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OBJECTIVES: This study aimed to investigate the differences in ASMs prescription, seizure characteristics and predictors of polypharmacy in patients with epilepsy and Intellectual disabilities (IDs) residing in group homes versus family homes. METHODS: This nine-year retrospective study analyzed patients with epilepsy and IDs who were admitted to the EMU, epilepsy clinics at LHSC and rehabilitation clinics for patients with IDs at Parkwood Institution. The study included individuals aged 16 years and older residing in either group homes or family homes. Data on demographics, epilepsy characteristics, and ASMs use were collected and analyzed using the Statistical Package for Social Sciences. The study utilized binary logistic regression to identify predictors of polypharmacy in patients with epilepsy and IDs. RESULTS: The study enrolled a total of 81 patients, of which 59.3 % resided in family homes. Group home residents were significantly older (41 vs. 24.5 years; p = 0.0001) and were prescribed more ASMs (3 vs. 2; p = 0.002). Specific ASMs were more common in group homes, including valproic acid (54.5 % vs. 25.0 %), lacosamide (54.5 % vs. 22.9 %), topiramate (33.3 % vs. 14.6 %), and phenytoin (30.3 % vs. 6.2 %). Admission to the EMU was more prevalent in group homes (93.9 % vs. 52.1 %; p = 0.0001). Living in a group home increased the risk of polypharmacy (OR = 10.293, p = 0.005), as did older epilepsy onset age (OR = 1.135, p = 0.031) and generalized or focal & generalized epilepsy (OR = 7.153, p = 0.032 and OR = 10.442, p = 0.025, respectively). SIGNIFICANCE: Our study identified notable differences in the demographic and clinical characteristics of patients with epilepsy and IDs living in group homes versus family homes. Age of epilepsy onset, EMU admissions, epilepsy types, and residency setting were significant predictors of polypharmacy. These findings highlight the need for personalized care strategies and increased awareness of the potential risks associated with polypharmacy.
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Epilepsias Parciales , Epilepsia , Discapacidad Intelectual , Humanos , Polifarmacia , Hogares para Grupos , Casas de Salud , Estudios Retrospectivos , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Epilepsias Parciales/tratamiento farmacológico , ConvulsionesRESUMEN
A BF3-catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides is reported. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C-F bonds through a halide recycling mechanism. The developed method provides access to 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivatives of known protein kinase inhibitors. Experimental and computational studies support a stepwise mechanism for the fluorocarbamoylation reaction involving a turnover-limiting cyclization step, followed by internal fluoride transfer from a BF3-coordinated carbamoyl adduct. For methylene oxindoles, a thermodynamically driven Z-E isomerization is facilitated by a transition state with aromatic character. In contrast, this aromatic stabilization is not relevant for γ-lactams, which results in a higher barrier for isomerization and the exclusive formation of the Z-isomer.
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Stereoinduction in complex organic reactions often involves the influence of multiple stereocontrol elements. The interaction among these can often result in the observation of significant cooperative effects that afford different rates and selectivities between the matched and mismatched sets of stereodifferentiating chiral elements. The elucidation of matched/mismatched effects in ground-state chemical reactions was a critically important theme in the maturation of modern stereocontrolled synthesis. The development of robust methods for the control of photochemical reactions, however, is a relatively recent development, and similar cooperative stereocontrolling effects in excited-state enantioselective photoreactions have not previously been documented. Herein, we describe a tandem chiral photocatalyst/Brønsted acid strategy for highly enantioselective [2 + 2] photocycloadditions of vinylpyridines. Importantly, the matched and mismatched chiral catalyst pairs exhibit different reaction rates and enantioselectivities across a range of coupling partners. We observe no evidence of ground-state interactions between the catalysts and conclude that these effects arise from their cooperative behavior in a transient excited-state assembly. These results suggest that similar matched/mismatched effects might be important in other classes of enantioselective dual-catalytic photochemical reactions.
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Estereoisomerismo , CatálisisRESUMEN
We report a method for the synthesis of carbamoyl fluorides from secondary amines using bench-stable, inexpensive, and readily accessible starting materials that, when combined, yield a surrogate for toxic difluorophosgene (COF2) gas. In contrast to state-of-the-art methods for the synthesis of carbamoyl fluorides, our protocol does not require the use of pre-functionalized substrates, the preparation of light-, temperature-, and/or moisture-sensitive chemicals, or the application of explosive fluorinating reagents.
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Fluoruros , Hidrocarburos Fluorados , Óxidos , PiridinasRESUMEN
OBJECTIVES: To evaluate the feasibility of a stepped care model, and establish the effect of a tailored cognitive behavioral therapy, the Aim to Decrease Anxiety and Pain Treatment (ADAPT), compared with standard medical treatment as usual on pain-related outcomes and anxiety. STUDY DESIGN: Eligible patients between the ages of 9 and 14 years with functional abdominal pain disorders (n = 139) received enhanced usual care during their medical visit to a gastroenterologist. Those that failed to respond to enhanced usual care were randomized to receive either a tailored cognitive behavioral therapy (ADAPT) plus medical treatment as usual, or medical treatment as usual only. ADAPT dose (4 sessions of pain management or 6 sessions of pain and anxiety management) was based on presence of clinically significant anxiety. Outcomes included feasibility, based on recruitment and retention rates. Response to ADAPT plus medical treatment as usual vs medical treatment as usual on pain-related outcomes and anxiety measures was also investigated using a structural equation modeling equivalent of a MANCOVA. Anxiety levels and ADAPT dose as moderators of treatment effects were also explored. RESULTS: Based on recruitment and retention rates, stepped care was feasible. Enhanced usual care was effective for only 8% of youth. Participants randomized to ADAPT plus medical treatment as usual showed significantly greater improvements in pain-related disability, but not pain levels, and greater improvements in anxiety symptoms compared with those randomized to medical treatment as usual only. Anxiety and ADAPT treatment dose did not moderate the effect of treatment on disability nor pain. CONCLUSIONS: Tailoring care based on patient need may be optimal for maximizing the use of limited psychotherapeutic resources while enhancing care. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03134950.
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Dolor Abdominal/terapia , Ansiedad/terapia , Terapia Cognitivo-Conductual/métodos , Dolor Abdominal/complicaciones , Dolor Abdominal/psicología , Adolescente , Ansiedad/complicaciones , Ansiedad/psicología , Niño , Estudios de Factibilidad , Femenino , Humanos , Manejo del Dolor/métodos , Atención Dirigida al Paciente/métodosRESUMEN
OBJECTIVES: In the management of cardiovascular disease, it is important to identify patients at risk early on, to provide interventions to prevent the disease and its complications. The goal of our study was to investigate the association between glucose levels and silent myocardial infarction (SMI) among patients, who consisted of veterans within the Veterans Affairs clinical system. METHODS: Among the group of patients with an initially normal electrocardiogram, a cohort of patients with a subsequent diagnosis of SMI was selected as the case cohort, whereas 4 patients for each study subject, without evidence of coronary artery disease and normal electrocardiogram within the previous 6 months, were identified and constituted the control cohort. We conducted an adjusted logistic regression model using the stepwise function to assess the association between glucose level and SMI. RESULTS: Of the 540 patients included in the study, 108 (20.0%) with an SMI diagnosis made up the case cohort. We observed that as compared with those who had normal levels of glucose, those who were prediabetic were 3.99 times as likely (95% confidence interval 1.48-12.85) to have SMI, whereas the diabetic patients were 3.80 times as likely (95% confidence interval 1.39-12.38) to experience SMI. CONCLUSIONS: SMIs have been shown to be predictive of subsequent cardiovascular events, including another MI and death, and that indicates the importance of identifying a group at high risk for a SMI. As such, our findings could be extremely beneficial for targeted intervention toward prediabetics and to improve health outcomes in the entire population.
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Infarto del Miocardio/clasificación , Estado Prediabético/complicaciones , Medición de Riesgo/estadística & datos numéricos , Veteranos/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Electrocardiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Infarto del Miocardio/fisiopatología , Estado Prediabético/epidemiología , Estado Prediabético/fisiopatología , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
The lumen-dwelling protozoan Giardia is an important parasitic cause of diarrheal disease worldwide. Infection can persist over extended periods with minimal intestinal inflammation, suggesting that Giardia may attenuate host responses to ensure its survival, although clearance eventually occurs in most cases. IL-10 is an anti-inflammatory regulator critical for intestinal homeostasis and controlling host responses to bacterial exposure, yet its potential role in coordinating antiprotozoal host defense in the intestine is not known. In this study, we found that murine infection with the natural enteric pathogen Giardia muris induced a transient IL-10 response after 2-4 wk at the primary site of infection in the upper small intestine, but parasite colonization and eradication were not affected by the absence of the cytokine in gene-targeted mice. However, IL-10 was critical for controlling infection-associated immunological sequelae in the colon because severe and persistent diarrhea and colitis were observed in IL-10-deficient mice within 1-2 wk postinfection but not in uninfected littermate controls. Inflammation was characterized by epithelial hyperplasia, neutrophil and macrophage expansion, and Th1 induction and could be prevented by blockade of IL-12/IL-23 p40 but not depletion of CD11c+ dendritic cells. Furthermore, the intestinal microbiota underwent characteristic shifts in composition and was required for disease because antibiotics and loss of TLR signaling in MyD88-deficient mice protected against colitis. Together, our data suggest that transient infection by a luminal and seemingly noninflammatory pathogen can trigger sustained colitis in genetically susceptible hosts, which has broader implications for understanding postinfectious syndromes and other chronic intestinal inflammatory conditions.
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Colitis/inmunología , Giardia/fisiología , Giardiasis/inmunología , Interleucina-10/metabolismo , Mucosa Intestinal/inmunología , Intestino Delgado/fisiología , Células TH1/inmunología , Animales , Células Cultivadas , Enfermedad Crónica , Predisposición Genética a la Enfermedad , Humanos , Interleucina-10/genética , Interleucina-12/metabolismo , Mucosa Intestinal/parasitología , Intestino Delgado/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Receptores Toll-Like/metabolismoRESUMEN
Giardia lamblia, one of the most common protozoal infections of the human intestine, is an important worldwide cause of diarrheal disease, malabsorption, malnutrition, delayed cognitive development in children, and protracted postinfectious syndromes. Despite its medical importance, no human vaccine is available against giardiasis. A crude veterinary vaccine has been developed, and experimental vaccines based on expression of multiple variant-specific surface proteins have been reported, but poorly defined vaccine components and excessive antigen variability are problematic for pharmaceutical vaccine production. To expand the repertoire of antigen candidates for vaccines, we reasoned that surface proteins may provide an enriched source of such antigens since key host effectors, such as secretory IgA, can directly bind to such antigens in the intestinal lumen and interfere with epithelial attachment. Here, we have applied a proteomics approach to identify 23 novel surface antigens of G. lamblia that show >90% amino acid sequence identity between the two human-pathogenic genetic assemblages (A and B) of the parasite. Surface localization of a representative subset of these proteins was confirmed by immunostaining. Four selected proteins, uridine phosphorylase-like protein-1, protein 21.1 (GL50803_27925), α1-giardin, and α11-giardin, were subsequently produced in recombinant form and shown to be immunogenic in mice and G. lamblia-infected humans and confer protection against G. lamblia infection upon intranasal immunization in rodent models of giardiasis. These results demonstrate that identification of conserved surface antigens provides a powerful approach for overcoming a key rate-limiting step in the design and construction of an effective vaccine against giardiasis.
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Antígenos de Protozoos/inmunología , Giardia lamblia/inmunología , Giardiasis/parasitología , Proteoma/inmunología , Proteínas Protozoarias/inmunología , Vacunas Antiprotozoos/inmunología , Adulto , Animales , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/química , Antígenos de Protozoos/genética , Reacciones Cruzadas , Femenino , Giardia lamblia/química , Giardia lamblia/genética , Giardiasis/inmunología , Giardiasis/prevención & control , Humanos , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Proteoma/química , Proteoma/genética , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Vacunas Antiprotozoos/química , Vacunas Antiprotozoos/genética , Adulto JovenRESUMEN
We report three brothers born to consanguineous parents of Syrian descent, with a homozygous novel c.324G>A (p.W108*) mutation in PTRH2 that encodes peptidyl-tRNA hydrolase 2, causing infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We describe the core clinical features of postnatal microcephaly, motor and language delay with regression, ataxia, and hearing loss. Additional features include epileptic seizures, pancreatic insufficiency, and peripheral neuropathy. Clinical phenotyping enabled a targeted approach to the investigation and identification of a novel homozygous nonsense mutation in PTRH2, c.324G>A (p.W108*). We compare our patients with those recently described and review the current literature for IMNEPD.
Compte-rendu d'un cas de maladie infantile multi-systémique neurologique-endocrinienne-pancréatique. Nous voulons nous pencher ici sur le cas de trois frères nés de parents consanguins d'origine syrienne et donnant à voir une mutation homozygote c.324G>A (p.W108*) du gène PTRH2 rarement vue. Ce gène est responsable d'encoder la protéine peptidyl-tRNA hydrolase 2. Un encodage déficient causera chez des enfants une maladie multi-systémique neurologique-endocrinienne-pancréatique. Dans cet article, nous entendons décrire les aspects cliniques principaux de la microcéphalie postnatale, à savoir des délais et des régressions sur le plan du développement moteur et langagier mais aussi de l'ataxie et de la perte auditive. D'autres aspects cliniques sont également abordés, notamment des crises épileptiques, l'insuffisance pancréatique et une neuropathie périphérique. À cet égard, des outils de phénotypage clinique nous ont permis de compter sur une approche de recherche et d'identification ciblée en ce qui regarde la mutation non-sens évoquée ci-dessus. Enfin, nous voulons comparer nos jeunes patients à d'autres récemment décrits et passer en revue la littérature scientifique actuelle qui porte sur la maladie infantile multi-systémique neurologique-endocrinienne-pancréatique.
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Anomalías Múltiples/genética , Hidrolasas de Éster Carboxílico/genética , Enfermedades del Sistema Endocrino/genética , Proteínas Mitocondriales/genética , Enfermedades del Sistema Nervioso/genética , Enfermedades Pancreáticas/genética , Homocigoto , Humanos , Masculino , Mutación Missense , LinajeRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Lemierre's syndrome is often misdiagnosed as a common cold or viral infection. Fusobacterium necrophorum is the most common causative organism. The recommended treatment regimen is 6 weeks of a beta-lactam antibiotic along with metronidazole. CASE DESCRIPTION: We present two cases of Lemierre's syndrome with internal jugular vein thrombophlebitis and positive blood cultures for F. necrophorum. The first case was successfully treated with 6 weeks of a beta-lactam antibiotic and 4 weeks of metronidazole, while the second case was successfully treated with 4 weeks of a beta-lactam antibiotic and 2 weeks of metronidazole. WHAT IS NEW AND CONCLUSION: Two cases of Lemierre's syndrome were treated successfully with only 2-4 weeks of metronidazole therapy. Shorter duration of metronidazole therapy should be explored in future studies.
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Antibacterianos/administración & dosificación , Infecciones por Fusobacterium/diagnóstico , Síndrome de Lemierre/diagnóstico , Tromboflebitis/etiología , Adulto , Femenino , Infecciones por Fusobacterium/tratamiento farmacológico , Infecciones por Fusobacterium/microbiología , Fusobacterium necrophorum/aislamiento & purificación , Humanos , Venas Yugulares/patología , Síndrome de Lemierre/tratamiento farmacológico , Síndrome de Lemierre/microbiología , Masculino , Metronidazol/administración & dosificación , Enfermedades Raras/diagnóstico , Enfermedades Raras/tratamiento farmacológico , Enfermedades Raras/microbiología , Tromboflebitis/microbiología , beta-Lactamas/administración & dosificaciónRESUMEN
Giardia lamblia is an important and ubiquitous cause of diarrheal disease. The primary agents in the treatment of giardiasis are nitroheterocyclic drugs, particularly the imidazoles metronidazole and tinidazole and the thiazole nitazoxanide. Although these drugs are generally effective, treatment failures occur in up to 20% of cases, and resistance has been demonstrated in vivo and in vitro Prior work had suggested that side chain modifications of the imidazole core can lead to new effective 5-nitroimidazole drugs that can combat nitro drug resistance, but the full potential of nitroheterocycles other than imidazole to yield effective new antigiardial agents has not been explored. Here, we generated derivatives of two clinically utilized nitroheterocycles, nitrothiazole and nitrofuran, as well as a third heterocycle, nitropyrrole, which is related to nitroimidazole but has not been systematically investigated as an antimicrobial drug scaffold. Click chemistry was employed to synthesize 442 novel nitroheterocyclic compounds with extensive side chain modifications. Screening of this library against representative G. lamblia strains showed a wide spectrum of in vitro activities, with many of the compounds exhibiting superior activity relative to reference drugs and several showing >100-fold increase in potency and the ability to overcome existing forms of metronidazole resistance. The majority of new compounds displayed no cytotoxicity against human cells, and several compounds were orally active against murine giardiasis in vivo These findings provide additional impetus for the systematic development of nitroheterocyclic compounds with nonimidazole cores as alternative and improved agents for the treatment of giardiasis and potentially other infectious agents.
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Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Química Clic/métodos , Giardia lamblia/efectos de los fármacos , Nitrofuranos/química , Nitrofuranos/farmacología , Pirroles/farmacología , Tiazoles/farmacología , Pruebas de Sensibilidad Parasitaria , Pirroles/química , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
We report a highly robust, general and stereoselective method for the synthesis of 3-(chloromethylene)oxindoles from alkyne-tethered carbamoyl chlorides using PdCl2(PhCN)2 as the catalyst. The transformation involves a stereo- and regioselective chloropalladation of an internal alkyne to generate a nucleophilic vinyl PdII species, which then undergoes an intramolecular cross-coupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture and air, and is readily scalable. The products obtained from this reaction are formed with >95:5 Z:E selectivity in nearly all cases and can be used to access biologically relevant oxindole cores. Through combined experimental and computational studies, we provide insight into stereo- and regioselectivity of the chloropalladation step, as well as the mechanism for the C-C bond forming process. Calculations provide support for a mechanism involving oxidative addition into the carbamoyl chloride bond to generate a high valent PdIV species, which then undergoes facile C-C reductive elimination to form the final product. Overall, the transformation constitutes a formal PdII-catalyzed intramolecular alkyne chlorocarbamoylation reaction.
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Our increased understanding of ovarian cancer's blueprints (mediated by DNA and RNA) and behavior (mediated by proteins) points to wide differences across patients that cannot be depicted by histology alone. Conventional diagnosis usually entails an adequate tissue biopsy, which limits serial testing. There is thus a motivation to shift towards easier to obtain clinical samples (e.g., ascites or blood). In response, investigators are increasingly leveraging alternative circulating biomarkers in blood or proximal fluids and harnessing novel profiling platforms to help explore treatment-related effects on such biomarkers in serial fashion. In this review, we discuss how new nanotechnologies we developed intersect with alternative ovarian cancer biomarkers for improved understanding of metastases and therapeutic response.
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Biomarcadores de Tumor/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Nanotecnología/métodos , Células Neoplásicas Circulantes/metabolismo , Neoplasias Ováricas/metabolismo , Femenino , Humanos , Espectroscopía de Resonancia Magnética/instrumentación , Nanotecnología/instrumentación , Neoplasias Ováricas/diagnóstico , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide. It colonizes the lumen and epithelial surface of the small intestine, but does not invade the mucosa. Acute infection causes only minimal mucosal inflammation. Effective immune defenses exist, yet their identity and mechanisms remain incompletely understood. Interleukin (IL)-17A has emerged as an important cytokine involved in inflammation and antimicrobial defense against bacterial pathogens at mucosal surfaces. In this study, we demonstrate that IL-17A has a crucial function in host defense against Giardia infection. Using murine infection models with G. muris and G. lamblia, we observed marked and selective induction of intestinal IL-17A with peak expression after 2 weeks. Th17 cells in the lamina propria and innate immune cells in the epithelial compartment of the small intestine were responsible for the IL-17A response. Experiments in gene-targeted mice revealed that the cytokine, and its cognate receptor IL-17RA, were required for eradication of the parasite. The actions of the cytokine were mediated by hematopoietic cells, and were required for the transport of IgA into the intestinal lumen, since IL-17A deficiency led to marked reduction of fecal IgA levels, as well as for increased intestinal expression of several other potential effectors, including ß-defensin 1 and resistin-like molecule ß. In contrast, intestinal hypermotility, another major antigiardial defense mechanism, was not impacted by IL-17A loss. Taken together, these findings demonstrate that IL-17A and IL-17 receptor signaling are essential for intestinal defense against the important lumen-dwelling intestinal parasite Giardia.
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Anticuerpos Antiprotozoarios/biosíntesis , Giardia/inmunología , Giardiasis/inmunología , Inmunoglobulina A/biosíntesis , Interleucina-17/metabolismo , Animales , Anticuerpos Antiprotozoarios/inmunología , Linfocitos T CD4-Positivos/inmunología , Quimera , Giardia lamblia/inmunología , Células Madre Hematopoyéticas/inmunología , Inmunoglobulina A/inmunología , Interleucina-17/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Intestino Delgado/inmunología , Intestino Delgado/parasitología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Transducción de Señal/inmunología , Organismos Libres de Patógenos Específicos , Células Th17/inmunologíaRESUMEN
Pharmaceutically relevant methylene oxindoles are synthesized by a palladium(0)-catalyzed intramolecular chlorocarbamoylation reaction of alkynes. A relatively underexplored class of caged phosphine ligands is uniquely suited for this transformation, enabling high levels of reactivity and exquisite trans selectivity. This report entails the first transition-metal-catalyzed atom-economic addition of a carbamoyl chloride across an alkyne.
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We report our finding that by exploiting the synergistic steric effects between substrate and catalyst, an intramolecular Pd-catalyzed alkyne carbohalogenation can be achieved. This operationally simple method uses the bulky Pd/Q-Phos combination and allows access to tetrasubstituted vinyl halides from the corresponding aryl chlorides, bromides, and iodides. Steric effects in the substrate play a key role by promoting C sp 2-halogen reductive elimination and enabling catalytic turnover. Through a reversible oxidative addition mechanism, a thermodynamically driven isomerization reaction is observed at elevated temperatures. Thus by changing the reaction temperature, both stereoisomers of the reaction become readily accessible.
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Interleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogen Citrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transient C. rodentium infection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppress in vitro Th17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolving C. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.
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Citrobacter rodentium , Infecciones por Enterobacteriaceae/microbiología , Inflamación/microbiología , Interleucina-10/metabolismo , Envejecimiento , Animales , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/patología , Femenino , Regulación de la Expresión Génica/inmunología , Interleucina-10/genética , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
OBJECTIVE: Ruptured aortic aneurysm is a condition with a high rate of mortality that requires prompt surgical intervention. It has been noted that in some conditions requiring such prompt intervention, in-hospital mortality is increased in patients admitted on the weekends compared with patients admitted on weekdays. We sought to determine if this was indeed the case for both ruptured thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA) and to elucidate the possible reasons. METHODS: Using the Nationwide Inpatient Sample, a publicly available database of inpatient care, we analyzed the incidence of mortality among 7200 patients admitted on the weekends compared with weekdays for ruptured aortic aneurysm. Among these patients, 19% had a TAA and 81% had an AAA, and each group was analyzed for differences in mortality during the hospitalization. We adjusted for demographics, comorbid conditions, hospital characteristics, rates of surgical intervention, timing of surgical intervention, and use of additional therapeutic measures. RESULTS: Patients admitted on the weekend for both ruptured TAA and AAA had a statistically significant increase in mortality compared with those admitted on the weekdays (TAA: odds ratio, 2.55; 95% confidence interval, 1.77-3.68; P = .03; AAA: odds ratio, 1.32; 95% confidence interval, 1.13-1.55; P = .0004). Among those with TAA, a surgical intervention was performed on day of admission in 62.1% of weekday admissions vs 34.9% of weekend admissions (P < .0001). This difference was much smaller among those with an aortic aneurysm; 79.6% had a surgical intervention on day of admission on a weekday vs 77.2% on the weekend (P < .0001). CONCLUSIONS: Weekend admission for ruptured aortic aneurysm is associated with an increased mortality compared with admission on a weekday, and this is likely due to several factors including a delay in prompt surgical intervention.
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Atención Posterior , Aneurisma de la Aorta Abdominal/cirugía , Aneurisma de la Aorta Torácica/cirugía , Rotura de la Aorta/cirugía , Accesibilidad a los Servicios de Salud , Admisión del Paciente , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/diagnóstico , Aneurisma de la Aorta Abdominal/mortalidad , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/mortalidad , Rotura de la Aorta/diagnóstico , Rotura de la Aorta/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Tiempo de Tratamiento , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
Silyl ketene acetals and enol ethers are employed as reactive and functional group tolerant nucleophiles in the enantioselective rhodium-catalyzed alkylative ring opening of a diverse class of oxa/azabicyclic alkenes. This method provides access to enantioenriched dihydronaphthalene and cyclohexene scaffolds, which have the potential to be derivatized toward core motifs of naphthoquinone and sesquiterpene natural products.
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Acetales/química , Alquenos/química , Éteres/química , Etilenos/química , Cetonas/química , Catálisis , EstereoisomerismoRESUMEN
We describe a palladium-catalyzed Suzuki-type cross-coupling reaction of 2-pyridyl carbamoyl fluorides with boronic acids, which provides entry to medicinally relevant pyridyl amides. Mechanistic studies, including the synthesis and reactivity of carbamoyl Pd-F complexes, reveal the importance of both the fluoride electrophile and nitrogen directing group for aiding reactivity.