetais/químicaRESUMO
BACKGROUND: Beginning June 2019, Children's Wisconsin was the first hospital to identify a cohort of adolescent patients hospitalized with symptoms likely associated with e-cigarette use. Our report adds to the growing literature describing the radiographic, gross and cytopathologic bronchoscopic findings, and short-term lung function outcomes in this cohort of adolescents with e-cigarette or vaping product use associated lung injury (EVALI). METHODS: We present 15 adolescents hospitalized from June to September, 2019 with confirmed EVALI. We abstracted data from inpatient hospitalization and first outpatient pulmonary clinic visit. RESULTS: There were 15 patients (11 male, 12 White) with a mean age of 17.1 years. All patients presented with subacute pulmonary, gastrointestinal and constitutional complaints. Diagnostic workup was guided by the Centers for Disease Control criteria for confirmed EVALI case surveillance. Flexible bronchoscopy was performed in 13/15 patients with 10/13 demonstrating gross pathologic abnormalities. Seven of 15 patients required intensive care and 2 met criteria for pediatric Acute Respiratory Distress Syndrome. Patients had dramatic improvement with systemic glucocorticoid therapy and 14/15 were discharged on room air. Eleven patients were seen as outpatients. Despite 11/11 patients reporting resolved or improved symptoms, 7/11 had abnormalities on pulmonary function testing. We initiated inhaled corticosteroids for 5/11 patients and 4/11 patients remained on their corticosteroid wean. CONCLUSIONS AND RELEVANCE: We report short-term outcomes of the first cohort of adolescent patients hospitalized with EVALI. An association is observed between clinical improvement and treatment with systemic corticosteroids. However, residual airway reactivity or diffusion abnormalities persisted when patients were re-evaluated in the short-term period (mean 4.5 weeks).
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Lesão Pulmonar/etiologia , Vaping/efeitos adversos , Adolescente , Corticosteroides/uso terapêutico , Broncoscopia , Cuidados Críticos , Feminino , Hospitalização , Hospitais Pediátricos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/fisiopatologia , Masculino , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/fisiopatologia , Testes de Função Respiratória , Vaping/tratamento farmacológico , Vaping/fisiopatologia , WisconsinRESUMO
A defined mixture of rho iso-alpha-acids (RIAA), a modified hop extract, was evaluated for anti-inflammatory efficacy and safety. RIAA inhibited LPS-stimulated PGE(2) formation with >200-fold selectivity of COX-2 (IC(50)=1.3 microg/ml) over COX-1 (IC(50)>289 microg/ml). This occurred only when RIAA was added prior to, but not post, LPS stimulation. Consistent with this observation, RIAA produced no physiologically relevant, direct inhibition of COX-1 or COX-2 peroxidase activity. This suggests that RIAA inhibits inducible but not constitutive COX-2. In support, we found RIAA showed minimal PGE(2) inhibition (IC(50)=21mug/ml) relative to celecoxib (IC(50)=0.024 microg/ml), aspirin (IC(50)=0.52 microg/ml) or ibuprofen (IC(50)=0.57 microg/ml) in the AGS gastric mucosal model, where COX-1 and -2 are expressed constitutively. Taken together these results predict RIAA may have lower potential for gastrointestinal and cardiovascular toxicity observed with COX enzyme inhibitors. Following confirmation of bioavailable RIAA administered orally, gastrointestinal safety was assessed using the fecal calprotectin biomarker in a 14-day human clinical study; RIAA (900 mg/day) produced no change compared to naproxen (1000 mg/day), which increased fecal calprotectin 200%. Cardiovascular safety was addressed by PGI-M measurements where RIAA (1000 mg) did not reduce PGI-M or affect the urinary PGI-M/TXB(2) ratio. Drug interaction potential was evaluated against six major CYPs; of relevance, RIAA inhibited CYP2C9. Toxicity was assessed in a 21-day oral, mouse subchronic toxicity study where no dose dependent histopathological effects were noted. Clinically, RIAA (1000 mg/day) produced a 54% reduction in WOMAC Global scores in a 6-week, open-label trial of human subjects exhibiting knee osteoarthritis.
Assuntos
Alcanos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Ciclopentanos/uso terapêutico , Humulus/química , Osteoartrite/prevenção & controle , Extratos Vegetais/uso terapêutico , Adulto , Idoso , Alcanos/efeitos adversos , Alcanos/farmacocinética , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/farmacocinética , Inibidores de Ciclo-Oxigenase/uso terapêutico , Ciclopentanos/efeitos adversos , Ciclopentanos/farmacocinética , Fezes/química , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Complexo Antígeno L1 Leucocitário/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Espectrometria de Massas , Camundongos , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Osteoartrite/patologia , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacocinética , Prostaglandinas/urina , Resultado do TratamentoRESUMO
Feeding experiments with isotope-labeled precursors rule out hydroxypyruvate and TCA cycle intermediates as the metabolic source of methoxymalonyl-ACP, the substrate for incorporation of "glycolate" units into ansamitocin P-3, soraphen A, and other antibiotics. They point to 1,3-bisphosphoglycerate as the source of the methoxymalonyl moiety and show that its C-1 gives rise to the thioester carbonyl group (and hence C-1 of the "glycolate" unit), and its C-3 becomes the free carboxyl group of methoxymalonyl-ACP, which is lost in the subsequent Claisen condensation on the type I modular polyketide synthases (PKS). d-[1,2-(13)C(2)]Glycerate is also incorporated specifically into the "glycolate" units of soraphen A, but not of ansamitocin P-3, suggesting differences in the ability of the producing organisms to activate glycerate. A biosynthetic pathway from 1,3-bisphosphoglycerate to methoxymalonyl-ACP is proposed. Two new syntheses of R- and S-[1,2-(13)C(2)]glycerol were developed as part of this work.
Assuntos
Proteína de Transporte de Acila/biossíntese , Glicolatos/química , Macrolídeos/metabolismo , Malonatos/química , Maitansina/análogos & derivados , Proteína de Transporte de Acila/química , Sequência de Aminoácidos , Isótopos de Carbono , Ciclo do Ácido Cítrico/fisiologia , Ácidos Difosfoglicéricos/química , Ácidos Difosfoglicéricos/metabolismo , Marcação por Isótopo , Macrolídeos/química , Maitansina/química , Maitansina/metabolismo , Modelos Químicos , Dados de Sequência Molecular , Policetídeo Sintases/química , Policetídeo Sintases/metabolismo , Piruvatos/metabolismoRESUMO
The functions of six genes in the ansamitocin biosynthetic gene cluster of Actinosynnema pretiosum have been investigated by gene inactivation and chemical analysis of the mutants. They encode a halogenase (asm12), a carbamoyltransferase (asm21), a 20-O-methyltransferase (asm7), a 3-O-acyltransferase (asm19), an epoxidase (asm11), and an N-methyltransferase (asm10), respectively, and are responsible for the six post-PKS modification steps in ansamitocin formation. Several of the enzymes have relaxed substrate specificities, resulting in multiple parallel pathways in a metabolic grid, albeit with a preferred sequence of reactions as listed above.
Assuntos
Actinomycetales/genética , Actinomycetales/metabolismo , Antibióticos Antineoplásicos/biossíntese , Maitansina/análogos & derivados , Maitansina/metabolismo , Complexos Multienzimáticos/metabolismo , Actinomycetales/enzimologiaRESUMO
The potent antitumor activity of the ansamitocins, polyketides isolated from Actinosynnema pretiosum, is absolutely dependent on a short acyl group esterified to the C-3 oxygen of the macrolactam ring. Asm19, a gene in the ansamitocin biosynthetic gene cluster with homology to macrolide O-acyltransferase genes, is thought to encode the enzyme catalyzing this esterification. A mutant carrying an inactivated asm19 no longer produced ansamitocins but accumulated N-desmethyl-4,5-desepoxymaytansinol, rather than maytansinol, indicating that the acylation is not the terminal step of the biosynthetic sequence. Bioconversion experiments and in vitro studies with recombinant Asm19, expressed in Escherichia coli, showed that the enzyme is very specific toward its alcohol substrate, converting N-desmethyl-4,5-desepoxymaytansinol (but not maytansinol) into ansamitocins, but rather promiscuous toward its acyl substrate, utilizing acetyl-, propionyl-, butyryl-, isobutyryl-, as well as isovaleryl-CoA.
Assuntos
Aciltransferases/metabolismo , Antibióticos Antineoplásicos/biossíntese , Maitansina/análogos & derivados , Maitansina/metabolismo , Actinomycetales/genética , Actinomycetales/metabolismo , Aciltransferases/genética , Antibióticos Antineoplásicos/metabolismoRESUMO
The unusual "glycolate" extender unit at C-9/C-10 of ansamitocin is not derived from 2-hydroxymalonyl-CoA or 2-methoxymalonyl-CoA, as demonstrated by feeding experiments with the corresponding 1-13C-labeled N-acetylcysteamine thioesters but is formed from an acyl carrier protein (ACP)-bound substrate, possibly 2-methoxymalonyl-ACP, elaborated by enzymes encoded by a subcluster of five genes, asm12-17, from the ansamitocin bisosynthetic gene cluster.