A parsimonious score with a free web tool for predicting disability after an ischemic stroke: the Parsifal Score.

BACKGROUND: Most of the models to predict prognosis after an ischemic stroke include complex mathematical equations or too many variables, making them difficult to use in the daily clinic. We want to predict disability 3 months after an ischemic stroke in an independent patient not receiving recanalization treatment within the first 24 h, using a minimum set of variables and an easy tool to facilitate its implementation. As a secondary aim, we calculated the capacity of the score to predict an excellent/devastating outcome and mortality. METHODS: Eight hundred and forty-four patients were evaluated. A multivariable ordinal logistic regression was used to obtain the score. The Modified Rankin Scale (mRS) was used to estimate disability at the third month. The results were replicated in another independent cohort (378 patients). The "polr" function of R was used to perform the regression, stratifying the sample into seven groups with different cutoffs (from mRS 0 to 6). RESULTS: The Parsifal score was generated with: age, previous mRS, initial NIHSS, glycemia on admission, and dyslipidemia. This score predicts disability with an accuracy of 80-76% (discovery-replication cohorts). It has an AUC of 0.86 in the discovery and replication cohort. The specificity was 90-80% (discovery-replication cohorts); while, the sensitivity was 64-74% (discovery-replication cohorts). The prediction of an excellent or devastating outcome, as well as mortality, obtained good discrimination with AUC > 0.80. CONCLUSIONS: The Parsifal Score is a model that predicts disability at the third month, with only five variables, with good discrimination and calibration, and being replicated in an independent cohort.

DNA-based nanoscaffolds as vehicles for 5-fluoro-2'-deoxyuridine oligomers in colorectal cancer therapy.

Fluoropyrimidines, such as 5-fluorouracil (5-FU) and related prodrugs, are considered one of the most successful agents in the treatment of colorectal cancer, yet poor specificity and tumor cell resistance remain the major limiting bottlenecks. Here, we exploited for the first time the ability of two DNA nanoscaffolds, a DNA tetrahedron (Td) and rectangle DNA origami, to incorporate 5-fluoro-2'-deoxyuridine (FdUn) oligomers. In addition, cholesterol moieties were synthetically attached to Td and DNA origami staples to enhance cellular uptake. DNA nanostructures functionalized with FdUn exhibited an enhanced cytotoxicity and higher ability to trigger apoptosis in colorectal cancer cells relative to conventional 5-FU and FdU, especially having cholesterol as an internalization helper. The cholesterol content mostly correlates with the increase of the FdUn nanostructure cytotoxicity. DNA nanoscaffolds bearing FdUn were able to circumvent the low sensitivity of colorectal cancer cells towards 5-FU. Both DNA nanostructures attained a comparable cytotoxic effect yet Td displays higher antiproliferative action. The ability to reduce the proliferation of cancer cells is mainly related to the concentration of DNA nanostructures. The present work suggests that self-assembled DNA nanoparticles are privileged vehicles for delivering fluoropyrimidines, opening new avenues to the development of promising therapeutics for cancer treatment.

La resistencia en el tratamiento secundario del ictus isquémico, el componente genético en la respuesta a ácido acetilsalicílico y clopidogrel / Drug resistance and secondary treatment of ischaemic stroke: The genetic component of the response to acetylsalicylic acid and clopidogrel

Introducción: Las enfermedades cerebrovasculares están entre las principales causas de mortalidad y discapacidad en los países desarrollados. El ácido acetilsalicílico (AAS) y el clopidogrel son los tratamientos antiagregantes plaquetarios más utilizados para la profilaxis de nuevos eventos tromboembólicos. Sin embargo, se han observado casos en los que el tratamiento antiagregante no inhibe la actividad plaquetaria, un fenómeno llamado resistencia y que posiblemente puede estar modulado a nivel genético. Desarrollo: Tras una búsqueda bibliográfica se realizó una revisión sobre el estado actual del tratamiento antiagregante plaquetario. Se tratan los diferentes tipos de resistencia a la terapia antiagregante, de qué manera se mide, la problemática y limitaciones actuales, así como los factores genéticos que se han asociado a esta resistencia. Principalmente se analizan los estudios genéticos realizados en el campo de la resistencia a AAS y clopidogrel mediante Genome Wide Association. Conclusiones: Parece existir una asociación entre diferentes factores genéticos y la resistencia a los fármacos antiagregantes medida mediante la actividad plaquetaria; no obstante, no hay una asociación evidente entre estos factores genéticos y el riesgo de nuevos eventos tromboembólicos

Introduction: Cerebrovascular diseases are among the leading causes of death and disability in developed countries. Acetylsalicylic acid (ASA) and clopidogrel are the most widely-used antiplatelet drugs for secondary prevention of recurrent thromboembolic events. However, there have been cases in which antiplatelet drugs did not inhibit platelet activity; this phenomenon is called resistance, and it may be modulated at the genetic level. Development: Following a literature search, we reviewed the current state of antiplatelet therapy and covered the different types of resistance to antiplatelet therapy, how it is measured, current problems and limitations, and any genetic factors that have been associated with resistance. We mainly used the Genome Wide Association Studies in the field of ASA and clopidogrel resistance. Conclusions: We observed an association between different genetic factors and antiplatelet drug resistance as measured by platelet activity. However, there is no evident association between these genetic factors and risk of new thromboembolic events

Drug resistance and secondary treatment of ischaemic stroke: The genetic component of the response to acetylsalicylic acid and clopidogrel.

INTRODUCTION: Cerebrovascular diseases are among the leading causes of death and disability in developed countries. Acetylsalicylic acid (ASA) and clopidogrel are the most widely-used antiplatelet drugs for secondary prevention of recurrent thromboembolic events. However, there have been cases in which antiplatelet drugs did not inhibit platelet activity; this phenomenon is called resistance, and it may be modulated at the genetic level. DEVELOPMENT: Following a literature search, we reviewed the current state of antiplatelet therapy and covered the different types of resistance to antiplatelet therapy, how it is measured, current problems and limitations, and any genetic factors that have been associated with resistance. We mainly used the Genome Wide Association Studies in the field of ASA and clopidogrel resistance. CONCLUSIONS: We observed an association between different genetic factors and antiplatelet drug resistance as measured by platelet activity. However, there is no evident association between these genetic factors and risk of new thromboembolic events.

Registro de ensayos clínicos en pediatría / No disponible

No disponible

Synthesis and properties of oligonucleotides containing 8-bromo-2'-deoxyguanosine.

The preparation of oligonucleotides containing 8-bromo-2'-deoxyguanosine is described. Substitution of G by 8-bromoguanine on an alternating CG decamer stabilizes the Z-form in such a way that the B-form was not observed. Melting temperatures showed that duplexes in which 8-bromo-2'-deoxyguanosine paired with natural bases were much less stable.

An aminoacyl tRNA synthetase whose sequence fits into neither of the two known classes.

Aminoacyl transfer RNA synthetases catalyse the first step of protein synthesis and establish the rules of the genetic code through the aminoacylation of tRNAs. There is a distinct synthetase for each of the 20 amino acids and throughout evolution these enzymes have been divided into two classes of ten enzymes each. These classes are defined by the distinct architectures of their active sites, which are associated with specific and universal sequence motifs. Because the synthesis of aminoacyl-tRNAs containing each of the twenty amino acids is a universally conserved, essential reaction, the absence of a recognizable gene for cysteinyl tRNA synthetase in the genomes of Archae such as Methanococcus jannaschii and Methanobacterium thermoautotrophicum has been difficult to interpret. Here we describe a different cysteinyl-tRNA synthetase from M. jannaschii and Deinococcus radiodurans and its characterization in vitro and in vivo. This protein lacks the characteristic sequence motifs seen in the more than 700 known members of the two canonical classes of tRNA synthetase and may be of ancient origin. The existence of this protein contrasts with proposals that aminoacylation with cysteine in M. jannaschii is an auxiliary function of a canonical prolyl-tRNA synthetase.

Studies on the synthesis of oligonucleotides containing photoreactive nucleosides: 2-azido-2'-deoxyinosine and 8-azido-2'-deoxyadenosine.

Oligonucleotides containing the photoreactive nucleosides 2-azido-2'-deoxyinosine and 8-azido-2'-deoxyadenosine have been prepared using protected 2-fluoro-2'-deoxyinosine and 8-bromo-2'-deoxyadenosine phosphoramidites. After the assembly of the oligonucleotides, the nucleoside derivatives are converted to the corresponding azido derivatives by treatment with lithium azide in dry DMF. Deprotection of oligonucleotides carrying these azidonucleosides is performed with concentrated ammonia at room temperature.

NMR study of the conformation of the 2-aminopurine:cytosine mismatch in DNA.

DNA polymerase makes errors by misincorporating natural DNA bases and base analogs. Because of the wide variety of possible mismatches and the varying efficiency with which they are repaired, structural studies are necessary to understand in detail how these mispairs differ and can be distinguished from standard Watson-Crick base pairs. 2-Aminopurine (AP) is a highly mutagenic base analog. The objective of this study was to determine the geometry of the AP x C mispair in DNA at neutral pH. Although several studies have focused on the AP x C mispair in DNA, there is not as of yet consensus on its structure. At least four models have been proposed for this mispair. Through the use of NMR spectroscopy with selective 15N-labeling of exocyclic amino nitrogens on bases of interest, we are able to resolve ambiguities in previous studies. We find here that, in two different DNA sequences, the AP x C mispair at neutral and high pH is in a wobble geometry. The structure and stability of this base mispair is dependent upon the local base sequence.

Synthesis and properties of oligonucleotides containing the mutagenic base O4-benzylthymidine.

The preparation of synthetic oligodeoxynucleotides containing O4-benzylthymidine (Tbn) is described. The use of standard and t-butylphenoxyacetyl amino protecting groups is compared. The thermal stabilities of duplexes containing Tbn paired with adenine and guanine have been measured.

A simple method for N-15 labelling of exocyclic amino groups in synthetic oligodeoxynucleotides.

The use of the ammonia deprotection step to introduce (15)N labels at specific exocyclic amino positions of adenine, cytosine, guanine or 2-aminopurine of oligodeoxynucleotides is described.

[Diagnosis of ornithine carbamoyl transferase deficiency and heterozygote detection with allopurinol loading test]. / Diagnóstico de la deficiencia de ornitina carbamil transferasa y detección de heterozigotas mediante la prueba de sobrecarga de alopurinol.

BACKGROUND: Allopurinol loading test is based on the inhibition of pyrimidine biosynthesis and the subsequent increase in orotic acid excretion caused by a single dose of allopurinol. Abnormally elevated amounts of orotic acid excretion are demonstrated in ornithine carbamoyl transferase (OCT) deficiency patients and heterozygotes as well as in other disorders of urea cycle. Biochemical studies performed for the diagnosis of one patient and carrier detection in her family are presented. METHODS: Amino acids: ion exchange chromatography; ammonium: method of Van Anken and Shiphorst; orotic acid: modification of Adachi et al, and allopurinol test following Brusilow et al. RESULTS: The characteristic amino acid profile of the patient together with her clinical history suggested the diagnosis of OCT deficiency, which was confirmed with protein and allopurinol loading test. The heterozygote condition became evident only by means of allopurinol test in 2/5 female relatives. CONCLUSIONS: Allopurinol test is a useful tool for the preliminary investigation of urea cycle function, avoiding the possible hyperammonemia caused by other test, and permitting extensive familial studies without hospitalization. It results more informative than the protein loading test.

[Biliary peritonitis after hepatic biopsy: favorable course with conservative medical treatment]. / Peritonitis biliar postbiopsia hepática: evolución favorable con tratamiento médico conservador.

In a 53-year-old woman a percutaneous liver biopsy was performed with tru-cut to study persistent hypertransaminasemia. The patient did not present extrahepatic cholestasis. Immediately after biopsy the patient had a picture of biliary peritonitis that evolved favorably with conservative medical treatment, including hemodynamic resuscitation, antibiotic therapy, analgesic treatment and monitoring by the resuscitation service. A review is made of the literature on this complication of liver biopsy and treatment is discussed.

Endoscopic hemostasis by injection therapy and electro-hydro-coagulation in high-risk patients with active gastroduodenal bleeding ulcer.

For the purpose of arresting hemorrhage from bleeding gastric or duodenal ulcers we developed, in 28 high-risk patients, a new method of endoscopic local injection of epinephrine (1:10,000) followed by electro-hydro monopolar coagulation and injection of Polidocanol (1%). Nine patients had signs of shock at the time of admission. The average blood requirements were 3.9 units in the first 24 hours. All patients had important factors militating against surgery, namely age and serious primary disease. In 26 out of 28 patients (92.8%) hemostasis was accomplished during endoscopy. Three patients (10.7%) rebled within the first 36 hours, requiring emergency surgery. Thus definitive hemostasis was achieved in 23 patients (82.1%). There were no complications as a result of endoscopic treatment.