Literature Review: Investigating Drug Transport at the Blood-Brain Barrier and the Effects of P-glycoprotein on the Brain Distribution of Drugs.

The blood-brain barrier (BBB) is a unique barrier that strictly regulates the entry of endogenous substrates and xenobiotics into the brain. This is due to its tight junctions and the array of transporters and metabolic enzymes that are expressed. The determination of brain concentrations in vivo is difficult, laborious and expensive which means that there is interest in developing predictive tools of brain distribution. Predicting brain concentrations is important even in early drug development to ensure efficacy of central nervous system (CNS) targeted drugs and safety of non-CNS drugs. The literature review covers the most common current in vitro, in vivo and in silico methods of studying transport into the brain, concentrating on transporter effects. The consequences of efflux mediated by p-glycoprotein, the most widely characterized transporter expressed at the BBB, is also discussed. The aim of the experimental study was to build a pharmacokinetic (PK) model to describe p-glycoprotein substrate drug concentrations in the brain using commonly measured in vivo parameters of brain distribution. The possibility of replacing in vivo parameter values with their in vitro counterparts was also studied. All data for the study was taken from the literature. A simple 2-compartment PK model was built using the Stella™ software. Brain concentrations of morphine, loperamide and quinidine were simulated and compared with published studies. Correlation of in vitro measured efflux ratio (ER) from different studies was evaluated in addition to studying correlation between in vitro and in vivo measured ER. A Stella™ model was also constructed to simulate an in vitro transcellular monolayer experiment, to study the sensitivity of measured ER to changes in passive permeability and Michaelis-Menten kinetic parameter values. Interspecies differences in rats and mice were investigated with regards to brain permeability and drug binding in brain tissue. Although the PK brain model was able to capture the concentration-time profiles for all 3 compounds in both brain and plasma and performed fairly well for morphine, for quinidine it underestimated and for loperamide it overestimated brain concentrations. Because the ratio of concentrations in brain and blood is dependent on the ER, it is suggested that the variable values cited for this parameter and its inaccuracy could be one explanation for the failure of predictions. Validation of the model with more compounds is needed to draw further conclusions. In vitro ER showed variable correlation between studies, indicating variability due to experimental factors such as test concentration, but overall differences were small. Good correlation between in vitro and in vivo ER at low concentrations supports the possibility of using of in vitro ER in the PK model. The in vitro simulation illustrated that in the simulation setting, efflux is significant only with low passive permeability, which highlights the fact that the cell model used to measure ER must have low enough paracellular permeability to correctly mimic the in vivo situation.

Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature

Purpose: Congenital hereditary endothelial dystrophy 2 (CHED2) is an autosomal recessive disorder caused by mutations in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene. The purpose of this study was to identify the genetic cause of CHED2 in six Indian families and catalog all known mutations in the SLC4A11 gene. Methods: Peripheral blood samples were collected from individuals of the families with CHED2 and used in genomic DNA isolation. PCR primers were used to amplify the entire coding region including intron-exon junctions of SLC4A11. Amplicons were subsequently sequenced to identify the mutations. Results: DNA sequence analysis of the six families identified four novel (viz., p.Thr262Ile, p.Gly417Arg, p.Cys611Arg, and p.His724Asp) mutations and one known p.Arg869His homozygous mutation in the SLC4A11 gene. The mutation p.Gly417Arg was identified in two families. Conclusions: This study increases the mutation spectrum of the SLC4A11 gene. A review of the literature showed that the total number of mutations in the SLC4A11 gene described to date is 78. Most of the mutations are missense, followed by insertions-deletions. The present study will be helpful in genetic diagnosis of the families reported here.

Identification of miRNAs from French bean (Phaseolus vulgaris) under low nitrate stress

Objective: In this study, we report the role of miRNAs involved under nitrogen starvation from widely grown vegetable crop, French bean. In recent years, a great deal of attention has been paid to the elucidation of miRNAs involved in low nitrate stress. Methods: To identify miRNAs expressed under stress, cDNA libraries were analyzed. Results: We reported the nine potential miRNAs with 67 targets involved in nutrient transporters and other stress specific genes. Among the miRNA sequences obtained 6 sequences belong to miR172 family, one with miR169. RT-PCR analysis of expression of miR172 family was induced upon low nitrate stress while miR169 family was repressed. In addition, Pvu-SN7b and Pvu-miR16 may be new members of miRNA172 and miR169 families, respectively. Conclusion: The targets of Pvu-SN7b were major protein kinases, one among which is the Protein Kinase CK2. CK2 Kinase is found to involve in transcription-directed signaling, gene control and cell-cycle regulation. Other targets of Pvu-SN7b were involved in DNA-dependent transcription regulation, photo-periodism, calcium-mediated signaling. Pvu-miR16 targets Thymidine kinase, the key enzyme of deoxy-nucleotide synthesis. The cleavage of these targets affects cell proliferation there by affecting nodule formation. Pvu-miR8 inhibits translation of its target protein Pre-protein translocase, a membrane-bound protein transporter involved in trans-membrane protein transportation. Together these results denote the response and role of miRNAs to nitrate-limiting conditions in French bean.

A literature survey on the real-time computational simulation of biological organs

This paper lists some references that could in some way be relevant in the context of the real-time computational simulation of biological organs, the research area being defined in a very broad sense. This paper contains 198 references.

Peptide delta-Turn: Literature Survey and Recent Progress

Among the various types of a-peptide folding motifs, delta-turn, which requires a central cis-amide disposition, has been one of the least extensively investigated. In particular, this main-chain reversal topology has been studied in-depth neither in linear/cyclic peptides nor in proteins. This Minireview article assembles and critically analyzes relevant data from a literature survey on the d-turn conformation in those compounds. Unpublished results from recent conformational energy calculations and a preliminary solution-state analysis on a small model peptide, currently ongoing in our laboratories, are also briefly outlined.

Revenue management in remanufacturing: perspectives, review of current literature and research directions

The pace of development in the world has increased over the years and with it, the use of hi-tech gadgets, consumer durables, automobiles, etc. has also gone up. In this context, as resources become more and more scarce, there are multiple challenges that emerge both from a sustainable development perspective, and from the perspective of meeting profitability objectives of a firm. Remanufacturing has come up in a big way as an answer to these challenges, but firms are struggling with respect to revenue management of this nascent area. We assess the current literature and distil the key factors that firms need to consider as they assimilate remanufacturing in their operations and revenue management strategy. We provide an assessment of white spaces in research in this area and also outline the directions for future research.

La maurofilia en la poesía épica medieval

Resumen: El hispanista francés Georges Cirot fue el primero en emplear el término “maurofilia literaria” (maurophilie littéraire) en 1938 para referirse a la representación del valor y la nobleza de los moros en la literatura española del siglo XVI. Pero como señaló Ramón Menéndez Pidal (1957, 202), ya en los siglos XIV y XV los castellanos se habían sentido atraídos por los musulmanes de Granada, por su exótica civilización, su lujo en el vestir, la espléndida ornamentación de sus edificios y su modo de cabalgar, armarse y combatir. Francisco Márquez Villanueva (1984, 117-118) indicó que aunque la literatura maurófila del siglo XVI fue elaborada bajo el signo avanzado del humanismo cristiano, cuyas características fueron “el inconformismo y la sensibilidad para toda suerte de realidades en divergencia del mundo oficial”, las raíces de la maurofilia literaria se encuentran en el viejo romancero fronterizo y morisco elaborado en el siglo XV. En su opinión, el Romancero fue la patria de la “maurofilia pura” y es donde encontramos un cuadro de referencias temáticas “hecho de toponimia y onomástica, armas, indumentaria, policromía y cabalgadas” tendiente a caracterizar al moro como un ser refinado y superior. Para María Rosa Lida (1960, 355), en cambio, la imagen caballeresca del moro se remonta a don Juan Manuel, pues en sus obras aparecen las cortes musulmanas como “centros de molicie refinada y suntuosa”. En efecto, en el Libro de los estados se afirma el valor del moro como guerrero y en el Conde Lucanor aparecen una serie de reyes moros magnánimos y discretos. Sin embargo, el árabe como personaje sabio o “ejemplar” figura ya en una de las fuentes del Conde Lucanor, la Disciplina clericalis, obra compuesta a principios del siglo XII por el judío converso Pedro Alfonso. Por otra parte, el análisis de la representación de los moros en textos épicos, Avengalvón en el Poema de mio Cid y Almanzor en la Los siete infantes de Lara, nos permite descubrir un importante e insoslayable antecedente de la maurofilia de los últimos siglos de la Edad Media

La leyenda artúrica en la literatura alemana : el Parzival de Wolfram von Eschenbach

Integran este número de la revista ponencias presentadas en Studia Hispanica Medievalia VIII: Actas de las IX Jornadas Internacionales de Literatura Española Medieval, 2008, y de Homenaje al Quinto Centenario de Amadis de Gaula.

Del sueño cartesiano a la muerte encefálica

Resumen: Entre el sueño y la muerte hay “sólo una distancia”. El dormir encierra un misterio que se aviva con los sueños y, al parecer, habrían prefigurado al mismo método científico moderno. Descartes pensó que en sus sueños se transmitía el espíritu de la verdad. El alma soñadora e inmortal adquirió notoriedad en su dualismo, al tiempo que dejó de asociársela con la muerte. Tres siglos después, la medicina permitió identificar individuos que estaban muertos, aunque pareciesen dormidos (coma dépassé). Así reapareció la asociación sueño-muerte, pero ahora con médicos provistos del “diagnóstico anátomo-clínico” que, por su herencia cartesiana, demandará evidencias. La duda metódica integrada al pensamiento científico, aportaría incertidumbre a las formulaciones cerebrales de la muerte. Este trabajo repasa el valor de los sueños para el pensamiento occidental, busca al “hombre-máquina” dentro de los criterios neurológicos del fallecido y, con la ayuda de la Filosofía, intenta comprender algunas objeciones en torno a la licitud del diagnóstico de “muerte encefálica”. Se propone una revisión sucinta de la obra del filósofo francés y su reflejo en aspectos del debate ofrecido por la literatura médica.

Perseverancia y bien morir : el Baladro de Burgos visto desde su marco

Integran este número de la revista ponencias presentadas en Studia Hispanica Medievalia VIII: Actas de las IX Jornadas Internacionales de Literatura Española Medieval, 2008, y de Homenaje al Quinto Centenario de Amadis de Gaula

Las Prophetiae Merlini de Geoffrey de Monmouth en los Baladros castellanos: estado de la cuestión

Resumen: La Historia regum Britanniae (circa 1139) del obispo galés Geoffrey de Monmouth, texto destacado en el corpus latino medieval a causa de sus proyecciones tanto historiográficas como ficcionales, tiene como objeto referir los actos de todos los monarcas célticos de la Gran Bretaña anteriores a la conquista germánica. En este propósito, sus capítulos 112 a 117 obran como una mise en abîme puesto que las Prophetiae Merlini que allí se leen, atribuidas al famoso mago pero inspiradas en la literatura apocalíptica vétero y neotestamentaria, reproducen proféticamente las grandes líneas de contenido de la propia crónica, e incluso anticipan la restauración definitiva de los celtas derrotados. Aunque Wace, Chrétien de Troyes y la tradición romancística francesa posterior, deudora de la Historia en muchos puntos, desecharon el texto a causa de su agudo hermetismo, el mismo sí se difundió por el continente y reapareció asombrosamente interpolado, en versión castellana, dentro de dos tardíos ejemplares del género caballeresco hispánico, el Baladro del sabio Merlín con sus profecías (Burgos, 1498) y la primera parte de la Demanda del santo Grial (Sevilla, 1535). La presente comunicación tiene como objetivos reseñar los actuales conocimientos de la crítica acerca de esta versión castellana de las Prophetiae y señalar los problemas aún pendientes de resolución; serán consideradas las contribuciones fundamentales relativas al original latino y, también, a las versiones francesas conservadas, dada la posibilidad de que nuestra traducción tenga una fuente gala