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Electromagnetic time reversal is commonly used for field imaging and focusing. This Letter builds upon the concept of the time-reversal cavity, which constitutes the main theoretical framework of time reversal theory. We study the behavior of the fields using modern methods of mathematical physics involving Colombeau generalized functions. This approach allows for a direct expression of time-reversed electric and magnetic fields in anisotropic time-reversal-invariant and nonreciprocal media. Moreover, the results hold for any arbitrary localized source and can readily be applied beyond the dipole approximation. Finally, a general result allows the prediction of the quality of focusing of the time-reversed fields as a function of the electrical permittivity and the magnetic permeability tensors in homogeneous anisotropic media, which contributes to the understanding of time reversal in complex media such as super-resolution enabling metamaterials.
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This paper presents a technique, based on the matrix pencil method (MPM), for the compression of underwater acoustic signals produced by boat engines. The compressed signal, represented by its complex resonance expansion, is intended to be sent over a low-bit-rate wireless communication channel. We demonstrate that the method can provide data compression greater than 60%, ensuring a correlation greater than 93% between the reconstructed and the original signal, at a sampling frequency of 2.2 kHz. Once the signal was reconstituted, a localization process was carried out with the time reversal method (TR) using information from four different sensors in a simulation environment. This process sought to achieve the identification of the position of the ship using only passive sensors, considering two different sensor arrangements.
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Time-domain solutions of Maxwell's equations in homogeneous and isotropic media are paramount to studying transient or broadband phenomena. However, analytical solutions are generally unavailable for practical applications, while numerical solutions are computationally intensive and require significant memory. Semi-analytical solutions (e.g., series expansion), such as those provided by the current theoretical framework of the multipole expansion, can be discouraging for practical case studies. This paper shows how sophisticated mathematical tools standard in modern physics can be leveraged to find semi-analytical solutions for arbitrary localized time-varying current distributions thanks to the novel time-domain Cartesian multipole expansion. We present the theory, apply it to a concrete application involving the imaging of an intricate current distribution, verify our results with an existing analytical approach, and compare the proposed method to a finite-difference time-domain numerical simulation. Thanks to the concept of current "pixels" introduced in this paper, we derive time-domain semi-analytical solutions of Maxwell's equations for arbitrary planar geometries.
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The increasing presence of cyanotoxin producers in several regions of the world is hazardous for humans and animals. Cylindrospermopsin (CYN) is nowadays recognized as a widely distributed freshwater cyanobacterial toxin. This toxin has been shown to induce protein synthesis inhibition as well as inhibition of glutathione synthesis. Given that the liver seems to be the main target of cylindrospermopsin, in this work we used cultures of primary rat hepatocytes to study the type of cell death induced by CYN nanomolar concentrations. The involvement of reactive oxygen species in toxin induced cell death, the relationship between protein synthesis inhibition and toxicity, and the cell endogenous antioxidant response regulation were studied. We show that cylindrospermopsin induces apoptosis in primary rat hepatocytes. At the concentrations used in this work, protein synthesis inhibition and oxidative stress were involved in the cytotoxic effect elicited by the toxin. Finally, activation of the cell antioxidant response was observed at the transcriptional and translational levels.
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Apoptosis/efectos de los fármacos , Toxinas Bacterianas/toxicidad , Hepatocitos/efectos de los fármacos , Toxinas Marinas/toxicidad , Microcistinas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Uracilo/análogos & derivados , Alcaloides , Animales , Antioxidantes/metabolismo , Células Cultivadas , Cianobacterias/química , Toxinas de Cianobacterias , Hepatocitos/citología , Hepatocitos/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Uracilo/toxicidadRESUMEN
In this paper, we show the effect of crambescidin-816, -800, and -830 on Saccharomyces cerevisiae viability. We determined that, of the three molecules tested, crambescidin-816 was the most potent. Based on this result, we continued by determining the effect of crambescidin-816 on the cell cycle of this yeast. The compound induced cell cycle arrest in G2/M followed by an increase in cell DNA content and size. When the type of cell death was analyzed, we observed that crambescidin-816 induced apoptosis. The antifungal effect indicates that crambescidins, and mostly crambescidin-816, could serve as a lead compound to fight fungal infections.
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Alcaloides/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Fungicidas Industriales/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Compuestos de Espiro/farmacología , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Fase G2/efectos de los fármacos , Guanidina/análogos & derivados , Guanidina/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Polysorbates (PS) are widely used as oil-in-water emulsifiers, stabilizers, wetting agents, solubilizers, and dispersants in the agricultural, food, personal care, and pharmaceutical industries due to their cost effectiveness, biocompatibility, formulation flexibility, low toxicity, and good stabilizing and protecting properties. The polysorbates are often pictured as polyoxyethylated sorbitan monoesters of saturated and/or unsaturated fatty acids. In reality, polysorbates are complex mixtures of multiple components, as follows from the reactions involved in their production. In this work, we report a novel application of liquid chromatography-mass spectrometry (LC-MS) for the characterization of polysorbates. This method takes advantage of accurate mass measurements and information on the identity of a fatty acid from "in-source" generated characteristic dioxolanylium ions. The method allowed us to perform quick profiling of fatty acids in PS 20 and 80 which, combined with a computer-aided peak assignment algorithm, facilitated detailed characterization of their constituents. As a major finding, we determined that different samples of PS 20 varied from 0% to 15% in relative amounts of unsaturated oleic acid. Although the consequences of this difference were not fully evaluated in this work, one might expect that PS 20 with larger amounts of oleic acid will be more prone to autoxidation, thus potentially having greater impact on the oxidative degradation of the biotherapeutics it formulates.
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Cromatografía Líquida de Alta Presión/métodos , Polisorbatos/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Ácidos Grasos/química , Ácido Oléico/química , Procesamiento de Señales Asistido por ComputadorRESUMEN
PURPOSE: Thoracic central venous obstruction is a common clinical complication in dialysis patients utilizing hemodialysis catheters. Thoracic central venous obstruction can lead to inability to utilize affected veins for catheter placement and sequential use of less preferred alternative venous access sites. The latter can affect the ability to create and/or mature permanent arteriovenous access and contribute to the future loss of thoracic veins for venous access. While alternative procedures exist for gaining venous access in patients who have exhausted routine venous access options, these procedures are complex, time-consuming, and associated with high patient risk. The Surfacer System provides a new approach in patients with right-sided thoracic central venous obstruction, enabling the ability to establish repeated access from the right side of the neck to the right atrium. METHODS: We describe the use of the Surfacer System to facilitate placement of hemodialysis catheters in a series of nine patients with thoracic central venous obstruction involving one or more central veins. Patient characteristics and procedure-related outcomes were recorded for all patients. RESULTS: Central venous access was successfully achieved in eight of nine patients using the Surfacer System. Significant venous tortuosity resulted in the inability to achieve venous access in one patient and prolonged procedural time to achieve access in another patient. The mean time required for Surfacer-related procedural steps and associated fluoroscopy time in the remaining seven patients was 13.3 and 3.7 min, respectively. CONCLUSION: The Surfacer System provides an efficient low-complexity alternative for gaining repeated right-sided central venous access in hemodialysis patients with obstructed thoracic veins.
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Cateterismo Venoso Central/instrumentación , Catéteres de Permanencia , Catéteres Venosos Centrales , Diálisis Renal , Tórax/irrigación sanguínea , Enfermedades Vasculares/fisiopatología , Venas/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Cateterismo Venoso Central/efectos adversos , Constricción Patológica , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía Intervencional , Diálisis Renal/efectos adversos , Resultado del Tratamiento , Enfermedades Vasculares/diagnóstico por imagen , Venas/diagnóstico por imagen , Adulto JovenRESUMEN
Oxidative stress is recognized as an important factor in the development of liver pathologies. The reactive oxygen species endogenously generated or as a consequence of xenobiotic metabolism are eliminated by enzymatic and nonenzymatic cellular systems. Besides endogen defences, the antioxidant consumption in the diet has an important role in the protection against the development of diseases product of oxidative damage. Resveratrol is a naturally occurring compound which is part of the human diet. This molecule has been shown to have many biological properties, including antioxidant activity. We decided to test if resveratrol could protect primary hepatocytes in culture from oxidative stress damage and if so, to determine if this compound affects the cellular detoxifying systems and their regulation through the Nrf2 transcription factor that regulates the expression of antioxidant and phase II detoxifying enzymes. Cell death by necrosis was detected by measuring the activity of lactate dehydrogenase liberated to the medium. The activities of antioxidant and phase II enzymes were measured using previously described methods. Activation of the Nrf2 transcription factor was studied by confocal microscopy and the Nrf2 and its coding mRNA levels were determined by western blot and quantitative PCR respectively. Resveratrol pre-treatment effectively protected hepatocytes in culture exposed to oxidative stress, increasing the activities of catalase, superoxide dismutase, glutathione peroxidase, NADPH quinone oxidoreductase and glutathione-S-transferase. Resveratrol increases the level of Nrf2 and induces its translocation to the nucleus. Also, it increases the concentration of the coding mRNA for Nrf2. In this work we show that resveratrol could be a useful drug for the protection of liver cells from oxidative stress induced damage.
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Antioxidantes/farmacología , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estilbenos/farmacología , Animales , Antioxidantes/metabolismo , Western Blotting , Células Cultivadas , Enzimas/efectos de los fármacos , Enzimas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Necrosis/etiología , Reacción en Cadena de la Polimerasa , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , ResveratrolRESUMEN
AIMS: The blood pressure-lowering effect of percutaneous renal denervation (RDN) is controversial. The success of RDN may be device-dependent. We sought to compare the efficacy of RDN by chemical neurolysis using alcohol (Peregrine System Infusion Catheter; Ablative Solutions, Inc., Menlo Park, CA, USA) to RDN by radiofrequency (RF) ablation with the single-electrode RF catheter (Symplicity Flex; Medtronic, Minneapolis, MN, USA) in a porcine model. METHODS AND RESULTS: This was a prospective, randomised, blinded study. Pigs were assigned to undergo bilateral RF ablation or chemical neurolysis. Primary endpoints were ablation depth and renal tissue norepinephrine (NE) concentrations at three-month follow-up. Twelve pigs underwent RF ablation (n=4) or chemical neurolysis by infusion of 0.3 mL (n=4) or 0.6 mL (n=4) alcohol. Ninety days after RF ablation and chemical neurolysis with 0.3 mL and 0.6 mL of alcohol, mean maximal tissue injury depth was 3.9±1.2 mm, 6.6±1.7 mm and 8.2±2.2 mm, respectively (p<0.001 for either dose of alcohol vs. RF ablation). Compared with historical controls, median renal tissue NE concentration reductions were 66%, 78% and 83% after RF ablation and chemical neurolysis using 0.3 mL and 0.6 mL alcohol, respectively (p=0.107 for chemical neurolysis vs. RF ablation). Mean total ablation area was significantly greater in both (0.3 mL and 0.6 mL) alcohol groups (p=0.0001 for both) than the RF ablation group (30.8±13.7 mm2, 41.6±12.4 mm2 and 11.0±7.5 mm2, respectively). CONCLUSIONS: RDN is more effective using chemical neurolysis than single-electrode RF ablation. Our findings suggest that the efficacy of RDN may be device-dependent.
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Ablación por Catéter/instrumentación , Hipertensión/cirugía , Riñón/cirugía , Arteria Renal/cirugía , Simpatectomía/instrumentación , Animales , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Ablación por Catéter/métodos , Modelos Animales , Norepinefrina/uso terapéutico , Estudios Prospectivos , Porcinos , Simpatectomía/métodosRESUMEN
OBJECTIVES: This study evaluated the first clinical use of a new endovascular approach to renal denervation, using chemical neurolysis, via periadventitial infusion of dehydrated alcohol (ethanol) to perform "perivascular" renal artery sympathetic denervation. BACKGROUND: Renal denervation remains a promising technology for the treatment of hypertension and other disorders. METHODS: A novel 3-needle delivery device (Peregrine System Infusion Catheter, Ablative Solutions, Inc., Kalamazoo, Michigan) was introduced into the renal arteries of 18 subjects with refractory hypertension. Microdoses of alcohol were infused bilaterally via the 3 needles into to the adventitial space (0.30 ml/artery, 37 arteries). Renal artery angiography was performed at the time of the procedure and at 6 months (n = 16). The primary safety endpoints were complications associated with the catheter insertion and delivery of the neurolytic agent or any major vascular access complications. The secondary performance endpoint was a reduction in office-based systolic blood pressure at 6 months compared with baseline. RESULTS: Procedural success was achieved in 100% of subjects (N = 18) and arteries (N = 37). There were no study-related adverse clinical events at follow-up. One death of a subject was recorded but determined by the investigator and an independent medical monitor to be non-study related. There were no angiographic observations of renal artery stenosis, aneurysms, or other renal artery abnormalities at 6 months (32 renal arteries). Sixteen of the 18 subjects had a 6-month follow-up. The mean office systolic blood pressure decreased from 175 ± 17 mm Hg to 151 ± 26 mm Hg (-24 mm Hg). There was an average reduction of antihypertensive medications from 3.4 (baseline) to 2.0 per subject at 6 months. CONCLUSIONS: Chemical renal denervation using the infusion of very low doses of alcohol directly into the adventitial space appears to be feasible and safe. This approach may be a promising alternative approach to perform catheter-based renal denervation. These results need to be confirmed in larger scale clinical studies.
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Presión Sanguínea , Etanol/administración & dosificación , Hipertensión/cirugía , Riñón/irrigación sanguínea , Arteria Renal/inervación , Simpatectomía/métodos , Técnicas de Ablación/efectos adversos , Técnicas de Ablación/instrumentación , Adulto , Anciano , Antihipertensivos/uso terapéutico , Catéteres , Diseño de Equipo , Etanol/efectos adversos , Estudios de Factibilidad , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Arteria Renal/diagnóstico por imagen , Simpatectomía/efectos adversos , Simpatectomía/instrumentación , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM: We used isolated hepatocytes to investigate how different concentrations of ATP in the University of Wisconsin (UW) solution affected both cellular ATP content and cell viability during the cold storage and the rewarming step. The mechanism involved in ATP transport and accumulation in hypothermia was also determined. METHODS: The cells were preserved up to 72 h in different conditions: UW solution without ATP (a-group), UW+5 mmol/L ATP (b-group), and UW+10 mmol/L ATP (c-group). The ATP content and the cell viability (LDH release) were determined during the cold storage and the rewarming step. In the groups a and c, the respiratory function of the cells at rewarming was studied. In addition, the cell volume of hepatocytes and the mechanism involved in ATP transport and accumulation were assessed. The extracellular degradation of exogenous nucleotides during transport experiments was investigated by a HPLC technique. RESULTS: After three days of cold storage a loss of cellular ATP content was observed in hepatocytes preserved either without nucleotides (a-group) or with 5 mmol/L ATP (b-group). In contrast, 10 mmol/L ATP (c-group) was able to maintain a normal ATP cellular content, with only a 6% diminution after 72 h of cold storage. The respiratory function was significantly different in hepatocytes preserved with 10 mmol/L ATP than without ATP. No significant change was detected for the three groups in cellular volume during the cold storage. We also report that the time course accumulation of (3H)-ATP by cold stored hepatocytes is a rapid process that is completed after 180 s with linear dependence on the extracellular ATP concentration (linear fitting results in a slope of 0.5624+/-0.1179 mmol/L ATP intracell/mmol/L ATP extracell). CONCLUSION: Our results show that, during hypothermic storage in UW solution, hepatocytes are permeable to ATP by a diffusive mechanism. Also, we found that it is ATP the main extracellular nucleotide available for transport and it is not the breakdown products.
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Adenosina Trifosfato/metabolismo , Adenosina/farmacología , Alopurinol/farmacología , Criopreservación , Glutatión/farmacología , Hepatocitos/citología , Hepatocitos/metabolismo , Insulina/farmacología , Soluciones Preservantes de Órganos/farmacología , Rafinosa/farmacología , Animales , Respiración de la Célula , Supervivencia Celular , Frío , Calor , Masculino , Ratas , Ratas Wistar , Tritio , Equilibrio HidroelectrolíticoRESUMEN
BACKGROUND/PURPOSE: We update the pre-clinical and early clinical results using a novel endovascular approach, to perform chemical renal denervation, via peri-adventitial injection of micro-doses of dehydrated alcohol (ethanol-EtOH). METHODS/MATERIALS: A novel, three-needle delivery device (Peregrine™) was used to denervate the renal arteries of adult swine (n = 17) and in a first-in-man feasibility study (n = 18). In the pre-clinical testing EtOH was infused bilaterally with one infusion per renal artery into to the perivascular space, using EtOH doses of 0.3 ml/artery (n = 8), and 0.6 ml/artery (n = 9), and with saline sham control (0.4 ml/artery n = 3). Renal parenchymal norepinephrine (NE) concentration (performed blindly), and safety were the primary endpoints. Data from the first-in-man study (n = 18) to evaluate device performance, safety and peri-procedural pain are reported. RESULTS: In the pre-clinical testing renal function was unchanged at 3-month follow-up. Angiography at 90 days (n = 34 arteries) demonstrated normal appearing renal arteries, unchanged from baseline, and without stenosis or other abnormalities. The reductions in mean renal parenchymal NE reductions at 3 months were 68% and 88% at doses of 0.3 and 0.6 ml, respectively (p < 0.001 vs. controls). In the first-in-man study, there was 100% device success, no complications, a mean treatment time of 4.3 ± 3 minutes/artery, and minimal or no patient discomfort during treatment. Angiography at 6-months showed no evidence of renal artery stenosis, and evidence of a reduction of blood pressure from baseline. CONCLUSION: Perivascular RDN using micro-doses of alcohol is a promising alternative to energy-based systems to achieve dose-dependent, predictable, safe and essentially painless renal denervation. Further clinical evaluation is warranted. SUMMARY: (For annotated table of contents) This paper describes the preclinical results, in a porcine model, and the early first-in-man results, using the Peregrine™ chemical renal denervation catheter to perform renal sympathetic denervation using micro-doses of alcohol.
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Etanol/farmacología , Riñón/cirugía , Obstrucción de la Arteria Renal/terapia , Arteria Renal/patología , Simpatectomía , Adulto , Animales , Presión Sanguínea/fisiología , Ablación por Catéter/instrumentación , Ablación por Catéter/métodos , Desnervación , Etanol/administración & dosificación , Humanos , Hipertensión/fisiopatología , Riñón/patología , Arteria Renal/cirugía , Obstrucción de la Arteria Renal/patología , Porcinos , Simpatectomía/instrumentación , Simpatectomía/métodosRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) is widely distributed in hospital environments, causing serious infections, mainly the bloodstream, surgical site infection and pneumonia. Vancomycin (VAN) is the antibiotic of choice for treating severe MRSA infections; however, nowadays worldwide resistant strains (VRSA), with intermediate susceptibility (VISA) and decreased susceptibility or hetero-resistance to VAN (hVISA) have been reported, related to treatment failure and increased mortality. This report describes the first confirmed isolation of MRSA with hVISA phenotype in a public hospital in Chile.
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Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/microbiología , Resistencia a la Vancomicina , Chile , Pruebas Antimicrobianas de Difusión por Disco , Femenino , Humanos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Persona de Mediana EdadRESUMEN
Harmful algal blooms caused by phytoplankton can occur in all aquatic environments. Some of the algae present in these blooms are capable of producing extremely potent toxins. Due to climate change and eutrophication, harmful algal blooms are increasing on a global scale. One kind of toxin producing algae are those that produce okadaic acid, its derivatives (dinophysistoxin-1 and 2), and microcystins. These toxins are potent inhibitors of protein phosphatase 2A, so this protein is used to detect the mentioned toxins in natural samples. Originally protein phosphatase 2A purified from animal tissues was used, but enzyme activity and stability fluctuations prevented the use of the enzyme in detection kits. Expression of the enzyme as a recombinant protein provided a solution to this problem. For this purpose, several strategies have been followed. We evaluated the activity, specificity and stability of the human protein phosphatase 2A catalytic subunit α expressed in insect larvae and showed that this expression system can be a reliable source of high quantities of stable enzyme.
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In vivo, after administration by gavage to mice and rats, okadaic acid has been reported to produce lesions in liver, small intestine and forestomach. Because several reports differ in the damage detected in different organs, and on okadaic acid distribution after consumption, we determined the toxicity of this compound after oral administration to mice. After 24 hours, histopathological examination showed necrotic foci and lipid vacuoles in the livers of intoxicated animals. By immunohistochemical analysis, we detected this toxin in the liver and kidneys of intoxicated animals. Okadaic acid induces oxidative stress and can be activated in vitro into reactive compounds by the post-mitochondrial S9 fraction, so we studied the okadaic effect on the gene expression of antioxidant and phase II detoxifying enzymes in liver. We observed a downregulation in the expression of these enzymes and a reduction of protein expression of catalase and superoxide dismutase 1 in intoxicated animals.
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Hígado/patología , Ácido Ocadaico/farmacocinética , Ácido Ocadaico/toxicidad , Estrés Oxidativo/efectos de los fármacos , Administración Oral , Animales , Antioxidantes/farmacología , Diarrea/inducido químicamente , Heces/química , Femenino , Expresión Génica , Inmunohistoquímica , Inactivación Metabólica , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Ratones , Ácido Ocadaico/sangre , Estómago/efectos de los fármacos , Estómago/patologíaRESUMEN
AIMS: We report the use of a novel endovascular approach using chemical neurolysis, via periadventitial injection of dehydrated ethanol (EtOH) to perform renal artery denervation. METHODS AND RESULTS: A novel, three-needle delivery device was introduced into the renal arteries of adult swine using fluoroscopic guidance. EtOH was injected bilaterally with one injection per artery, via the three needles into the adventitial and periadventitial space, using EtOH doses 0.15 ml/artery; n=3, 0.30 ml/artery; n=3, and 0.60 ml/artery; n=3, with saline injection as a sham control (0.4 ml/artery; n=3), and naive subjects (n=7) as a true negative control. The renal parenchymal norepinephrine (NE) concentration at two-week follow-up was the primary efficacy endpoint. The mean renal NE reduction was 54%, 78% and 88% at doses of 0.15 ml, 0.30 ml and 0.60 ml, respectively (p<0.0001 vs. controls). Histological examination revealed marked, and deep, circumferential renal nerve injury at depths of 2-8 mm from the intimal surface. There was no evidence of device-related or EtOH-induced injury to the intimal layers. In some samples at the higher EtOH doses, there was focal loss of smooth muscle cells in the outer media. Angiography at 45 days demonstrated normal appearing renal arteries with no detectable stenoses (n=8). CONCLUSIONS: Circumferential adventitial delivery of very low doses of EtOH may be a promising alternative to energy-based systems to achieve dose-dependent, and predictable renal denervation. Further study is warranted.
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Técnicas de Ablación , Procedimientos Endovasculares , Etanol/administración & dosificación , Riñón/irrigación sanguínea , Riñón/inervación , Simpatectomía Química/métodos , Animales , Relación Dosis-Respuesta a Droga , Riñón/metabolismo , Riñón/patología , Modelos Animales , Norepinefrina/metabolismo , Arteria Renal , Porcinos , Factores de TiempoRESUMEN
BACKGROUND: Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible. OBJECTIVE: Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment. METHODS: The total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma. RESULTS: Over 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3γ, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: These results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination.
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OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD). METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2(-/-)) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients. RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3ß (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3ß/γ; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls. CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.Clinical and Translational Gastroenterology (2012) 3, e10; doi:10.1038/ctg.2012.2; published online 16 February 2012.
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BACKGROUND: Embryo implantation failure is considered an important cause of infertility in women undergoing assisted reproductive protocols. Recent studies demonstrated that the cyclooxygenase-2 (COX-2) enzyme is implicated in biosynthesis of prostaglandins and play an important role in the molecular implantation mechanisms. According to this evidence, we evaluated the potential association between the -765G>C (rs20417) polymorphism at the COX-2 gene and the implantation failure susceptibility in a sample of Chilean women. METHODS: A total of 186 unrelated women matched by age were included in the present study, 106 patients (aged 31.9±4.17 y) with no history of successful pregnancy and a diagnosis of infertility undergoing assisted reproductive protocols and 80 healthy controls (aged 31.4 ± 4.05 y). The COX-2 -765G>C gene polymorphism was analyzed by PCR-RFLP. RESULTS: Genotype distribution and allelic frequencies for -765G>C polymorphism of COX-2 gene were significantly different between patients and controls (P=0.004 and P=0.002, respectively). The odds ratio for implantation failure associated to the -765C allelic variant was 2.14 (95% C.I., 1.35-3.39, P=0.00071). CONCLUSION: Our data suggest, by the first time, that the COX-2 -765G>C polymorphism is associated with recurrent implantation failure in Chilean women and may constituted a novel molecular biomarker of reproductive failure.