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Water is a key ingredient for life and plays a central role as solvent in many biochemical reactions. However, the intrinsically quantum nature of the hydrogen nucleus, revealing itself in a large variety of physical manifestations, including proton transfer, gives rise to unexpected phenomena whose description is still elusive. Here we study, by a combination of state-of-the-art quantum Monte Carlo methods and path-integral molecular dynamics, the structure and hydrogen-bond dynamics of the protonated water hexamer, the fundamental unit for the hydrated proton. We report a remarkably low thermal expansion of the hydrogen bond from zero temperature up to 300 K, owing to the presence of short-Zundel configurations, characterised by proton delocalisation and favoured by the synergy of nuclear quantum effects and thermal activation. The hydrogen bond strength progressively weakens above 300 K, when localised Eigen-like configurations become relevant. Our analysis, supported by the instanton statistics of shuttling protons, reveals that the near-room-temperature range from 250 K to 300 K is optimal for proton transfer in the protonated water hexamer.
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Platinum group elements (PGE) are considered to be very poorly soluble in aqueous fluids in most natural hydrothermal-magmatic contexts and industrial processes. Here, we combined in situ X-ray absorption spectroscopy and solubility experiments with atomistic and thermodynamic simulations to demonstrate that the trisulfur radical ion S3â¢- forms very stable and soluble complexes with both PtII and PtIV in sulfur-bearing aqueous solution at elevated temperatures (â¼300 °C). These Pt-bearing species enable (re)mobilization, transfer, and focused precipitation of platinum up to 10,000 times more efficiently than any other common inorganic ligand, such as hydroxide, chloride, sulfate, or sulfide. Our results imply a far more important contribution of sulfur-bearing hydrothermal fluids to PGE transfer and accumulation in the Earth's crust than believed previously. This discovery challenges traditional models of PGE economic concentration from silicate and sulfide melts and provides new possibilities for resource prospecting in hydrothermal shallow crust settings. The exceptionally high capacity of the S3â¢- ion to bind platinum may also offer new routes for PGE selective extraction from ore and hydrothermal synthesis of noble metal nanomaterials.
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Objective: Malnutrition is a severe complication in Systemic Sclerosis (SSc) and it is associated with significant mortality. Notwithstanding, there is no defined screening or clinical pathway for patients, which is hampering effective management and limiting the opportunity for early intervention. Here we aim to identify a combined index predictive of malnutrition at 12 months using clinical data and specific serum adipokines. Methods: This was an international, multicentre observational study involving 159 SSc patients in two independent discovery (n = 98) and validation (n = 61) cohorts. Besides routine clinical and serum data at baseline and 12 months, Malnutrition Universal Screening Tool (MUST) score and serum concentration of leptin and adiponectin were measured for each participant at baseline. The endpoint of malnutrition was defined according to European Society of Clinical Nutrition and Metabolism (ESPEN) recommendation. Significant parameters from univariate analysis were tested in logistic regression analysis to identify the predictive index of malnutrition in the derivation cohort. Results: The onset of malnutrition at 12 months correlated with adiponectin, leptin and their ratio (A/L), MUST, clinical subset, disease duration, Scl70 and Forced Vital Capaciy (FVC). Logistic regression analysis defined the formula: -2.13 + (A/L*0.45) + (Scl70*0.28) as the best PREdictor of MAlnutrition in SSc (PREMASS) (AUC = 0.96; 95% CI 0.93, 0.99). PREMASS < -1.46 had a positive predictive value (PPV) > 62% and negative predictive value (NPV) > 97% for malnutrition at 12 months. Conclusion: PREMASS is a feasible index which has shown very good performance in two independent cohorts for predicting malnutrition at 12 months in SSc. The implementation of PREMASS could aid both in clinical management and clinical trial stratification/enrichment to target malnutrition in SSc.
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BACKGROUND: Familial hypercholesterolemia (FH) is characterized by increased cardiovascular risk; despite-high intensity statins, only few patients with FH achieve the recommended low-density lipoprotein cholesterol (LDL-C) targets. OBJECTIVE: We aimed to evaluate the effectiveness of six-month add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) or ezetimibe on lipid profile and pulse wave velocity (PWV) in patients with FH. METHODS: In this observational study, we evaluated 98 genetically confirmed patients with FH with an LDL-C off-target despite high-intensity statins with or without ezetimibe; of these, 53 patients (statin plus ezetimibe) added PCSK9-i (PCSK9-i group) and 45 (statin only) added ezetimibe (EZE group) per applicable guidelines and reimbursement rules. All patients obtained biochemical analysis and PWV evaluation at baseline and after six months of optimized treatment. RESULTS: After 6 months of add-on therapy, most patients achieving LDL-C targets were in the PCSK9-i group (77.3% PCSK9-i group vs 37.8% EZE group, P < .001). The PCSK9-i group achieved both a greater LDL-C and PWV reduction than the EZE group [-51% vs -22.8%, P < .001 and -15% vs -8.5%, P < .01, respectively]. In a linear regression analysis, we showed a coefficient (r) of 0.334 for the relationship between ΔPWV and ΔLDL (P < .05); moreover, in an exploratory analysis, the relationship appeared to be stronger in patients with FH without cardiovascular events (r = 0.422, P < .01). CONCLUSIONS: Lipid and PWV profiles in patients with FH significantly improved after addition of PCSK9-i or ezetimibe to high-intensity statin therapy; moreover, ΔPWV was associated with ΔLDL. Our results are consistent with a beneficial role of these novel therapies in FH subjects.
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Ezetimiba/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de PCSK9 , Rigidez Vascular/efeitos dos fármacos , Adolescente , Adulto , Idoso , LDL-Colesterol/sangue , Interações Medicamentosas , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Fatores de Risco , Adulto JovemRESUMO
The mechanisms that modulate the response to tissue injury are not fully understood. Abnormalities in the repair response are associated with a variety of chronic disease states characterized by inflammation, followed subsequently by excessive ECM deposition. As cell-matrix interactions are able to regulate cellular homeostasis, modification of ECM integrity appears to be an unspecific factor in promoting the onset and progression of inflammatory diseases. Evidence is emerging to show that endogenous ECM molecules supply signals to damage tissues and cells in order to promote further ECM degradation and inflammation progression. Several investigations have been confirmed that HA fragments of different molecular sizes exhibit different biological effects and responses. In fact, the increased deposition of HA into the ECM is a strong hallmark of inflammation processes. In the context of inflammatory pathologies, highly polymerized HA is broken down into small components, which are able to exacerbate the inflammatory response by inducing the release of various detrimental mediators such as reactive oxygen species, cytokines, chemokines and destructive enzymes and by facilitating the recruitment of leukocytes. However, strategies involving the modulation of the HA fragment with specific receptors on cell surface could represent different promising effects for therapeutic scope. This review will focus on the inflammation action of small HA fragments in recent years obtained by in vivo reports.
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Matriz Extracelular/patologia , Ácido Hialurônico/imunologia , Inflamação/patologia , Animais , Citocinas/análise , Citocinas/imunologia , Matriz Extracelular/imunologia , Humanos , Ácido Hialurônico/análise , Inflamação/complicações , Inflamação/imunologia , Receptores Toll-Like/análise , Receptores Toll-Like/imunologiaRESUMO
Inflammation is a complex mechanism that plays a key role during diseases. Dynamic features of the extracellular matrix (ECM), in particular, during phases of tissue inflammation, have long been appreciated, and a great deal of several investigations has focused on the effects of ECM derivatives on cell function. It has been well defined that during inflammatory and tissue injury, ECM components were degraded. ECM degradation direct consequence is the loss of cell homeostasis, while a further consequence is the generation of fragments from larger precursor molecules. These bio-functional ECM shred defined matrikines as capable of playing different actions, especially when they function as powerful initiators, able to prime the inflammatory mechanism. Non-sulphated glycosaminoglycan hyaluronan (HA) is the major component of the ECM that undergoes specific modulation during tissue damage and inflammation. HA fragments at very low molecular weight are produced as a result of HA depolymerization. Several evidence has considered the plausibility that HA breakdown products play a modulatory action in the sequential stages of inflammation, although the effective mechanism of these HA derivative compounds act is not completely defined. This review will focus on the pro-inflammatory effects of HA fragments in recent years obtained by in vitro investigations.
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Ácido Hialurônico/metabolismo , Inflamação/metabolismo , Animais , Matriz Extracelular/metabolismo , Humanos , Ácido Hialurônico/química , Hialuronoglucosaminidase/metabolismo , Peso Molecular , PolimerizaçãoRESUMO
BACKGROUND: We examined the relative impact of arterial stiffness on the presence and/or severity of chronic mitral regurgitation (MR) in hypertensive patients. METHODS: We prospectively enrolled 141 untreated hypertensive patients (mean age 56.6⯱â¯11.5â¯years): 94 with MR, 47 without MR. As a measure of arterial stiffness, pulse wave velocity (PWV) was assessed by applanation tonometry. Assessment of MR severity was obtained through calculation of effective regurgitant orifice area (EROA) and vena contracta by standard two-dimensional transthoracic echocardiography. RESULTS: PWV appears to progressively increase according to the presence and severity of MR (no MRâ¯=â¯7.3⯱â¯1.1â¯m/s, mild MRâ¯=â¯7.9⯱â¯1.3â¯m/s, moderate MRâ¯=â¯9.0⯱â¯1.7â¯m/s, severe MRâ¯=â¯13.3⯱â¯4.1â¯m/s; Pâ¯<â¯0.001 for all comparisons). EROA was positively correlated with age (Pâ¯=â¯0.011), left atrial volume index (Pâ¯=â¯0.023), PWV (Pâ¯<â¯0.001) and augmentation index (Pâ¯<â¯0.001), and negatively correlated with left ventricular ejection fraction (Pâ¯=â¯0.002) and heart rate (HR) (Pâ¯=â¯0.018). On stepwise multivariate logistic regression analysis, only PWV (ORâ¯=â¯2.87, 95% CI 1.750-4.738, Pâ¯<â¯0.001) and HR (ORâ¯=â¯0.94, 95% CI 0.895-0.994, Pâ¯=â¯0.02) appeared to be independent predictors of severe MR. Receiver operating characteristic curves showed that a cutoff of 9â¯m/s for PWV provided the best sensitivity/specificity for predicting both the presence of any degree of MR (sensitivity 73%, specificity 87%, AUCâ¯=â¯0.863; Pâ¯<â¯0.001) and MR severity (sensitivity 100%, specificity 81%, AUCâ¯=â¯0.954; Pâ¯<â¯0.001). CONCLUSION: Reduced arterial elasticity because of increased stiffness may be an important marker for the presence and severity of MR in hypertensive patients.
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Pressão Arterial , Hipertensão/complicações , Insuficiência da Valva Mitral/etiologia , Rigidez Vascular , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Ecocardiografia , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Manometria , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/fisiopatologia , Análise de Onda de Pulso , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Rheumatic diseases are associated with accelerated atherosclerosis and with increased risk of cardiovascular morbidity and mortality. The mechanisms underlying the higher prevalence of cardiovascular disease are not completely clarified, but it is likely that a pivotal role is played by vascular inflammation and consequently to altered vascular endothelium homeostasis. Also, high prevalence of traditional risk factors, proatherogenic activation and endothelial dysfunction further contribute to vascular damage. Circulating endothelial progenitor cells (EPCs) can restore dysfunctional endothelium and protect against atherosclerotic vascular disease. However, abnormalities in number and function of these cells in patients with rheumatic condition have been extensively reported. During the last years, growing interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD has been shown; in addition, pioneering studies show that EPC dysfunction might be improved with pharmacological strategies. However, how to restore EPC function, and whether achieving this aim may be effective in preventing cardiovascular complications in rheumatic disease, remain to be established. In this review we report an overview on the current stand of knowledge on the effect of pharmaceutical and lifestyle intervention in improving EPCs number and function in rheumatic disease.
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Antirreumáticos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Células Progenitoras Endoteliais/efeitos dos fármacos , Doenças Reumáticas/tratamento farmacológico , Animais , Antirreumáticos/efeitos adversos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Proliferação de Células/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Fenótipo , Doenças Reumáticas/complicações , Doenças Reumáticas/metabolismo , Doenças Reumáticas/patologia , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
We demonstrate the capability of creating robust density functional tight binding (DFTB) models for chemical reactivity in prebiotic mixtures through force matching to short time scale quantum free energy estimates. Molecular dynamics using density functional theory (DFT) is a highly accurate approach to generate free energy surfaces for chemical reactions, but the extreme computational cost often limits the time scales and range of thermodynamic states that can feasibly be studied. In contrast, DFTB is a semiempirical quantum method that affords up to a thousandfold reduction in cost and can recover DFT-level accuracy. Here, we show that a force-matched DFTB model for aqueous glycine condensation reactions yields free energy surfaces that are consistent with experimental observations of reaction energetics. Convergence analysis reveals that multiple nanoseconds of combined trajectory are needed to reach a steady-fluctuating free energy estimate for glycine condensation. Predictive accuracy of force-matched DFTB is demonstrated by direct comparison to DFT, with the two approaches yielding surfaces with large regions that differ by only a few kcal mol-1.
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BACKGROUND AND AIMS: Cardiovascular (CV) morbidity is increased in inflammatory joint diseases (IJD), as rheumatoid (RA) and psoriatic arthritis (PsA). Whereas increased prevalence of subclinical atherosclerosis has been reported in these conditions, whether an early myocardial functionality is also impaired remains unknown. The aim of this study was to evaluate the myocardial functionality by speckle-tracking echocardiography (STE) in recent onset RA and PsA patients and its potential associations with the levels of circulating CD34â¯+â¯cells, vitamin D, and with disease activity. METHODS: STE was used to assess the myocardial functionality in patients with very early RA (nâ¯=â¯41) and PsA (nâ¯=â¯35) without traditional CV risk factors, and 58 matched healthy controls (HC). Global longitudinal and circumferential strain (GLS and GCS) was estimated. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were measured as surrogate markers of atherosclerosis. Circulating CD34â¯+â¯counts were evaluated by flow cytometry and vitamin D levels were quantified by HPLC. Disease activity was assessed by Disease Activity Score-28 (DAS28). RESULTS: RA patients exhibited impaired GLS and GCS (both p < 0.001) as compared to HC, GLS being also altered in PsA (pâ¯=â¯0.020 vs. HC). DAS28 was correlated to GLS (râ¯=â¯0.908, p < 0.001) and GCS (râ¯=â¯0.868, p < 0.001) in RA, these findings being confirmed by multivariate regression analyses adjusted for confounders and Principal Component Analyses. GLS and GCS were impaired in PsA patients with high disease activity as compared to HC, and GLS was found to be a predictor of cIMT in this condition. On the other hand, vitamin D was negatively associated with cIMT in HC (râ¯=â¯-0.308, pâ¯=â¯0.026) but not in PsA or RA, although decreased levels were observed (both p < 0.001). Vitamin D was an independent predictor of decreased CD34â¯+â¯levels in PsA and RA. CD34â¯+â¯counts negatively correlated DAS28, GLS and GCS in RA. CONCLUSIONS: Subclinical myocardial dysfunction is observed in IJD patients with preserved left-ventricular function and without traditional CV risk factors. Subclinical myocardial dysfunction was found to be a very early event in IJD. Disease activity was the main predictor of myocardial strain impairment. Interestingly, myocardial function was altered and associated with cIMT also in PsA patients with high disease activity.
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Antígenos CD34/sangue , Artrite Psoriásica/epidemiologia , Artrite Reumatoide/epidemiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/fisiopatologia , Mediadores da Inflamação/sangue , Contração Miocárdica , Função Ventricular Esquerda , Vitamina D/sangue , Adulto , Idoso , Artrite Psoriásica/diagnóstico , Artrite Reumatoide/diagnóstico , Doenças Assintomáticas , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Espessura Intima-Media Carotídea , Diagnóstico Precoce , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Espanha/epidemiologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Smoking cessation is correlated with several psychological, social, biological, and pharmacological aspects. The combined tendency to experience negative emotions and to inhibit the expression of these emotions is indicated as "type D personality," an independent risk marker for clinical outcome in cardiac disease. Despite this effect of type D personality on cardiovascular disease, it is still unclear whether this personality trait may influence smoking cessation after a myocardial infarction. HYPOTHESIS: we hypothesized that there is a relationship between type D personality and smoking persistence in acute coronary syndrome patients, and this association may predict a worse long-term prognosis. METHODS: The study enrolled 231 patients with ST-segment elevation myocardial infarction, treated with primary percutaneous coronary intervention. Type D scale 14 (ds 14) was administered upon admission to the hospital. RESULTS: After controlling for demographic and clinical confounders, non-type D patients reported statistically significant higher frequencies of smoking cessation when compared with the type D group. In addition, the presence of this psychological factor anticipates significantly the onset of smoking during adolescence. Furthermore, current type D smokers had a higher incidence of cardiovascular events during long-term follow-up. CONCLUSIONS: Type D personality and smoking status increase the risk of cardiac events. An emotionally stressed personality and persistence of smoking after the first cardiac event, and mostly their mutual influence, indicate a population at high cardiovascular risk.
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Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Fumar/efeitos adversos , Estresse Psicológico , Personalidade Tipo D , Feminino , Seguimentos , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Estudos Retrospectivos , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/psicologia , Abandono do Hábito de FumarRESUMO
Cartilage degeneration are hallmarks of wear, tear, mechanical and inflammatory damage of the joint cartilage. Tissue degradation as well as compromising the integrity and function of the organ, produces different intermediates, directly able to stimulate further inflammatory effect, therefore, amplifying the inflammation response. Biglycan is a soluble component of the extracellular matrix that is released during tissue injury. It has been reported that released biglycan is an endogenous ligand for TLR-2/4 in some cell type. We studied the role of biglycan in an experimental model of biglycan-induced inflammatory response in human chondrocytes and the effect of high polymerized HA on reducing its activity. Exposition of chondrocytes to LPS generated cell injury, including high levels of biglycan. Chondrocyte treatment with biglycan produces a high mRNA expression of several detrimental inflammation mediators such as IL-1ß, IL-6, MMP-13, and IL-17, as well as NF-kB and TLR-4 activation. Administration of high polymerized HA to chondrocytes exposed to biglycan was able to attenuate the inflammatory response by decreasing the expression of the inflammatory mediators. Involvement of the TLR-4 in the mediation of the biglycan action was confirmed using a specific silent agent (siRNA). Taken together, these data could be used to develop new anti-inflammatory approaches.
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Biglicano/metabolismo , Condrócitos/metabolismo , Ácido Hialurônico/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Polímeros/metabolismo , RNA Interferente Pequeno/genética , Receptor 4 Toll-Like/metabolismo , Células Cultivadas , Condrócitos/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Polímeros/química , Receptor 4 Toll-Like/genéticaRESUMO
INTRODUCTION: Our knowledge of extracellular matrix (ECM) structure and function has increased enormously over the last decade or so. There is evidence demonstrating that ECM provides signals affecting cell adhesion, shape, migration, proliferation, survival, and differentiation. ECM presents many domains that become active after proteolytic cleavage. These active ECM fragments are called matrikines which play different roles; in particular, they may act as potent inflammatory mediators during cartilage injury. FINDINGS: A major component of the ECM that undergoes dynamic regulation during cartilage damage and inflammation is the non-sulphated glycosaminoglycan (GAG) hyaluronan (HA). In this contest, HA is the most studied because of its different activity due to the different polymerization state. In vivo evidences have shown that low molecular weight HA exerts pro-inflammatory action, while high molecular weight HA possesses anti-inflammatory properties. Therefore, the beneficial HA effects on arthritis are not only limited to its viscosity and lubricant action on the joints, but it is especially due to a specific and effective anti-inflammatory activity. Several in vitro experimental investigations demonstrated that HA treatment may regulate different biochemical pathways involved during the cartilage damage. Emerging reports are suggesting that the ability to recognize receptors both for the HA degraded fragments, whether for the high-polymerized native HA involve interaction with integrins, toll-like receptors (TLRs), and the cluster determinant (CD44). The activation of these receptors induced by small HA fragments, via the nuclear factor kappa-light-chain enhancer of activated B cell (NF-kB) mediation, directly or other different pathways, produces the transcription of a large number of damaging intermediates that lead to cartilage erosion. CONCLUSIONS: This review briefly summarizes a number of findings of the recent studies focused on the protective effects of HA, at the different polymerization states, on experimental arthritis in vitro both in animal and human cultured chondrocytes.
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Cartilagem/lesões , Condrócitos/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Substâncias Protetoras/farmacologia , Animais , HumanosRESUMO
Joint disease is characterized by an imbalance between the synthesis and degradation of articular cartilage and subchondral bone accompanied by capsular fibrosis, osteophyte formation and varying degrees of inflammation of the synovial membrane. Many animal models have been developed to study arthritis and osteoarthritis that enable experimental conditions, diet and environmental risk factors to be carefully controlled. Animal-based studies have demonstrated the positive effects of exogenous HA on the preservation of joint cartilage in different models of arthritis and osteoarthritis. Although many promising effects of exogenous HA have been reported, there remains uncertainty as to its effectiveness in reversing cartilage injury and other manifestations of joint diseases because of difficulties in interpreting and unifying the results of these studies. A review of the literature of the last decade was conducted to report the results and to determine what we have learned from animal models in relation to joint inflammation induced by experimental models and HA treatment.
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Cartilagem Articular/efeitos dos fármacos , Ácido Hialurônico/metabolismo , Ácido Hialurônico/uso terapêutico , Animais , Osso e Ossos/metabolismo , Cartilagem Articular/lesões , Cartilagem Articular/metabolismo , Modelos Animais de Doenças , Humanos , Ácido Hialurônico/farmacologia , Inflamação/tratamento farmacológico , Injeções Intra-Articulares , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismoRESUMO
Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibroblast activation and fibrosis of the skin and internal organs. Alterations in cell-integrin interaction are sufficient to initiate profibrotic processes. SSc fibroblasts express both αvß3 and αvß5 integrins and their activation induces myofibroblasts differentiation. The aim of the present study was to evaluate the effect of the anb3 and anb5 inhibitor, cilengitide, on the development of vascular and fibrotic changes in the chronic oxidant stress murine model of systemic sclerosis. SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: HOCl alone (n=8), HOCl + Cilengitide (n=8), or Vehicle alone (n=8). Treatment with cilengitide 20 (mg/kg/i.p./day) was started 4 weeks after the first administration of HOCl and maintained throughout the remaining experimental period (2 weeks). Lung, skin, and heart fibrosis were evaluated by histology while kidney morphology by PAS staining. Collagen type I, focal adhesion kinase (FAK), and a-SMA were evaluated by immunostaining and p-FAK and TGF-ß1 by Western blot and gene expression. Both cutaneous and pulmonary fibrosis induced by HOCl were attenuated by cilengitide treatment. Cilengitide administration reduced a-SMA, TGF-ß1, and p-FAK expression and the increased deposition of fibrillar collagen in the heart and prevented glomeruli collapse in the kidneys. The inhibition of aνß3 and aνß5 integrin signaling prevented systemic fibrosis and renal vascular abnormalities in the reactive oxygen species model of SSc. Integrins aνß3 and aνß5 could prove useful as a therapeutic target in SSc.
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Artérias/efeitos dos fármacos , Integrina alfaVbeta3/antagonistas & inibidores , Fibrose Pulmonar/prevenção & controle , Receptores de Vitronectina/antagonistas & inibidores , Escleroderma Sistêmico/metabolismo , Venenos de Serpentes/farmacologia , Animais , Artérias/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/complicações , Fibrose/metabolismo , Fibrose/prevenção & controle , Expressão Gênica/efeitos dos fármacos , Humanos , Integrina alfaVbeta3/metabolismo , Camundongos Endogâmicos BALB C , Fibrose Pulmonar/complicações , Fibrose Pulmonar/metabolismo , Receptores de Vitronectina/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND Thrombophilia is a predisposition to thrombosis. Genetic causes include antithrombin III, protein C, protein S, factor V Leiden, prothrombin 20210A allele, and MTHFR mutations. Other genetic factors causing thrombosis and pulmonary embolism have been identified in recent studies, including 4G/4G polymorphism of the PAI-1 gene. CASE REPORT A patient with a personal and family history of recurrent thrombosis and pulmonary embolism was admitted to our Internal Medicine Department. After the most common acquired risk factors for thromboembolism were ruled out, the patient and her family members underwent genetic diagnostic testing. These tests showed homozygous 4G/4G polymorphism of the PAI-1 gene in 14 subjects, homozygous 4G/4G polymorphism of the PAI-1 gene and C677T/A1298C polymorphism of the MTHFR gene in 4 subjects, and heterozygous 4G/4G polymorphism of the PAI-1 gene and C677T/A1298C polymorphism of the MTHFR gene in 3 subjects. Afterwards, we initiated the administration of Rivaroxaban, with beneficial results. CONCLUSIONS No thrombotic recurrence has been observed in the patient since 2014. This case report shows the efficacy and superiority of Rivaroxaban over traditional anticoagulants in the treatment of hereditary thrombophilia. Further studies are clearly needed before Rivaroxaban can be recommended as a standard treatment in patients with inherited thrombophilia.
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Trombofilia/diagnóstico , Trombofilia/genética , Inibidores do Fator Xa/uso terapêutico , Feminino , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/genética , Rivaroxabana/uso terapêutico , Trombofilia/tratamento farmacológicoRESUMO
The Miller-Urey experiments pioneered modern research on the molecular origins of life, but their actual relevance in this field was later questioned because the gas mixture used in their research is considered too reducing with respect to the most accepted hypotheses for the conditions on primordial Earth. In particular, the production of only amino acids has been taken as evidence of the limited relevance of the results. Here, we report an experimental work, combined with state-of-the-art computational methods, in which both electric discharge and laser-driven plasma impact simulations were carried out in a reducing atmosphere containing NH3 + CO. We show that RNA nucleobases are synthesized in these experiments, strongly supporting the possibility of the emergence of biologically relevant molecules in a reducing atmosphere. The reconstructed synthetic pathways indicate that small radicals and formamide play a crucial role, in agreement with a number of recent experimental and theoretical results.
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RNA/química , Amônia/química , Atmosfera , Monóxido de Carbono/química , Evolução Química , Formamidas/química , Modelos Químicos , Origem da Vida , OxirreduçãoRESUMO
We introduce a novel approach for a fully quantum description of coupled electron-ion systems from first principles. It combines the variational quantum Monte Carlo solution of the electronic part with the path integral formalism for the quantum nuclear dynamics. On the one hand, the path integral molecular dynamics includes nuclear quantum effects by adding a set of fictitious classical particles (beads) aimed at reproducing nuclear quantum fluctuations via a harmonic kinetic term. On the other hand, variational quantum Monte Carlo can provide Born-Oppenheimer potential energy surfaces with a precision comparable to the most-advanced post-Hartree-Fock approaches, and with a favorable scaling with the system size. In order to cope with the intrinsic noise due to the stochastic nature of quantum Monte Carlo methods, we generalize the path integral molecular dynamics using a Langevin thermostat correlated according to the covariance matrix of quantum Monte Carlo nuclear forces. The variational parameters of the quantum Monte Carlo wave function are evolved during the nuclear dynamics, such that the Born-Oppenheimer potential energy surface is unbiased. Statistical errors on the wave function parameters are reduced by resorting to bead grouping average, which we show to be accurate and well-controlled. Our general algorithm relies on a Trotter breakup between the dynamics driven by ionic forces and the one set by the harmonic interbead couplings. The latter is exactly integrated, even in the presence of the Langevin thermostat, thanks to the mapping onto an Ornstein-Uhlenbeck process. This framework turns out to be also very efficient in the case of noiseless (deterministic) ionic forces. The new implementation is validated on the Zundel ion (H5O2+) by direct comparison with standard path integral Langevin dynamics calculations made with a coupled cluster potential energy surface. Nuclear quantum effects are confirmed to be dominant over thermal effects well beyond room temperature, giving the excess proton an increased mobility by quantum tunneling.