Impact of linked color imaging on the proximal adenoma miss rate: a multicenter tandem randomized controlled trial. The COCORICO trial.

OBJECTIVES: Missed lesions are common during standard colonoscopy and are correlated with post-colonoscopy colorectal cancer (PCCRC). Contrast-enhanced technologies have recently been developed to improve polyp detection. Our aim was to evaluate the impact of linked color imaging (LCI) on the proximal adenoma miss rate (pAMR) in routine colonoscopy. DESIGN AND METHODS: This national multicenter tandem randomized trial compared the outcomes of standard colonoscopy with white light imaging (WLI) to colonoscopy with LCI (Fujifilm), for polyp detection in the right colon. Two consecutive examinations of the right colon (upstream of the hepatic flexure) were made with WLI and LCI by the same operator. First-pass examination by WLI or LCI was randomized 1:1 after cecal intubation. According to statistical calculations, 10 endoscopy units had to include approximately 700 patients with a 1:1 randomization. The primary outcome was pAMR. Secondary outcomes were the proximal sessile serrated lesion miss rate (pSSLMR), the proximal advanced adenoma miss rate (pAdvAMR), and the proximal polyp miss rate (pPMR). RESULTS: 764 patients were included from January 1, 2020 to December 22, 2022. 686 patients were randomized (WLI-first group: 345 versus LCI-first group: 341). Both groups were comparable in terms of demographics and indications. pAMR was not significantly higher in the WLI-first group (36.7%) versus the LCI-first group (31.8%) (estimated mean absolute difference: 4.9% [-5.2%; 15.0%], P=0.340). There was no significant difference regarding pSSLMR, pAdvAMR, and pPMR. CONCLUSIONS: In contrast to previous data, this study does not support the benefit of LCI regarding pAMR in routine colonoscopy. CLINICALTRIALS: gov ID: NCT04440865.

Multicenter randomized trial comparing diagnostic sensitivity and cellular abundance with aggressive versus standard biliary brushing for bile duct stenosis without mass syndrome.

BACKGROUND : The diagnosis of cholangiocarcinoma in patients with a biliary stricture without mass syndrome can be obtained by biliary brushing with a sensitivity of ~50 %. We performed a multicenter randomized crossover trial comparing the aggressive Infinity brush with the standard RX Cytology Brush. The aims were to compare sensitivity for cholangiocarcinoma diagnosis and cellularity obtained. METHODS : Biliary brushing was performed consecutively with each brush, in a randomized order. Cytological material was studied with blinding to the brush type used and order. The primary end point was sensitivity for cholangiocarcinoma diagnosis; the secondary end point was the abundance of cellularity obtained with each brush, with cellularity quantified in order to determine if one brush strongly outperformed the other. RESULTS : 51 patients were included. Final diagnoses were cholangiocarcinoma (n = 43; 84 %), benign (n = 7; 14 %), and indeterminate (n = 1; 2 %). Sensitivity for cholangiocarcinoma was 79 % (34 /43) for the Infinity brush versus 67 % (29/43) for the RX Cytology Brush (P = 0.10). Cellularity was rich in 31/51 cases (61 %) with the Infinity brush and in 10/51 cases (20 %) with the RX Cytology Brush (P < 0.001). In terms of quantification of cellularity, the Infinity brush strongly outperformed the RX Cytology Brush in 28/51 cases (55 %), while the RX Cytology Brush strongly outperformed the Infinity brush in 4/51 cases (8 %; P < 0.001). CONCLUSIONS : This randomized crossover trial showed that the Infinity brush is not significantly more effective than the RX Cytology Brush for biliary stenosis without mass syndrome in terms of sensitivity for cholangiocarcinoma diagnosis, but does offer a significantly higher abundance of cellularity.

Endoscopic mucosal resection with anchoring of the snare tip: multicenter retrospective evaluation of effectiveness and safety.

Background Endoscopic mucosal resection (EMR) with snare is the recommended technique to resect non-invasive colorectal neoplastic lesions between 10 and 30 mm in diameter. The objective of EMR is to resect completely the neoplastic tissue en bloc and preferably with free margins (R0), avoiding recurrences. Anchoring the tip of the snare in the submucosa is a technical trick that allows snare sliding to be reduced and larger pieces to be caught. The aim of the present study was to evaluate the effectiveness and safety of anchoring-EMR (A-EMR). Methods This was a retrospective analysis of A-EMR procedures for lesions of diameter between 10 and 30 mm (endoscopic evaluation) performed consecutively in four French centers between May 2017 and January 2018. A-EMR was routinely performed for all EMR using Olympus conventional snares (10 or 25 mm). The primary outcome was evaluation of the proportion of R0 resections. Results A total of 141 A-EMR procedures were performed by 10 operators. Mean lesion size was 19.8 mm. Anchoring was feasible in 96.5 % of cases. There were 81.6 % en bloc resections and 70.2 % R0 resections, with the percentage of procedures decreasing with increasing lesion size (82.8 % < 20 mm, 55.3 % 21 - 30 mm, and 50.0 % > 30 mm, P  = 0.002). Complete perforations closed endoscopically occurred in 3/141 cases (2.1 %); none occurred in lesions < 20 mm in size (0 /87). Conclusion The A-EMR technique appears to be promising with a high proportion of R0 for lesions of 10 - 20 mm in size without any perforations. It could also offer an alternative to endoscopic submucosal dissection (ESD), or to hybrid techniques to reach R0 for lesions between 20 and 30 mm in size.

Identification of protein features encoded by alternative exons using Exon Ontology.

Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing variation in physiological- or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named "Exon Ontology," based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encoded protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splicing. We also show that Exon Ontology helps to unravel biological processes that depend on suites of coregulated alternative exons, as we uncovered a role of epithelial cell-enriched splicing factors in the AKT signaling pathway and of mesenchymal cell-enriched splicing factors in driving splicing events impacting on autophagy. Freely available on the web, Exon Ontology is the first computational resource that allows getting a quick insight into the protein features encoded by alternative exons and investigating whether coregulated exons contain the same biological information.

The Mmachc gene is required for pre-implantation embryogenesis in the mouse.

Patients with mutations in MMACHC have the autosomal recessive disease of cobalamin metabolism known as cblC. These patients are unable to convert cobalamin into the two active forms, methylcobalamin and adenosylcobalamin and consequently have elevated homocysteine and methylmalonic acid in blood and urine. In addition, some cblC patients have structural abnormalities, including congenital heart defects. MMACHC is conserved in the mouse and shows tissue and stage-specific expression pattern in midgestation stage embryos. To create a mouse model of cblC we generated a line of mice with a gene-trap insertion in intron 1 of the Mmachc gene, (Mmachc(Gt(AZ0348)Wtsi)). Heterozygous mice show a 50% reduction of MMACHC protein, and have significantly higher levels of homocysteine and methylmalonic acid in their blood. The Mmachc(Gt) allele was inherited with a transmission ratio distortion in matings with heterozygous animals. Furthermore, homozygous Mmachc(Gt) embryos were not found after embryonic day 3.5 and these embryos were unable to generate giant cells in outgrowth assays. Our findings confirm that cblC is modeled in mice with reduced levels of Mmachc and suggest an early requirement for Mmachc in mouse development.

Vitamin B(12) metabolism during pregnancy and in embryonic mouse models.

Vitamin B(12) (cobalamin, Cbl) is required for cellular metabolism. It is an essential coenzyme in mammals for two reactions: the conversion of homocysteine to methionine by the enzyme methionine synthase and the conversion of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase. Symptoms of Cbl deficiency are hematological, neurological and cognitive, including megaloblastic anaemia, tingling and numbness of the extremities, gait abnormalities, visual disturbances, memory loss and dementia. During pregnancy Cbl is essential, presumably because of its role in DNA synthesis and methionine synthesis; however, there are conflicting studies regarding an association between early pregnancy loss and Cbl deficiency. We here review the literature about the requirement for Cbl during pregnancy, and summarized what is known of the expression pattern and function of genes required for Cbl metabolism in embryonic mouse models.

The methylmalonic aciduria related genes, Mmaa, Mmab, and Mut, are broadly expressed in placental and embryonic tissues during mouse organogenesis.

Organ-specific birth defects are seen in patients with some inborn errors of vitamin B(12) metabolism. To determine whether three mouse genes, whose human counterparts are associated with isolated methylmalonic aciduria (Mmaa, Mmab and Mut), show tissue-specific expression during organogenesis, we used in situ hybridization to characterize their pattern of expression in wild type embryos and placentas at embryonic days (E) E10.5, E11.5 and E12.5. These three genes are ubiquitously expressed in the placenta and in embryos at E10.5. At E11.5, we observed tissue specific expression patterns for these three genes in lung, head and Rathke's pouch. At E12.5, although Mut expression was ubiquitous, we found cell-type specific expression patterns for Mmaa and Mmab in the developing craniofacial region, the lung, the liver, and the gut. These results suggest that during organogenesis the proteins encoded by these three genes may interact in only a subset of cells.

Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomethylation and decreased ER-α, ERR-α, and HNF-4α in the rat liver.

BACKGROUND & AIMS: Folate and cobalamin are methyl donors needed for the synthesis of methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic, and epigenomic pathways. Methyl donor deficiency produces liver steatosis and predisposes to metabolic syndrome. Whether impaired fatty acid oxidation contributes to this steatosis remains unknown. METHODS: We evaluated the consequences of methyl donor deficient diet in liver of pups from dams subjected to deficiency during gestation and lactation. RESULTS: The deprived rats had microvesicular steatosis, with increased triglycerides, decreased methionine synthase activity, S-adenosylmethionine, and S-adenosylmethionine/S-adenosylhomocysteine ratio. We observed no change in apoptosis markers, oxidant and reticulum stresses, and carnityl-palmitoyl transferase 1 activity, and a decreased expression of SREBP-1c. Impaired beta-oxidation of fatty acids and carnitine deficit were the predominant changes, with decreased free and total carnitines, increased C14:1/C16 acylcarnitine ratio, decrease of oxidation rate of palmitoyl-CoA and palmitoyl-L-carnitine and decrease of expression of novel organic cation transporter 1, acylCoA-dehydrogenase and trifunctional enzyme subunit alpha and decreased activity of complexes I and II. These changes were related to lower protein expression of ER-α, ERR-α and HNF-4α, and hypomethylation of PGC-1α co-activator that reduced its binding with PPAR-α, ERR-α, and HNF-4α. CONCLUSIONS: The liver steatosis resulted predominantly from hypomethylation of PGC1-α, decreased binding with its partners and subsequent impaired mitochondrial fatty acid oxidation. This link between methyl donor deficiency and epigenomic deregulations of energy metabolism opens new insights into the pathogenesis of fatty liver disease, in particular, in relation to the fetal programming hypothesis.

Homocysteine is a determinant of ApoA-I and both are associated with ankle brachial index, in an ambulatory elderly population.

OBJECTIVE: The ankle brachial index (ABI) is an indicator of lower extremity peripheral arterial disease (PAD) and a predictor of atherothrombosis. ApoA-I and HDL are associated with PAD, in humans. Homocysteine influences the liver expression of ApoA-I and decreases its blood level and HDL in genetic mice models. We aimed therefore to evaluate whether homocysteine and its nutritional determinants, folate and vitamin B12 are associated with ABI by influencing HDL metabolism, in an ambulatory elderly population. METHODS: 667 elderly volunteers from rural Sicily were assessed for ABI, homocysteine and its determinants, lipid markers and other predictors of PAD. HDL size was assessed in 15 sera in upper and lower quartiles of Hcy distribution. RESULTS: In multivariate analysis, ApoA-I and homocysteine were two predictors of ABI (ß-coefficient = 2.86, P<0.004 and ß-coefficient = -3.41, P<0.001, respectively). Homocysteine correlated negatively with ApoA-I (R = -0.147, P<0.001) and with HDL-Cholesterol (R = -0.113, P = 0.003). The associations of homocysteine, vitamin B12 and methylmalonic acid with ApoA-I and HDL2a particles and that of homocysteine with increased small size HDL3c suggested mechanisms related with impaired synthesis of ApoA-I and HDL and abnormal maturation of HDL particles. CONCLUSION: The influence of homocysteine on ApoA-I and HDL metabolism provides new insights on its role on vascular diseases, at a cross-point between atherosclerosis and atherothrombosis.

Determinación del estadio ninfal y la edad reproductiva de la hembra de Rhodnius prolixus, Stal 1859 (Heteroptera, Triatominae) por medio de Resonancia Magnética Nuclear / Instar and female reproductive ages of Rhodnius prolixus by nuclear magnetic resonance

En este trabajo se determinó cualitativa y cuantitativamente la composición química de un extracto en benceno de ejemplares de Rhodnius prolixus en diferentes estadios ninfales y edades reproductivas de las hembras. El análisis fue realizado mediante técnicas uni- y bidimensionales (1D y 2D) de Resonancia Magnética Nuclear (RMN). Se han clasificado los compuestos químicos presentes en el extracto como A, B y C, según sus zonas de desplazamiento químico. El compuesto A, situado en la zona entre d 5,0 y 5,33 ppm, puede ser atribuido a hidrógenos olefínicos (alquenos) y está presente en todo los estadios ninfales y edades reproductivas, por lo que no es de utilidad para ser marcador de edades. El Compuesto C, situado en la zona entre 2,5 ppm y 3,5 ppm, representa distintas señales las cuales presumiblemente según sus desplazamientos químicos corresponden a hidrógenos sobre carbonos nitrogenados y sirve como marcador de edad para diferenciar entre los estadios ninfales y el comienzo de la edad adulta. El Compuesto B, presente en la zona entre 4 y 5 ppm, corresponde a un triacilglicerol, y es un marcador importante para diferenciar entre las hembras no ovipositoras (HNO) y ovipositoras (HO), ya que esta última edad carece de este compuesto. También es útil usar la relación de concentraciones de los compuestos A y B, que viene dada por la integral de la señal para determinar la diferencia de edades entre los estadios ninfales. Se proponen estas técnicas para determinar los estadios ninfales y las edades reproductivas de las hembras en una muestra de triatominos colectados en condiciones de campo, lo que revelaría información importante para conocer algunas de las variables de las que depende la capacidad vectora de estos insectos en la transmisión de la Enfermedad de Chagas.