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BACKGROUND: Gastric dysplasia in the absence of an endoscopically defined lesion is rare, usually either a false positive diagnosis or a previously unidentified precancerous lesion during esophagogastroduodenoscopy (EGD). AIMS: Evaluate factors associated with the presence of an endoscopically visible lesion during follow-up in patients with histologic diagnosis of gastric dysplasia in random biopsies. METHODS: Retrospective cohort study including patients referred to our institution for gastric dysplasia in random biopsies during Index EGD. Endoscopic evaluation was performed with a high-definition endoscope using narrow band imaging (HD EGD-0). If no lesion was detected, endoscopic surveillance (HD EGD-FU) was conducted within 6 months for high grade dysplasia (HGD) or 12 months for low grade (LGD) or indefinite for dysplasia (IFD). RESULTS: From a total sample of 96 patients, 5 (5.2%) presented with an endoscopically visible lesion during HD EGD-0, while 10 lesions (10.4%) were identified during HD EGD-FU. Patients with Helicobacter pylori infection at Index EDG and with regular alcohol consumption (≥25 g/day) were 8 and 4 times more likely to have an endoscopically visible lesion on HD EGD-FU (p = 0.012 and p = 0.047). In binary logistic regression, both factors were independent predictors of the presence of gastric lesion on HD EGD-FU (OR 9.284, p = 0.009 and OR 5.025, p = 0.033). CONCLUSIONS: The presence of an endoscopically visible lesion after the histologic diagnosis of gastric dysplasia in random biopsies was more frequent during HD EGD-FU. H. pylori infection at Index EGD and regular alcohol consumption were significant predictors of the presence of gastric lesion on HD EGD-FU.
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Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Infecciones por Helicobacter/epidemiología , Estudios Retrospectivos , Biopsia , Neoplasias Gástricas/patología , Consumo de Bebidas Alcohólicas/efectos adversos , Lesiones Precancerosas/patologíaRESUMEN
Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism's fitness. In the brain, ageing is highly associated with cognitive decline and neurodegenerative diseases. With the rise in life expectancy, characterizing the brain ageing process becomes fundamental for developing therapeutic interventions against the increased incidence of age-related neurodegenerative diseases and to aim for an increase in human life span and, more importantly, health span. In this review, we start by introducing the molecular/cellular hallmarks associated with brain ageing and their impact on brain cell populations. Subsequently, we assess emerging evidence on how systemic ageing translates into brain ageing. Finally, we revisit the mainstream and the novel rejuvenating strategies, discussing the most successful ones in delaying brain ageing and related diseases.
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Envejecimiento , Enfermedades Neurodegenerativas , Humanos , Encéfalo , LongevidadRESUMEN
OBJECTIVE: Crohn's disease (CD) is heterogeneous, and proximal involvement in the small bowel (SB) is associated with worse outcomes. Nonetheless, studies on the impact of duodenal and jejunal lesions in SB CD are limited. This study aimed to investigate the clinical characteristics and outcomes of individuals diagnosed with SB CD, comparing those with and without proximal inflammation. METHODS: A cohort of 53 treatment-naive SB CD patients that underwent Capsule Endoscopy at diagnosis were retrospectively selected. The inflammatory activity was quantified using the Lewis Score for each SB tertile. RESULTS: Thirty-seven (69.8%) patients displayed inflammatory activity in the first and/or second tertile together with third tertile involvement (Proximal+T3 group). Sixteen (30.2%) had inflammation in the third tertile only (T3 group). Individuals in the Proximal+T3 group had a higher risk for moderate-to-severe inflammation (OR 4.93, 95% CI: 1.3-18.3, p=0.013). A subgroup analysis for those with mild inflammatory activity showed that individuals in the Proximal+T3 group initiated biologic drugs more often (OR 11, 95% CI: 1.1-109.7, p=0.036). CONCLUSION: Proximal SB lesions are associated with increased inflammatory activity, necessitating more frequent use of biologics in patients with mild disease. Early detection of proximal SB CD with Capsule Endoscopy may contribute to timely treatment.
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BACKGROUND: Currently, bismuth quadruple therapy (BQT) is indicated as a first-line treatment for Helicobacter pylori eradication in areas with high dual metronidazole and clarithromycin resistance, with its use being limited by its low tolerability and significant cost. A novel regimen with high-dose amoxicillin dual therapy (HDADT) has emerged as an alternative. The aim of this study was to compare the results of these two treatments on HP eradication. MATERIALS AND METHODS: Prospective randomized study including 100 consecutive patients undergoing H. pylori eradication. Each patient was randomized (in a 1:1 ratio) to one group of treatment: BQT (bismuth 140 mg + metronidazole 125 mg + tetracycline 125 mg, four times a day, for 10 days) or HDADT (amoxicillin 1000 mg alternating with amoxicillin 500 mg, four times a day, for 14 days), both associated with esomeprazole 40 mg twice a day. The primary aim was to compare treatments' efficacies. Secondary aims were to assess symptoms persistence and tolerability. RESULTS: A total of 100 patients were included, 54% women, with a mean age of 55 ± 14 years. From these, five were lost to follow-up. Effective eradication proven by negative stool antigen test was significantly higher in patients randomized to HDADT when compared to BQT for both intention-to-treat (ITT) (96.2% vs. 81.4%; p = .022) and per-protocol (PP) (95.9% vs. 81%; p = .025) analysis. These differences were even more pronounced when only considering second line treatment (100% vs. 62.5%; p = .028). Side effects did not differ significantly between BQT and HDADT groups for both ITT (7.0% vs. 2.0%; p = .254) and PP (4.8% vs. 0%; p = .210) analysis. CONCLUSIONS: When compared to BQT, treatment with HDADT presented higher and near 100% efficacy in eradicating H. pylori, without differences in reported side effects or compliance. This treatment represents an important alternative for populations with increasing incidences of resistance to the currently recommended antibiotic regimens.
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Infecciones por Helicobacter , Helicobacter pylori , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Amoxicilina , Bismuto , Metronidazol/uso terapéutico , Metronidazol/farmacología , Infecciones por Helicobacter/tratamiento farmacológico , Estudios Prospectivos , Quimioterapia Combinada , Antibacterianos , Resultado del TratamientoRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) patients have a higher risk of metabolic dysfunction-associated fatty liver disease (MAFLD) compared with the general population. However, it is not known whether available non-invasive hepatic steatosis scores are useful in predicting MAFLD in IBD patients. We aimed to analyze the performances of MAFLD screening score (MAFLD-S), Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI) and Clinical Prediction Tool for NAFLD in Crohn's Disease (CPN-CD), in identifying MAFLD in IBD patients. METHODS: A cross-sectional study was carried out including consecutive adult IBD outpatients submitted to transient elastography (TE). MAFLD criteria were assessed, and hepatic steatosis (HS) was defined by a controlled attenuation parameter (CAP) >248 dB/m using TE. MAFLD-S, FLI, HSI, and CPN-CD were calculated and their accuracy for the prediction of MAFLD was evaluated through their areas under the receiver-operating characteristic (AUROC) curves. RESULTS: Of 168 patients, body mass index ≥25, type 2 diabetes mellitus, dyslipidemia and arterial hypertension were present in 76 (45.2%), 10 (6.0%), 53 (31.5%), 20 (11.9%), respectively. HS was identified in 77 (45.8%) patients, of which 65 (84.4%) fulfilled MAFLD criteria. MAFLD-S (AUROC, 0.929 [95% CI, 0.888-0.971]) had outstanding and FLI (AUROC, 0.882 [95% CI, 0.830-0.934]), HSI (AUROC, 0.803 [95% CI, 0.736-0.871]), and CPN-CD (AUROC, 0.822 [95% CI, 0.753-0.890) had excellent discrimination in predicting MAFLD. CONCLUSIONS: MAFLD-S, FLI, HSI and CPN-CD scores can accurately identify MAFLD in IBD patients, allowing the selection of those in whom hepatic steatosis and metabolic risk factors assessment may be particularly beneficial.
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Diabetes Mellitus Tipo 2 , Enfermedades Inflamatorias del Intestino , Enfermedad del Hígado Graso no Alcohólico , Adulto , Humanos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Estudios Transversales , Enfermedades Inflamatorias del Intestino/complicacionesRESUMEN
A 50-years old male with irrelevant medical history underwent colonoscopy for colorectal cancer screening. On the distal rectum, a subpedunculated (Paris classification Isp) lesion with 15mm was detected. This lesion presented yellowish mucosa and had irregular surfaces, suggesting a subepithelial lesion. Bite-on-bite biopsy confirmed a well-differentiated neuroendocrine tumor (r-NET), positive for synaptophysin, with a low-proliferative index. As r-NETs with 10-20mm fall on a grey area between endoscopic or surgical treatment, a lower endoscopic ultrasound (EUS) was performed, showing a round hypoechoic "salt and pepper" lesion of the mucosa, with focal involvement of the submucosa (3rd layer), but without muscularis propria invasion or regional lymph node involvement (uT1N0). No distal metastases were detected on computed tomography. Thus, the patient was proposed for endoscopic submucosal dissection. With this case we aim to recall EUS importance in large r-NETs, as adequate staging is crucial when deciding optimal therapeutic options.
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Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNß or IFNAR1, the receptor for IFNα/ß, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNß-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNß-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNß-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb-/- mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches.
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Demencia , Interferón beta/metabolismo , Enfermedad de Parkinson , Proteínas Inhibidoras de STAT Activados , Transducción de Señal , Animales , Demencia/genética , Neuronas Dopaminérgicas/metabolismo , Humanos , Ratones , Ratones Noqueados , Degeneración Nerviosa , Enfermedad de Parkinson/genética , Proteínas Inhibidoras de STAT Activados/genética , alfa-Sinucleína/metabolismoRESUMEN
OBJECTIVE: COVID-19 vaccines have shown efficacy and safety in healthy people. However, cancer patients under active immunosuppressive treatment were not included in the clinical trials conducted to test vaccines' efficacy and safety. This study aimed to evaluate the COVID-19 vaccine acceptance in cancer patients undergoing immunosuppressive therapy. METHODS: A total of 200 adult cancer patients received a questionnaire between March 8 and April 2, 2021, before the beginning of cancer patients' vaccination in Portugal. The questionnaire adapted from previously conducted studies included 11 close-ended items, evaluating variables such as patient sociodemographic and clinical characteristics, and the acceptance and underlying reasons to be or not to be vaccinated. The primary outcome was the intended acceptance of the COVID-19 vaccine in cancer patients. Multiple logistic regression was performed to identify factors associated with intended acceptance. RESULTS: Among the 200 delivered questionnaires, only 169 were included in this study. From those, 142 (84%) patients intended to be vaccinated against COVID-19. Only 27 participants (16%) had not yet decided or were reluctant to COVID-19 vaccination. High school degree (odds ratio (OR) 0.133, 95% confidence interval (C.I.) 0.031-0.579, p = 0.007], rural residence (OR 0.282, 95% C.I. 0.081-0.984, p = 0.047), and reluctance in believing in the vaccine efficacy (OR 0.058, 95% C.I. 0.016-0.204, p < 0.001] were identified predictors factor for COVID-19 vaccine hesitancy. CONCLUSION: Most patients intended to be vaccinated against COVID-19, and specific factors such as education level, rural residence and the belief in vaccine efficacy were related to vaccine acceptance.
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COVID-19 , Neoplasias , Adulto , Actitud , COVID-19/prevención & control , Vacunas contra la COVID-19 , Estudios Transversales , Humanos , Portugal , SARS-CoV-2 , VacunaciónRESUMEN
Cortical interneurons born in the subpallium reach the cortex through tangential migration, whereas pyramidal cells reach their final position by radial migration. Purinergic signaling via P2Y1 receptors controls the migration of intermediate precursor cells from the ventricular zone to the subventricular zone. It was also reported that the blockade of A2A receptors (A2AR) controls the tangential migration of somatostatin+ interneurons. Here we found that A2AR control radial migration of cortical projection neurons. In A2AR-knockout (KO) mouse embryos or naïve mouse embryos exposed to an A2AR antagonist, we observed an accumulation of early-born migrating neurons in the lower intermediate zone at late embryogenesis. In utero knockdown of A2AR also caused an accumulation of neurons at the lower intermediate zone before birth. This entails the presently identified ability of A2AR to promote multipolar-bipolar transition and axon formation, critical for the transition of migrating neurons from the intermediate zone to the cortical plate. This effect seems to require extracellular ATP-derived adenosine since a similar accumulation of neurons at the lower intermediate zone was observed in mice lacking ecto-5'-nucleotidase (CD73-KO). These findings frame adenosine as a fine-tune regulator of the wiring of cortical inhibitory and excitatory networks.
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Neuronas , Receptor de Adenosina A2A , Animales , Axones , Movimiento Celular/fisiología , Interneuronas , Ratones , Neuronas/fisiología , Células Piramidales/fisiología , Receptor de Adenosina A2A/genéticaRESUMEN
Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways.
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Amiloidosis/etiología , Prealbúmina/metabolismo , Amiloidosis/metabolismo , Sistema Nervioso Central/metabolismo , Humanos , Neuronas/citología , Neuronas/metabolismo , Prealbúmina/química , Prealbúmina/genética , Agregado de Proteínas/fisiología , Especies Reactivas de Oxígeno/metabolismo , Tiroxina/química , Tiroxina/metabolismo , Vitamina A/química , Vitamina A/metabolismoRESUMEN
OBJECTIVES: A recent ultrasonographic score (Ultrasonographic fatty liver indicator (US-FLI)) allows to grade steatosis severity on ultrasound (US).We aimed to evaluate the agreement of US-FLI with the controlled attenuation parameter (CAP) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Initially, inter-observer agreement for the score was assessed between 3 physicians using a sample of 31 patients.Later, 96 patients with NAFLD were included and several anthropometric/clinical/analytical parameters were assessed and US and transient elastography was performed. RESULTS: Physicians showed an excellent absolute agreement regarding the total score, with an average Interclass Correlation Coefficient of 0.972(95% CI 0.949-0.986). Comparing US-FLI with CAP, considering the previously defined cut-off for steatosis >S1(268dB/m) and > S2(280dB/m), US-FLI had a good discriminative capacity for both grades, with areas under the curve (AUC) of 0.88(p < 0.001) and 0.90(p < 0.001), respectively.Also, US-FLI ≤ 3 points had a negative predictive value of 100% for steatosis >S2 and US-FLI ≥6 points had a positive predictive value (PPV) of 94.0% for steatosis >S2. When comparing the clinical score Fatty Liver Index (FLI) for the same CAP cut-offs, it showed a weak discriminative capacity for both grades, with AUC of 0.65(p = 0.030) and 0.66(p = 0.017). AUC for US-FLI and FLI were significantly different for both cut-offs (p < 0.001). CONCLUSION: US-FLI has an excellent reproducibility and a good discriminative capacity for the different steatosis grades.Scores ≤3points exclude significant steatosis and scores ≥6 points have a PPV of 94,0% for steatosis >S2.US-FLI was significantly superior to the clinical score FLI in the discrimination between steatosis grades.
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Hígado Graso/diagnóstico , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Ultrasonografía , Biopsia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/diagnóstico por imagen , Diabetes Mellitus/patología , Dislipidemias/complicaciones , Dislipidemias/diagnóstico , Dislipidemias/diagnóstico por imagen , Dislipidemias/patología , Diagnóstico por Imagen de Elasticidad , Hígado Graso/clasificación , Hígado Graso/diagnóstico por imagen , Hígado Graso/patología , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertensión/diagnóstico por imagen , Hipertensión/patología , Hígado/ultraestructura , Síndrome Metabólico/complicaciones , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/diagnóstico por imagen , Síndrome Metabólico/patología , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/diagnóstico por imagen , Obesidad/patología , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Increasing evidence suggests an association between metabolic-associated fatty liver disease (MAFLD) and CKD. Timely prediction of early kidney dysfunction (EKD) is thus essential in this population although a screening method is not stablished. We aimed to evaluate the role of transient elastography (TE) in predicting EKD in patients with MAFLD. MATERIALS AND METHODS: A prospective cohort study that included patients with MAFLD scheduled for evaluation was performed between May 2019 and January 2020. Demographic, clinical, and laboratory data and TE parameters were prospectively obtained. EKD was defined as microalbuminuria (urinary albumin-to-Cr ratio 30-300 mg/g) and estimated glomerular filtration rate ≥60 mL/min/1.73 m2. Significant liver fibrosis was defined as liver stiffness measurement (LSM) ≥8.2 kPa. RESULTS: Of the included 45 patients with MALFD, 53.3% were of female gender with mean age of 53.5 ± 10.9 years. EKD was found in 17.8% of patients. MAFLD patients with EKD were significantly more obese (BMI ≥30) (75.0 vs. 32.4%, p = 0.045) and had significantly higher LSM (8.5 ± 4.1 vs. 5.8 ± 2.2 kPa, p = 0.01). After adjustment of potential confounders for EKD, the presence of liver fibrosis remained a significant predictor of EKD, being associated with a 14.3-fold increased risk of EKD (p = 0.04). The optimal cutoff value of LSM to predict EKD was 6.1 kPa (sensitivity: 85.7%; specificity: 67.6%). CONCLUSION: Significant liver fibrosis is associated with a significant increased risk of EKD in patients with MAFLD, regardless of other comorbidities. Higher levels of LSM, particularly >6.1 kPa, alert for timely identification of EKD and associated comorbidities, as well as their control, in order to prevent the development of CKD in the long term.
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Diagnóstico por Imagen de Elasticidad , Adulto , Femenino , Humanos , Riñón , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Tamizaje Masivo , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: The liver-renal-risk (LIRER) score was developed to predict adverse outcomes in cirrhotic patients with Model for End-stage Liver Disease (MELD)<18, helping the allocation to liver transplantation in this population. We aimed to assess its prognostic performance compared to other prognostic scores in first admission for hepatic cirrhosis decompensation. METHODS: Retrospective study that included patients admitted for initial decompensation of cirrhosis between January 2010 and February 2017. The LIRER, Child-Pugh (CP), MELD and MELD-sodium (MELD-Na) scores were calculated at admission. RESULTS: One-hundred and forty-six patients were included, 65.1% with MELD < 18. LIRER was a predictor of in-stay (AUC 0.70; p = .04), first-year (0.70; p < .001), two-years (0.72; p < .001) and overall mortality (0.70; p < .001), being the only score with an acceptable discriminating ability (AUC ≥ 0.70). Stratifying patients in MELD < 18 and ≥18, LIRER was found to be an independent predictor of first-year, two-years and overall-mortality only in MELD < 18 patients (AUC 0.67; 0.70; 0.72), being superior to all other scores predicting first-year mortality and the only with an AUC with a reasonable discriminating ability for predicting two-years and overall-mortality. The LIRER was also a predictor of 30-days hospital readmission (AUC 0.75; p < .001), independently of MELD, with patients with LIRER > 15.9 having a significantly higher probability to be readmitted at 30 days. CONCLUSIONS: The LIRER score is a predictor of first-year, two-years and overall-mortality in decompensated cirrhosis, particularly in patients with MELD < 18. LIRER is therefore an important tool to predict medium-long-term outcomes in this population. Besides, it allows predicting the 30-days readmission probability in overall patients, independently of MELD.
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Enfermedad Hepática en Estado Terminal , Humanos , Cirrosis Hepática/complicaciones , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Osteoarthritis (OA) remains a prevalent chronic disease without effective prevention and treatment. Amentadione (YP), a meroditerpenoid purified from the alga Cystoseira usneoides, has demonstrated anti-inflammatory activity. Here, we investigated the YP anti-osteoarthritic potential, by using a novel OA preclinical drug development pipeline designed to evaluate the anti-inflammatory and anti-mineralizing activities of potential OA-protective compounds. The workflow was based on in vitro primary cell cultures followed by human cartilage explants assays and a new OA co-culture model, combining cartilage explants with synoviocytes under interleukin-1ß (IL-1ß) or hydroxyapatite (HAP) stimulation. A combination of gene expression analysis and measurement of inflammatory mediators showed that the proposed model mimicked early disease stages, while YP counteracted inflammatory responses by downregulation of COX-2 and IL-6, improved cartilage homeostasis by downregulation of MMP3 and the chondrocytes hypertrophic differentiation factors Col10 and Runx2. Importantly, YP downregulated NF-κB gene expression and decreased phosphorylated IkBα/total IkBα ratio in chondrocytes. These results indicate the co-culture as a relevant pre-clinical OA model, and strongly suggest YP as a cartilage protective factor by inhibiting inflammatory, mineralizing, catabolic and differentiation processes during OA development, through inhibition of NF-κB signaling pathways, with high therapeutic potential.
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Antirreumáticos/farmacología , Cianobacterias/química , Diterpenos/farmacología , Osteoartritis/prevención & control , Antiinflamatorios no Esteroideos/farmacología , Antirreumáticos/química , Calcificación Fisiológica/efectos de los fármacos , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Condrocitos/efectos de los fármacos , Técnicas de Cocultivo , Diterpenos/química , Durapatita , Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1beta , Osteoartritis/patología , Cultivo Primario de Células , Sinoviocitos/efectos de los fármacosRESUMEN
Osteoarthritis is the most prevalent rheumatic disease. During disease progression, differences have been described in the prevalence of chondroitin sulfate (CS) isomers. Marine derived-CS present a higher proportion of the 6S isomer, offering therapeutic potential. Accordingly, we evaluated the effect of exogenous supplementation of CS, derived from the small spotted catshark (Scyliorhinus canicula), blue shark (Prionace glauca), thornback skate (Raja clavata) and bovine CS (reference), on the proliferation of osteochondral cell lines (MG-63 and T/C-28a2) and the chondrogenic differentiation of mesenchymal stromal cells (MSCs). MG-G3 proliferation was comparable between R. clavata (CS-6 intermediate ratio) and bovine CS (CS-4 enrichment), for concentrations below 0.5 mg/mL, defined as a toxicity threshold. T/C-28a2 proliferation was significantly improved by intermediate ratios of CS-6 and -4 isomers (S. canicula and R. clavata). A dose-dependent response was observed for S. canicula (200 µg/mL vs 50 and 10 µg/mL) and bovine CS (200 and 100 µg/mL vs 10 µg/mL). CS sulfation patterns discretely affected MSCs chondrogenesis; even though S. canicula and R. clavata CS up-regulated chondrogenic markers expression (aggrecan and collagen type II) these were not statistically significant. We demonstrate that intermediate values of CS-4 and -6 isomers improve cell proliferation and offer potential for chondrogenic promotion, although more studies are needed to elucidate its mechanism of action.
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Proliferación Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Condrogénesis/efectos de los fármacos , Sulfatos de Condroitina/farmacología , Anciano , Anciano de 80 o más Años , Animales , Bovinos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Condrocitos/metabolismo , Sulfatos de Condroitina/química , Sulfatos de Condroitina/aislamiento & purificación , Femenino , Humanos , Isomerismo , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Tiburones , RajidaeRESUMEN
Background: Obesity is one of the main factors of transient elastography (TE) failure, considering body mass index (BMI) ≥28 kg/m2 as a limiting factor. The XL probe was designed to overcome this limitation. Aim: To compare the feasibility of the M and XL probes in patients with BMI ≥ 28 kg/m2, to evaluate differences in mean values of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) between the two probes and find predictive factors of TE failure. Material and methods: Prospective study, including all patients with BMI ≥ 28 kg/m2 consecutively admitted for TE. Results: Included 161 patients. Measurements with M probe were reliable in 69.6% of the patients, with 68.2% of valid measurements in obese population and 58.9% in patients with skin-capsule distance (SCD) >25 mm. In 40 patients (81.6%) with an invalid M probe measurement, a reliable result was obtained with XL probe. We found that SCD >25 mm was the only predictor of M probe failure (OR: 4.9, CI: 1.64-14.63, p = .004). In those patients in which TE was possible with both probes (n = 112), mean CAP was 304 ± 49 dB/m2 with M probe and 301 ± 50 dB/m2 with XL probe (p = .59). Regarding liver stiffness, a mean value of 7.58 ± 3.47 kpas was obtained with the M probe and 6.21 ± 3.44 kpas with the XL probe (p < .001). Conclusion: There is a reliable applicability of the M probe in a high number (68.2%) of patients with a BMI ≥30 kg/m2. A SCD >25 mm was the only predictive factor of M probe failure. Mean values of LSM with XL probe were lower than those obtained with M probe.
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Diagnóstico por Imagen de Elasticidad/instrumentación , Cirrosis Hepática/diagnóstico por imagen , Sobrepeso/diagnóstico por imagen , Transductores , Adulto , Índice de Masa Corporal , Diseño de Equipo , Femenino , Humanos , Hígado/diagnóstico por imagen , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Obesidad/diagnóstico por imagen , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The lack of efficacy of current antibacterials to treat multidrug resistant bacteria poses a life-threatening alarm. In order to develop enhancers of the antibacterial activity, we carried out a medicinal chemistry campaign aiming to develop inhibitors of enzymes that synthesise cysteine and belong to the reductive sulphur assimilation pathway, absent in mammals. Previous studies have provided a novel series of inhibitors for O-acetylsulfhydrylase - a key enzyme involved in cysteine biosynthesis. Despite displaying nanomolar affinity, the most active representative of the series was not able to interfere with bacterial growth, likely due to poor permeability. Therefore, we rationally modified the structure of the hit compound with the aim of promoting their passage through the outer cell membrane porins. The new series was evaluated on the recombinant enzyme from Salmonella enterica serovar Typhimurium, with several compounds able to keep nanomolar binding affinity despite the extent of chemical manipulation.
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Antibacterianos/farmacología , Ácidos Carboxílicos/farmacología , Ciclopropanos/farmacología , Cisteína Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ciclopropanos/síntesis química , Ciclopropanos/química , Cisteína Sintasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Escherichia coli/efectos de los fármacos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Salmonella typhimurium/enzimología , Relación Estructura-ActividadRESUMEN
Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD.
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Glucosilceramidasa/genética , Neuronas/metabolismo , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Proteínas de Unión al GTP rab/genética , Animales , Autofagia/genética , Encéfalo/metabolismo , Encéfalo/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/patología , Glucosilceramidasa/metabolismo , Humanos , Lisosomas/genética , Lisosomas/metabolismo , Ratones , Mutación , Neuronas/patología , Enfermedad de Parkinson/patología , Proteínas de Unión a GTP rab7RESUMEN
OBJECTIVES: Perianal Crohn's disease (CD) prevalence varies according to the disease location, being particularly frequent in patients with colonic involvement. We aimed to evaluate small bowel involvement and compare small bowel capsule endoscopy findings and inflammatory activity between patients with and without perianal disease. MATERIALS AND METHODS: Retrospective single-center study including 71 patients - all patients with perianal CD (17 patients) who performed a small bowel capsule endoscopy were included, and non-perianal CD patients were randomly selected (54 patients). Clinical and analytical variables at diagnosis were reviewed. Statistical analysis was performed with SPSS v21.0 and a two-tailed p value <.05 was defined as indicating statistical significance. RESULTS: Patients had a median age of 30 ± 16 years with 52.1% females. Perianal disease was present in 23.9%. Patients with perianal disease had significantly more relevant findings (94.1% vs 66.6%, p = .03) and erosions (70.6% vs 42.6%, p = .04), however, no differences were found between the two groups regarding ulcer, villous edema and stenosis detection. Overall, patients with perianal disease had more frequently significant small bowel inflammatory activity, defined as a Lewis Score ≥135 (94.1% vs 64.8%, p = .03), and higher Lewis scores in the first and second tertiles (450 ± 1129 vs 0 ± 169, p = .02 and 675 ± 1941 vs 0 ± 478, p = .04, respectively). No differences were found between the two groups regarding third tertile inflammatory activity assessed with the Lewis Score. CONCLUSION: Patients with perianal CD have significantly higher inflammatory activity in the small bowel, particularly in proximal small bowel segments, when compared with patients without perianal disease.