Role of Muscle Ultrasound for the Study of Frailty in Elderly Patients with Diabetes: A Pilot Study.

BACKGROUND: Sarcopenia and diabetes contribute to the development of frailty. Therefore, accessible methods, such as muscle ultrasounds (MUSs), to screen for sarcopenia should be implemented in clinical practice. METHODS: We conducted a cross-sectional pilot study including 47 patients with diabetes (mean age: 77.72 ± 5.08 years, mean weight: 75.8 kg ± 15.89 kg, and body mass index: 31.19 ± 6.65 kg/m2) categorized as frail by the FRAIL Scale or Clinical Frailty Scale and confirmed by Fried's Frailty Phenotype or Rockwood's 36-item Frailty Index. We used the SARC-F questionnaire to identify sarcopenia. The Short Physical Performance Battery (SPPB) and the Timed Up and Go (TUG) tests were used to assess physical performance and the risk of falls, respectively. In addition, other variables were measured: fat-free mass (FFM) and Sarcopenia Risk Index (SRI) with the bioimpedance analysis (BIA); thigh muscle thickness (TMT) of the quadriceps with MUS; and hand-grip strength with dynamometry. RESULTS: We observed correlations between the SARC-F and FFM (R = -0.4; p < 0.002) and hand-grip strength (R = -0.5; p < 0.0002), as well as between the TMT and FFM of the right leg (R = 0.4; p < 0.02) and the SRI (R = 0.6; p < 0.0001). We could predict sarcopenia using a logistic regression model with a ROC curve (AUC = 0.78) including FFM, handgrip strength, and TMT. The optimal cut-off point for maximum efficiency was 1.58 cm for TMT (sensitivity = 71.4% and specificity = 51.5%). However, we did not observe differences in the TMT among groups of greater/less frailty based on the SARC-F, SPPB, and TUG (p > 0.05). CONCLUSIONS: MUSs, which correlated with the BIA (R = 0.4; p < 0.02), complemented the diagnosis, identifying regional sarcopenia of the quadriceps in frail patients with diabetes and improving the ROC curve to AUC = 0.78. In addition, a TMT cut-off point for the diagnosis of sarcopenia of 1.58 cm was obtained. Larger studies to validate the MUS technique as a screening strategy are warranted.

Terapia de resincronización cardíaca. Incidencia y mecanismos involucrados en la reducción de la insuficiencia mitral funcional / Cardiac Resynchronization Therapy. Incidence and Mechanisms Involved in the Reduction of Functional Mitral Regurgitation

RESUMEN Introducción: La insuficiencia mitral funcional (IMF) es común en pacientes con insuficiencia cardíaca (IC). La IMF moderada/ grave (M/G) se asocia a peor pronóstico. Objetivo: Describir la prevalencia de IMF y los mecanismos involucrados en su reducción en respondedores a la terapia de resincronización cardíaca (TRC) a los 6 meses comparados con 12 y 24 meses. Métodos: Entre 2009 y 2018 fueron tratados 338 pts. Respondedores: reducción de CF NYHA ≥1 grado o aumento de la fracción de eyección ventricular izquierda (FEVI) ≥5% (absoluto). La IMF se graduó en 4 puntos: No-IMF, leve, M y G, y se la relacionó con las mediciones ecocardiográficas. Características Basales: edad 64 ±10 años, hombres 71%, CF-NYHA IIIII 92%, bloqueo de rama izquierda (BRI) 67%, QRS ≥150 ms 75%, diámetro diastólico del VI (DDVI) 68 ± 9 mm, diámetro sistólico del VI (DSVI) 52 ± 12 mm, FEVI 24 ± 7%. Resultados: La prevalencia de IMF fue del 92,6%. A los 6 meses, 86% fueron respondedores y 23% de ellos mejoraron de IMF-M/G a IMF-Leve/No-IMF. Hubo un fuerte remodelado inverso: DDVI 68 ± 10 vs 63 ± 11 mm, (p = 0,0001), DSVI 55 ± 12 vs 50 ± 13 mm, (p = 0,0006) y FEVI 25 ± 11 vs 33 ± 10%, (p = 0,00001). Comparando 6 con 12 meses 89,4% fueron respondedores, 8% mejoraron de IMF-M/G a IMF-Leve/No-IMF. Comparando 6 con 24 meses 88% fueron respondedores, 14,6% mejoraron de IMF-M/G a IMF-Leve/No-IMF. Entre 6 y 12 y 6 y 24 meses no hubo remodelado inverso significativo. Conclusiones: La prevalencia de IMF fue elevada. El mayor remodelado inverso y reducción de la IMF se observaron a los 6 meses, siendo el primero el principal mecanismo en la reducción de la IMF. Esta mejoría se sostuvo a los 12 y 24 meses.

ABSTRACT Background: Functional mitral regurgitation (FMR) is common in heart failure, and moderate/severe (M/S) FMR is associated with worse prognosis. Objective: The aim of this study was to describe the prevalence of FMR and the mechanisms involved in its reduction in responders to cardiac resynchronization therapy (CRT) at 6 months compared with 12 and 24 months. Methods: Between 2009 and 2018, 338 patients received CRT. Patients showing NYHA functional class (FC) reduction ≥1 or left ventricular ejection fraction (LVEF) absolute increase ≥5% were considered responders. Functional mitral regurgitation was graded using a 4-point scale into none-, mild-, M- and S-FMR, and was related to echocardiographic measurements. Baseline patient characteristics were: age 64±10 years, men 71%, NYHA FC II-III 92%, left bundle branch block (LBBB) 67%, QRS ≥150 ms 75%, LV diastolic diameter (LVDD) 68±9 mm, LV systolic diameter (LVSD) 52±12 mm, and LVEF 24±7%. Results: The prevalence of FMR was 92.6%. At 6 months, 86% were responders, 23% improved from M/S-FMR to mild/none-FMR and there was strong reverse remodeling: LVDD 68±10 vs. 63±11 mm, (p=0.0001), LVSD 55±12 vs. 50±13 mm, (p=0.0006) and LVEF 25±11 vs. 33±10%, (p=0.00001). Comparing 6 with 12 months, 89.4% were responders and 8% improved M/S-FMR to mild/none-FMR. Comparing 6 with 24 months, 88% were responders and 14.6% improved M/S-FMR to mild/none-FMR. Between 6 and 12 and 6 and 24 months, there was no significant reverse remodeling. Conclusions: The prevalence of FMR was high. The highest reverse remodeling and FMR reduction was observed at 6 months, the former being the main mechanism of FMR reduction. This improvement persisted at 12 and 24 months.

A rationally designed orthogonal synthetase for genetically encoded fluorescent amino acids.

The incorporation of non-canonical amino acids into proteins has emerged as a promising strategy to manipulate and study protein structure-function relationships with superior precision in vitro and in vivo. To date, fluorescent non-canonical amino acids (f-ncAA) have been successfully incorporated in proteins expressed in bacterial systems, Xenopus oocytes, and HEK-293T cells. Here, we describe the rational generation of a novel orthogonal aminoacyl-tRNA synthetase based on the E. coli tyrosine synthetase that is capable of encoding the f-ncAA tyr-coumarin in HEK-293T cells.

The Contribution of the Ankyrin Repeat Domain of TRPV1 as a Thermal Module.

The TRPV1 cation nonselective ion channel plays an essential role in thermosensation and perception of other noxious stimuli. TRPV1 can be activated by low extracellular pH, high temperature, or naturally occurring pungent molecules such as allicin, capsaicin, or resiniferatoxin. Its noxious thermal sensitivity makes it an important participant as a thermal sensor in mammals. However, details of the mechanism of channel activation by increases in temperature remain unclear. Here, we used a combination of approaches to try to understand the role of the ankyrin repeat domain (ARD) in channel behavior. First, a computational modeling approach by coarse-grained molecular dynamics simulation of the whole TRPV1 embedded in a phosphatidylcholine and phosphatidylethanolamine membrane provides insight into the dynamics of this channel domain. Global analysis of the structural ensemble shows that the ARD is a region that sustains high fluctuations during dynamics at different temperatures. We then performed biochemical and thermal stability studies of the purified ARD by the means of circular dichroism and tryptophan fluorescence and demonstrate that this region undergoes structural changes at similar temperatures that lead to TRPV1 activation. Our data suggest that the ARD is a dynamic module and that it may participate in controlling the temperature sensitivity of TRPV1.

FRET-based analysis and molecular modeling of the human GPN-loop GTPases 1 and 3 heterodimer unveils a dominant-negative protein complex.

GPN-loop GTPases 1 and 3 are required for RNA polymerase II (RNAPII) nuclear import. Gpn1 and Gpn3 display some sequence similarity, physically associate, and their protein expression levels are mutually dependent in human cells. We performed here Fluorescence Resonance Energy Transfer (FRET), molecular modeling, and cell biology experiments to understand, and eventually disrupt, human Gpn1-Gpn3 interaction in live HEK293-AD cells. Transiently expressed EYFP-Gpn1 and Gpn3-CFP generated a strong FRET signal, indicative of a very close proximity, in the cytoplasm of HEK293-AD cells. Molecular modeling of the human Gpn1-Gpn3 heterodimer based on the crystallographic structure of Npa3, the Saccharomyces cerevisiae Gpn1 ortholog, revealed that human Gpn1 and Gpn3 associate through a large interaction surface formed by internal α-helix 7, insertion 2, and the GPN-loop from each protein. In site-directed mutagenesis experiments of interface residues, we identified the W132D and M227D EYFP-Gpn1 mutants as defective to produce a FRET signal when coexpressed with Gpn3-CFP. Simultaneous but not individual expression of Gpn1 and Gpn3, with either or both proteins fused to EYFP, retained RNAPII in the cytoplasm and markedly inhibited global transcription in HEK293-AD cells. Interestingly, the W132D and M227D Gpn1 mutants that showed an impaired ability to interact with Gpn3 by FRET were also unable to delocalize RNAPII in this assay, indicating that an intact Gpn1-Gpn3 interaction is required to display the dominant-negative effect on endogenous Gpn1/Gpn3 function we described here. Altogether, our results suggest that a Gpn1-Gpn3 strong interaction is critical for their cellular function.

Irreversible temperature gating in trpv1 sheds light on channel activation.

Temperature-activated TRP channels or thermoTRPs are among the only proteins that can directly convert temperature changes into changes in channel open probability. In spite of a wealth of functional and structural information, the mechanism of temperature activation remains unknown. We have carefully characterized the repeated activation of TRPV1 by thermal stimuli and discovered a previously unknown inactivation process, which is irreversible. We propose that this form of gating in TRPV1 channels is a consequence of the heat absorption process that leads to channel opening.

Conformational dynamics in TRPV1 channels reported by an encoded coumarin amino acid.

TRPV1 channels support the detection of noxious and nociceptive input. Currently available functional and structural data suggest that TRPV1 channels have two gates within their permeation pathway: one formed by a 'bundle-crossing' at the intracellular entrance and a second constriction at the selectivity filter. To describe conformational changes associated with channel gating, the fluorescent non-canonical amino acid coumarin-tyrosine was genetically encoded at Y671, a residue proximal to the selectivity filter. Total internal reflection fluorescence microscopy was performed to image the conformational dynamics of the channels in live cells. Photon counts and optical fluctuations from coumarin encoded within TRPV1 tetramers correlates with channel activation by capsaicin, providing an optical marker of conformational dynamics at the selectivity filter. In agreement with the fluorescence data, molecular dynamics simulations display alternating solvent exposure of Y671 in the closed and open states. Overall, the data point to a dynamic selectivity filter that may serve as a gate for permeation.

Cells use proteins on their surface as sensors to help them to assess and explore their environments and adapt to external conditions. The transient receptor potential (TRP) ion channels form one such family of proteins. Sodium, potassium and calcium ions can move through TRP channels to enter and exit cells, and by doing so trigger changes in the cell that help it respond to an external stimulus. The channels have physical "gates" that can open and close to control the flow of the ions. When the TRP channel detects a stimulus ­ which could take the form of specific chemicals, or a change in temperature, pressure or voltage ­ it changes shape, causing the gate to open. Researchers have a number of unanswered questions about how TRP channels work. Where in the channels are gates located? How do the channels control the flow of ions, and how do they communicate with each other? And which regions of the protein sense environmental cues? As a result, new technologies are being developed to make it easier to study the types of rearrangements that TRP channels experience when they activate. Steinberg, Kasimova et al. have used total internal reflection microscopy ­ a method that images fluorescent molecules ­ to measure the conformational change of a single TRP channel in a living cell. This channel, called TRPV1, senses external heat and plays an important role in pain perception. Its gate can also be opened by the pungent compound of chili pepper, capsaicin. The results of the experiments suggest that a selectivity filter region in TRPV1 channels changes its shape when the channel opens in response to capsaicin. Then, this selectivity filter appears to do double duty ­ it controls which types of ions pass through the channels as well as controlling their flow rate. Because of its role in pain perception, having a better understanding of how TRPV1 works will be valuable for researchers who are trying to develop new pain relief treatments. The so-called 'seeing is believing' method used by Steinberg, Kasimova et al. could also be used to study other membrane proteins, both to guide drug development and to improve our understanding of how cells interact with their environment.

Coarse architecture of the transient receptor potential vanilloid 1 (TRPV1) ion channel determined by fluorescence resonance energy transfer.

The transient receptor potential vanilloid 1 ion channel is responsible for the perception of high temperatures and low extracellular pH, and it is also involved in the response to some pungent compounds. Importantly, it is also associated with the perception of pain and noxious stimuli. Here, we attempt to discern the molecular organization and location of the N and C termini of the transient receptor potential vanilloid 1 ion channel by measuring FRET between genetically attached enhanced yellow and cyan fluorescent protein to the N or C terminus of the channel protein, expressed in transfected HEK 293 cells or Xenopus laevis oocytes. The static measurements of the domain organization were mapped into an available cryo-electron microscopy density of the channel with good agreement. These measurements also provide novel insights into the organization of terminal domains and their proximity to the plasma membrane.

Patient perspectives on improving oral health-care practices among people living with HIV/AIDS.

This qualitative study explored the impact on oral health-care knowledge, attitudes, and practices among 39 people living with HIV/AIDS (PLWHA) participating in a national initiative aimed at increasing access to oral health care. Personal values and childhood dental experiences, beliefs about the importance of oral health in relation to HIV health, and concerns for appearance and self-esteem were found to be determinants of oral health knowledge and practice. Program participation resulted in better hygiene practices, improved self-esteem and appearance, relief of pain, and better physical and emotional health. In-depth exploration of the causes for these changes revealed a desire to continue with dental care due to the dental staff and environmental setting, and a desire to maintain overall HIV health, including oral health. Our findings emphasize the importance of addressing both personal values and contextual factors in providing oral health-care services to PLWHA.

Identification of a binding motif in the S5 helix that confers cholesterol sensitivity to the TRPV1 ion channel.

The TRPV1 ion channel serves as an integrator of noxious stimuli with its activation linked to pain and neurogenic inflammation. Cholesterol, a major component of cell membranes, modifies the function of several types of ion channels. Here, using measurements of capsaicin-activated currents in excised patches from TRPV1-expressing HEK cells, we show that enrichment with cholesterol, but not its diastereoisomer epicholesterol, markedly decreased wild-type rat TRPV1 currents. Substitutions in the S5 helix, rTRPV1-R579D, and rTRPV1-F582Q, decreased this cholesterol response and rTRPV1-L585I was insensitive to cholesterol addition. Two human TRPV1 variants, with different amino acids at position 585, had different responses to cholesterol with hTRPV1-Ile(585) being insensitive to this molecule. However, hTRPV1-I585L was inhibited by cholesterol addition similar to rTRPV1 with the same S5 sequence. In the absence of capsaicin, cholesterol enrichment also inhibited TRPV1 currents induced by elevated temperature and voltage. These data suggest that there is a cholesterol-binding site in TRPV1 and that the functions of TRPV1 depend on the genetic variant and membrane cholesterol content.

Influencia del sulfato de magnesio inhalado en la resolución de la crisis asmática / Influence of the magnesium sulfate inhalad in the resolution of the asthmatic crisis

La crisis aguda de asma constituye un motivo frecuente de consulta en nuestras emergencias; que en muchas ocasiones conlleva a hospitalización e incluso a la necesidad de ingrero a UVI y ventilación mecánica. El siguiente estudio clínico tiene como propósito el evaluar el rol del Sulfato de Magnesio (MgSO4) inhalado en el manejo de las crisis asmáticas, haciendo énfasis más que en la actividad broncodilatadora del MgSO4, contra salbutamol (un ß2-agonista que se ha convertido en el standard de tratamiento de la crisis de asma, según el reporte del II panel de expertos); en evaluar la posible contribución a la broncodilatación, de añadir al tratamiento convencional una dosis de 3 ml de MgSO4 nebulizado. Los hallazgos de este estudio evidenciaron que el MgSO4 nebulizado tiene una débil acción broncodilatadora utilizado solo (lo cual ya había sido demostrado en otros trabajos) 4 pero, que añadido a dosis de Salbutamol recomendadas en los últimos lineamientos para el manejo de crisis asmáticas-6 aumenta el efecto broncodilatador del mismo y que este aumento alcanza significancia estadística en los pacientes más severamente obstruidos

Fístula gastrocólica como complicación de tumor carcinoide maligno de colon / Fistula gastrocolic how complication of malignant carcinoid tumor of colon

Se presenta el primer caso en la literatura nacional de una paciente femenina de 70 años quien consulta por dolor abdominal, pérdida de peso, vómitos fecaloideos y masa palpable abdominal en hipocondrió izquierdo. Se realizan estudios preoperatorios pertinentes, evidenciándose: fistula gastrocólica amplia (de 2 cm. de diametro) producto por Tumor de Angulo Esplénico del Colon de 10 cm de diámetro, anatomomatológicamente descrito como Tumor Carcinoide Maligno ulcerovegetante con infiltración de la pared y extensión hacia el meso, con boca de fístula con presencia de tumor. Se realiza intervención quirúrgica: Gastrectomía parcial (Antrectomía), y resección de Colon Izquierdo con Transversosigmodoanastomosis distal termino-terminal. Posteriormente la paciente recibe Radioterapia (5.000 rads en 28 sesiones) sin complicaciones. Actualmente la paciente se encuentra asintomática y sin evidencias clínicas o paraclínicas de recidiva de la enfermedad

Cáncer de pulmón: clínica, epidemiología, histología y terapéutica / Lung cancer: clinical, epidemiological, histology and therapeutical

El Cáncer de Pulmón es la primera causa de muerte por Cáncer en EUA y otros países desarrollados y la segunda en Venezuela, con una baja sobrevida en 5 años, en ambos casos. Existen varios factores plenamente identificados en su origen. Todos estos factores hacen del Cáncer de Pulmón una patología sobre la cual se unen numerosos esfuerzos y focos de atención, por lo que decidimos realizar esta investigación con el fin de observar las caracterticas de esta enfermedad de nuestra población. Pudimos darnos cuenta de que la forma en que ésta se presenta es esencialmente la misma que la encontrada en ámbitos internacionales, en cuanto a clínica, epidemiología e histología; también, que los procedimientos de diagnóstico y tratamiento se ciñen a las pautas internacionales. igualmente, se evidenció una relación estrecha de factores clínicos, epidemiológicos, terapéuticos e histológicos entre sí

El marxismo en América Latina

Esta antología reúne textos marxistas latinoamericanos de carácter diverso, análisis sociales, propuestas políticas, de épocas también diversas, pero con algo en común: todos ellos se refieren a América Latina y tienden a ejemplificar los diversos niveles en que ha sido instrumentada la teoría marxista en el continente

El marxismo en América Latina

Esta antología reúne textos marxistas latinoamericanos de carácter diverso, análisis sociales, propuestas políticas, de épocas también diversas, pero con algo en común: todos ellos se refieren a América Latina y tienden a ejemplificar los diversos niveles en que ha sido instrumentada la teoría marxista en el continente