RESUMEN
We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides.
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Compuestos Macrocíclicos , Péptidos , Técnicas de Síntesis en Fase Sólida , Sulfuros , Sulfuros/química , Sulfuros/síntesis química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/síntesis química , Péptidos/química , Péptidos/síntesis química , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Estructura Molecular , CiclizaciónRESUMEN
OBJECTIVE: To determine whether compliance with guidelines for cervical cancer screening, particularly use of the human papillomavirus (HPV) test in adult (aged ≥21 y) women, improves with the implementation of educational prompts in the electronic health record (EHR). MATERIALS AND METHODS: Two EHR-based interventions aimed at reducing unindicated HPV tests were implemented in the EHR in late June 2010. The Pap order form was revised with a descriptor next to the cotest (Pap plus HPV test) option advising that this is not for screening in women younger than 30 years, and a link to the American Society for Colposcopy and Cervical Pathology Web site was made available on the EHR home page. Charts of adult women with HPV results from January to December 2010 were reviewed. Appropriateness of HPV test ordering before (period A: from January to June) and after (period B: from July to December) the interventions were compared using the χ(2) test of association. RESULTS: A total of 3,564 HPV tests were performed on adult women at Loyola University Medical Center in 2010. During period A, 1,709 tests were ordered compared with 1,855 tests ordered during period B (p = .014). The proportion of HPV tests without an appropriate indication decreased significantly after the EHR changes (20% for period A vs 13% for period B, p < .0005). This significant decrease was seen in both primary care (22% in period A vs 12% in period B, p < .0005) and obstetrics and gynecology (Ob/Gyn) (19% vs 13%, p < .0005). CONCLUSIONS: Electronic health record-based tools improve compliance with cervical cancer screening guidelines.
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Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Registros Electrónicos de Salud , Pruebas de ADN del Papillomavirus Humano/métodos , Pruebas de ADN del Papillomavirus Humano/estadística & datos numéricos , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/diagnóstico , Adulto , Femenino , Adhesión a Directriz/estadística & datos numéricos , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: To investigate the probiotic Escherichia coli Nissle 1917 (EcN) in canine idiopathic diarrhea and urinary tract infections. ANIMALS/SAMPLES: The utility of EcN was explored in a 3-phase study from March 2017 to June 2020. Eighty-nine dogs with idiopathic diarrhea were included in phase 1, 3 healthy dogs were included in phase 2, and uropathogenic E coli (UPEC) isolates from 38 dogs with urinary tract infections were included in phase 3. PROCEDURES: In phase 1, dogs with diarrhea were prospectively enrolled in a randomized study to receive EcN (108 EcN bacteria/mL; < 10 kg received 5 mL/dose, 10 to 25 kg received 10 mL/dose, or > 25 kg received 15 mL/dose) or placebo for 3 days, followed by a 15-day observation phase. In phase 2, healthy dogs received EcN as described in phase 1, with feces analyzed for E coli populations and microbiome composition at days 0, 3, and 7. In phase 3, EcN efficacy was tested by in vitro plate assay against UPEC isolates. RESULTS: Median duration of abnormal stool consistency, time to response, and duration of diarrhea were shorter for dogs that received EcN (5.0, 3.0, and 2.0 days, respectively) versus the placebo (7.0, 5.0, and 4.0 days, respectively) (P = .21, P = .05, and P = .039, respectively). EcN induced shifts in E coli diversity in healthy dogs while having minimal impact on overall microbiome structure. Furthermore, 68% of the canine UPEC isolates were susceptible to EcN in vitro. CLINICAL RELEVANCE: EcN improved the treatment of idiopathic diarrhea, colonized the gastrointestinal tract during the trial, and displayed in vitro competition with UPEC.
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Escherichia coli , Probióticos , Animales , Perros , Diarrea/tratamiento farmacológico , Diarrea/veterinaria , Heces , Tracto Gastrointestinal , Probióticos/farmacología , Probióticos/uso terapéuticoRESUMEN
The ring oxidation of 2H-oxazole, or C2-unsubstituted oxazole, to 2-oxazolone, a cyclic carbamate, was observed on various 4- or 5-substituted oxazoles. Using 5-(3-bromophenyl)oxazole as a model compound, its 2-oxazolone metabolite M1 was fully characterized by liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance. The reaction mainly occurred in the liver cytosolic fraction without the requirement of cytochrome P450 enzymes and cofactor NADPH. Investigations into the mechanism of formation of 2-oxazolone using various chemical inhibitors indicated that the reaction was primarily catalyzed by aldehyde oxidase and not by xanthine oxidase. In addition, cytosol incubation of 5-(3-bromophenyl)oxazole in the medium containing H2¹8O led to the ¹8O incorporation into M1, substantiating the reaction mechanism of a typical molybdenum hydroxylase. The rank order of liver cytosols for the 2-oxazolone formation was mouse > monkey â« rat and human liver cytosol, whereas M1 was not formed in dog liver cytosol. Because the reaction was observed with a number of 4- or 5-substituted 2H-oxazoles in mouse liver cytosols, 2H-oxazoles represent a new substrate chemotype for ring oxidation catalyzed by aldehyde oxidase.
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Aldehído Oxidasa/metabolismo , Citosol/enzimología , Hígado/enzimología , Oxazoles/metabolismo , Oxazolona/metabolismo , Aldehído Oxidasa/antagonistas & inhibidores , Animales , Biotransformación , Catálisis , Cromatografía Líquida de Alta Presión , Perros , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Hígado/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Microsomas Hepáticos/enzimología , Estructura Molecular , Oxazoles/química , Oxazolona/análogos & derivados , Oxazolona/química , Oxidación-Reducción , Isótopos de Oxígeno , Ratas , Especificidad de la Especie , Especificidad por Sustrato , Espectrometría de Masas en Tándem , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismoRESUMEN
(S)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1H)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0-7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.
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Pirazinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Bilis/química , Biotransformación , Ácido Glucurónico/metabolismo , Glutatión/metabolismo , Humanos , Hígado/enzimología , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Microsomas Hepáticos/enzimología , Modelos Químicos , Estructura Molecular , Pirazinas/sangre , Pirazinas/metabolismo , Pirazinas/orina , Ratas , Ratas Sprague-Dawley , Espectrofotometría UltravioletaRESUMEN
Embodied emissions in trade have been widely studied; however, there is still a lack of studies that explore whether a country is benefitting from its inter-regional trade in terms of pollutant emissions. This study took sulfur dioxide (SO2) emissions as an example and employed modified input-output (MIO) model and traditional input-output (IO) model to quantify emissions under no-trade and trade conditions, and further investigated environmental efficiency and equality of inter-regional trade in China in 2010. The results show that inter-regional trade had increased emissions by 28% compared to no-trade emissions, which confirms the environmental inefficiency of inter-regional trade in China. This was largely because regions with better technology and low emission intensities tended to outsource the production of pollution-intensive but low value-added goods to regions with high emission intensities through inter-regional trade. The exchanges of pollution-intensive products in inter-regional trade have led to notable environmental inequities. Eastern regions usually gained the greatest environmental benefits from trade, while central regions (especially Shanxi, Henan, and Hebei) suffered the largest environmental loss induced by trade. Specifically, Guangdong plundered other regions the most (796â¯G gram (Gg)), while Shanxi was plundered the most by other regions (790 Gg). Polices to differentiate reduction criteria for emission intensity in different regions and adjust trade patterns within China could be recommended in order to achieve trade-related environmental efficiency as well as environmental equality.
RESUMEN
In order to improve aqueous solubility of nocathiacin I (1), a potent antibacterial agent, N-demethylation of the amino-sugar moiety was sought. Irradiation of 1 in DMF/CH(2)Cl(2) with UV light of 380 nm led to a cyclic product 2, which was hydrolyzed to yield the desired nocathiacin VI (3). Treatment of 1 with shorter UV light caused trans-cis isomerization of a c-c double bond.
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Oxígeno/química , Péptidos/química , Antiinfecciosos/farmacología , Química Farmacéutica/métodos , Diseño de Fármacos , Hidrólisis , Péptidos y Proteínas de Señalización Intercelular , Luz , Metilación , Modelos Químicos , Estructura Molecular , Oxidación-Reducción , Solubilidad , Solventes/química , Relación Estructura-Actividad , Rayos UltravioletaRESUMEN
OBJECTIVE: To identify clinical and demographic factors associated with long-term disability in patients with relapsing-remitting multiple sclerosis. DATA SOURCES: We searched the MEDLINE (1966-May 2005), EMBASE, CINAHL, Cochrane, and PsycINFO computerized databases, and reviewed reference lists of retrieved articles. STUDY SELECTION: We included studies that examined predictors of long-term disability in patients with relapsing-remitting multiple sclerosis. We excluded studies that did not distinguish relapsing-remitting multiple sclerosis from primary progressive multiple sclerosis, enrolled fewer than 40 subjects, observed subjects for less than 5 years, or collected follow-up information in less than 80% of the inception cohort. DATA EXTRACTION: Two reviewers assessed study quality in 4 domains: cohort assembly, definitions and assessments of prognostic factors and outcomes, and statistical methods. One reviewer extracted data on the direction, magnitude, precision, and statistical significance of the effect of each predictor on prognosis. DATA SYNTHESIS: Heterogeneity of study designs precluded us from pooling the results of 27 eligible studies. Study quality was limited by cross-sectional design, enrollment of prevalent cases from referral centers, and lack of multivariate adjustment. Sphincter symptoms at onset (hazard ratio, 1.1-3.1), incomplete recovery from the first attack (hazard ratio, 1.3-3.3), and a short interval between the first and second attack (hazard ratio, 1.6-1.9) were most strongly and consistently associated with poor prognosis. Other factors widely believed to be of prognostic importance, including sex and age at onset, demonstrated inconsistent or weak effects on prognosis. CONCLUSIONS: The most robust predictors of long-term physical disability in relapsing-remitting multiple sclerosis are sphincter symptoms at onset and early disease course outcomes. These factors can be used to guide treatment decisions for drugs with significant toxicities.
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Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Adulto , Edad de Inicio , Anciano , Canal Anal/fisiopatología , Estudios Transversales , Interpretación Estadística de Datos , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Proyectos de Investigación , Factores Sexuales , Resultado del TratamientoRESUMEN
[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
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Carbazoles/síntesis química , Carbono/química , Inhibidores Enzimáticos/síntesis química , Flúor/química , Glicósidos/síntesis química , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Hidrocarburos Fluorados/síntesis química , Indoles/síntesis química , Inhibidores de Topoisomerasa I , Animales , Carbazoles/farmacología , Inhibidores Enzimáticos/farmacología , Glicósidos/farmacología , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Hidrocarburos Fluorados/química , Indoles/química , Leucemia P388 , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 3-aryloxindole derivatives were synthesized and evaluated as activators of the cloned maxi-K channel mSlo expressed in Xenopus laevis oocytes using electrophysiological methods. The most promising maxi-K openers to emerge from this study were (+/-)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one ((+/-)-8c) and its 3-des-hydroxy analogue (+/-)-11b. The individual enantiomers of (+/-)-8c were synthesized, and the maxi-K channel-opening properties were shown to depend on the absolute configuration of the single stereogenic center with the efficacy of (-)-8c superior to that of both (+)-8c and the racemic mixture when evaluated at a concentration of 20 microM. Racemic 11b exhibited greater efficacy than either the racemic 8c or the more active enantiomer in the electrophysiological evaluation. In vitro metabolic stability studies conducted with (+/-)-8c and (+/-)-11b in rat liver S9 microsomal fractions revealed significant oxidative degradation with two hydroxylated metabolites observed by liquid chromatography/mass spectrometry for each compound in addition to the production of 8c from 11b. The pharmacokinetic properties of (+/-)-8c and (+/-)-11b were determined in rats as a prelude to evaluation in a rat model of stroke that involved permanent occlusion of the middle cerebral artery (MCAO model). In the MCAO model, conducted in the spontaneously hypertensive rat, the more polar 3-hydroxy derivative (+/-)-8c did not demonstrate a significant reduction in cortical infarct volume when administered intravenously at doses ranging from 0.1 to 10 mg/kg as a single bolus 2 h after middle cerebral artery occlusion when compared to vehicle-treated controls. In contrast, intravenous administration of (+/-)-11b at a dose of 0.03 mg/kg was found to reduce the measured cortical infarct volume by approximately 18% when compared to vehicle-treated control animals. Intraperitoneal administration of (+/-)-11b at a dose of 10 mg/kg 2 h following artery occlusion was shown to reduce infarct volume by 26% when compared to vehicle-treated controls. To further probe the effects of compounds (+/-)-8c and (+/-)-11b on neurotransmitter release in vitro, both compounds were examined for their ability to reduce electrically stimulated [3H]-glutamate release from rat hippocampal slices that had been preloaded with [3H]-glutamate. Only (+/-)-11b was able to demonstrate a significant inhibition [3H]-glutamate release in this assay at a concentration of 20 microM, providing concordance with the profile of these compounds in the MCAO model. Although (+/-)-11b showed some promise as a potential developmental candidate for the treatment of the sequelae of stroke based on its efficacy in the rat MCAO model, the pharmacokinetic profile of this compound was considered to be less than optimal and was not pursued in favor of derivatives with enhanced metabolic stability.
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Calcio/química , Indoles/química , Indoles/farmacología , Neuronas/efectos de los fármacos , Canales de Potasio Calcio-Activados/química , Animales , Células COS , Calcio/metabolismo , Arterias Cerebrales/metabolismo , Relación Dosis-Respuesta a Droga , Electrofisiología , Ácido Glutámico/química , Hipocampo/efectos de los fármacos , Canales de Potasio de Gran Conductancia Activados por el Calcio , Masculino , Modelos Químicos , Modelos Moleculares , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Unión Proteica , Estructura Terciaria de Proteína , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temperatura , Xenopus , Xenopus laevisRESUMEN
Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.
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Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Indoles/farmacología , Piperazinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Antagonistas de los Receptores CCR5 , Perros , Humanos , Indoles/química , Indoles/farmacocinética , Infusiones Intravenosas , Macaca fascicularis , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Receptores CXCR4/antagonistas & inhibidoresRESUMEN
A new group of thiazolyl peptide antibiotics, the nocathiacins, was isolated from cultured broth of Nocardia sp. The major analogs nocathiacins I-III (1-3) were purified using silica gel and Sephadex LH-20 chromatography techniques. The structures of nocathiacins I-III were determined by spectroscopic (2D-NMR, MSn) methods, and share structural similarities to glycothiohexide-alpha (4).
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Antibacterianos/química , Antibacterianos/aislamiento & purificación , Nocardia/química , Péptidos , Cromatografía en Gel , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría UltravioletaRESUMEN
OBJECTIVE: To determine whether low levels of 25-hydroxyvitamin D (25[OH]D) contribute to the increased risk of postpartum multiple sclerosis (MS) relapses. DESIGN: Prospective cohort study. SETTING: Outpatients identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. PATIENTS: Twenty-eight pregnant women with MS. INTERVENTIONS: We prospectively followed up patients through the postpartum year and assessed exposures and symptoms through structured interviews. Total serum 25(OH)D levels were measured using the DiaSorin Liaison Assay during the third trimester and 2, 4, and 6 months after giving birth. The data were analyzed using longitudinal multivariable methods. MAIN OUTCOME MEASURES: Levels of 25(OH)D and relapse rate. RESULTS: Fourteen (50%) women breastfed exclusively, and 12 women (43%) relapsed within 6 months after giving birth. During pregnancy, the average 25(OH)D levels were 25.4 ng/mL (range, 13.7-42.6) and were affected only by season (P=.009). In contrast, in the postpartum period, 25(OH)D levels were significantly affected by breastfeeding and relapse status. Levels of 25(OH)D remained low in the exclusive breastfeeding group, yet rose significantly in the nonexclusive breastfeeding group regardless of season (P=.007, unadjusted; P=.02, adjusted for season). By 4 and 6 months after childbirth, 25(OH)D levels were, on average, 5 ng/mL lower in the women who breastfed exclusively compared with the nonbreastfeeding group (P=.001). CONCLUSIONS: Pregnancy and exclusive breastfeeding are strongly associated with low 25(OH)D levels in women with MS. However, these lower vitamin D levels were not associated with an increased risk of postpartum MS relapses. These data suggest that low vitamin D in isolation is not an important risk factor for postpartum MS relapses.
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Lactancia Materna , Esclerosis Múltiple/complicaciones , Periodo Posparto , Deficiencia de Vitamina D/complicaciones , Adulto , Estudios de Cohortes , Suplementos Dietéticos , Femenino , Humanos , Hidroxicolecalciferoles/sangre , Estudios Longitudinales , Embarazo , Fenómenos Fisiologicos de la Nutrición Prenatal , Estudios Prospectivos , Recurrencia , Estaciones del Año , Vitamina D/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
Bacteria can coordinate several multicellular behaviors in response to environmental changes. Among these, swarming and biofilm formation have attracted significant attention for their correlation with bacterial pathogenicity. However, little is known about when and where the signaling occurs to trigger either swarming or biofilm formation. We have previously identified an RssAB two-component system involved in the regulation of swarming motility and biofilm formation in Serratia marcescens. Here we monitored the RssAB signaling status within single cells by tracing the location of the translational fusion protein EGFP-RssB following development of swarming or biofilm formation. RssAB signaling is specifically activated before surface migration in swarming development and during the early stage of biofilm formation. The activation results in the release of RssB from its cognate inner membrane sensor kinase, RssA, to the cytoplasm where the downstream gene promoters are located. Such dynamic localization of RssB requires phosphorylation of this regulator. By revealing the temporal activation of RssAB signaling following development of surface multicellular behavior, our findings contribute to an improved understanding of how bacteria coordinate their lifestyle on a surface.
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Proteínas Bacterianas/metabolismo , Serratia marcescens/citología , Transducción de Señal , Biopelículas , Fosforilación , Transporte de Proteínas , Serratia marcescens/metabolismoRESUMEN
OBJECTIVE: To determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period. DESIGN: Case-control study. SETTING: Kaiser Permanente Northern California and Stanford University. PARTICIPANTS: Twenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum. MAIN OUTCOME MEASURES: Sixteen functional cell types, including interferon-gamma (IFN-gamma)- and tumor necrosis factor-producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors. RESULTS: Fifteen women with MS (58%) had relapses during the postpartum year. CD4(+)IFN-gamma-producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4(+)IFN-gamma-producing cells in women with MS (P = .009). In contrast, CD4(+) tumor necrosis factor-producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8(+)IFN-gamma-producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses. CONCLUSIONS: Our findings suggest that a decline in circulating CD4(+)IFN-gamma-producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.
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Tolerancia Inmunológica/inmunología , Interferón gamma/metabolismo , Esclerosis Múltiple Recurrente-Remitente/inmunología , Periodo Posparto/inmunología , Trimestres del Embarazo/inmunología , Embarazo/inmunología , Linfocitos T/inmunología , Adulto , Amenorrea/inmunología , Lactancia Materna , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Estudios de Casos y Controles , Recuento de Células , Proliferación Celular , Regulación hacia Abajo/inmunología , Femenino , Humanos , Lactancia/inmunología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Estudios Prospectivos , Recurrencia , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To determine if exclusive breastfeeding protects against postpartum relapses of multiple sclerosis (MS) and, if so, whether this protection is related to prolonged lactational amenorrhea. DESIGN: We conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and 2, 4, 6, 9, and 12 months postpartum and collected neurological examination findings from the treating physicians of women with MS. Hazards ratios (HRs) were adjusted for measures of disease severity and age. SETTING: Kaiser Permanente Northern California and Stanford University. PARTICIPANTS: We prospectively enrolled 32 pregnant women with MS and 29 age-matched, pregnant controls. Main Outcome Measure Postpartum relapse. RESULTS: Of the 52% of women with MS who did not breastfeed or began regular supplemental feedings within 2 months postpartum, 87% had a postpartum relapse, compared with 36% of the women with MS who breastfed exclusively for at least 2 months postpartum (unadjusted HR, 5.0; 95% confidence interval, 1.7-14.2; P = .003; adjusted HR, 7.1; 95% confidence interval, 2.1-24.3; P = .002). Sixty percent reported that the primary reason for foregoing exclusive breastfeeding was to resume MS therapies. Women who breastfed exclusively had a later return of menses (P = .001) than women who did not, and lactational amenorrhea was associated with a reduced risk of postpartum relapses (P = .01). CONCLUSIONS: Our findings suggest that exclusive breastfeeding and concomitant suppression of menses significantly reduce the risk of postpartum relapses in MS. Our findings call into question the benefit of foregoing breastfeeding to start MS therapies and should be confirmed in a larger study.
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Lactancia Materna/efectos adversos , Esclerosis Múltiple/etiología , Trastornos Puerperales/etiología , Estudios de Cohortes , Evaluación de la Discapacidad , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Estimación de Kaplan-Meier , Esclerosis Múltiple/diagnóstico , Embarazo , Complicaciones del Embarazo/diagnóstico , Estudios Prospectivos , Recurrencia , RiesgoRESUMEN
Two new cytotoxic xanthones were isolated from extracts of the Madagascar rain forest plant Psorospermum cf. molluscum using bioassay-guided fractionation with the Escherichia coli SOS chromotest. The structures of the new dihydrofuranoxanthones, designated 3',4'-deoxy-4'-chloropsoroxanthin-(3',5'-diol) ( 1) and psoroxanthin ( 4), were determined on the basis of 2D-NMR, MS, and UV spectroscopic data and are structurally related to the psorospermins, a known class of plant antitumor agents. A new hydroxyprenylated xanthone ( 5) is also described. Xanthones 1 and 4 showed selective in vitro cytotoxicity against ABAE cells (bovine endothelial cell line).
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Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Clusiaceae/química , Plantas Medicinales/química , Xantonas/aislamiento & purificación , Xantonas/farmacología , Animales , Antineoplásicos Fitogénicos/química , Bovinos , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales/efectos de los fármacos , Humanos , Madagascar , Xantonas/químicaRESUMEN
8-Aryl-1,3a,8-triaza-cyclopenta[a]indenes represent a novel series of high binding affinity corticotropin-releasing factor 1 receptor antagonists. Here, we report their synthesis, SAR, and pharmacokinetic properties of compound 8e (K(i) = 23 nM).
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Bencimidazoles/química , Bencimidazoles/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Humanos , Estructura Molecular , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
Nocathiacin I (1) and nocathiacin IV (2) are novel indole-containing thiazolyl peptide antibiotics, which exhibit potent activity against key Gram-positive bacterial pathogens, including multi drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. New nocathiacins 7-12 were prepared from 2 by a condensation with glycolaldehyde followed by tandem reductive amination of the 2-oxoethyl intermediate 4. The latter was formed via Amadori rearrangement from initial 2-hydroxyethylideneamide 3. This transformation readily tolerates the complex architecture of nocathiacins and allows selective incorporation of water solubilizing groups to the primary amide in 2 without protecting group manipulation.
Asunto(s)
Acetaldehído/análogos & derivados , Acetaldehído/química , Antibacterianos/síntesis química , Técnicas Químicas Combinatorias , Péptidos Cíclicos/síntesis química , Péptidos , Tiazoles/síntesis química , Amidas/química , Antibacterianos/farmacología , Catálisis , Farmacorresistencia Bacteriana Múltiple , Enterococcus faecium/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos Cíclicos/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/farmacología , Agua/químicaRESUMEN
Nocathiacin I (BMS-249524) is a highly cross-linked thiazolyl peptide that displays potent activity against Gram-positive bacteria, including a number of antibiotic-resistant strains. This natural product contains 10 chiral centers. NMR studies have been performed to characterize the solution structure of nocathiacin I. A uniformly 13C,15N-labeled sample was used to obtain NMR assignments. Restrained simulated annealing calculations were performed by using accurately determined NOE distance restraints. All of the chiral centers were allowed to float during the simulated annealing protocol. Two clusters of structures were obtained that satisfy the NOE restraints very well and that are reasonably consistent with vicinal J-coupling constants. Within each cluster, all 10 chiral centers are uniquely defined. The two clusters are effectively mirror images of each other: all chiral centers that have the R(S) configuration in one cluster have the S(R) configuration in the other. The single threonine residue in nocathiacin I was subsequently determined to be l-threonine by chiral capillary electrophoresis, allowing the absolute configurations of all 10 chiral centers to be defined.