Ca2+-regulated mitochondrial carriers of ATP-Mg2+/Pi: Evolutionary insights in protozoans.

In addition to its uptake across the Ca2+ uniporter, intracellular calcium signals can stimulate mitochondrial metabolism activating metabolite exchangers of the inner mitochondrial membrane belonging to the mitochondrial carrier family (SLC25). One of these Ca2+-regulated mitochondrial carriers (CaMCs) are the reversible ATP-Mg2+/Pi transporters, or SCaMCs, required for maintaining optimal adenine nucleotide (AdN) levels in the mitochondrial matrix representing an alternative transporter to the ADP/ATP translocases (AAC). This CaMC has a distinctive Calmodulin-like (CaM-like) domain fused to the carrier domain that makes its transport activity strictly dependent on cytosolic Ca2+ signals. Here we investigate about its origin analysing its distribution and features in unicellular eukaryotes. Unexpectedly, we find two types of ATP-Mg2+/Pi carriers, the canonical ones and shortened variants lacking the CaM-like domain. Phylogenetic analysis shows that both SCaMC variants have a common origin, unrelated to AACs, suggesting in turn that recurrent losses of the regulatory module have occurred in the different phyla. They are excluding variants that show a more limited distribution and less conservation than AACs. Interestingly, these truncated variants of SCaMC are found almost exclusively in parasitic protists, such as apicomplexans, kinetoplastides or animal-patogenic oomycetes, and in green algae, suggesting that its lost could be related to certain life-styles. In addition, we find an intricate structural diversity in these variants that may be associated with their pathogenicity. The consequences on SCaMC functions of these new SCaMC-b variants are discussed.

[Does a clinical prediction rule anticipate the diagnosis for streptococcal pharyngitis in children aged 2 to 15?] / Una regla de predicción clínica ¿anticipa el diagnóstico de la faringitis estreptocóccica en niños de 2 a 15 años?

BACKGROUND: The etiology of a streptococcal pharyngitis must be documented by laboratory techniques to avoid unnecessary antimicrobial treatment, but this strategy increases cost for the patient. Available scores applied in children or adults are imperfect. AIM: To develop a clinical prediction rule to aid the diagnostic process of streptococcal pharyngitis (SP) in children in a low-resource setting. METHODS: Three hundred and eighteen patients aged 2 to 15 years who were evaluated for suspected SP at the Pediatric Emergency Department and the Pediatric Ambulatory Unit of Red Salud UC-Christus entered the study. A throat culture and a rapid antigen detection test for Streptococcus pyogenes were obtained from each patient. Data were analyzed for possible clinical predictors of SP with univariate and multiple regression analyses. RESULTS: Seventy-three cases of SP were diagnosed (23.9%). In the univariate analysis, fever was inversely associated with SP (p = 0.002). Odynophagia, palatal petechiae, and season of the year (autumn and winter) were positively associated with SP (p = 0.007, p < 0.001 and p = 0.03 respectively). In multiple regression analysis the models did not have sufficient power to predict streptococcal etiology. CONCLUSION: Clinical predictors, even those systematically included in clinical prediction rules, did not show sufficient predictive power to safely include or exclude SP in this setting, and thus, it is necessary to improve access to confirmatory tests.

Una regla de predicción clínica ¿anticipa el diagnóstico de la faringitis estreptocóccica en niños de 2 a 15 años? / Does a clinical prediction rule anticipate the diagnosis for streptococcal pharyngitis in children aged 2 to 15?

Resumen Introducción: La etiología estreptocóccica de una faringitis debe ser confirmada con métodos de laboratorio para evitar un sobre-tratamiento antimicrobiano, exámenes que agregan costo a la atención del paciente. Los scores diseñados para aplicar en niños y adultos son imperfectos. Objetivo: Desarrollar una regla de predicción clínica para contribuir al diagnóstico de la faringitis estreptocóccica (FE) en niños. Pacientes y Métodos: Se incluyeron 318 pacientes de 2 a 15 años que fueron evaluados por sospecha de FE en el Servicio de Urgencias Pediátricas y la Unidad de Pediatría Ambulatoria de la Red Salud UC-Christus. Se obtuvo un cultivo faríngeo y una prueba rápida de detección de antígeno para Streptococcus pyogenes de cada paciente. Los datos se analizaron para posibles predictores clínicos de FE con análisis de regresión múltiple. Resultados. Setenta y tres casos de FE fueron diagnosticados (23,9%). En el análisis univariado, la fiebre se asoció inversamente con FE (p = 0,002). La odinofagia, las petequias palatinas y la estación del año (otoño e invierno) se asociaron positivamente con FE (p = 0,007, p < 0,001 y p = 0,03 respectivamente). En el análisis de regresión múltiple, los modelos no tuvieron suficiente poder para predecir etiología por S. pyogenes. Conclusión: Los predictores clínicos analizados, incluso los incluidos sistemáticamente en reglas de predicción clínica, no mostraron suficiente poder predictor para incluir o excluir de forma segura la FE en este contexto y, por lo tanto, sería necesario mejorar el acceso a las pruebas de confirmación.

Background: The etiology of a streptococcal pharyngitis must be documented by laboratory techniques to avoid unnecessary antimicrobial treatment, but this strategy increases cost for the patient. Available scores applied in children or adults are imperfect. Aim: To develop a clinical prediction rule to aid the diagnostic process of streptococcal pharyngitis (SP) in children in a low-resource setting. Methods: Three hundred and eighteen patients aged 2 to 15 years who were evaluated for suspected SP at the Pediatric Emergency Department and the Pediatric Ambulatory Unit of Red Salud UC-Christus entered the study. A throat culture and a rapid antigen detection test for Streptococcus pyogenes were obtained from each patient. Data were analyzed for possible clinical predictors of SP with univariate and multiple regression analyses. Results: Seventy-three cases of SP were diagnosed (23.9%). In the univariate analysis, fever was inversely associated with SP (p = 0.002). Odynophagia, palatal petechiae, and season of the year (autumn and winter) were positively associated with SP (p = 0.007, p < 0.001 and p = 0.03 respectively). In multiple regression analysis the models did not have sufficient power to predict streptococcal etiology. Conclusion: Clinical predictors, even those systematically included in clinical prediction rules, did not show sufficient predictive power to safely include or exclude SP in this setting, and thus, it is necessary to improve access to confirmatory tests.

Characterization of Help Desk issues After the Implementation of an Emergency Department Electronic Health Record.

Electronic health records (EHRs) can produce significant disruption when first implemented. Successful implementations depend on the availability of technical and clinical support. We present a description of the frequency and types of issues raised during the first 12 months after the implementation of an EHR at a teaching hospital in Santiago, Chile.

Evaluating the data completeness in the Electronic Health Record after the Implementation of an Outpatient Electronic Health Record.

Electronic health records (EHRs) present an opportunity for quality improvement in health organitations, particularly at the primary health level. However, EHR implementation impacts clinical workflows, and physicians frequently prefer to document in a non-structured way, which ultimately hinders the ability to measure quality indicators. We present an assessment of data completeness-a key data quality indicator-during the first 12 months after the implementation of an EHR at a teaching outpatient center in Santiago, Chile.

Asymmetric Synthesis of Fluorinated Isoindolinones through Palladium-Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates.

The asymmetric synthesis of fluorinated isoindolinones has been achieved by a palladium-catalyzed aminocarbonylation reaction of the corresponding α-fluoroalkyl o-iodobenzylamines. A base-mediated anti ß-hydride elimination process was suggested to explain the partial erosion of the optical purity observed in some cases. This mechanistic rationale enabled the minimization of this partial racemization by fine-tuning the pKa of the base.

Unique reactivity of fluorinated molecules with transition metals.

Organofluorine and organometallic chemistry by themselves constitute two potent areas in organic synthesis. Thus, the combination of both offers many chemical possibilities and represents a powerful tool for the design and development of new synthetic methodologies leading to diverse molecular structures in an efficient manner. Given the importance of the selective introduction of fluorine atoms into organic molecules and the effectiveness of transition metals in C-C and C-heteroatom bond formation, this review represents an interesting read for this aim.

Gold-catalyzed intramolecular hydroamination of o-alkynylbenzyl carbamates: a route to chiral fluorinated isoindoline and isoquinoline derivatives.

Enantiomerically pure fluorinated isoindoline and dihydroisoquinoline scaffolds have been prepared through a diastereoselective addition of fluorinated nucleophiles to Ellman's N-(tert-butanesulfinyl)imines followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate. A more favored 5-exo-dig mechanism was observed mainly due to an electronic effect of the fluorinated group.

Synthetic and biological applications of fluorous reagents as phase tags.

The search for new and better techniques for the purification of organic compounds has made the recent emergence of fluorous chemistry in the field of organic synthesis possible. Using fluorous reagents as phase tags allows for the access of different synthetic routes, and this has been translated into a time reduction and higher simplicity compared to standard, nonfluorous procedures. The synthesis in fluorous phase of target molecules can be pursued in a parallel or combinatorial manner in order to access chemical libraries with structural and/or stereochemical diversity. The preparation of radiolabeled molecules also benefits from the advantages of fluorous synthesis. Finally, biochemical tools such as microarrays or proteomic techniques are improved by means of fluorous-tagged compounds.

Molecular structures of citrus flavonoids determine their effects on lipid metabolism in HepG2 cells by primarily suppressing apoB secretion.

This study investigated the underlying mechanisms of action for blood lipid lowering effects of citrus flavonoids and their methoxylated analogues (n = 19; dose range: 0-100 µM) in HepG2 cells. Cholesterol (CH) and triglyceride (TG) syntheses were assessed by measuring the incorporation of (14)C-acetate and (14)C-glycerol, respectively, whereas apoB secretion was determined by ELISA. Results show that two polymethoxylated citrus flavonoids (PMFs), tangeretin and nobiletin, potently inhibited apoB secretion (IC(50) = 13 and 29 µM, respectively) and modestly inhibited CH synthesis (IC(50) = 49 and 68 µM) and TG synthesis (IC(50) = 14 and 73 µM), without effecting LDL-receptor activity. Other PMFs (e.g., sinensetin) and non-PMFs (e.g., hesperetin and naringenin) had only weak effects on CH and TG syntheses and apoB secretion (IC(50) > 100 µM). The structure-activity analysis indicated that a fully methoxylated A-ring of the flavonoid structure was associated with a potent inhibitory activity on hepatic apoB secretion. In conclusion, this study using HepG2 cells indicates that citrus flavonoids with a fully methoxylated A-ring may lower blood CH and TG concentrations primarily by suppressing hepatic apoB secretion as a main underlying mode of action.

Tandem asymmetric Michael reaction-intramolecular Michael addition. An easy entry to chiral fluorinated 1,4-dihydropyridines.

A novel one-pot tandem asymmetric Hantzsch-type process has been employed to generate fluorinated 1,4-dihydropyridines (1,4-DHPs) as single diastereoisomers. It involves the condensation of (R)-(+)-allyl p-tolyl sulfoxide, fluorinated nitriles, and alkyl propiolates, giving access to a new family of enantiomerically pure fluorine-containing 1,4-DHPs.

Asymmetric synthesis of indolines through intramolecular shifting of aromatic sulfinyl groups. Role of the pi,pi-stacking interactions in these unusual S(N)Ar processes.

Cyclization of N-aryl substituted 1-aryl-2[2-p-tolylsulfinyl]phenyl propylamines under LDA, LHMDS, or KHMDS provides a new approach for synthesizing optically pure 2,3-disubstituted indolines. Both the scope and the limitations of this method have been investigated. The pi,pi-stacking interactions are crucial for these unprecedented intramolecular S(N)Ar processes, in which a sulfinyl group located on a slightly deactivated ring is substituted by amide anions under mild conditions. X-ray and NMR proofs supporting these pi,pi-stacking interactions are presented.

A new strategy for the synthesis of optically pure beta-fluoroalkyl beta-amino acid derivatives.

The first general approach for the diastereoselective formation of a variety of optically pure anti-beta-fluoroalkyl beta-amino acid derivatives is described. The process relies on the stereocontrolled reaction, mediated by a remote sulfoxide, of fluorinated imines with sulfinylated benzyl carbanions, which are used as synthetic equivalents of chiral ester enolates.

Selective formal transesterification of fluorinated 2-(trimethylsilyl)ethyl alpha-imino esters mediated by TBAF.

The scope of the transesterification reaction between beta-fluorinated alpha-imino esters and various electrophiles in the presence of TBAF as fluorine source is described. The reaction is highly selective for alkyl iodides, bromides, and mesylates, while alkyl chlorides react at a significantly slower rate and tosylates do not react under the reaction conditions. This methodology represents a simple and useful alternative for the preparation of a wide variety of fluorinated alpha-imino esters.

Ausencia de correlación de variables clínicas con estudio etiológico en faringoamigdalitis aguda: estudio prospectivo de casos y controles / Absence of correlation between clinical variables and etiology of acute pharyngotonsillitis: prospective study of cases and controls

Introducción: La faringoamigdalitis aguda (FAA) es un cuadro infeccioso producido por numerosos agentes etiológicos, siendo Streptococcus pyogenes (SP) el más frecuentemente involucrado y el principal responsable de potenciales complicaciones. Objetivo: El objetivo del estudio fue determinar la prevalencia de éste y otros microorganismos en una muestra de población pediátrica y adulta. Material y método: Se diseñó un estudio prospectivo de casos y controles en pacientes que consultaron en forma consecutiva por odinofagia con signos de inflamación faringoamigdalina. Resultados: Se obtuvo un examen completo incluyendo un cultivo faríngeo en 159 pacientes entre 3 y 55 años. Entre los síntomas relevantes destacaron: cefalea, fiebre, adenopatíasy exudado. En adultos, 29 por ciento de las FAA fueron causadas por SP, mientras que en niños sólo 17 por ciento. En ningún paciente control se objetivó la presencia de SP. Conclusión: No existió correlación entre las características clínicas y la presencia de SP. De acuerdo a estos resultados se sugiere la realización rutinaria de un estudio etiológico al enfrentarse a una FAA.

Acute pharyngotonsillitis (APT) is an infectious disease that can be caused by numerous etiologic agents, with Streptococcus pyogenes (SP) being the most frequently involved and the main cause of potential complications. This study was aimed to determine the prevalence of this and other microorganisms in a sample of a pediatric and adult population. A prospective study of cases and controls was designed in patients that presented consecutively with odynophagia and pharyngotonsilar inflammation. A complete exam was performed, including pharyngeal culture in 159 patients between 3 and 55 years of age. Among relevant symptoms we found: headache, fever, lymphadenopathy and tonsilar exúdate. 29 percentofAPTs were caused by SP in adults, and only 17 percent In children. Conclusions: There was no correlation between clinical characteristics and SP presence. According to these results, a routine etiologic study is suggested when facing an APT.

Enantioselective organocatalytic intramolecular aza-Michael reaction: a concise synthesis of (+)-sedamine, (+)-allosedamine, and (+)-coniine.

The intramolecular aza-Michael reaction of carbamates bearing remote alpha,beta-unsaturated aldehydes under organocatalytic conditions took place with good yields and excellent ee's when Jørgensen catalyst IV was used in the process, giving rise to the enantioselective formation of several five- and six-membered heterocycles. The developed methodology was applied to the synthesis of three piperidine alkaloids.

Synthesis and biological evaluation of new bicyclic fluorinated uracils through ring-closing metathesis.

Two families of bicyclic fluorinated uracils have been prepared starting from a gem-difluorinated unsaturated nitrile, by means of a ring-closing metathesis reaction to form the new ring, which is fused at the C-5/C-6 or N-1/C-6 positions of the uracil moiety. The selective formation of olefin regioisomers in the metathesis process can be controlled according to the reaction conditions (catalyst, solvent, and temperature). The acaricidal activities of the resulting compounds have also been investigated.

A versatile synthesis of fluorinated uracils in solution and on solid-phase.

[reaction: see text] An efficient and convenient two-step synthesis of new fluorinated uracils is described. The first step involves the condensation of an ester enolate with a fluorinated nitrile to furnish fluorinated beta-enamino esters. In turn, these compounds react with organic isocyanates or isothiocyanates to give C-6 fluorinated uracils or thiouracils, respectively, in excellent yields. This synthesis has been successfully adapted to solid-phase conditions with high diversity, thereby facilitating the creation of small (thio)uracil libraries.