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Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3-7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7-8. We identify compounds that bind to apo(a) KIV7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).
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Descubrimiento de Drogas , Lipoproteína(a) , Macaca fascicularis , Animales , Femenino , Humanos , Masculino , Ratones , Administración Oral , Kringles , Lipoproteína(a)/antagonistas & inhibidores , Lipoproteína(a)/sangre , Lipoproteína(a)/química , Lipoproteína(a)/metabolismo , Ratones Transgénicos , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Plasminógeno/química , Plasminógeno/metabolismo , Especificidad de la Especie , Ensayos Clínicos Fase II como Asunto , Apolipoproteínas A/química , Apolipoproteínas A/metabolismoRESUMEN
Alzheimer's, Parkinson's and Huntington's diseases can be caused by mutations that enhance protein aggregation, but we still do not know enough about the molecular players of these pathways to develop treatments for these devastating diseases. Here, we screen for mutations that might enhance aggregation in Caenorhabditis elegans, to investigate the mechanisms that protect against dysregulated homeostasis. We report that the stomatin homologue UNC-1 activates neurohormonal signalling from the sulfotransferase SSU-1 in ASJ sensory/endocrine neurons. A putative hormone, produced in ASJ, targets the nuclear receptor NHR-1, which acts cell autonomously in the muscles to modulate polyglutamine repeat (polyQ) aggregation. A second nuclear receptor, DAF-12, functions oppositely to NHR-1 to maintain protein homeostasis. Transcriptomics analyses of unc-1 mutants revealed changes in the expression of genes involved in fat metabolism, suggesting that fat metabolism changes, controlled by neurohormonal signalling, contribute to protein homeostasis. Furthermore, the enzymes involved in the identified signalling pathway are potential targets for treating neurodegenerative diseases caused by disrupted protein homeostasis.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteostasis , Metabolismo de los Lípidos/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Esteroides/metabolismoRESUMEN
National and international organizations have introduced policies aimed at sustainable development. These policies are designed to encourage sustainable forms of business to meet the Sustainable Development Goals (SDGs) of the 2030 Agenda. Regional inequalities in sustainable development may be exacerbated by disparate levels of innovation. This paper analyzes the variations between clusters of countries according to the degree to which they have achieved the SDGs and their levels of innovation facilitators. Two types of analyses were employed. First, cluster analysis was used to examine changes in groups of regions with similar innovation characteristics between 2015 and 2020. Data for 122 countries were gathered from the World Bank, the SDG Index, and the Global Innovation Index. Second, multiple linear regression analysis was used to assess the power of the variables in the model to explain the level of sustainable development. The results reveal four clusters (low, medium, high, and very high innovative facilitators and sustainable development), as well as movements between those clusters from 2015 to 2020. The multiple linear regression analysis shows that the variables have explanatory power with respect to the dependent variable of sustainable development. This analysis also reveals different degrees of importance of the variables for each cluster. The findings highlight the need to consider the limitations of economic growth in terms of innovation facilitators to promote sustainable development. If policymakers recognize the limitations of economic growth and the physical ecosystem, degradation of the environment can be avoided, even when there is innovation. Global and individual social welfare can thus be ensured. This study offers valuable insights into how to achieve sustainable development through innovation facilitators by providing in-depth knowledge of the individual characteristics of innovation systems and considering the limitations of economic growth.
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OBJECTIVE: To assess the efficacy of abatacept (ABA) in RA patients with interstitial lung disease (ILD) (RA-ILD). METHODS: This was an observational, multicentre study of RA-ILD patients treated with at least one dose of ABA. ILD was diagnosed by high-resolution CT (HRCT). We analysed the following variables at baseline (ABA initiation), 12 months and at the end of the follow-up: Modified Medical Research Council (MMRC) scale (1-point change), forced vital capacity (FVC) or diffusion lung capacity for carbon monoxide (DLCO) (improvement or worsening ≥10%), HRCT, DAS on 28 joints evaluated using the ESR (DAS28ESR) and CS-sparing effect. RESULTS: We studied 263 RA-ILD patients [150 women/113 men; mean (s.d.) age 64.6 (10) years]. At baseline, they had a median duration of ILD of 1 (interquartile range 0.25-3.44) years, moderate or severe degree of dyspnoea (MMRC grade 2, 3 or 4) (40.3%), FVC (% of the predicted) mean (s.d.) 85.9 (21.8)%, DLCO (% of the predicted) 65.7 (18.3) and DAS28ESR 4.5 (1.5). The ILD patterns were: usual interstitial pneumonia (UIP) (40.3%), non-specific interstitial pneumonia (NSIP) (31.9%) and others (27.8%). ABA was prescribed at standard dose, i.v. (25.5%) or s.c. (74.5%). After a median follow-up of 12 (6-36) months the following variables did not show worsening: dyspnoea (MMRC) (91.9%); FVC (87.7%); DLCO (90.6%); and chest HRCT (76.6%). A significant improvement of DAS28ESR from 4.5 (1.5) to 3.1 (1.3) at the end of follow-up (P < 0.001) and a CS-sparing effect from a median 7.5 (5-10) to 5 (2.5-7.5) mg/day at the end of follow-up (P < 0.001) was also observed. ABA was withdrawn in 62 (23.6%) patients due to adverse events (n = 30), articular inefficacy (n = 27), ILD worsening (n = 3) and other causes (n = 2). CONCLUSION: ABA may be an effective and safe treatment for patients with RA-ILD.
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Abatacept/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/complicaciones , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Abatacept/efectos adversos , Antirreumáticos/efectos adversos , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVES: To assess the plasma apolipoprotein B/apolipoprotein A1 ratio and its potential association with cardiovascular events (CVE) in patients with rheumatoid arthritis (RA). METHODS: A baseline analysis was made of the CARdiovascular in rheuMAtology Project (CARMA), a 10-year prospective study evaluating the presence of at least one CVE in 775 Spanish patients with RA. Of them, 29 had already experienced CVE prior to the inclusion in the study. We assessed the association between the elevation of the apoB/apoA1 ratio with the presence of CVE according to a logistic regression model for possible confounding factors. We also analysed the main parameters of activity of RA and parameters related to lipid metabolism. RA patients were classified according to treatment: patients treated with disease-modifying anti-rheumatic drugs without biologics and those undergoing biologic therapy (anti-TNF-α, anti-IL-6 receptor, and other biologic agents). RESULTS: The apoB/apoA1 ratio of patients who had experienced CVE was higher than that of patients without previous CVE (0.65 vs. 0.60). However, the difference between both subgroups did not reach statistical significance (p=0.197). It was also the case after the multivariate analysis [OR: 1.48 (95% CI: 0.15-14.4); p=0.735]. RA patients from the group with CVE were more commonly receiving lipid-lowering treatment with statins than those without CVE history (41.4% vs. 20%, p=0.005). High HAQ and high atherogenic index were significantly associated with the presence of CVE. There was no statistical association between the type of biologic therapy used in RA and the presence of CVE. CONCLUSIONS: No association between ApoB/apoA1 ratio and CVE was found at the baseline visit of patients with RA from the CARMA study.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Cardiovasculares , Apolipoproteína A-I , Apolipoproteínas B , Humanos , Estudios Prospectivos , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
The aim of this study was to examine the association between auditory and visual working memory (WM) performance and salivary alpha-amylase (sAA) and salivary flow rate (SFR) in a sample of 63 children (38 boys). WM was assessed by means of WISC-V subtests: four auditory subtests (Digit Span and Letter-Number Sequencing) and one visual subtest (Picture Span). SAA activity, output, and SFR were measured at baseline (10 min prior to testing), one minute prior to testing, one minute after the end of the auditory WM subtests and one minute after the end of the visual WM subtest. Our statistical analyses showed an association among SAA activity, output and SFR levels and the number of recalled digits in the last attempt score in Letter-Number Sequencing subtest. Specifically, our results showed that working performance in this task was associated with a concurrent decrease in SFR (r(63) = -0.423, p < .05). This salivary measure was the best predictor of this specific index of working memory performance (ß = -0.423, p < .05). These results show that the changes in SFR, which represents changes in parasympathetic tone, could be employed in future studies as a noninvasive marker of working memory performance in child studies.
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Memoria a Corto Plazo/fisiología , alfa-Amilasas Salivales/metabolismo , Niño , Femenino , Humanos , Masculino , alfa-Amilasas Salivales/fisiologíaRESUMEN
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
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Isoquinolinas/farmacología , Dolor/tratamiento farmacológico , Profármacos/farmacología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Tetrazoles/farmacología , Administración Oral , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Isoquinolinas/química , Masculino , Datos de Secuencia Molecular , Profármacos/química , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Kaínico/química , Relación Estructura-Actividad , Tetrazoles/químicaRESUMEN
The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
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Isoquinolinas/farmacología , Dolor/tratamiento farmacológico , Profármacos/farmacología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Administración Oral , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Haplorrinos , Isoquinolinas/química , Datos de Secuencia Molecular , Profármacos/química , Receptores de Ácido Kaínico/química , Relación Estructura-ActividadRESUMEN
This study aims to examine the impact of the different waves of the COVID-19 pandemic on the connectedness of the BRICS (Brazil, Russia, India, China, and South Africa) term structure of interest rates and its components (level, slope and curvature). For that purpose, this research applies the time-varying parameter vector autoregression (TVP-VAR) approach in order to assess the direction of spillovers among countries and factors and measure their contribution to the connectedness system. Our results show that the total connectedness measure changes over time, and the level and curvature components show connectedness that persists longer than the slope component, both in the first wave of the COVID-19 pandemic. Brazil and South Africa would appear as net transmitters of shocks, whereas China and India are net receivers. Finally, the most significant differences in the net dynamic connectedness between transmitters and receivers were focused on before and during the first wave of the COVID-19 pandemic crisis. Some additional impacts were observed during the last waves of the coronavirus pandemic. To our best knowledge, this is the first study on the connectedness between the yield curves of the BRICS economies and the COVID-19 crisis uncertainty according to the coronavirus MCI, by decomposing the yield curve into its factors (level, slope, and curvature).
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INTRODUCTION: Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system. Although there is currently no definite cure for MS, new therapies have recently been developed based on a continuous search for new biomarkers. DEVELOPMENT: MS diagnosis relies on the integration of clinical, imaging and laboratory findings as there is still no singlepathognomonicclinical feature or diagnostic laboratory biomarker. The most commonly laboratory test used is the presence of immunoglobulin G oligoclonal bands (OCB) in cerebrospinal fluid of MS patients. This test is now included in the 2017 McDonald criteria as a biomarker of dissemination in time. Nevertheless, there are other biomarkers currently in use such as kappa free light chain, which has shown higher sensitivity and specificity for MS diagnosis than OCB. In addition, other potential laboratory tests involved in neuronal damage, demyelination and/or inflammation could be used for detecting MS. CONCLUSIONS: CSF and serum biomarkers have been reviewed for their use in MS diagnosis and prognosis to stablish an accurate and prompt MS diagnosis, crucial to implement an adequate treatment and to optimize clinical outcomes over time.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/líquido cefalorraquídeo , Biomarcadores , Bandas Oligoclonales/líquido cefalorraquídeo , Cadenas Ligeras de Inmunoglobulina , Cadenas kappa de Inmunoglobulina/líquido cefalorraquídeoRESUMEN
BACKGROUND: Since the first confirmed case of severe acute respiratory syndrome coronavirus 2 in Spain in January 2020, the susceptibility of patients with rheumatic disease has remained unclear. In this report, we will describe the main features of coronavirus disease 2019 (COVID-19) that occurred in rheumatic patients with inflammatory disorders and try to identify features associated with severe disease. METHODS: We included all rheumatic patients with immune-mediated diseases followed at 6 centers belonging to the public healthcare system in the Basque Country (Spain) and diagnosed with COVID-19 from March 1, 2020, to May 31, 2020. RESULTS: In total, 131 patients were included in this study. The most frequent rheumatic disease was rheumatoid arthritis (46.6%), and the main comorbidities were arterial hypertension (45%). Fortyseven percent were taking glucocorticoids (GC) (62 patients), 61.8% were under treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and 25 patients (19.1%) were receiving targeted therapies (TT). Thirty-eight percent of patients required hospital admission, 2.3% required transfer to intensive care uni, and the rate of mortality was 9.2%. Associated factors in univariate analysis for a bad outcome were older age, use of GC, obesity, previous cardiovascular disease, and lymphopenia. Use of GC and lymphopenia remained within the multivariate model. CONCLUSION: The frequency of COVID-19 seems to be similar in rheumatic patients as in the general population. Advanced age, obesity, heart disease, glucocorticoids, and low levels of lymphocytes were more common among the patients with a bad outcome. Neither exposure to csDMARD nor TT was associated with severe cases.
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This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.
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Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Diseño de Fármacos , Hipolipemiantes/síntesis química , Quinolinas/química , Tetrazoles/síntesis química , Animales , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/efectos de los fármacos , HDL-Colesterol/metabolismo , Perros , Femenino , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Inyecciones Intravenosas , Masculino , Ratones , Ratones Transgénicos , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacocinéticaRESUMEN
This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.
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Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Naftiridinas/farmacología , Animales , HDL-Colesterol , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Naftiridinas/síntesis química , Relación Estructura-ActividadRESUMEN
Neurodegenerative disorders, caused by prone-to-aggregation proteins, such as Alzheimer disease or Huntington disease, share other traits such as disrupted homeostasis of essential metal ions, like copper. In this context, in an attempt to identify Cu2+ chelating agents, we study several organic compounds (ethylenediaminetetraacetic acid, phenylenediamine, metformin, salicylate, and trehalose) and organic extracts obtained from Bacopa monnieri L., which has been used in Ayurvedic therapies and presented a broad spectrum of biological properties. For this purpose, UV-visible spectroscopy analysis and electrochemical measurements were performed. Further, biological assays were performed in Caenorhabditis elegans models of polyQ toxicity, in an attempt to obtain better insights on neurodegenerative disorders.
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Data from manual healthspan assays of the nematode Caenorhabditis elegans (C. elegans) can be complex to quantify. The first attempts to quantify motor performance were done manually, using the so-called thrashing or body bends assay. Some laboratories have automated these approaches using methods that help substantially to quantify these characteristic movements in small well plates. Even so, it is sometimes difficult to find differences in motor behaviour between strains, and/or between treated vs untreated worms. For this reason, we present here a new automated method that increases the resolution flexibility, in order to capture more movement details in large standard Petri dishes, in such way that those movements are less restricted. This method is based on a Cartesian robot, which enables high-resolution images capture in standard Petri dishes. Several cameras mounted strategically on the robot and working with different fields of view, capture the required C. elegans visual information. We have performed a locomotion-based healthspan experiment with several mutant strains, and we have been able to detect statistically significant differences between two strains that show very similar movement patterns.
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Bioensayo/instrumentación , Caenorhabditis elegans/fisiología , Locomoción , Longevidad , Monitoreo Fisiológico/métodos , Robótica/métodos , AnimalesRESUMEN
Purpose: Surgical stress is a phenomenon not completely understood from the biochemical point of view, although it produces alterations in the oxidative balance and inflammatory status. The present study aimed to investigate the alterations of the circulating levels of paraoxonase-1 (PON1)-related variables and markers of inflammation in hospitalized patients who underwent surgery. Methods: We recruited 285 hospitalized patients. Of those, 115 were hospitalized due to a surgical intervention and 170 for reasons other than surgery. The control group consisted of 128 healthy volunteers. A blood sample was obtained for the measurement of serum PON1-related variables, and C-reactive protein (CRP), chemokine (C-C motif) ligand 2 (CCL2), and procalcitonin concentrations. Results: Hospitalized patients had lower serum PON1 activities [paraoxonase: 215.6 (168.6 - 277.8) vs. 298.7 (229.7 - 382.6) U/L, p < 0.001; lactonase: 3.0 (2.3 - 3.7) vs. 5.7 (4.6 - 6.5) U/L, p < 0.001], and higher CCL2, CRP and procalcitonin concentrations than the healthy individuals. The days elapsed following surgery and the duration of the procedure itself inversely correlated with PON1-related variables, and directly correlated with CRP concentrations. Patients that were operated on by laparotomy had higher PON1 activity than patients operated on by laparoscopy. Local and regional anesthesia was associated with higher PON1 activities and lower CRP concentrations. Conclusion: These results show a decrease in PON1 activities and an increase in acute phase response in hospitalized patients undergoing surgery and support the hypothesis that these phenomena are related to post-surgical metabolic alterations.
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Arildialquilfosfatasa , Inflamación , Biomarcadores , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Humanos , Inflamación/diagnóstico , Inflamación/etiologíaRESUMEN
Myotonic Dystrophy type 1 (DM1) is a muscular dystrophy with a multi-systemic nature. It was one of the first diseases in which repeat associated non-ATG (RAN) translation was described in 2011, but has not been further explored since. In order to enhance our knowledge of RAN translation in DM1, we decided to study the presence of DM1 antisense (DM1-AS) transcripts (the origin of the polyglutamine (polyGln) RAN protein) using RT-PCR and FISH, and that of RAN translation via immunoblotting and immunofluorescence in distinct DM1 primary cell cultures, e.g., myoblasts, skin fibroblasts and lymphoblastoids, from ten patients. DM1-AS transcripts were found in all DM1 cells, with a lower expression in patients compared to controls. Antisense RNA foci were found in the nuclei and cytoplasm of a subset of DM1 cells. The polyGln RAN protein was undetectable in all three cell types with both approaches. Immunoblots revealed a 42 kD polyGln containing protein, which was most likely the TATA-box-binding protein. Immunofluorescence revealed a cytoplasmic aggregate, which co-localized with the Golgi apparatus. Taken together, DM1-AS transcript levels were lower in patients compared to controls and a small portion of the transcripts included the expanded repeat. However, RAN translation was not present in patient-derived DM1 cells, or was in undetectable quantities for the available methods.
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INTRODUCTION: To assess the clinical and cost-effectiveness of therapeutic drug monitoring (TDM) based on serum adalimumab levels compared to standard of care in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. METHODS: This was a non-inferiority, multicentric, non-randomized, pragmatic trial including adult patients diagnosed with moderate-to-severe, clinically stable rheumatic diseases treated with adalimumab. Consecutive patients were assigned 1:2 to the control (CG) or the intervention group (IG), based on the site of inclusion, and followed up for 18 months. Adalimumab serum levels were measured at each study visit and released to the IG only to modify dosing strategy. Data on disease activity, healthcare resource utilization and health-related quality of life (HRQoL) measured through the EQ-5D-5L were collected. Number of persistent and overall flares, time to first flare, days experiencing high disease activity, total direct costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. RESULTS: Of the 169 recruited patients, 150 were included in the analysis (52 and 98 patients in the CG and IG, respectively). The primary endpoint was not met as persistent flares were not significantly lower in the IG, although mean (SD) number of flares was numerically lower in the IG (0.67 [0.70] versus 0.90 [0.82], P = 0.073), respectively. Based on EQ-5D-5L utilities, HRQoL was significantly higher in the IG at 3 (P = 0.001) and 6 months (P = 0.035), which overall translated into 0.075 QALYs gained per patient for the IG at month 18. Overall, direct costs were significantly lower for the IG patients (15,311.59 [4,870.04] versus 17,378.46 [6,556.51], P = 0.030), resulting in the intervention being dominant, leading to increased QALY at a lower overall cost CONCLUSION: Adalimumab dose tapering based on TDM for rheumatic patients led to an increased quality of life and QALY gain and entailed lower costs, being a more cost-effective alternative than clinically guided management.
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Huntington disease (HD) is a neurodegenerative condition and one of the so-called rare or minority diseases, due to its low prevalence (affecting 1-10 of every 100,000 people in western countries). The causative gene, HTT, encodes huntingtin, a protein with a yet unknown function. Mutant huntingtin causes a range of phenotypes, including oxidative stress and the activation of microglia and astrocytes, which leads to chronic inflammation of the brain. Although substantial efforts have been made to find a cure for HD, there is currently no medical intervention able to stop or even delay progression of the disease. Among the many targets of therapeutic intervention, oxidative stress and inflammation have been extensively studied and some clinical trials have been promoted to target them. In the present work, we review the basic research on oxidative stress in HD and the strategies used to fight it. Many of the strategies to reduce the phenotypes associated with oxidative stress have produced positive results, yet no substantial functional recovery has been observed in animal models or patients with the disease. We discuss possible explanations for this and suggest potential ways to overcome it.
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OBJECTIVE: To investigate PGRMC1-precipitating proteins in human endometrial stromal cells (ESC) to understand its role during in vitro decidualization. DESIGN: Prospective observational study. SETTING: Academic fertility center. PATIENT(S): Fifteen fertile oocyte donors. INTERVENTION(S): Isolated ESCs decidualized in vitro and used in pulldown assays. MAIN OUTCOME MEASURE(S): GST-PGRMC1-precipitated proteins identified in nondecidualized ESC (ndESC) and ESC decidualized via a long (8 days) or short (4 days) decidualization protocol (dESC). RESULT(S): Using pulldown assays and mass spectrometry, decidualization was evaluated by prolactin secretion (ELISA) and cytoskeleton morphology (F-actin staining). The protein interactions were validated by colocalization and coimmunoprecipitation. The pulldown and mass spectrometry analysis identified 21, 24, and 24 new significant GST-PGRMC1-precipitated proteins in ndESC, long dESC, and short dESC, respectively, compared with controls. The functional annotation analysis categorized these proteins mainly into endomembrane system and mitochondria cellular components, both related to adenosine triphosphate (ATP) generation and transport activity, protein biosynthesis and posttranslational processing, vesicle trafficking, and protection against oxidative stress activities. Monoamine oxidase B (MAOB) and B-cell receptor-associated protein 31 (BAP31) were identified in dESC from both decidualization protocols. PGRMC1-MAOB/BAP31 interactions were confirmed by immunofluorescence and coimmunoprecipitation in dESC. CONCLUSION(S): Novel GST-PGRMC1-precipitated proteins discovered in ESC suggest that this protein is implicated in deep remodeling of ESC during decidualization and aggregates mainly with proteins involved in biosynthesis, intracellular transport, and mitochondrial activity.