Effect of sitagliptin on down-regulation of KAT7 and SIRT1 gene expression in breast cancer cell line MCF7.

BACKGROUND: To date, the main clinical interest in DPP4 is focused on its inhibition in diabetic patients to prolong the half-life of incretins. Epigenetic alterations resulting from DPP4 inhibition have been poorly explored. OBJECTIVE: The objective of this study was to determine, whether sitagliptin, a DPP4 inhibitor, has effects on the expression of KAT7 and SIRT1 (genes encoding a histone acetyltransferase and a histone deacetylase, respectively) in MCF7 breast cancer cells, which play an essential role in modulating the epigenetic landscape of chromatin. MATERIAL AND METHODS: MCF7 cells were incubated for 20 h with sitagliptin at concentrations of 0.5, 1.0 and 2.0 µM. Total RNA was isolated and the relative mRNA expression of KAT7 and SIRT1 was determined by RT-qPCR. RESULTS: There was downregulation in the relative expression of both genes; for KAT7, downregulation reached up to 0.49 (p = 0.027) and for SIRT1, it reached up to 0.55 (p = 0.037). CONCLUSIONS: These results suggest that sitagliptin has effects on the histone epigenetic landscape. This topic deserves further study due to the current sample use of DPP4 inhibitors in diabetic patients.

ANTECEDENTES: Hasta la fecha, el principal interés clínico de la DPP4 se centra en su inhibición en pacientes diabéticos para prolongar la vida media de las incretinas. Las alteraciones epigenéticas resultantes de la inhibición de DPP4 han sido poco exploradas. OBJETIVO: Determinar si la sitagliptina, un inhibidor de DPP4, tiene efectos sobre la expresión de KAT7 y SIRT1 (genes que codifican una histona acetiltransferasa y una histona desacetilasa, respectivamente) en células de cáncer de mama MCF7, que desempeñan un papel esencial en la modulación del paisaje epigenético de la cromatina. MÉTODO: Las células MCF7 se incubaron durante 20 h con sitagliptina a concentraciones de 0.5, 1.0 y 2.0 µM. Se aisló el ARN total y se determinó la expresión relativa de ARNm de KAT7 y SIRT1 mediante RT-qPCR. RESULTADOS: Hubo una regulación a la baja en la expresión relativa de ambos genes; para KAT7, la regulación negativa alcanzó hasta 0.49 (p = 0.027) y para SIRT1 alcanzó hasta 0.55 (p = 0.037). CONCLUSIONES: Estos resultados sugieren que la sitagliptina tiene efectos sobre el paisaje epigenético de las histonas. Este tema merece más estudios debido al uso actual de inhibidores de DPP4 en pacientes diabéticos.

Effect of Tithonia diversifolia (Hemsl.) A. Gray intake on in vivo methane (CH4) emission and milk production in dual-purpose cows in the Colombian Amazonian piedmont.

The inclusion of Tithonia diversifolia in pasture-based diets is a promising alternative to increase bovine productivity, due to its chemical composition and wide adaptation, but there are few in vivo studies to determine its effect on methane yield and animal production in grazing systems. The objective of this study was to determine the effects of the T. diversifolia inclusion in a basal diet of Brachiaria humidicola on methane (CH4) emissions by enteric fermentation, and on milk yield and quality in dual-purpose cows. The polytunnel technique was used for the determination of methane yield and two diets were evaluated (Diet 1: Brachiaria humidicola 100%; Diet 2: T. diversifolia 15% + B. humidicola 85% dry matter basis) in the moderate rainy and rainy seasons using a cross-over experimental design; milk production was measured by daily milk weighing, and milk quality was determined using a LACTOSCAN analyzer. The inclusion of T. diversifolia did not increase the dry matter intake (P = 0.369), but increased the intake of crude protein and minerals, and reduced fiber intake, resulting in the increased yield of milk and its components in the moderate rainy season (P = 0.012). The inclusion of T. diversifolia reduced the absolute CH4 emissions (P = 0.016), Ym and emission intensity (per unit of fat, protein and kilogram fat and protein corrected milk yields) both in the moderate rainy and rainy seasons (P < 0.05). We conclude that the inclusion of T. diversifolia in the forage feed base in the humid tropics such as the Amazon piedmont can be used as a tool to both mitigate enteric CH4 emissions and to increase animal productivity and hence reduce emissions intensity, and thus reduce pressure on the agricultural frontier in critical areas such as the Amazon.

Metal-Mediated Organocatalysis in Water: Serendipitous Discovery of Aldol Reaction Catalyzed by the [Ru(bpy)2(nornicotine)2]2+ Complex.

The [Ru(bpy)2(Nor)2]2+ complex (Nor = nornicotine) is an efficient catalyst for the aldol reaction of acetone with activated benzaldehydes in a buffered aqueous solution. The metal plays the role of an activator for the nornicotine organocatalyst ligands. The resulting catalytic activity is potentiated by a factor of about 4.5 as compared to free nornicotine. Similar rate enhancements can be achieved by using Zn(II) cations as the activator. The observations are rationalized with the reduced basicity of the pyrrolidine N in nornicotine due to the enhanced electron withdrawal of the metal-complexed pyridyl moiety.

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial.

AIM: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. METHODS AND RESULTS: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44-0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46-0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. CONCLUSION: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03321032.

Dronabinol en manejo de apetito y pérdida de peso en pacientes con cáncer terminal, VIH, cuidados paliativos y vejez. Revisión de la literatura / Dronabinol in appetite management and weight loss in patients with terminal cancer, HIV, palliative care and old age. Literature review

Resumen: Introducción: La caquexia es un síndrome asociado al cáncer avanzado, VIH, pacientes en quimioterapia y quienes tienen seguimiento en cuidados paliativos. La prevalencia es de 25% de los pacientes con diagnóstico de cáncer, 26% en quienes reciben quimioterapia y de 14 a 38% de pacientes con VIH. Un pilar para el manejo es el cannabis debido al efecto del delta-9-tetrahidrocanabinol (THC), del cual se derivó el dronabinol, un fármaco desarrollado para estimular apetito y ganancia de peso. El objetivo de esta revisión bibliográfica es obtener la información sobre los cannabinoides y la evidencia más sólida existente con respecto al uso del dronabinol en pacientes que han presentado pérdida de peso y apetito. Material y métodos: Revisión de la bibliografía con buscador PubMed con las palabras clave Palliative care (cuidados paliativos), Cannabinoids (cannabinoides), cachexia (caquexia), Dronabinol (dronabinol), Appetite (apetito), de 1990 a 2018, limitado a humanos, obteniendo 259 artículos, eliminando 222 por repetirse o tener poca relevancia, dejando 37 artículos para análisis. Resultados: De 37 artículos revisados, nueve fueron estudios experimentales, 10 revisiones sistematizadas, un metaanálisis y 16 artículos de recomendaciones y sugerencias de manejo. Conclusión: El manejo del apetito y pérdida de peso en pacientes en cuidados paliativos, VIH, ancianos o en quimioterapia debe ser multidisciplinario, involucrando nutriólogos, psicólogos y médicos, ajustando el manejo a las características individuales que manifiesten. El dronabinol es un fármaco de primera elección para el manejo de dichos síntomas cuando la historia natural de la enfermedad se acompaña de náusea, vómito o dolor.

Abstract: Introduction: Cachexia is a syndrome associated with advanced cancer, HIV, patients on chemotherapy and those who are followed in palliative care. The prevalence is 25% of patients diagnosed with cancer, 26% in those receiving chemotherapy and 14 to 38% of patients with HIV. A mainstay for management is cannabis, due to the effect of delta-9-tetrahydrocannabinol (THC) from which dronabinol, a drug developed to stimulate appetite and weight gain, was derived. The aim of this literature review is to obtain information on cannabinoids and the strongest existing evidence regarding the use of dronabinol in patients who have presented weight and appetite loss. Material and methods: Literature review with PubMed search engine with the keywords Palliative care, Cannabinoids, cachexia, Dronabinol, Appetite, from 1990 to 2018, limited to humans, obtaining 259 articles, eliminating 222 for repetition or low relevance, leaving 37 articles for analysis. Results: Out of 37 articles reviewed 9 were experimental studies, 10 systematized reviews, 1 meta-analysis and 16 articles of recommendations and management suggestions. Conclusion: The management of appetite and weight loss in palliative care, HIV, elderly or chemotherapy patients should be multidisciplinary, involving nutritionists, psychologists and physicians, adjusting the management to the individual characteristics manifested. Dronabinol is a drug of first choice for the management of these symptoms when the natural history of the disease is accompanied by nausea, vomiting or pain.

Visible Light-Gated Organocatalysis Using a RuII -Photocage.

The light-gated organocatalysis via the release of 4-N,N-dimethylaminopyridine (DMAP) by irradiation of the [Ru(bpy)2 (DMAP)2 ]2+ complex with visible light was investigated. As model reaction the acetylation of benzyl alcohols with acetic anhydride was chosen. The pre-catalyst releases one DMAP molecule on irradiation at wavelengths longer than 455 nm. The photochemical process was characterized by steady-state irradiation and ultrafast transient absorption spectroscopy. The latter enabled the observation of the 3 MLCT state and the spectral features of the penta-coordinated intermediate [Ru(bpy)2 (DMAP)]2+ . The released DMAP catalyzes the acetylation of a wide range of benzyl alcohols with chemical yields of up to 99 %. Control experiments revealed unequivocally that it is the released DMAP which takes the role of the catalyst.

Chemical signal cascading in a supramolecular network.

A chemically-triggered signalling cascade between cucurbituril host-guest complexes by means of multi-step competitive displacement is demonstrated. The inter-complex communication of chemical information yields the release of bio-relevant cargo, reminiscent of cellular signalling pathways.

Optical Supramolecular Sensing of Creatinine.

Calix[4]pyrrole phosphonate-cavitands were used as receptors for the design of supramolecular sensors for creatinine and its lipophilic derivative hexylcreatinine. The sensing principle is based on indicator displacement assays of an inherently fluorescent guest dye or a black-hole quencher from the receptor's cavity by means of competition with the creatinine analytes. The systems were thermodynamically and kinetically characterized regarding their 1:1 binding properties by means of nuclear magnetic resonance spectroscopy (1H and 31P NMR), isothermal titration calorimetry, and optical spectroscopies (UV/vis absorption and fluorescence). For the use of the black-hole indicator dye, the calix[4]pyrrole was modified with a dansyl chromophore as a signaling unit that engages in Förster resonance energy transfer with the indicator dye. The 1:1 binding constants of the indicator dyes are in the range of 107 M-1, while hexylcreatinine showed values around (2-4) × 105 M-1. The competitive displacement of the indicators by hexylcreatinine produced supramolecular fluorescence turn-on sensors that work at micromolar analyte concentrations that are compatible with those observed for healthy as well as sick patients. The limit of detection for one of the systems reached submicromolar ranges (110 nM).

Binding of Flavylium Ions to Sulfonatocalix[4]arene and Implication in the Photorelease of Biologically Relevant Guests in Water.

The formation of host-guest complexes between seven flavylium cations and water-soluble p-sulfonatocalix[4]arene (SC4) was investigated by UV/vis absorption, fluorescence, and NMR spectroscopies. The results show the cationic guests form complexes with affinities in the submillimolar range. A representative chalcone/flavylium photoswitch was investigated in more detail regarding its pH- and light-triggered interconversion between the two forms. The dramatic affinity differentiation of the SC4 binding of the two switchable species (40 M-1 for the trans-chalcone versus 3.5 × 104 M-1 for the flavylium cation) enables the pH-gated photocontrol of the complexation process. These responsive properties were explored to demonstrate the competitive and selective release of biologically relevant guests from their supramolecular complexes with p-sulfonatocalix[4]arene (SC4), following the principle of AND logic. The guest release can be reverted by the thermally activated reaction of the flavylium ion back to the trans-chalcone.

Light-induced cargo release from a cucurbit[8]uril host by means of a sequential logic operation.

The logically controlled and light-induced release of a tripeptide model cargo from a cucurbit[8]uril host macrocycle by means of a photoswitch was shown in water. This provides a new approach to photoresponsive and selective release in a meaningful pH window.

Effect of oral magnesium supplementation on the transcription of TRPM6, TRPM7, and SLC41A1 in individuals newly diagnosed of pre-hypertension. A randomized, double-blind, placebo-controlled trial.

A stringent regulation of influx and efflux of magnesium by cation transporters seems to play an important role in the regulation of blood pressure (BP). With this regard, we evaluate the effect of oral magnesium supplementation on the transcription of TRPM6, TRPM7, and SLC41A1, in individuals with incident pre-hypertension (preHTN). For such purpose, we conducted a randomized, double-blind, placebo-controlled trial that compared 18 individuals who received oral magnesium lactate (360 mg elemental magnesium) versus 18 individuals who received placebo, during 4 months. Diagnosis of hypertension or normal BP, diabetes, alcohol intake, chronic diarrhea, use of diuretics, intake of magnesium supplementation, and reduced renal function were exclusion criteria. Regarding the transcription analysis of TRPM6, TRPM7, and SLC41A1 using RT-qPCR, leukocyte-rich plasma was obtained and total RNA was isolated with the kit Direct-zol™ RNA MiniPrep (Zymo). The leukocyte TRPM6 mRNA relative expression showed a significant increase (2.1 ± 1.37 and 0.8 ± 0.4, P<0.05), whereas the mRNA relative expression of both leukocyte TRPM7 (0.8 ± 1.1 and 0.9 ± 0.6, pNS) and SLC41A1 (0.9 ± 1.0 and 0.7 ± 0.6, pNS) showed no significant differences, between the magnesium and placebo groups, respectively. Oral magnesium supplementation increases the leukocyte TRPM6 mRNA relative expression, in subjects with new diagnosis of preHTN.

CAPRRESI: Chimera Assembly by Plasmid Recovery and Restriction Enzyme Site Insertion.

Here, we present chimera assembly by plasmid recovery and restriction enzyme site insertion (CAPRRESI). CAPRRESI benefits from many strengths of the original plasmid recovery method and introduces restriction enzyme digestion to ease DNA ligation reactions (required for chimera assembly). For this protocol, users clone wildtype genes into the same plasmid (pUC18 or pUC19). After the in silico selection of amino acid sequence regions where chimeras should be assembled, users obtain all the synonym DNA sequences that encode them. Ad hoc Perl scripts enable users to determine all synonym DNA sequences. After this step, another Perl script searches for restriction enzyme sites on all synonym DNA sequences. This in silico analysis is also performed using the ampicillin resistance gene (ampR) found on pUC18/19 plasmids. Users design oligonucleotides inside synonym regions to disrupt wildtype and ampR genes by PCR. After obtaining and purifying complementary DNA fragments, restriction enzyme digestion is accomplished. Chimera assembly is achieved by ligating appropriate complementary DNA fragments. pUC18/19 vectors are selected for CAPRRESI because they offer technical advantages, such as small size (2,686 base pairs), high copy number, advantageous sequencing reaction features, and commercial availability. The usage of restriction enzymes for chimera assembly eliminates the need for DNA polymerases yielding blunt-ended products. CAPRRESI is a fast and low-cost method for fusing protein-coding genes.

Photocaged Competitor Guests: A General Approach Toward Light-Activated Cargo Release From Cucurbiturils.

A general approach toward the light-induced guest release from cucurbit[7]uril by means of a photoactivatable competitor was devised. An o-nitrobenzyl-caged competitor is photolyzed to generate a competitive guest that can displace cargo from the host macrocycle solely based on considerations of chemical equilibrium. With this method the release of terpene guests from inclusion complexes with cucurbit[7]uril was demonstrated. The binding of the herein investigated terpenes, all being lead fragrant components in essential oils, has been characterized for the first time. They feature binding constants of up to 108  L mol-1 and a high differential binding selectivity (spanning four orders of magnitude for the binding constants for the particular set of terpenes). By fine-tuning the photoactivatable competitor guest, selective and also sequential release of the terpenes was achieved.

Actualización en deficiencia de lipasa ácida lisosomal: diagnóstico, tratamiento y seguimiento de los pacientes / Update on lysosomal acid lipase deficiency: Diagnosis, treatment and patient management

La deficiencia de lipasa ácida lisosomal (DLAL) es una enfermedad ultrarrara causada por un error congénito del metabolismo lipídico, que se caracteriza por el depósito de ésteres de colesterol y triglicéridos en el organismo. En pacientes con nula función enzimática la enfermedad se inicia en el período perinatal y es inevitablemente mortal durante el primer año de vida. En el resto de los casos el fenotipo es heterogéneo, aunque la mayoría de los pacientes desarrollan hepatopatía crónica y pueden presentar enfermedad cardiovascular prematura. Clásicamente, el tratamiento de la DLAL ha consistido en el uso de medidas de soporte, que no evitan su progresión. En 2015, las agencias reguladoras aprobaron el uso de una LAL recombinante humana para el tratamiento de la DLAL. Dicho tratamiento de sustitución enzimática a largo plazo se ha asociado con mejorías significativas de los parámetros lipídicos y hepáticos, incrementándose la supervivencia en lactantes con enfermedad rápidamente progresiva. La gravedad de la enfermedad, junto con la reciente disponibilidad de un tratamiento específico, hace especialmente relevante la necesidad de identificar a estos pacientes en la práctica clínica, aunque la baja prevalencia de la DLAL y el solapamiento clínico con otras enfermedades más frecuentes dificulta su reconocimiento. Con base en la evidencia científica publicada y la experiencia clínica e investigacional de los autores, el presente documento incluye recomendaciones prácticas para la identificación y la monitorización de los pacientes con DLAL, incluyendo un algoritmo diagnóstico, junto con una actualización de su tratamiento (AU)

Lysosomal acid lipase deficiency (LALD) is an ultra-rare disease caused by a congenital disorder of the lipid metabolism, characterized by the deposition of cholesterol esters and triglycerides in the organism. In patients with no enzyme function, the disease develops during the perinatal period and is invariably associated with death during the first year of life. In all other cases, the phenotype is heterogeneous, although most patients develop chronic liver diseases and may also develop an early cardiovascular disease. Treatment for LALD has classically included the use of supportive measures that do not prevent the progression of the disease. In 2015, regulatory agencies approved the use of a human recombinant LAL for the treatment of LALD. This long-term enzyme replacement therapy has been associated with significant improvements in the hepatic and lipid profiles of patients with LALD, increasing survival rates in infants with a rapidly progressive disease. Both the severity of LALD and the availability of a specific treatment highlight the need to identify these patients in clinical settings, although its low prevalence and the existing clinical overlap with other more frequent pathologies limit its diagnosis. In this paper we set out practical recommendations to identify and monitor patients with LALD, including a diagnostic algorithm, along with an updated treatment (AU)

Update on lysosomal acid lipase deficiency: Diagnosis, treatment and patient management. / Actualización en deficiencia de lipasa ácida lisosomal: diagnóstico, tratamiento y seguimiento de los pacientes.

Lysosomal acid lipase deficiency (LALD) is an ultra-rare disease caused by a congenital disorder of the lipid metabolism, characterized by the deposition of cholesterol esters and triglycerides in the organism. In patients with no enzyme function, the disease develops during the perinatal period and is invariably associated with death during the first year of life. In all other cases, the phenotype is heterogeneous, although most patients develop chronic liver diseases and may also develop an early cardiovascular disease. Treatment for LALD has classically included the use of supportive measures that do not prevent the progression of the disease. In 2015, regulatory agencies approved the use of a human recombinant LAL for the treatment of LALD. This long-term enzyme replacement therapy has been associated with significant improvements in the hepatic and lipid profiles of patients with LALD, increasing survival rates in infants with a rapidly progressive disease. Both the severity of LALD and the availability of a specific treatment highlight the need to identify these patients in clinical settings, although its low prevalence and the existing clinical overlap with other more frequent pathologies limit its diagnosis. In this paper we set out practical recommendations to identify and monitor patients with LALD, including a diagnostic algorithm, along with an updated treatment.

Universal access to megastigmanes through controlled cyclisation towards highly substituted cyclohexenes.

We report the selective formation of cyclohexenes with a tetrasubstituted double bond, the structural key element of megastigmanes. For this purpose the ZrCl4-mediated epoxide ring opening of epoxy-geranylacetone was employed. This approach provides a universal entry to the preparation of the members of the megastigmane family, which was exemplified in the asymmetric synthesis of tectoionol B.

Impacto del remodelado del anillo mitral tras el procedimiento MitraClip en la reducción de la insuficiencia mitral funcional / Effects of mitral annulus remodeling following MitraClip procedure on reduction of functional mitral regurgitation

Introducción y objetivos: El procedimiento de reparación mitral percutánea (MitraClip) parece reducir los diámetros del anillo mitral de pacientes con etiología funcional, pero no se ha demostrado la relación con la intensidad de la regurgitación. El objetivo es evaluar si el remodelado del anillo mitral tiene algún impacto en la reducción de la regurgitación mitral en pacientes con insuficiencia mitral funcional. Métodos: Se incluyó a todos los pacientes con etiología funcional tratados con MitraClip en el centro hasta enero de 2015. Se les realizó ecocardiograma inmediatamente después de la colocación del dispositivo (equipo iE33, Philips). Los cambios en el anillo mitral se correlacionaron con la intensidad de la regurgitación mitral evaluada por el orificio regurgitante efectivo. Resultados: Se incluyó a 23 pacientes (edad, 65 ± 14 años; el 74% varones; fracción de eyección del ventrículo izquierdo, 31 ± 13%; presión sistólica de la arteria pulmonar, 47 ± 10 mmHg). Tras el procedimiento, el orificio regurgitante disminuyó en 0,30 ± 0,04 cm2 (p < 0,0005), desde un valor basal de 0,49 ± 0,9 cm2. Se observó una reducción del diámetro anteroposterior de 3,14 ± 1,01 mm (p < 0,0005) desde un valor basal de 28,27 ± 4,9 mm, sin cambios en el diámetro intercomisural (0,50 ± 0,91 frente a 40,68 ± 4,7 mm; p = 0,26). Se observó una relación significativa entre la reducción del diámetro anteroposterior y la reducción del orificio regurgitante (r = 0,49; p = 0,020). Conclusiones: El dispositivo MitraClip produce una inmediata reducción del diámetro anteroposterior en pacientes con insuficiencia mitral funcional. Este remodelado podría relacionarse con la reducción de la regurgitación mitral (AU)

Introduction and objectives: The percutaneous mitral valve repair procedure (MitraClip) appears to reduce mitral annulus diameter in patients with functional mitral regurgitation, but the relationship between this and regurgitation severity has not been demonstrated. The aim of this study was to determine the effect of mitral annulus remodeling on the reduction of mitral regurgitation in patients with functional etiology. Methods: The study included all patients with functional mitral regurgitation treated with MitraClip at our hospital until January 2015. Echocardiogram (iE33 model, Philips) was performed in all patients immediately after device positioning. Changes in the mitral annulus correlated with mitral regurgitation severity, as assessed using the effective regurgitant orifice area. Results: The study included 23 patients (age, 65 ± 14 years; 74% men; left ventricular ejection fraction, 31% ± 13%; systolic pulmonary artery pressure, 47 ± 10 mmHg). After the procedure, the regurgitant orifice area decreased by 0.30 cm2 ± 0.04 cm2 (P < .0005), from a baseline of 0.49 cm2 ± 0.09 cm2. Anteroposterior diameter decreased by 3.14 mm ± 1.01 mm (P < .0005) from a baseline of 28.27 mm ± 4.9 mm, with no changes in the intercommissural diameter (0.50 mm ± 0.91 mm vs 40.68 mm ± 4.7 mm; P = .26). A significant association was seen between anteroposterior diameter reduction and regurgitant orifice area reduction (r = .49; P = .020). Conclusions: In patients with functional mitral regurgitation, the MitraClip device produces an immediate reduction in the anteroposterior diameter. This remodeling may be related to the reduction in mitral regurgitation (AU)

Importancia de la sospecha clínica en el diagnóstico de la enfermedad de Pompe de inicio tardío / Importance of clinical suspicion in the diagnosis of late-onset Pompe disease

No disponible

Region 4 of Rhizobium etli Primary Sigma Factor (SigA) Confers Transcriptional Laxity in Escherichia coli.

Sigma factors are RNA polymerase subunits engaged in promoter recognition and DNA strand separation during transcription initiation in bacteria. Primary sigma factors are responsible for the expression of housekeeping genes and are essential for survival. RpoD, the primary sigma factor of Escherichia coli, a γ-proteobacteria, recognizes consensus promoter sequences highly similar to those of some α-proteobacteria species. Despite this resemblance, RpoD is unable to sustain transcription from most of the α-proteobacterial promoters tested so far. In contrast, we have found that SigA, the primary sigma factor of Rhizobium etli, an α-proteobacteria, is able to transcribe E. coli promoters, although it exhibits only 48% identity (98% coverage) to RpoD. We have called this the transcriptional laxity phenomenon. Here, we show that SigA partially complements the thermo-sensitive deficiency of RpoD285 from E. coli strain UQ285 and that the SigA region σ4 is responsible for this phenotype. Sixteen out of 74 residues (21.6%) within region σ4 are variable between RpoD and SigA. Mutating these residues significantly improves SigA ability to complement E. coli UQ285. Only six of these residues fall into positions already known to interact with promoter DNA and to comprise a helix-turn-helix motif. The remaining variable positions are located on previously unexplored sites inside region σ4, specifically into the first two α-helices of the region. Neither of the variable positions confined to these helices seem to interact directly with promoter sequence; instead, we adduce that these residues participate allosterically by contributing to correct region folding and/or positioning of the HTH motif. We propose that transcriptional laxity is a mechanism for ensuring transcription in spite of naturally occurring mutations from endogenous promoters and/or horizontally transferred DNA sequences, allowing survival and fast environmental adaptation of α-proteobacteria.