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Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Adulto , Criança , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Suplementos Nutricionais , Cirrose Hepática/complicações , Doenças Cardiovasculares/prevenção & controle , Lipídeos/uso terapêuticoRESUMO
BACKGROUND: Opioid and cocaine use epidemics continue to be substantial in the United States and intersect with the HIV epidemic. Antiretroviral medication (ARV) adherence is critical for optimum HIV outcomes. While previous research explored harm reduction strategies to prevent HIV spread for people who use drugs (PWUD), little is known about strategies used by PWUD living with HIV to maintain ARV adherence. Methods: We explored whether PWUD modify their drug use explicitly to maintain ARV adherence, and identified factors associated with this process. We conducted 23 semi-structured interviews. Data were analyzed using a modified framework analysis approach. Results: Participants had a mean age of 54 years and were predominantly male (70%) and non-Hispanic black (65%). Most described periods of being able to adhere to ARVs while still using drugs, difficulty adhering to ARVs while using drugs, and abstinence/near abstinence from drug use. In exploring factors that influenced changes in drug use and ARV adherence behaviors, we noted consistent acknowledgment of the roles of family, partners, or providers. Conclusions: PWUD living with HIV often modify their drug use to improve ARV adherence. Providers caring for this population might consider family or group education models to encourage harm reduction to improve outcomes.
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Infecções por HIV , Transtornos Relacionados ao Uso de Substâncias , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Redução do Dano , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-IdadeRESUMO
Recently, concerns regarding the safety of red yeast rice (RYR) have been raised after the publication of some case reports claiming toxicity. Since the previous meta-analyses on the effects of RYR were mainly focused on its efficacy to improve lipid profile and other cardiovascular parameters, we carried out a meta-analysis on safety data derived from the available randomized controlled clinical trials (RCTs). Primary outcomes were musculoskeletal disorders (MuD). Secondary outcomes were non-musculoskeletal adverse events (Non-MuD) and serious adverse events (SAE). Subgroups analyses were carried out considering the intervention (RYR alone or in association with other nutraceutical compounds), monacolin K administered daily dose (≤3, 3.1-5 or >5 mg/day), follow-up (>12 or ≤12 weeks), with statin therapy or statin-intolerance and type of control treatment (placebo or statin treatment). Data were pooled from 53 RCTs comprising 112 treatment arms, which included 8535 subjects, with 4437 in the RYR arm and 4303 in the control one. Monacolin K administration was not associated with increased risk of MuD (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.53,1.65). Moreover, we showed reduced risk of Non-MuD (OR = 0.59, 95%CI 0.50, 0.69) and SAE (OR = 0.54, 95%CI 0.46, 0.64) vs. control. Subgroups analyses confirmed the high tolerability profile of RYR. Furthermore, increasing daily doses of monacolin K were negatively associated with increasing risk of Non-MuD (slope: -0.10; 95%CI: -0.17, -0.03; two-tailed p < 0.01). Based on our data, RYR use as lipid-lowering dietary supplement seems to be overall tolerable and safe in a large kind of moderately hypercolesterolaemic subjects.
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Produtos Biológicos/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Humanos , Doenças Musculoesqueléticas , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip(+/-)), we observed increased lung compliance and spontaneous emphysema in Hhip(+/-) mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip(+/-) vs. Hhip(+/+) mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip(+/-) mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip(+/-) mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip(+/-) mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.
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Proteínas de Transporte/genética , Enfisema/etiologia , Haploinsuficiência , Glicoproteínas de Membrana/genética , Acetilcisteína/farmacologia , Fatores Etários , Animais , Glutationa/metabolismo , Glutationa S-Transferase pi/fisiologia , Pulmão/patologia , Pulmão/fisiologia , Complacência Pulmonar , Camundongos , Camundongos Endogâmicos C57BL , Estresse OxidativoRESUMO
This Review summarizes recent research on vibrational predissociation (VP) of hydrogen-bonded clusters. Specifically, the focus is on breaking of hydrogen bonds following excitation of an intramolecular vibration of the cluster. VP of the water dimer and trimer, HCl clusters, and mixed HCl-water clusters are the major topics, but related work on hydrogen halide dimers and trimers, ammonia clusters, and mixed dimers with polyatomic units are reviewed for completion and comparison. The theoretical focus is on generating accurate potential energy surfaces (PESs) that can be used in detailed dynamical calculations, mainly using the quasiclassical trajectory approach. These PESs have to extend from the region describing large amplitude motion around the minimum to regions where fragments are formed. The experimental methodology exploits velocity map imaging to generate pair-correlated product translational energy distributions from which accurate bond dissociation energies of dimers and trimers and energy disposal in fragments are obtained. The excellent agreement between theory and experiment on bond dissociation energies, energy disposal in fragments, and the contributions of cooperativity demonstrates that it is now possible, with state-of-the-art experimental and theoretical methods, to make accurate predictions about dynamical and energetic properties of dissociating clusters.
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RATIONALE: A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies. However, the mechanisms by which FAM13A contributes to COPD susceptibility are unknown. OBJECTIVES: To determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility. METHODS: Fam13a null mice (Fam13a(-/-)) were generated and exposed to cigarette smoke. The lung inflammatory response and airspace size were assessed in Fam13a(-/-) and Fam13a(+/+) littermate control mice. Cellular localization of FAM13A protein and mRNA levels of FAM13A in COPD lungs were assessed using immunofluorescence, Western blotting, and reverse transcriptase-polymerase chain reaction, respectively. Immunoprecipitation followed by mass spectrometry identified cellular proteins that interact with FAM13A to reveal insights on FAM13A's function. MEASUREMENTS AND MAIN RESULTS: In murine and human lungs, FAM13A is expressed in airway and alveolar type II epithelial cells and macrophages. Fam13a null mice (Fam13a(-/-)) were resistant to chronic cigarette smoke-induced emphysema compared with Fam13a(+/+) mice. In vitro, FAM13A interacts with protein phosphatase 2A and recruits protein phosphatase 2A with glycogen synthase kinase 3ß and ß-catenin, inducing ß-catenin degradation. Fam13a(-/-) mice were also resistant to elastase-induced emphysema, and this resistance was reversed by coadministration of a ß-catenin inhibitor, suggesting that FAM13A could increase the susceptibility of mice to emphysema development by inhibiting ß-catenin signaling. Moreover, human COPD lungs had decreased protein levels of ß-catenin and increased protein levels of FAM13A. CONCLUSIONS: We show that FAM13A may influence COPD susceptibility by promoting ß-catenin degradation.
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Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , beta Catenina/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estabilidade Proteica , Transdução de Sinais , beta Catenina/genética , beta Catenina/fisiologiaRESUMO
The immune responses of type 2 T helper cells (Th2) play an important role in asthma and promote the differentiation of alternatively activated (M2) macrophages. M2 macrophages have been increasingly understood to contribute to Th2 immunity. We hypothesized that M2 macrophages are altered in asthma and modulate Th2 responses. The aim of this study was to characterize the phenotype and function of human monocyte-derived M2 and bronchoalveolar lavage fluid (BALF) macrophages from healthy control subjects and subjects with asthma. Phenotypic characteristics and effector function of M2 macrophages were examined using monocyte-derived and BALF macrophages obtained from subjects with asthma (n = 28) and healthy volunteers (n = 9) by flow cytometry and quantitative PCR. Resting monocyte-derived (M0) and M2 macrophages were generated by the addition of macrophage colony-stimulating factor or macrophage colony-stimulating factor plus IL-4, respectively. M2 macrophage cytokine expression and their impact on dendritic and CD4+ T cell activation were examined in vitro. High levels of CD206 and major histocompatibility complex class II expression identify macrophages with an M2 phenotype that are increased 2.9-fold in the BALF of subjects with asthma compared with control subjects. M2 macrophages have elevated IL-6, IL-10, and IL-12p40 production compared with conventional macrophages and modulate dendritic and CD4+ T cell interactions. Histamine receptor 1 and E-cadherin expression identify M2 macrophage subsets associated with increased airflow obstruction. M2 macrophages have a distinct cell surface and effector phenotype and are found in increased numbers in subjects with asthma. These findings suggest that M2 macrophages may play an important role in allergic asthma through their bidirectional interactions with immune and structural cells, and inflammatory mediators.
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Water is one of the most pervasive molecules on earth and other planetary bodies; it is the molecule that is searched for as the presumptive precursor to extraterrestrial life. It is also the paradigm substance illustrating ubiquitous hydrogen bonding (H-bonding) in the gas phase, liquids, crystals, and amorphous solids. Moreover, H-bonding with other molecules and between different molecules is of the utmost importance in chemistry and biology. It is no wonder, then, that for nearly a century theoreticians and experimentalists have tried to understand all aspects of H-bonding and its influence on reactivity. It is somewhat surprising, therefore, that several fundamental aspects of H-bonding that are particularly important for benchmarking theoretical models have remained unexplored experimentally. For example, even the binding strength between two gas-phase water molecules has never been determined with sufficient accuracy for comparison with high-level electronic structure calculations. Likewise, the effect of cooperativity (nonadditivity) in small H-bonded networks is not known with sufficient accuracy. An even greater challenge for both theory and experiment is the description of the dissociation dynamics of H-bonded small clusters upon acquiring vibrational excitation. This is because of the long lifetimes of many clusters, which requires running classical trajectories for many nanoseconds to achieve dissociation. In this Account, we describe recent progress and ongoing research that demonstrates how the combined and complementary efforts of theory and experiment are enlisted to determine bond dissociation energies (D0) of small dimers and cyclic trimers of water and HCl with unprecedented accuracy, describe dissociation dynamics, and assess the effects of cooperativity. The experimental techniques rely on IR excitation of H-bonded X-H stretch vibrations, measuring velocity distributions of fragments in specific rovibrational states, and determining product state distributions at the pair-correlation level. The theoretical methods are based on high-level ab initio potential energy surfaces used in quantum and classical dynamical calculations. We achieve excellent agreement on D0 between theory and experiments for all of the clusters that we have compared, as well as for cooperativity in ring trimers of water and HCl. We also show that both the long-range and the repulsive parts of the potential must be involved in bond breaking. We explain why H-bonds are so resilient and hard to break, and we propose that a common motif in the breaking of cyclic trimers is the opening of the ring following transfer of one quantum of stretch excitation to form open-chain structures that are weakly bound. However, it still takes many vibrational periods to release one monomer fragment from the open-chain structures. Our success with water and HCl dimers and trimers led us to embark on a more ambitious project: studies of mixed water and HCl small clusters. These clusters eventually lead to ionization of HCl and serve as prototypes of acid dissociation in water. Measurements and calculations of such ionizations are yet to be achieved, and we are now characterizing these systems by adding monomers one at a time. We describe our completed work on the HCl-H2O dimer and mention our recent theoretical results on larger mixed clusters.
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The centrally important role of acids in aqueous chemistry has stimulated the search for the smallest droplet of hydrochloric acid. Based on several independent quantum calculations, this appears to be the HCl(H2O)4 cluster, which dissociates into the so-called solvent ion pair (SIP), H3O(+)(H2O)3Cl(-). Experimental verification of this prediction via infra-red spectroscopy is a major challenge and despite several recent reports of this SIP, there remains uncertainty about these observations. In this report, we present a calculation of the IR spectrum of the SIP in a fashion that isolates the contribution from the signature hydronium ion, H3O(+). The computed spectrum indicates that the vibrational states of H3O(+) are highly mixed, resulting in dispersed spectral features between 1300 and 3000 cm(-1), with the region between 2100 and 2900 cm(-1) being especially rich. These predictions point out the complexity of the SIP spectrum and offer guidelines for experiment. The energies of the HCl stretch fundamentals for three minima of the undissociated HCl(H2O)4 cluster are also reported.
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Ácido Clorídrico/química , Espectrofotometria Infravermelho/métodos , IsomerismoRESUMO
A semiglobal potential energy surface (PES) and quartic force field (QFF) based on fitting high-level electronic structure energies are presented to describe the structures and spectroscopic properties of NNHNN(+). The equilibrium structure of NNHNN(+) is linear with the proton equidistant between the two nitrogen groups and thus of D(∞h) symmetry. Vibrational second-order perturbation theory (VPT2) calculations based on the QFF fails to describe the proton "rattle" motion, i.e., the antisymmetric proton stretch, due to the very flat nature of PES around the global minimum but performs properly for other modes with sharper potential wells. Vibrational self-consistent field/virtual state configuration interaction (VSCF/VCI) calculations using a version of MULTIMODE without angular momentum terms successfully describe this motion and predict the fundamental to be at 759 cm(-1). This is in good agreement with the value of 746 cm(-1) from a fixed-node diffusion Monte Carlo calculation and the experimental Ar-tagged result of 743 cm(-1). Other VSCF/VCI energies are in good agreement with other experimentally reported ones. Both double-harmonic intensity and rigorous MULTIMODE intensity calculations show the proton-transfer fundamental has strong intensity.
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Even though quartic force fields (QFFs) and highly accurate coupled cluster computations describe the OCHCO(+) cation at equilibrium as a complex between carbon monoxide and the formyl cation, two notable and typical interstellar and atmospheric molecules, the prediction from the present study is that the equilibrium C(∞v) structure is less relevant to observables than the saddle-point D(∞h) structure. This is the conclusion from diffusion Monte Carlo and vibrational self-consistent field/virtual state configuration interaction calculations utilizing a semi-global potential energy surface. These calculations demonstrate that the proton "rattle" motion (ν6) has centrosymmetric delocalization of the proton over the D(∞h) barrier lying only 393.6 cm(-1) above the double-well OCHCO(+) C(∞v) minima. As a result, this molecule will likely appear D∞h, and the rotational spectrum will be significantly dimmer than the computed equilibrium 2.975 D center-of-mass dipole moment indicates. However, the proton transfer fundamental, determined to be at roughly 300 cm(-1), has a very strong intensity. This prediction as well as those of other fundamentals should provide useful guides for laboratory detection of this cation. Finally, it is shown that the two highest energy QFF-determined modes are actually in good agreement with their vibrational configuration interaction counterparts. These high-level quantum chemical methods provide novel insights into this fascinating and potentially common interstellar molecule.
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Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHIP) on chromosome 4q31 have been strongly associated with pulmonary function levels and moderate-to-severe chronic obstructive pulmonary disease (COPD). However, whether the effects of variants in this region are related to HHIP or another gene has not been proven. We confirmed genetic association of SNPs in the 4q31 COPD genome-wide association study (GWAS) region in a Polish cohort containing severe COPD cases and healthy smoking controls (P = 0.001 to 0.002). We found that HHIP expression at both mRNA and protein levels is reduced in COPD lung tissues. We identified a genomic region located â¼85 kb upstream of HHIP which contains a subset of associated SNPs, interacts with the HHIP promoter through a chromatin loop and functions as an HHIP enhancer. The COPD risk haplotype of two SNPs within this enhancer region (rs6537296A and rs1542725C) was associated with statistically significant reductions in HHIP promoter activity. Moreover, rs1542725 demonstrates differential binding to the transcription factor Sp3; the COPD-associated allele exhibits increased Sp3 binding, which is consistent with Sp3's usual function as a transcriptional repressor. Thus, increased Sp3 binding at a functional SNP within the chromosome 4q31 COPD GWAS locus leads to reduced HHIP expression and increased susceptibility to COPD through distal transcriptional regulation. Together, our findings reveal one mechanism through which SNPs upstream of the HHIP gene modulate the expression of HHIP and functionally implicate reduced HHIP gene expression in the pathogenesis of COPD.
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Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Elementos Facilitadores Genéticos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Western Blotting , Brônquios/citologia , Brônquios/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Imunoprecipitação da Cromatina , Mapeamento Cromossômico , Cromossomos Humanos Par 4/genética , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Pulmão/citologia , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fumar/genética , Fator de Transcrição Sp3/metabolismoRESUMO
The hydrogen bond has been studied by chemists for nearly a century. Interest in this ubiquitous bond has led to several prototypical systems emerging to studying its behavior. Hydrogen chloride clusters stand as one such example. We present here a new many-body potential energy surface for (HCl)n constructed from one-, two-, and three-body interactions. The surface is constructed from previous highly accurate, semiempirical monomer and dimer surfaces, and a new high-level ab initio permutationally invariant full-dimensional three-body potential. The new three-body potential is based on fitting roughly 52,000 three-body energies computed using coupled cluster with single, doubles, perturbative triples, and explicit correlation and the augmented correlation consistent double-ζ basis set. The first application, described here, is to the ring HCl trimer, for which the many-body representation is exact. The new potential describes all known stationary points of the trimer as well its dissociation to either three monomers or a monomer and a dimer. The anharmonic vibrational energies are computed for the three H-Cl stretches, using explicit three-mode coupling calculations and local-monomer calculations with Hückel-type coupling. Both methods produce frequencies within 5 cm(-1) of experiment. A wavepacket calculation based on the Hückel model and full-dimensional classical calculation are performed to study the monomer H-Cl stretch vibration-vibration transfer process in the ring HCl trimer. Somewhat surprisingly, the results of the quantum and classical calculations are virtually identical, both exhibiting coherent beating of the excitation between the three monomers. Finally, this representation of the potential is used to study properties of larger clusters, namely to compute optimized geometries of the tetramer, pentamer, and hexamer and to perform explicit four-mode coupling calculations of the tetramer's anharmonic stretch frequencies. The optimized geometries are found to be in agreement with those of previous ab initio studies and the tetramer's anharmonic frequencies are computed within 11 cm(-1) of experiment.
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The breaking of hydrogen bonds in molecular systems has profound effects on liquids, e.g., water, biomolecules, e.g., DNA, etc., and so it is no exaggeration to assert the importance of these bonds to living systems. However, despite years of extensive research on hydrogen bonds, many of the details of how these bonds break and the corresponding energy redistribution processes remain poorly understood. Here we report extensive experimental and theoretical insights into the breakup of two or three hydrogen bonds in the dissociation of a paradigm system of a hydrogen-bonded network, the ring HCl trimer. Experimental state-to-state vibrational predissociation dynamics of the trimer following vibrational excitation were studied by using velocity map imaging and resonance-enhanced multiphoton ionization, providing dissociation energies and product state distributions for the trimer's breakup into three separate monomers or into dimer + monomer. Accompanying the experiments are high-level calculations using diffusion Monte Carlo and quasiclassical simulations, whose results validate the experimental ones and further elucidate energy distributions in the products. The calculations make use of a new, highly accurate potential energy surface. Simulations indicate that the dissociation mechanism requires the excitation to first relax into low-frequency motions of the trimer, resulting in the breaking of a single hydrogen bond. This allows the system to explore a critical van der Waals minimum region from which dissociation occurs readily to monomer + dimer.
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Hedgehog interacting protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis.
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Proteínas de Transporte/metabolismo , Células Epiteliais/metabolismo , Glicoproteínas de Membrana/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Transcriptoma , Brônquios/metabolismo , Brônquios/patologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Pulmão/metabolismo , Pulmão/patologia , Glicoproteínas de Membrana/genética , Anotação de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Doença Pulmonar Obstrutiva Crônica/genética , RNA Interferente Pequeno/genética , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Regulação para CimaRESUMO
BACKGROUND: Physician underprescribing and patient nonadherence are major barriers to the benefits of guideline-directed medical therapy. An important contributor to both underprescribing and patient nonadherence is concern about medication-related side effects. Yet, there are few to no data on approaches used by physicians to: (1) elicit medication-related side effects, (2) attribute these side effects to specific medications, and (3) take appropriate action. METHODS AND RESULTS: The authors conducted semistructured interviews with physicians to identify facilitators and barriers to each critical step of heart failure medication management: elicitation of side effects, attribution of side effects to a medication, and action in response to attributed side effects. Interviews were transcribed and coded using directed content analysis. For elicitation of potential side effects, limited patient communication and family discordance in reporting were key barriers, whereas guiding questions, measurement, and open channels of communication were key facilitators. For attribution of side effects, confounding from other medications, limited time for clinical encounters, and nonspecific symptoms were key barriers, whereas time-limited medication discontinuation trials and medication rechallenges were key facilitators. For taking action, challenges with weighing risks and benefits and physician fear about causing harm or interfering with other clinicians were barriers, whereas patient-physician communication and the results of a medication discontinuation trials and medication rechallenge were facilitators. CONCLUSIONS: This study generated key facilitators and barriers to 3 key aspects of heart failure medication management related to side effects that should drive future work to improve heart failure medication management.
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Insuficiência Cardíaca , Adesão à Medicação , Relações Médico-Paciente , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Feminino , Masculino , Padrões de Prática Médica , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/uso terapêutico , Atitude do Pessoal de Saúde , Pessoa de Meia-Idade , Entrevistas como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Cardiologistas , ComunicaçãoRESUMO
Antiplatelet therapy (APT) is the foundation of treatment and prevention of atherothrombotic events in patients with atherosclerotic cardiovascular disease. Selecting the optimal APT strategies to reduce major adverse cardiovascular events, while balancing bleeding risk, requires ongoing review of clinical trials. Appended, the focused update of the Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology guidelines for the use of APT provides recommendations on the following topics: (1) use of acetylsalicylic acid in primary prevention of atherosclerotic cardiovascular disease; (2) dual APT (DAPT) duration after percutaneous coronary intervention (PCI) in patients at high bleeding risk; (3) potent DAPT (P2Y12 inhibitor) choice in patients who present with an acute coronary syndrome (ACS) and possible DAPT de-escalation strategies after PCI; (4) choice and duration of DAPT in ACS patients who are medically treated without revascularization; (5) pretreatment with DAPT (P2Y12 inhibitor) before elective or nonelective coronary angiography; (6) perioperative and longer-term APT management in patients who require coronary artery bypass grafting surgery; and (7) use of APT in patients with atrial fibrillation who require oral anticoagulation after PCI or medically managed ACS. These recommendations are all on the basis of systematic reviews and meta-analyses conducted as part of the development of these guidelines, provided in the Supplementary Material.
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Síndrome Coronariana Aguda , Cardiologia , Intervenção Coronária Percutânea , Humanos , Inibidores da Agregação Plaquetária , Canadá , Revisões Sistemáticas como Assunto , Síndrome Coronariana Aguda/tratamento farmacológico , Resultado do TratamentoRESUMO
Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)-2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)-2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM.
Assuntos
Estradiol/análogos & derivados , Estradiol/efeitos adversos , Matriz Extracelular/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Linfangioleiomiomatose/patologia , Remodelação das Vias Aéreas , Animais , Antineoplásicos/farmacologia , Colágeno Tipo IV/metabolismo , Avaliação Pré-Clínica de Medicamentos , Estradiol/farmacologia , Matriz Extracelular/metabolismo , Feminino , Fulvestranto , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Linfangioleiomiomatose/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos SCID , Ratos , Receptores de Estradiol/antagonistas & inibidores , Análise de Sobrevida , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: The acoustic lens of the Modularis electromagnetic shock wave lithotripter (Siemens, Malvern, Pennsylvania) was modified to produce a pressure waveform and focal zone more closely resembling that of the original HM3 device (Dornier Medtech, Wessling, Germany). We assessed the newly designed acoustic lens in vivo in an animal model. MATERIALS AND METHODS: Stone fragmentation and tissue injury produced by the original and modified lenses of the Modularis lithotripter were evaluated in a swine model under equivalent acoustic pulse energy (about 45 mJ) at 1 Hz pulse repetition frequency. Stone fragmentation was determined by the weight percent of stone fragments less than 2 mm. To assess tissue injury, shock wave treated kidneys were perfused, dehydrated, cast in paraffin wax and sectioned. Digital images were captured every 120 µm and processed to determine functional renal volume damage. RESULTS: After 500 shocks, the mean ± SD stone fragmentation efficiency produced by the original and modified lenses was 48% ± 12% and 52% ± 17%, respectively (p = 0.60). However, after 2,000 shocks, the modified lens showed significantly improved stone fragmentation compared to the original lens (mean 86% ± 10% vs 72% ± 12%, p = 0.02). Tissue injury caused by the original and modified lenses was minimal at a mean of 0.57% ± 0.44% and 0.25% ± 0.25%, respectively (p = 0.27). CONCLUSIONS: With lens modification the Modularis lithotripter demonstrates significantly improved stone fragmentation with minimal tissue injury at a clinically relevant acoustic pulse energy. This new lens design could potentially be retrofitted to existing lithotripters, improving the effectiveness of electromagnetic lithotripters.
Assuntos
Cálculos Renais/terapia , Litotripsia/instrumentação , Microscopia Acústica/instrumentação , Animais , Modelos Animais de Doenças , Campos Eletromagnéticos , Desenho de Equipamento , Segurança de Equipamentos , Feminino , Litotripsia/métodos , Microscopia Acústica/métodos , Sensibilidade e Especificidade , Sus scrofa , SuínosRESUMO
We present an on-the-fly quantum mechanical method to obtain anharmonic vibrational frequencies for molecular clusters. The basis for the method is the local-monomer model, a "divide and conquer" approach to theoretical spectroscopy, previously applied using full-dimensional surfaces [Y. Wang and J. M. Bowman, J. Chem. Phys. 134, 154510 (2011)]. The model consists of performing a local normal-mode analysis for each monomer in a cluster in the field of the surrounding monomers. Anharmonic vibrational frequencies are then determined for each monomer by numerically solving the Schrödinger equation in terms of the local coordinates using ab initio energies obtained directly. Residual monomer-monomer coupling is accounted for using the Hückel-coupling extension [Y. Wang and J. M. Bowman, J. Chem. Phys. 136, 144113 (2012)]. In addition to the direct local-monomer approach, we propose and demonstrate a composite ab initio technique to reduce computational costs for calculating the anharmonic frequencies of large clusters. This technique utilizes two ab initio methods, a lower level of theory to compute geometries and perform harmonic analyses and a subsequent higher level of theory to compute the energies used in the anharmonic frequency calculations. We demonstrate the on-the-fly approach on hydrogen chloride clusters ranging in size from the dimer to the hexamer. Comparisons of the theoretical frequencies are made to previous experiments. We find the method to be an effective and computationally efficient approach to compute anharmonic frequencies.