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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Índice Glucémico , Carga Glucémica , Neoplasias , Humanos , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Neoplasias/mortalidad , Neoplasias/sangre , Índice Glucémico/fisiología , Glucemia/análisis , MasculinoRESUMEN
Unlike other members of the voltage-gated ion channel superfamily, voltage-gated proton (Hv) channels are solely composed of voltage sensor domains without separate ion-conducting pores. Due to their unique dependence on both voltage and transmembrane pH gradients, Hv channels normally open to mediate proton efflux. Multiple cellular ligands were also found to regulate the function of Hv channels, including Zn2+, cholesterol, polyunsaturated arachidonic acid, and albumin. Our previous work showed that Zn2+ and cholesterol inhibit the human voltage-gated proton channel (hHv1) by stabilizing its S4 segment at resting state conformations. Released from phospholipids by phospholipase A2 in cells upon infection or injury, arachidonic acid regulates the function of many ion channels, including hHv1. In the present work, we examined the effects of arachidonic acid on purified hHv1 channels using liposome flux assays and revealed underlying structural mechanisms using single-molecule FRET. Our data indicated that arachidonic acid strongly activates hHv1 channels by promoting transitions of the S4 segment toward opening or "preopening" conformations. Moreover, we found that arachidonic acid even activates hHv1 channels inhibited by Zn2+ and cholesterol, providing a biophysical mechanism to activate hHv1 channels in nonexcitable cells upon infection or injury.
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Ácido Araquidónico , Colesterol , Activación del Canal Iónico , Canales Iónicos , Protones , Zinc , Humanos , Albúminas/farmacología , Ácido Araquidónico/farmacología , Colesterol/farmacología , Transferencia Resonante de Energía de Fluorescencia , Activación del Canal Iónico/efectos de los fármacos , Canales Iónicos/agonistas , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/química , Canales Iónicos/metabolismo , Liposomas/metabolismo , Fosfolipasas A2/metabolismo , Imagen Individual de Molécula , Zinc/farmacología , Concentración de Iones de HidrógenoRESUMEN
High-resolution structures of voltage-gated sodium channels (Nav) were first obtained from a prokaryotic ortholog NavAb, which provided important mechanistic insights into Na+ selectivity and voltage gating. Unlike eukaryotic Navs, the NavAb channel is formed by four identical subunits, but its ion selectivity and pharmacological profiles are very similar to eukaryotic Navs. Recently, the structures of the NavAb voltage sensor at resting and activated states were obtained by cryo-EM, but its intermediate states and transition dynamics remain unclear. In the present work, we used liposome flux assays to show that purified NavAb proteins were functional to conduct both H+ and Na+ and were blocked by the local anesthetic lidocaine. Additionally, we examined the real-time conformational dynamics of the NavAb voltage sensor using single-molecule FRET. Our single-molecule FRET measurements on the tandem NavAb channel labeled with Cy3/5 FRET fluorophore pair revealed spontaneous transitions of the NavAb S4 segment among three conformational states, which fitted well with the kinetic model developed for the S4 segment of the human voltage-gated proton channel hHv1. Interestingly, even under strong activating voltage, the NavAb S4 segment seems to adopt a conformational distribution similar to that of the hHv1 S4 segment at a deep resting state. The conformational behaviors of the NavAb voltage sensor under different voltages need to be further examined to understand the mechanisms of voltage sensing and gating in the canonical voltage-gated ion channel superfamily.
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Proteínas Bacterianas , Activación del Canal Iónico , Canales de Sodio Activados por Voltaje , Conformación Proteica , Canales de Sodio Activados por Voltaje/metabolismo , Bacterias , Proteínas Bacterianas/metabolismoRESUMEN
BACKGROUND: There is limited information on surgical site infections (SSI) and the related antibiotic resistance needed to guide their management and prevention in Sierra Leone. In this study, we aimed to establish the incidence and risk factors of SSI and the related antibiotic resistance among adults attending a tertiary hospital, and a secondary health facility in Freetown, Sierra Leone. METHODS: This is a prospective cohort study designed to collect data from adult (18 years or older) patients who attended elective and emergency surgeries at two hospitals in Freetown between February and July, 2021. Data analysis was done using STATA version 16. RESULTS: Of 338 patients, 245 (72.5%) and 93 (27.5%) had their surgeries at the tertiary and secondary hospitals, respectively. Many were males 192 (56.8%), less than 35 years 164 (48.5%), and 39 (11.5%) developed an SSI. Of the 39 patients who acquired an SSI, 7 (17.9%) and 32 (82.1%) had their surgeries at the secondary and tertiary hospitals, respectively. The incidence of SSI is higher in contaminated 17 (43.6%) than in clean-contaminated 12 (30.8%) and clean 10 (25.6%) wounds. Wound swabs were collected in 29 (74.4%) patients, of which 18 (62.1%) had bacterial growth. In total, 49 isolates of 14 different bacteria including gram-negative 41 (83.7%) and gram-positive 8 (16.3%) isolates were identified. Of these, 32 (65.3%) were Enterobacteriaceae, 9 (18.4%) were Non-fermenting gram-negative bacilli and 10 (12.2%) were Enterococci. The most common isolates were Escherichia coli (12, 24.5%), Klebsiella pneumoniae (10, 20.4%), Acinetobacter baumannii (5, 10.2%), Klebsiella oxytoca (4, 8.2%) and Enterococcus faecalis (4, 8.2%). The Enterobacteriaceae were either resistance to carbapenems (4, 8.2%) or were extended-spectrum beta-lactamase (ESBL) producing organisms (29, 59.2%). Male sex [p = 0.031], an ASA score ≥ 2 [p = 0.020), administration of general anaesthesia [p = 0.018] and elevated fasting glucose [p = 0.033] were predictive of SSI. CONCLUSION: The incidence of SSI in this study is comparable to other low- and middle-income countries, but a substantial proportion of these postoperative wounds have an ESBL-producing Enterobacteriaceae. Therefore, routine surveillance of SSI and related antibiotic resistance is required in resource-limited settings.
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Antibacterianos , Infección de la Herida Quirúrgica , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Microbiana , Humanos , Incidencia , Masculino , Estudios Prospectivos , Factores de Riesgo , Sierra Leona/epidemiología , Infección de la Herida Quirúrgica/tratamiento farmacológico , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/microbiologíaRESUMEN
Evolutionary ecology aims to better understand how ecologically important traits respond to environmental heterogeneity. Environments vary both naturally and as a result of human activities, and investigations that simultaneously consider how natural and human-induced environmental variation affect diverse trait types grow increasingly important as human activities drive species endangerment. Here, we examined how habitat fragmentation and structural habitat complexity affect disparate trait types in Bahamas mosquitofish Gambusia hubbsi inhabiting tidal creeks. We tested a priori predictions for how these factors might influence exploratory behaviour, stress reactivity and brain anatomy. We examined approximately 350 adult Bahamas mosquitofish from seven tidal-creek populations across Andros Island, The Bahamas that varied in both human-caused fragmentation (three fragmented and four unfragmented) and natural habitat complexity (e.g. fivefold variation in rock habitat). Populations that had experienced severe human-induced fragmentation, and thus restriction of tidal exchange from the ocean, exhibited greater exploration of a novel environment, stronger physiological stress responses to a mildly stressful event and smaller telencephala (relative to body size). These changes matched adaptive predictions based mostly on (a) reduced chronic predation risk and (b) decreased demands for navigating tidally dynamic habitats. Populations from sites with greater structural habitat complexity showed a higher propensity for exploration and a relatively larger optic tectum and cerebellum. These patterns matched adaptive predictions related to increased demands for navigating complex environments. Our findings demonstrate environmental variation, including recent anthropogenic impacts (<50 years), can significantly affect complex, ecologically important traits. Yet trait-specific patterns may not be easily predicted, as we found strong support for only six of 12 predictions. Our results further highlight the utility of simultaneously quantifying multiple environmental factors-for example had we failed to account for habitat complexity, we would not have detected the effects of fragmentation on exploratory behaviours. These responses, and their ecological consequences, may be complex: rapid and adaptive phenotypic responses to anthropogenic impacts can facilitate persistence in human-altered environments, but may come at a cost of population vulnerability if ecological restoration was to occur without consideration of the altered traits.
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Ciprinodontiformes , Conducta Exploratoria , Animales , Encéfalo , Ecosistema , Conducta PredatoriaRESUMEN
The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.
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Antihipertensivos/farmacología , Descubrimiento de Drogas , Hipertensión/tratamiento farmacológico , Guanilil Ciclasa Soluble/metabolismo , Antihipertensivos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND & AIMS: Liver fibrosis assessed by liver biopsy is predictive of clinical liver events in patients with nonalcoholic fatty liver disease (NAFLD). Magnetic resonance elastography (MRE) correlates with liver biopsy in assessing liver fibrosis. However, data assessing the relationship between MRE and clinical liver events are lacking. We investigated the association between MRE and clinical liver events/death and identified the cut-off to predict clinical liver events in NAFLD patients. METHODS: We conducted a multicenter retrospective study of NAFLD patients who underwent MRE between 2016 and 2019. Clinical liver events were defined as decompensation events and death. We categorized patients into noncirrhosis, compensated cirrhosis and decompensated cirrhosis. Fisher's exact test was used to test association strength. Receiver operative curve methods were used to determine the optimal cut-off of MRE liver stiffness and to maximize the accuracy for classifying noncirrhosis, compensated cirrhosis and decompensated cirrhosis. Logistic regression modelling was used to predict decompensation. RESULTS: The study included 320 NAFLD patients who underwent MRE. The best threshold for distinguishing cirrhosis from noncirrhosis was 4.39 kPa (AUROC 0.92) and from decompensated cirrhosis was 6.48 kPa (AUROC 0.71). Odds of decompensation increased as liver stiffness increased (OR 3.28) (P < .001). Increased liver stiffness was associated with ascites, hepatic encephalopathy, oesophageal variceal bleeding and mortality (median 7.10, 10.15 and 10.15 kPa respectively). CONCLUSION: In NAFLD patients, liver stiffness measured by MRE with a cut-off of ≥6.48 kPa is associated with decompensation and mortality, and specific MRE cut-offs are predictive of individual clinical liver events.
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Diagnóstico por Imagen de Elasticidad , Várices Esofágicas y Gástricas , Enfermedad del Hígado Graso no Alcohólico , Biopsia , Várices Esofágicas y Gástricas/patología , Hemorragia Gastrointestinal/patología , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Imagen por Resonancia Magnética , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/patología , Estudios Prospectivos , Curva ROC , Estudios RetrospectivosRESUMEN
In the current climate of increased global terrorism, the threat of a radiological incident is becoming more realistic than ever, and as such, the necessity of early-warning detection is paramount to national security. To assist with this need, we have investigated the detection of uncharged particle emissions from radiological sources using charged-coupled devices (CCDs), which are contained within a variety of products, including consumer cellphones and traffic cameras. Because the CCD is intrinsically sensitive to charge accumulation as a result of linear energy transfer by the incident particles, each event can be counted and quantified using video-image processing and an estimated energy band assessed by the properties of the pixels. In an effort to make this process applicable to the widest possible range of CCDs available, this experiment was conducted using low-quality CCDs contained within consumer-grade, budget web cameras. Within a Pu-Be neutron howitzer, particles were detected using several camera models: Gigaware X76, Z76 and Logitech C170, C270. Particle detection events were counted by post-processing with Matlab, and an efficiency for each CCD was determined relative to both a theoretical flux model and a calibrated He tube detector. The relative detection efficiencies for the cameras tested fell within the range 14-18% and showed a linear correlation between incident energy and pixel response.
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Equipos y Suministros Eléctricos , Trazadores Radiactivos , Calibración , Modelos Teóricos , RadiologíaRESUMEN
BACKGROUND: Previous systematic reviews and meta-analyses explaining the relationship between carbohydrate quality and health have usually examined a single marker and a limited number of clinical outcomes. We aimed to more precisely quantify the predictive potential of several markers, to determine which markers are most useful, and to establish an evidence base for quantitative recommendations for intakes of dietary fibre. METHODS: We did a series of systematic reviews and meta-analyses of prospective studies published from database inception to April 30, 2017, and randomised controlled trials published from database inception to Feb 28, 2018, which reported on indicators of carbohydrate quality and non-communicable disease incidence, mortality, and risk factors. Studies were identified by searches in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and by hand searching of previous publications. We excluded prospective studies and trials reporting on participants with a chronic disease, and weight loss trials or trials involving supplements. Searches, data extraction, and bias assessment were duplicated independently. Robustness of pooled estimates from random-effects models was considered with sensitivity analyses, meta-regression, dose-response testing, and subgroup analyses. The GRADE approach was used to assess quality of evidence. FINDINGS: Just under 135 million person-years of data from 185 prospective studies and 58 clinical trials with 4635 adult participants were included in the analyses. Observational data suggest a 15-30% decrease in all-cause and cardiovascular related mortality, and incidence of coronary heart disease, stroke incidence and mortality, type 2 diabetes, and colorectal cancer when comparing the highest dietary fibre consumers with the lowest consumers Clinical trials show significantly lower bodyweight, systolic blood pressure, and total cholesterol when comparing higher with lower intakes of dietary fibre. Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer. Similar findings for whole grain intake were observed. Smaller or no risk reductions were found with the observational data when comparing the effects of diets characterised by low rather than higher glycaemic index or load. The certainty of evidence for relationships between carbohydrate quality and critical outcomes was graded as moderate for dietary fibre, low to moderate for whole grains, and low to very low for dietary glycaemic index and glycaemic load. Data relating to other dietary exposures are scarce. INTERPRETATION: Findings from prospective studies and clinical trials associated with relatively high intakes of dietary fibre and whole grains were complementary, and striking dose-response evidence indicates that the relationships to several non-communicable diseases could be causal. Implementation of recommendations to increase dietary fibre intake and to replace refined grains with whole grains is expected to benefit human health. A major strength of the study was the ability to examine key indicators of carbohydrate quality in relation to a range of non-communicable disease outcomes from cohort studies and randomised trials in a single study. Our findings are limited to risk reduction in the population at large rather than those with chronic disease. FUNDING: Health Research Council of New Zealand, WHO, Riddet Centre of Research Excellence, Healthier Lives National Science Challenge, University of Otago, and the Otago Southland Diabetes Research Trust.
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Carbohidratos de la Dieta/uso terapéutico , Enfermedades no Transmisibles/prevención & control , Prevención Primaria , Fibras de la Dieta/uso terapéutico , HumanosRESUMEN
Preparation of thin films by dissolving polymers in a common solvent followed by evaporation of the solvent has become a routine processing procedure. However, modeling of thin film formation in an evaporating solvent has been challenging due to a need to simulate processes at multiple length and time scales. In this work, we present a methodology based on the principles of linear non-equilibrium thermodynamics, which allows systematic study of various effects such as the changes in the solvent properties due to phase transformation from liquid to vapor and polymer thermodynamics resulting from such solvent transformations. The methodology allows for the derivation of evaporative flux and boundary conditions near each surface for simulations of systems close to the equilibrium. We apply it to study thin film microstructural evolution in phase segregating polymer blends dissolved in a common volatile solvent and deposited on a planar substrate. Effects of the evaporation rates, interactions of the polymers with the underlying substrate and concentration dependent mobilities on the kinetics of thin film formation are studied.
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For more than 200 years the fibre in plant foods has been known by animal nutritionists to have significant effects on digestion. Its role in human nutrition began to be investigated towards the end of the 19th century. However, between 1966 and 1972, Denis Burkitt, a surgeon who had recently returned from Africa, brought together ideas from a range of disciplines together with observations from his own experience to propose a radical view of the role of fibre in human health. Burkitt came late to the fibre story but built on the work of three physicians (Peter Cleave, G. D. Campbell and Hugh Trowell), a surgeon (Neil Painter) and a biochemist (Alec Walker) to propose that diets low in fibre increase the risk of CHD, obesity, diabetes, dental caries, various vascular disorders and large bowel conditions such as cancer, appendicitis and diverticulosis. Simply grouping these diseases together as having a common cause was groundbreaking. Proposing fibre as the key stimulated much research but also controversy. Credit for the dietary fibre hypothesis is given largely to Burkitt who became known as the 'Fibre Man'. This paper sets out the story of the development of the fibre hypothesis, and the contribution to it of these individuals.
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Enfermedades Cardiovasculares/historia , Caries Dental/etiología , Diabetes Mellitus/historia , Fibras de la Dieta/historia , Enfermedades Intestinales/historia , Obesidad/historia , África , Bioquímica/historia , Enfermedades Cardiovasculares/etiología , Caries Dental/historia , Diabetes Mellitus/etiología , Fibras de la Dieta/deficiencia , Cirugía General/historia , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Enfermedades Intestinales/etiología , Obesidad/etiología , Sudáfrica , Reino UnidoRESUMEN
The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes.
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Benzofuranos/química , Benzofuranos/farmacología , Propionatos/química , Propionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzofuranos/sangre , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratones , Propionatos/sangre , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
BACKGROUND: Choosing the correct surgical staple height is dependent on knowledge of specific tissue thickness and compressibility. The purpose of this study was to measure the thickness of cadaveric human lung tissue. MATERIALS AND METHODS: Between December 2012 and February 2013, whole lungs were procured from 12 donors. Inclusion criteria included negative serology, no prior thoracic surgery, and completion of measurements within 72 hours of death. Tissue thickness was measured in the anterior-to-posterior direction using a tissue measuring device (TMD) at 41 lung locations. The tissue measuring device applied a constant pressure (8 g/mm2) via a plunger for 15 seconds before reading the thickness. RESULTS: Cadaveric lung tissue thickness displayed a large variation by location and within each location. Mean thickness in the anterior-to-posterior direction ranged from 1.5 mm (right middle lobe [inferior peripheral] location) to 9.0 mm (right inferior lobe [mid-central] location). In general, the periphery of the lung lobes was thinner than the central locations (e.g., mean peripheral location thickness: 4.1 mm; mean central location thickness: 5.9 mm). The thinnest tissues among the 12 donor cadaveric lung specimens were found in the one donor with a history of severe emphysema/chronic bronchitis. Height (P = 0.012) and weight (P = 0.036) were positively correlated with tissue thickness. Additionally, after adjusting for height, cadaveric lung tissue was 3.0 mm thicker for females than males. CONCLUSIONS: Large variations of lung tissue thickness were demonstrated throughout the lung as well as within each measured location across different cadaveric specimens. Generally, peripheral locations were thinner than the central locations of the lobes. There was a strong positive correlation between thickness and height, and females had slightly thicker lung tissue than males of the same height.
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Pulmón/anatomía & histología , Cadáver , Femenino , Humanos , Masculino , Valores de Referencia , SuturasRESUMEN
OBJECTIVE: Current endoscopic transection devices are not optimized to meet the unique challenges posed by the task of vessel transection in difficult-to-access locations within the pleural cavity. The ECHELON FLEX™ powered vascular stapler (PVS) has been designed with four rows of staples instead of six, to decrease its size and enable more precise placement on fragile pulmonary vessels, using a narrower anvil than other commercially available transecting devices. This study was performed to determine whether the reduced number of staple rows affects haemostasis, and to assess surgeons' initial impression of the smaller stapler during in vivo usage. METHODS: The new four-row stapler was compared with commercially available six-row articulating staplers via expert graders using a validated scale of haemostasis in vivo after application on porcine gastroepiploic pedicles and other thin- and thick-walled vessels. The new stapler was then compared with current products by practising thoracic surgeons (n = 27) during in vivo usage of simulated pulmonary procedures in a porcine model. The surgeons were also surveyed on the key attributes of the four-row stapler in relation to the six-row predicates. RESULTS: Haemostasis evaluated on an ordered scale was clinically equivalent between the test and predicate staplers, and was deemed acceptable for all thin- and thick-vascular tissue applications. Surgeons found no difference in haemostasis between the four- and six-row staplers (P = 0.486), and judged the four-row stapler superior in terms of access, reduced need for dissection, reduced stress of surgeon and precise control (P < 0.001 for all). CONCLUSIONS: The new ECHELON FLEX™ PVS provides haemostasis equivalent to six-row staplers. With a smaller anvil, narrower shaft and wider angle of articulation, the PVS demonstrated improved access capability for pulmonary vessel procedures.
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Hemostasis Endoscópica/instrumentación , Hemostasis Quirúrgica/instrumentación , Engrapadoras Quirúrgicas , Grapado Quirúrgico/instrumentación , Cirugía Torácica Asistida por Video/instrumentación , Animales , Actitud del Personal de Salud , Diseño de Equipo , Hemostasis Endoscópica/métodos , Hemostasis Quirúrgica/métodos , Neumonectomía/instrumentación , Neumonectomía/métodos , Cirujanos/psicología , Grapado Quirúrgico/métodos , Porcinos , Cirugía Torácica Asistida por Video/métodosRESUMEN
Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.
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Pirimidinas/química , Pirimidinas/farmacología , ARN Bacteriano/química , ARN Bacteriano/efectos de los fármacos , Riboswitch/efectos de los fármacos , Animales , Aptámeros de Nucleótidos/química , Bacterias/citología , Bacterias/efectos de los fármacos , Bacterias/crecimiento & desarrollo , Secuencia de Bases , Cristalografía por Rayos X , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Proteínas de Escherichia coli/genética , Femenino , Mononucleótido de Flavina/metabolismo , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico/genética , Transferasas Intramoleculares/genética , Ligandos , Ratones , Ratones Endogámicos DBA , Modelos Moleculares , Datos de Secuencia Molecular , Pirimidinas/aislamiento & purificación , Pirimidinas/uso terapéutico , ARN Bacteriano/genética , Reproducibilidad de los Resultados , Riboflavina/biosíntesis , Riboswitch/genética , Especificidad por SustratoRESUMEN
BACKGROUND: Sacroiliac joint (SI) pain is an often-overlooked cause of lower-back pain, due in part to a lack of specific findings on radiographs and a symptom profile similar to other back-related disorders. A minimally invasive surgical (MIS) approach to SI joint fusion using a series of triangular, titanium plasma spray-coated implants has shown favorable outcomes in patients with SI joint pain refractory to conservative care. The aim of this study was to provide a multicenter experience of MIS SI joint fusion using a patient-level analysis. PATIENTS AND METHODS: We report a patient-level analysis from 144 patients with a mean of 16 months postoperative follow-up. Demographic information, perioperative measures, complications, and clinical outcomes using a visual analog scale for pain were collected prospectively. Random-effects regression models were used to account for intersite variability. RESULTS: The mean age was 58 years, 71% of patients were female, and 62% had a history of lumbar spinal fusion. Mean (95% confidence interval [CI]) operative time was 73 minutes (25.4-118), blood loss was minimal, and hospital stay was 0.8 days (0.1-1.5). At follow-up, mean (95% CI) visual analog scale pain scores improved by 6.1 points (5.7-6.6). Substantial clinical benefit, defined as a decrease in pain by >2.5 points or a score of 3.5 or less, was achieved in 91.9% of patients (95% CI 83.9%-96.1%), and 96% (95% CI 86.3%-98.8%) of patients indicated they would have the same surgery again. CONCLUSION: When conservative measures fail to relieve symptoms resulting from degeneration or disruption of the SI joint, MIS SI joint fusion using a series of triangular, porous, titanium plasma spray-coated implants is a safe and effective treatment option.
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This work summarizes the pharmaceutical evaluation of a preclinical drug candidate with poor physicochemical properties. Compound 1 is a weakly basic, GPR-119 agonist designated to Biopharmaceutics Classification System Class II because of good permeability in a Caco-2 cell line model and poor solubility. Compound 1 showed good oral bioavailability from a solution formulation at low doses and oral exposure sufficient for toxicological evaluation at high doses from a nanosuspension of Form A-the only known polymorph of 1 during drug discovery. The identification of the thermodynamically stable polymorph, Form B, during early development adversely affected the bioperformance of the nanosuspension. The poor solubility of Form B resulted in a significant reduction in the oral exposure from a nanosuspension to a level that was insufficient for toxicological evaluation of compound 1. Subsequent to the discovery of Form B, multiple form and formulation engineering strategies were evaluated for their ability to enhance the oral exposure of 1. Formulations based on cocrystals and amorphous solid dispersions showed a statistically significant increase in exposure, sixfold and sevenfold, respectively, over the benchmark formulation, a suspension of Form B. The physicochemical characterization of 1, and the solid form and formulation engineering approaches explored to address the insufficient oral exposure of Form B are discussed along with insights on improving the physicochemical properties of the follow-on drug candidates in discovery.
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Química Farmacéutica , Evaluación Preclínica de Medicamentos , Animales , Rastreo Diferencial de Calorimetría , Cromatografía Líquida de Alta Presión , Concentración de Iones de Hidrógeno , Masculino , Difracción de Polvo , Ratas , Ratas Sprague-Dawley , SolubilidadRESUMEN
BACKGROUND: The mainstay of sacroiliac joint disruption/degenerative sacroiliitis therapy has been nonoperative management. This nonoperative management often includes a regimen of physical therapy, chiropractic treatment, therapeutic injections, and possibly radiofrequency ablation at the discretion of the treating physician. When these clinical treatments fail, sacroiliac joint fusion has been recommended as the standard treatment. Open and minimally invasive (MIS) surgical techniques are typical procedures. This study aims to compare the perioperative measures and Oswestry Disability Index (ODI) outcomes associated with each of these techniques. METHODS: A comparative retrospective chart review of patients with sacroiliac joint fusion and a minimum of 1 year of follow-up was performed. Perioperative measures and ODI scores were compared using the Fisher's exact test and two nonparametric tests, ie, the Mann-Whitney U test and the Wilcoxon signed-rank test. The results are presented as percent or median with range, as appropriate. RESULTS: Forty-nine patients from two institutions underwent sacroiliac joint fusion between 2006 and 2012. Ten patients were excluded because of incomplete data, leaving 39 evaluable patients, of whom 22 underwent open and 17 underwent MIS sacroiliac joint fusion. The MIS group was significantly older (median age 66 [39-82] years) than the open group (median age 51 [34-74] years). Surgical time and hospital stay were significantly shorter in the MIS group than in the open group. Preoperative ODI was significantly greater in the open group (median 64 [44-78]) than in the MIS group (median 53 [14-84]). Postoperative improvement in ODI was statistically significant within and between groups, with MIS resulting in greater improvement. CONCLUSION: The open and MIS sacroiliac joint fusion techniques resulted in statistically and clinically significant improvement for patients with degenerative sacroiliitis refractory to nonoperative management. However, the number of patients reaching the minimal clinically important difference and those showing overall improvement were greater in the MIS group.