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Hepatic encephalopathy (HE) is a neurological condition linked to liver failure. Acute HE (Type A) occurs with acute liver failure, while chronic HE (Type C) is tied to cirrhosis and portal hypertension. HE treatments lag due to gaps in understanding its development by gender and age. We studied how sex and age impact HE and its severity with combined liver toxins. Our findings indicate that drug-induced (thioacetamide, TAA) brain edema was more severe in aged males than in young males or young/aged female rats. However, adding alcohol (ethanol, EtOH) worsens TAA's brain edema in both young and aged females, with females experiencing a more severe effect than males. These patterns also apply to Type A HE induced by azoxymethane (AZO) in mice. Similarly, TAA-induced behavioral deficits in Type C HE were milder in young and aged females than in males. Conversely, EtOH and TAA in young/aged males led to severe brain edema and fatality without noticeable behavioral changes. TAA metabolism was slower in aged males than in young or middle-aged rats. When TAA-treated aged male rats received EtOH, there was a slow and sustained plasma level of thioacetamide sulfoxide (TASO). This suggests that with EtOH, TAA-induced HE is more severe in aged males. TAA metabolism was similar in young, middle-aged, and aged female rats. However, with EtOH, young and aged females experience more severe drug-induced HE as compared to middle-aged adult rats. These findings strongly suggest that gender and age play a role in the severity of HE development and that the presence of one or more liver toxins may aggravate the severity of the disease progression.
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Panoramic images are one of the most requested exams by dentists for allowing the visualization of the entire mouth. Interpreting X-ray images is a time-consuming task in which misdiagnoses can occur due to the inexperience or fatigue of professionals. In this work, we applied different image enhancement techniques as a pre-processing step to determine which image features correlate with improvements in teeth detection in panoramic images using deep learning architectures. We contrasted the performance of five object-detection architectures using 300 panoramic images of a public dataset. We evaluated the enhancement in the pre-processing step and the detection performance. Quality and detection metrics were considered, and the cross-correlation between them was computed for every object-detection method contemplated. We observe the dependence of the detection performance with some image enhancement techniques, especially those that introduce less noise and preserve the global contrast of the image.
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Aprendizaje Profundo , Diente , Benchmarking , Radiografía Panorámica , Rayos XRESUMEN
PURPOSE: To evaluate the repeatability and reproducibility of the segmentation of 12 layers of the retina and the choroid, performed manually by SD-OCT, along the horizontal meridian at three different temporal moments, and to evaluate its concordance with the same measurements performed by two other operators in intermediate AMD. METHODS: A cross-sectional study of 40 eyes from 40 subjects with intermediate AMD was conducted. The segmentation was performed manually, using SD-OCT. The 169 measurements per eye were repeated at three time points to study the intra-operator variability. The same process was repeated a single time by two different trained operators for the inter-operator variability. RESULTS: Forty participants (28 women and 12 men) were enrolled in this study, with an average age of 76.4 ± 8.2 (range, 55-92 years). Overall, the maximum values of the various structures were found in the 3 mm of the macula. Intra-operator variability: the highest ICC values turned out to be discovered in thicker locations. Inter-operator variability: except correlation values of 0.826 (0.727; 0.898) obtained in the OPL (T2.5) and 0.634 (0.469; 0.771) obtained in the IPL (N2), all other correlation values were > 0.92, in most cases approaching higher values like 0.98. CONCLUSION: The measurements of several layers of the retina and the choroid achieved at 13 locations presented a good repeatability and reproducibility. Manual quantification is still an alternative for the weaknesses of automatic segmentation. Locations of greatest concordance should be those used for the clinical control and monitoring.
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The organophosphate, diisopropyl fluorophosphate (DFP), may impair cardiovascular, autonomic and immune function while exercise training is thougt to be restorative. Experiments determined effects of wheel exercise in C57B1 male mice, testing cardiovascular and autonomic function and characterization of the immunological profile. Sedentary (S) and exercise (ET) groups were treated with corticosterone (CORT) followed by injection of DFP. This model was associated with systolic and diastolic dysfunction in the S group, measured using echocardiography (ECHO). Chronic exercise ameliorated the cardiac deficit. Autonomic balance, accessed by heart rate variability (HRV), showed increased sympathetic and decreased parasympathetic modulation in S group. Autonomic balance in ET mice was not affected by DFP. Our DFP model resulted in mild neuroinflammation seen by increased IL5, IL12 and MIP2 in brain and plasma IL6 and IL1a. DFP had a negative impact on cardiac/autonomic function and inflammatory markers, effects reduced by exercise. Data suggest a beneficial effect of exercise training on the cardiovascular and autonomic responses to DFP/CORT.
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AIM: We studied externally controlled anticancer effects of binding tumor growth inhibiting synthetic peptides to magnetoelectric nanoparticles (MENs) on treatment of glioblastomas. METHODS: Hydrothermally synthesized 30-nm MENs had the core-shell composition of CoFe2O4@BaTiO3. Molecules of growth hormone-releasing hormone antagonist of the MIA class (MIA690) were chemically bound to MENs. In vitro experiments utilized human glioblastoma cells (U-87MG) and human brain microvascular endothelial cells. RESULTS: The studies demonstrated externally controlled high-efficacy binding of MIA690 to MENs, targeted specificity to glioblastoma cells and on-demand release of the peptide by application of d.c. and a.c. magnetic fields, respectively. CONCLUSION: The results support the use of MENs as an effective drug delivery carrier for growth hormone-releasing hormone antagonists in the treatment of human glioblastomas.
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Antineoplásicos/química , Neoplasias Encefálicas/tratamiento farmacológico , Portadores de Fármacos/química , Glioblastoma/tratamiento farmacológico , Hormona del Crecimiento/antagonistas & inhibidores , Nanopartículas de Magnetita/química , Péptidos/química , Antineoplásicos/administración & dosificación , Compuestos de Bario/química , Encéfalo/irrigación sanguínea , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cobalto/química , Liberación de Fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Compuestos Férricos/química , Hormona del Crecimiento/metabolismo , Antagonistas de Hormonas/uso terapéutico , Humanos , Campos Magnéticos , Microvasos/citología , Nanosferas/química , Tamaño de la Partícula , Péptidos/administración & dosificación , Titanio/químicaRESUMEN
The synthesis of analogues of hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) is an efficient strategy for designing new therapeutic agents. Several promising synthetic agonist and antagonist analogues of GHRH have been developed based on amino acid mutations of the GHRH (1-29) sequence. Because structural information on the activity of the GHRH agonists or antagonists is limited, there is a need for more effective analytical workflows capable of correlating the peptide sequence with biological activity. In the present work, three GHRH agonists-MR-356, MR-406, and MR-409-and three GHRH antagonists-MIA-602, MIA-606, and MIA-690-were investigated to assess the role of substitutions in the amino acid sequence on structural motifs and receptor binding affinities. The use of high resolution trapped ion mobility spectrometry coupled to mass spectrometry allowed the observation of a large number of peptide-specific mobility bands (or structural motif descriptors) as a function of the amino acid sequence and the starting solution environment. A direct correlation was observed between the amino acid substitutions (i.e., basic residues and d/l-amino acids), the structural motif descriptors, and the biological function (i.e., receptor binding affinities of the GHRH agonists and antagonists). The simplicity, ease, and high throughput of the proposed workflow based on the structural motif descriptors can significantly reduce the cost and time during screening of new synthetic peptide analogues.
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The etiology of benign prostatic hyperplasia (BPH) is multifactorial, and chronic inflammation plays a pivotal role in its pathogenesis. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that has been shown to act as paracrine/autocrine factor in various malignancies including prostate cancer. GHRH and its receptors are expressed in experimental models of BPH, in which antagonists of GHRH suppressed the levels of proinflammatory cytokines and altered the expression of genes related to epithelial-to-mesenchymal transition (EMT). We investigated the effects of GHRH antagonist on prostatic enlargement induced by inflammation. Autoimmune prostatitis in Balb/C mice was induced by a homogenate of reproductive tissues of male rats. During the 8-wk induction of chronic prostatitis, we detected a progressive increase in prostatic volume reaching 92% at week 8 compared with control (P < 0.001). Daily treatment for 1 mo with GHRH antagonist MIA-690 caused a 30% reduction in prostate volume (P < 0.05). Conditioned medium derived from macrophages increased the average volume of spheres by 82.7% (P < 0.001) and elevated the expression of mRNA for N-cadherin, Snail, and GHRH GHRH antagonist reduced the average volume of spheres stimulated by inflammation by 75.5% (P < 0.05), and TGF-ß2 by 91.8% (P < 0.01). The proliferation of primary epithelial cells stimulated by IL-17A or TGF-ß2 was also inhibited by 124.1% and 69.9%, respectively. GHRH stimulated the growth of BPH-1 and primary prostate spheres. This study provides evidence that GHRH plays important roles in prostatic inflammation and EMT and suggests the merit of further investigation to elucidate the effects of GHRH antagonists in prostatitis and BPH.
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Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Hormona Liberadora de Hormona del Crecimiento/análogos & derivados , Hormona Liberadora de Hormona del Crecimiento/antagonistas & inhibidores , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Proliferación Celular/genética , Células Cultivadas , Células Epiteliales/metabolismo , Expresión Génica/efectos de los fármacos , Hormona Liberadora de Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hormona Liberadora de Hormona del Crecimiento/farmacología , Humanos , Masculino , Ratones Endogámicos BALB C , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Prostatitis/genética , Prostatitis/metabolismo , Prostatitis/patología , Ratas , Factor de Crecimiento Transformador beta2/farmacologíaRESUMEN
The chemokine stromal cell-derived factor-1 (SDF-1) plays a critical role in mobilizing precursor cells in the bone marrow and is essential for efficient vascular regeneration and repair. We recently reported that calcium augments the expression of chemokine receptor CXCR4 and enhances the angiogenic potential of bone marrow derived cells (BMCs). Neovascularization is impaired by aging therefore we suggested that aging may cause defects of CXCR4 expression and cellular responses to calcium. Indeed we found that both the basal and calcium-induced surface expression of CXCR4 on BMCs was significantly reduced in 25-month-old mice compared with 2-month-old mice. Reduced Ca-induced CXCR4 expression in BMC from aged mice was associated with defective calcium influx. Diminished CXCR4 surface expression in BMC from aged mice correlated with diminished neovascularization in an ischemic hindlimb model with less accumulation of CD34(+) progenitor cells in the ischemic muscle with or without local overexpression of SDF-1. Intravenous injection of BMCs from old mice homed less efficiently to ischemic muscle and stimulated significantly less neovascularization compared with the BMCs from young mice. Transplantation of old BMCs into young mice did not reconstitute CXCR4 functions suggesting that the defects were not reversible by changing the environment. We conclude that defects of basal and calcium-regulated functions of the CXCR4/SDF-1 axis in BMCs contribute significantly to the age-related loss of vasculogenic responses.