Efficacy and safety of FOLFIRI/aflibercept (FA) in an elderly population with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen.

BACKGROUND: The VELOUR study showed the benefit of FOLFIRI-Aflibercept (FA) versus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in second-line treatment. However, only 36% of the included patients were ≥65 years. Thus, we seek to evaluate the efficacy and safety of FA in the elderly population in the context of routine practice. MATERIALS AND METHODS: We conducted an observational, retrospective, multicenter, observational study of patients ≥70 years with mCRC treated with FA after progression to oxaliplatin chemotherapy in routine clinical practice in 9 hospitals of the GITuD group. RESULTS: Of 388 patients treated with FA between June 2013 and November 2018, 75 patients ≥70 years were included. The median number of cycles was 10 and the objective response (ORR) and disease control rates (DCR) were 33.8% and 72.0%, respectively. With a median follow-up of 27.1 months, median Progression-free survival (PFS) was 6.6 months and median Overall Survival (OS) was 15.1 months. One third fewer metastasectomies were performed in the ≥75 years' subgroup (24 vs. 52%, p = 0.024) and more initial FOLFIRI dose reductions (68 vs. 36%, p = 0.014). ORR (23.8% vs. 38.3%), DCR (42.8% vs. 85.1%), and PFS (4 vs. 7.8 months; p = 0.017) were significantly less, without difference in OS (9.9 vs. 17.1 months; p = 0.129). The presence of prior hypertension (HT) (PFS 7.9 vs. 5.7 months, p = 0.049) and HT ≥ grade 3 during treatment (PFS 7.6 vs. 6.6 months, p = 0.024) were associated with longer PFS. The most frequent grade 3/4 adverse events were: asthenia (21.3%), neutropenia (14.7%), and diarrhea (14.7%). 57.3% required FOLFIRI dose reduction; 34.7% of aflibercept, including discontinuation (5.3% and 18.7%, respectively). CONCLUSIONS: FA combination is effective in patients ≥70 years. The occurrence of HT is predictive of efficacy. Close monitoring of toxicity and initial dose adjustment is recommended.

Depresión y ansiedad y su relación con el perfil antropométrico de los pacientes en rehabilitación cardíaca fases I y II / Depression and anxiety and their relationship with the anthropometric profile of patients in Cardiac Rehabilitation Phases I and II

RESUMEN Introducción: La depresión es una alteración del estado mental que afecta a muchas personas alrededor del mundo y que, junto con la ansiedad, constituye un problema a nivel mundial que puede afectar a los pacientes en el período posquirúrgico cardiovascular. Objetivo: Determinar los niveles de depresión y ansiedad, y su relación con el sobrepeso y la obesidad, en pacientes que asisten a rehabilitación cardíaca fases I y II. Método: Se hizo la selección de 50 participantes de rehabilitación cardíaca (25 de fase I y 25 en fase II). Se utilizó la Hospital Anxiety and Depression Scale (HADS) para la detección de trastornos de ansiedad y depresión. Además, se valoró la antropometría de los participantes y se realizaron pruebas de normalidad de Kolmogorov-Smirnov y Shapiro-Wilk; como también, la media, desviación estándar y el coeficiente de correlación de Pearson con un grado significativo de p<0,05. Resultados: Los 50 participantes (66% hombres) tenían una edad promedio de 63,86±10,99, con diagnósticos posoperatorios de revascularización miocárdica (44%), angioplastia coronaria (40%), enfermedad aterosclerótica (4%), reemplazo de válvula aórtica (4%), cierre de comunicación interauricular (4%), marcapasos implantado (2%) y desacondicionamiento físico (2%). Se encontró una depresión de 36% y ansiedad de 30%. Conclusiones: Existe una alta prevalencia de depresión y ansiedad en los programas de rehabilitación cardíaca, su frecuencia es mayor en la fase I en comparación con la II. Además, se encontró que existe una correlación moderada leve entre la ansiedad y el normopeso y la obesidad, al igual que entre la depresión frente al sobrepeso.

ABSTRACT Introduction: Depression is a mental state disorder that affects a good number of people around the world and that, along with anxiety, is a wide-reaching problem that can strike patients after undergoing heart surgery. Objective: To determine the levels of depression and anxiety, and their relationship with overweight and obesity, in patients attending cardiac rehabilitation phases I and II. Method: Fifty patients receiving cardiac rehabilitation (25 in phase I and 25 in phase II) were selected. The Hospital Anxiety and Depression Scale (HADS) was used to screen anxiety and depression disorders. In addition, the anthropometry of the participants was examined and Kolmogorov-Smirnov and Shapiro-Wilk normality tests were performed. Mean, standard deviation and Pearson correlation coefficient with a significant degree of p<0.050 were also applied. Results: The 50 participants (66% men) had an average age of 63.86±10.99, with postoperative diagnosis of coronary-artery bypass grafting (44%), coronary angioplasty (40%), atherosclerotic disease (4%), aortic valve replacement (4%), atrial septal defect closure (4%), implanted pacemaker (2%) and physical deconditioning (2%). Depression was found at 36% and anxiety at 30%. Conclusions: There is a high prevalence of depression and anxiety in cardiac rehabilitation programs; its frequency is higher in phase I compared to phase II. Moreover, we found that there is a slight-mild correlation between anxiety versus normal weight and obesity, as well as depression versus overweight.

Anti-herpetic and anti-dengue activity of abietane ferruginol analogues synthesized from (+)-dehydroabietylamine.

The abietane-type diterpenoid (+)-ferruginol (1), a bioactive compound isolated from several plants, has attracted much attention as consequence of its pharmacological properties, which includes antibacterial, antifungal, antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and antitumor actions. In this study, we report on the antiviral evaluation of ferruginol (1) and several analogues synthesized from commercial (+)-dehydroabietylamine. Thus, the activity against Human Herpesvirus type 1, Human Herpesvirus type 2 and Dengue Virus type 2, was studied. Two ferruginol analogues showed high antiviral selectivity index and reduced viral plaque-size in post-infection stages against both Herpes and Dengue viruses. A promising lead, compound 8, was ten-fold more potent (EC50 = 1.4 µM) than the control ribavirin against Dengue Virus type 2. Our findings suggest that the 12-hydroxyabieta-8,11,13-triene skeleton, which is characteristic of the diterpenoid ferruginol (1), is an interesting molecular scaffold for development of novel antivirals. In addition, the cytotoxic and antifungal activities of the synthesized ferruginol analogues have also been investigated. (©)20155 Elsevier Science. All rights reserved.

Computational Identification of Dengue Virus MicroRNA-Like Structures and their Cellular Targets.

MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate transcriptional and posttranscriptional gene regulation of the cell. Experimental evidence shows that miRNAs have a direct role in different cellular processes, such as immune function, apoptosis, and tumorigenesis. In a viral infection context, miRNAs have been connected with the interplay between host and pathogen, occupying a major role in pathogenesis. While numerous viral miRNAs from DNA viruses have been identified, characterization of functional RNA virus-encoded miRNAs and their potential targets is still ongoing. Here, we used an in silico approach to analyze dengue Virus genome sequences. Pre-miRNAs were extracted through VMir software, and the identification of putative pre-miRNAs and mature miRNAs was accessed using Support Vector Machine web tools. The targets were scanned using miRanda software and functionally annotated using ClueGo. Via computational tools, eight putative miRNAs were found to hybridize with numerous targets of morphogenesis, differentiation, migration, and growth pathways that may play a major role in the interaction of the virus and its host. Future approaches will focus on experimental validation of their presence and target messenger RNA genes to further elucidate their biological functions in human and mosquito cells.

Utilidad del EuroSCORE en la predicción de mortalidad intrahospitalaria en una institución de enfermedades cardiovasculares de Colombia / Usefulness of EuroSCORE in predicting hospital mortality in an institution of cardiovascular diseases in Colombia

Introducción: en ausencia de datos nacionales sobre el tema, los autores se propusieron evaluar la utilidad del European System for Cardiac Operative Risk Evaluation (EuroSCORE) en la predicción de mortalidad intrahospitalaria en una institución cardiovascular de Colombia. Métodos: desde agosto de 2008 a diciembre de 2010, se siguió una cohorte de 750 pacientes adultos sometidos a procedimientos como: revascularización miocárdica, cambios valvular aórtico o mitral u otras cirugías cardiacas. Para todos ellos se calculó el EuroSCORE logístico y se estimó su relación con la mortalidad intrahospitalaria. Resultados: la mortalidad observada fue significativamente inferior a la esperada según el EuroSCORE (5,9% vs. 8,1%; RR = 0,73; IC95%: 0,51-0,94; p=0,03). El EuroSCORE mostró un área bajo la curva ROC de 86,1% (IC95%: 80,4%-90,7%) para la predicción de este evento. Se observó un patrón de incremento de la mortalidad por un factor de 1,07 (IC95%: 1,05-1,08; p<0,001) por cada cambio de un punto en el EuroSCORE. Al agrupar los pacientes sometidos a revascularización y cambios valvulares, el área bajo la curva ROC del EuroSCORE alcanzó el 90,3% (IC95%: 80,3%-100%), superior a lo observado en otros procedimientos (80,9%; IC95%: 72,7%-89%). Sin embargo, esta diferencia no alcanzó significancia estadística (p=0,15). Conclusiones: EuroSCORE fue útil para predecir mortalidad; sin embargo, los valores observados estuvieron por debajo de los esperados y su utilidad pareció variar de acuerdo con la intervención. Por tanto, se justifica realizar estudios de mayor magnitud para validar esta escala en diferentes procedimientos o proponer una escala basada en datos locales.

Introducción: en ausencia de datos nacionales sobre el tema, los autores se propusieron evaluar la utilidad del European System for Cardiac Operative Risk Evaluation (EuroSCORE) en la predicción de mortalidad intrahospitalaria en una institución cardiovascular de Colombia. Métodos: desde agosto de 2008 a diciembre de 2010, se siguió una cohorte de 750 pacientes adultos sometidos a procedimientos como: revascularización miocárdica, cambios valvular aórtico o mitral u otras cirugías cardiacas. Para todos ellos se calculó el EuroSCORE logístico y se estimó su relación con la mortalidad intrahospitalaria. Resultados: la mortalidad observada fue significativamente inferior a la esperada según el EuroSCORE (5,9% vs. 8,1%; RR = 0,73; IC95%: 0,51-0,94; p=0,03). El EuroSCORE mostró un área bajo la curva ROC de 86,1% (IC95%: 80,4%-90,7%) para la predicción de este evento. Se observó un patrón de incremento de la mortalidad por un factor de 1,07 (IC95%: 1,05-1,08; p<0,001) por cada cambio de un punto en el EuroSCORE. Al agrupar los pacientes sometidos a revascularización y cambios valvulares, el área bajo la curva ROC del EuroSCORE alcanzó el 90,3% (IC95%: 80,3%-100%), superior a lo observado en otros procedimientos (80,9%; IC95%: 72,7%-89%). Sin embargo, esta diferencia no alcanzó significancia estadística (p=0,15). Conclusiones: EuroSCORE fue útil para predecir mortalidad; sin embargo, los valores observados estuvieron por debajo de los esperados y su utilidad pareció variar de acuerdo con la intervención. Por tanto, se justifica realizar estudios de mayor magnitud para validar esta escala en diferentes procedimientos o proponer una escala basada en datos locales.

Implementación de un control interno en la detección molecular de las principales especies de micoplasmas contaminantes de cultivos celulares / Implementation of an internal control in molecular detection of the main mycoplasma species contaminating cell cultures

Objetivo: Construir e implementar un control interno para la detección molecular de micoplasmas en cultivos celulares. Materiales y métodos: Se alinearon secuencias del RNA ribosomal 16S de las principales especies de micoplasmas reportadas como contaminantes de cultivos, y diseñaron oligonucleótidos para la detección de las mismas. Para la construcción del control interno se amplificó una secuencia espadadora, además de las secuencias de hibridación de los oligonucleótidos usados para detección. La amplificación desde dicho control generó un fragmento con tamaño diferente al obtenido desde una muestra positiva. Posteriormente, para la evaluación del efecto del control interno sobre la amplificación de una muestra positiva se realizó la prueba sobre diluciones seriadas de la muestra, en presencia y ausencia del control interno. Finalmente, se ensayó el protocolo utilizando sobrenadantes de cultivo provenientes de diferentes laboratorios. Resultados: Se observó alta homogeneidad al comparar los géneros Mycoplasma y Acholeplasma; no obstante se realizó el diseño de oligonucleótidos degenerados para aumentar teóricamente la eficiencia en la detección de todas las especies. Se demostró que la aplicación del control interno no afecta la sensibilidad de detección de la prueba. Los resultados obtenidos con muestras problema resaltan la importancia del control interno al realizar la prueba desde sobrenadantes de cultivo. Conclusiones: El uso del control interno evita la obtención de resultados falsos negativos, generados por presencia de inhibidores en la muestra. La implementación de la prueba beneficiará los laboratorios en cuyas investigaciones utilicen cultivos celulares y permitirá ejercer un control de calidad, lo cual hará más confiables los resultados/productos obtenidos.

Objective: to construct and implement an internal control for molecular detection of mycoplasma in cell cultures. Materials and Methods: Sequences of 16S ribosomal RNA of the major species of mycoplasma reported as contaminants in cell cultures were aligned, and oligonucleotides for detection were designed. For the construction of the internal control, a spacer sequence as well as sequences for hybridization of the oligonucleotides used for detection, were amplified. Amplification from the internal control and positive samples generated fragments with different sizes. Subsequently, to evaluate the effect of the internal control on the amplification of a positive sample, the assay was performed on serial dilutions of the sample in the presence and absence of the internal control. Finally, the protocol was tested using culture supernatants from different laboratories. Results: High homogeneity was observed when Mycoplasma and Acholeplasma genera were compared; however, degenerated oligonucleotides were designed to increase the efficiency of detection in all the analyzed species. It was shown that implementation of the internal control does not affect the sensitivity of detection. The results obtained with cell cultures samples highlighted the importance of the internal control. Conclusions: The use of an internal control facilitates the detection of false negative results generated by the presence of inhibitors in the sample. Implementation of the test as a quality control will benefit laboratories using cell cultures, making the results and / or products obtained more reliable.

Detección molecular y tipificación del virus dengue por RT-PCR y PCR anidada usando oligonucleótidos mejorados / Molecular detection and typing of dengue virus by RT-PCR and nested PCR using degenerated oligonucleotides

Objetivos: Modificar los oligonucleótidos comúnmente utilizados para la detección y tipificación del virus dengue y evaluar su desempeño sobre ARNs provenientes de muestras clínicas. Materiales y métodos: A partir del alineamiento de secuencias disponibles en el GenBank para la región C-prM/M se determinó la variabilidad genética dentro de cada serotipo del virus dengue, lo cual permitió realizar modificaciones a los oligonucleótidos convencionalmente usados en la tipificación. Tales modificaciones incluyeron la adición y eliminación de nucleótidos en el extremo 3', teniendo en cuenta la posición del codón, así como la inclusión de sitios degenerados en posiciones altamente variables. Los oligonucleótidos se evaluaron a diferentes concentraciones sobre ARNs extraídos a partir de cultivos celulares infectados y posteriormente de sueros de pacientes con diagnóstico probable de dengue. Resultados: Los oligonucleótidos amplificaron específicamente cada serotipo del virus dengue, tanto desde sobrenadantes de cultivo como desde muestras clínicas en prueba piloto. Conclusiones: El rediseño de los oligonucleótidos consideró la variabilidad genética acumulada en más de 15 años, mostrándose experimentalmente su valor y utilidad en la detección y tipificación del virus dengue.

Objective: To modify the commonly used primers for detecting and typing of dengue viruses and evaluate their performance on RNAs derived from clinical samples. Materials and methods: To determine the genetic variability within each dengue virus serotype, sequences of C-prM/M region available on GenBank were aligned allowing modifications to the primers conventionally used for virus typing. Modifications include nucleotide insertion and deletion in the 3' end taking into account the codon position, and also the inclusion of degenerated sites in highly variable positions. Primers were evaluated at different concentrations on extracted RNAs from infected cell cultures and subsequently from sera of probable dengue diagnosed patients. Results: All primers specifically amplified each dengue virus serotype from cell culture supernatants and clinical samples in a pilot test. Conclusions: The re-designed primers took into account the accumulated variability during more than 15 years, experimentally showing their value and utility for detecting and typing of dengue viruses.

Phylogenetic reconstruction of dengue virus type 2 in Colombia.

BACKGROUND: Dengue fever is perhaps the most important viral re-emergent disease especially in tropical and sub-tropical countries, affecting about 50 million people around the world yearly. In Colombia, dengue virus was first detected in 1971 and still remains as a major public health issue. Although four viral serotypes have been recurrently identified, dengue virus type 2 (DENV-2) has been involved in the most important outbreaks during the last 20 years, including 2010 when the fatality rate highly increased. As there are no major studies reviewing virus origin and genotype distribution in this country, the present study attempts to reconstruct the phylogenetic history of DENV-2 using a sequence analysis from a 224 bp PCR-amplified product corresponding to the carboxyl terminus of the envelope (E) gene from 48 Colombian isolates. RESULTS: As expected, the oldest isolates belonged to the American genotype (subtype V), but the strains collected since 1990 represent the American/Asian genotype (subtype IIIb) as previously reported in different American countries. Interestingly, the introduction of this genotype coincides with the first report of dengue hemorrhagic fever in Colombia at the end of 1989 and the increase of cases during the next years. CONCLUSION: After replacement of the American genotype, several lineages of American/Asian subtype have rapidly spread all over the country evolving in new clades. Nevertheless, the direct association of these new variants in the raise of lethality rate observed during the last outbreak has to be demonstrated.

Statins reduce dengue virus production via decreased virion assembly.

BACKGROUND: Most of the effects of statins can be explained by pleiotropic effects independent of their lowering of serum cholesterol; in some cases, these effects have been shown to be a result of the role of statins in the prenylation of cellular proteins, some of which are involved in the life cycle of animal viruses. This study evaluated the potential antiviral activity of lovastatin (LOV) against dengue virus (DENV) infection of epithelial and endothelial cells (VERO cells, epithelial cells derived from African green monkey kidney, and HMEC-1 cells, human dermal microvascular endothelial cells). METHODS: To evaluate its potential antiviral effects, LOV was used before, during and after inoculation of cell cultures with DENV. RESULTS: Before and after viral inoculation, LOV caused a reduction in virus yield (80% for HMECs and 25% for VERO cells). However, with LOV treatment after inoculation induced a marked increase (2- to 9-fold) in viral-positive RNA while the amount of viral protein increased only by 13-23%. A moderate reduction (1 log unit) in viral titer occurred concurrent with the increase in DENV genomic RNA and protein within the cells. CONCLUSIONS: According to our results, LOV appears to have a greater effect on viral assembly than on replication, resulting in the cellular presence of viral genomic RNA and proteins that fail to take the normal assembly pathway.

Phylogenetic history demonstrates two different lineages of dengue type 1 virus in Colombia.

BACKGROUND: Dengue Fever is one of the most important viral re-emergent diseases affecting about 50 million people around the world especially in tropical and sub-tropical countries. In Colombia, the virus was first detected in the earliest 70's when the disease became a major public health concern. Since then, all four serotypes of the virus have been reported. Although most of the huge outbreaks reported in this country have involved dengue virus serotype 1 (DENV-1), there are not studies about its origin, genetic diversity and distribution. RESULTS: We used 224 bp corresponding to the carboxyl terminus of envelope (E) gene from 74 Colombian isolates in order to reconstruct phylogenetic relationships and to estimate time divergences. Analyzed DENV-1 Colombian isolates belonged to the formerly defined genotype V. Only one virus isolate was clasified in the genotype I, likely representing a sole introduction that did not spread. The oldest strains were closely related to those detected for the first time in America in 1977 from the Caribbean and were detected for two years until their disappearance about six years later. Around 1987, a split up generated 2 lineages that have been evolving separately, although not major amino acid changes in the analyzed region were found. CONCLUSION: DENV-1 has been circulating since 1978 in Colombia. Yet, the phylogenetic relationships between strains isolated along the covered period of time suggests that viral strains detected in some years, although belonging to the same genotype V, have different recent origins corresponding to multiple re-introduction events of viral strains that were circulating in neighbor countries. Viral strains used in the present study did not form a monophyletic group, which is evidence of a polyphyletic origin. We report the rapid spread patterns and high evolution rate of the different DENV-1 lineages.

Celiac disease serology in patients with different pretest probabilities: is biopsy avoidable?

AIM: To establish the diagnostic performance of several serological tests, individually and in combination, for diagnosing celiac disease (CD) in patients with different pretest probabilities, and to explore potential serological algorithms to reduce the necessity for biopsy. METHODS: We prospectively performed duodenal biopsy and serology in 679 adults who had either high risk (n = 161) or low risk (n = 518) for CD. Blood samples were tested using six assays (enzyme-linked immunosorbent assay) that detected antibodies to tissue transglutaminase (tTG) and deamidated gliadin peptide (DGP). RESULTS: CD prevalence was 39.1% in the high-risk population and 3.3% in the low-risk group. In high-risk patients, all individual assays had a high diagnostic efficacy [area under receiving operator characteristic curves (AU ROC): 0.968 to 0.999]. In contrast, assays had a lower diagnostic efficacy (AU ROC: 0.835 to 0.972) in the low-risk group. Using assay combinations, it would be possible to reach or rule out diagnosis of CD without biopsy in 92% of cases in both pretest populations. We observed that the new DGP/tTG Screen assay resulted in a surplus compared to more conventional assays in any clinical situation. CONCLUSION: The DGP/tTG Screen assay could be considered as the best initial test for CD. Combinations of two tests, including a DGP/tTG Screen, might be able to diagnose CD accurately in different clinical scenarios making biopsy avoidable in a high proportion of subjects.

ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy.

Resistance to Imatinib Mesylate (IM) is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described. In the present report we aim to study the role of several MAPK in IM resistance not associate to BCR/ABL mutations. Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM (K562, Lama 84) as well as primary material from resistant and responder patient without BCR/ABL mutations. Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype. However, Erk2, but not Erk1, is critical for the acquired resistance to IM. In fact, Bcr/Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein. Finally, we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM. In summary our data support the use of therapeutic approaches based on Erk2 inhibition, which could be added to the therapeutic armamentarium to fight CML, especially when IM resistance develops secondary to Erk2 activation.

A prospective evaluation of endoscopic markers for identifying celiac disease in patients with high and low probability of having the disease.

BACKGROUND/OBJECTIVES: the usefulness of duodenoscopic markers for predicting celiac disease (CD) has been questioned. We assessed the diagnostic efficacy of endoscopic markers of mucosal atrophy in individuals with different pretest probability of CD. METHODS: we prospectively performed endoscopic intestinal biopsies and CD-related serology tests in 661 individuals, including 143 consecutive patients attending a malabsorption clinic (high pretest probability) and 518 subjects randomly selected fom those undergoing routine endoscopy because of upper GI symptoms (low pretest probability). Duodenoscopic markers reported were: mosaic pattern, scalloped folds, and reduction in number or loss of Kerkring's folds. RESULTS: sixty-three (44.1%) and 18 (3.5%) patients were diagnosed with CD in the high and low risk groups, respectively Among high pretest subjects, the presence of any marker had very high sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for the identification of CD (92.1%, 93.8%, 92.1%, 93.8% and 93.0%, respectively). The performance of these parameters for the presence of any marker in the low pretest population were 61.1%, 96.8%, 40.7%, 98.6% and 95.6%, respectively. Sensitivity (p < 0.004) and positive predictive value (p < 0.0001) of markers were significantly higher for the high risk patients. The identification of a reduction in number or loss of Kerkring'sfolds was not a reliable finding unless other signs were also present. CONCLUSIONS: we confirm that endoscopic markers are useful in predicting CD in different clinical scenarios. The high negative predictive value in the low probability group suggests that intestinal biopsy is not required if endoscopic markers are absent.

Síndrome de Jaffe-Campanacci: reporte de un caso / Jaffe-Campanacci syndrome: case report

El síndrome de Jaffe-Campanacci es una rara entidad caracterizada por múltiples fibromas no osificantes con máculas café-au-lait; está asociado a malformaciones congénitas extraesqueléticas y retardo mental. Reportamos el caso de un hombre de 22 años con las características del síndrome de Jaffe-Campanacci pero sin malformaciones extraesqueléticas, y lo comparamos con los diferentes casos reportados en la literatura de los últimos 15 años, a fi n de seguir buscando patrones epidemiológicos que nos ayuden a descubrir su etiología.

Antibodies against synthetic deamidated gliadin peptides as predictors of celiac disease: prospective assessment in an adult population with a high pretest probability of disease.

BACKGROUND: Noninvasive serologic tests have shown high diagnostic accuracy for celiac disease (CD) in selected populations. Our aim was to determine prospectively the performance of CD-related serology in individuals undergoing intestinal biopsy because of clinical suspicion of small-bowel disorders. METHODS: We enrolled 141 unselected consecutive adult patients attending a small-bowel disease clinic. Patients underwent endoscopy and biopsy; serum samples were obtained at that time for measurements of anti-tissue transglutaminase (a-tTG), IgA and IgG anti-deamidated gliadin-related peptide (a-DGP), and IgA antiactin antibodies (AAAs). Characterization of patients was based on histological criteria (Marsh type II lesion or greater). RESULTS: The prevalence of CD was 42.5%. Sensitivity, specificity, and positive and negative predictive values were >90% for most assays. Diagnostic accuracy based on ROC curve analysis was similar for all assays [area under the curve (95% CI): 0.996 (0.967-0.998) for a-tTG, 0.995 (0.964-0.998) for IgA a-DGP, 0.989 (0.954-0.999) for IgG a-DGP, 0.996 (0.966-0.998) for blended conjugated of IgA + IgG a-DGP in a single assay, and 0.967 (0.922-0.990) for AAA]. The combinations of 2 tests, IgG a-DGP plus IgA a-tTG or the single blended conjugate detecting IgA + IgG a-DGP plus IgA a-tTG had 100% positive and negative predictive values if concentrations of both tests in either combination were above or below the cutoff. CONCLUSIONS: In a population with high pretest probability, the newly developed a-DGP tests have diagnostic accuracy that is at least equivalent to that of established assays.

Esquizencefalia: un trastorno de la migración neuronal / Schizencephaly: a disorder of neuronal migration

La esquizencefalia es el trastorno más frecuente de la migración neuronal y ocurre entre el tercero y quinto meses de la gestación. Se describen en este artículo sus posibles causas genéticas (EMX2), vasculares e infecciosas, así como sus manifestaciones clínicas, radiológicas y electroencefalográficas. El tratamiento es sintomático y multidisciplinario.

Schizencephaly is the most frequent neuronal migration disorder and it develops between the third and fifth gestational months. Genetic (EMX2), vascular and infectious etiologies have been described. Its clinical, radiological and electroencephalographic characteristics are described in this article. Treatment should be symptomatic and multidisciplinary.

Clinical utility of counting intraepithelial lymphocytes in celiac disease intestinal mucosa.

BACKGROUND/AIMS: Our aims were to establish the clinical utility of assessing the intraepithelial lymphocyte (IEL) density in intestinal biopsies from a large series of individuals and to determine the best threshold discriminating celiac disease (CD) patients and controls in two populations with different pre-test prevalence. METHODS: We prospectively performed intestinal biopsy and CD-related serology in 349 subjects undergoing upper GI endoscopy. While 116 had symptoms suggestive of a small bowel disorder (high prevalence), 233 individuals were randomly selected from patients referred to endoscopy because upper GIsymptoms (low prevalence). Diagnosis of CD was based on the concordance of classical histological features and a positive CD serology. RESULTS: While 58 patients had a newly diagnosed CD (52 in the high and 6 in the low prevalence groups), 291 subjects did not meet diagnostic criteria of the disorder. Patients had a highly significant greater IEL density than controls (p < 0.00001). Based on the ROC curve, a count of 22.8 IEL/100 epithelial cells had the highest performance for diagnosing CD in the overall population and for subjects in the high pre-test probability subgroup and 22.5% was ,he best cut-off for those diagnosed in the low risk population (area under the curves: 0.979, 0.979 and 0.993, respectively). An abnormal CD serology confirmed the diagnosis of CD in all the four patients with counts below 22.8%. CONCLUSIONS: Our study confirms that an IEL density of 22.8% is an adequate threshold to discriminate CD patients and controls in individuals irrespective of the prevalence of the disorder.

Accuracy of testing for antibodies to synthetic gliadin-related peptides in celiac disease.

BACKGROUND & AIMS: Our aim was to explore the diagnostic value of a newly developed synthetic peptide antibody assay addressing specific synthetic gliadin-derived deamidated peptides (AGA II) for the diagnosis of celiac disease (CD). METHODS: We assayed serum samples obtained prospectively at diagnosis from a population of 92 consecutive adult patients with CD and 113 non-CD controls. Patients were reevaluated after 6 months (n = 56) and 1 year (n = 20) of treatment. All patients and controls underwent intestinal biopsy and a set of CD-related serology tests. A newly developed enzyme-linked immunosorbent assay (ELISA) for detecting IgA and IgG antibodies against synthetic deamidated gliadin epitopes was used. RESULTS: At diagnosis, sensitivity and specificity were 94.6% and 99.1% for AGA II IgA and 92.4% and 100% for AGA II IgG. Absolute values and the proportion of positive samples for both antibodies were significantly reduced at 6 months (P < .0000) and 1 year (P < .001) after initiation of a gluten-free diet. Compared with conventional AGA, the peptide antibodies had greater sensitivity, specificity, positive and negative predictive values, accuracy, and likelihood ratios. Compared with antitissue transglutaminase antibodies, AGA II had similar sensitivity but greater specificity and predictive values, better likelihood ratios, and an excellent agreement (kappa statistic = .92). CONCLUSIONS: This study assessed the value of an ELISA assay in detecting antibodies to gliadin-related peptides. This assay appears to be a reliable tool for diagnosing CD and suggests promising accuracy that may be very useful in clinical practice.

Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity.

Notch signaling has been extensively implicated in cell-fate determination along the development of the immune system. However, a role for Notch signaling in fully differentiated immune cells has not been clearly defined. We have analyzed the expression of Notch protein family members during macrophage activation. Resting macrophages express Notch-1, -2, and -4, as well as the Notch ligands Jagged-1 and -2. After treatment with LPS and/or IFN-gamma, we observed a p38 MAPK-dependent increase in Notch-1 and Jagged-1 mRNA and protein levels. To study the role of Notch signaling in macrophage activation, we forced the transient expression of truncated, active intracellular Notch-1 (Notch-IC) proteins in Raw 264.7 cells and analyzed their effects on the activity of transcription factors involved in macrophage activation. Notch-IC increased STAT-1-dependent transcription. Furthermore, Raw 264.7 Notch-IC stable transfectants increased STAT1-dependent transcription in response to IFN-gamma, leading to higher expression of IFN regulatory factor-1, suppressor of cytokine signaling-1, ICAM-1, and MHC class II proteins. This effect was independent from an increase of STAT1 Tyr or Ser phosphorylation. However, inducible NO synthase expression and NO production decreased under the same conditions. Our results show that Notch up-regulation and subsequent signaling following macrophage activation modulate gene expression patterns known to affect the function of mature macrophages.

Detección radioinmunoguiada de perforación del tracto gastrointestinal Estudio experimental / Radioimmunogided detection of perforation of the gastrointestinal tract

Se presenta un estudio experimental que tiene por objetivo evaluar la sensibilidad y especificidad de la detección de solución de continuidad del tracto gastrointestinal con la utilización de partículas pesadas marcadas con Tecnecio 99. Se diseñó un estudio experimental prospectivo triple ciego, con un cálculo de tamaño de muestra teniendo en cuenta una sensibilidad y especificidad superiores al 95 por ciento, con un error alfa del 0.05 y una precisión de 0.05. Inicialmente se evaluaron 4 conejos de la raza Nueva Zelanda para determinar: el anestésico y la dosis a utilizar, la capacidad del estómago en mililitros; los tiempos promedios de tránsito gastrointestinal, la capacidad de la cavidad abdominal en mililitros y la biodistribución del radiofármaco (absorción gastrointestinal, diseminación y distribución hemática y eliminación renal). Se utilizaron 40 conejos de la raza Nueva Zelanda y se analizaron en tres estaciones de trabajo independientes, asignando aleatoriamente 20 conejos en cada grupo de estudio (perforados y no perforados). El radiofármaco utilizado fue Tecnecio 99 sulfuro coloidal > 100 nm, 2.5 mCi a 140 –Kev de energía preparado en una dilución de solución salina al 0.9 por ciento quedando una concentración de 0.0025 mCi por mililitro. El rastreo se realizó con una sonda gamma a 10X. El análisis estadístico se realizó con el programa Episet V:1 aplicando la prueba de Chi Cuadrado.Todos los 20 conejos que tenían disrupción del estómago, presentaron una prueba positiva para detección de radioactividad en el líquido peritoneal analizado con un valor promedio de 467 y un rango de 37 a 1748. En los 20 conejos restantes que no tenían perforación de la pared gástrica la prueba fue negativa.La sensibilidad de la metodología diagnóstica fue de 0.98 y la especificidad de 0.98 con un intervalo...