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OBJECTIVE: To review evidence for dosing antihypertensives at bedtime and possible cardiovascular risk reduction. DATA SOURCES: A PubMed, EMBASE, and Cochrane Controlled Trials database literature search (1990-September 2014) limited to human subjects was performed using the search terms hypertension, chronotherapy, ambulatory blood pressure, morning administration, evening administration, and antihypertensives. Additional references were identified from literature citations. STUDY SELECTION: All prospective studies assessing cardiovascular outcomes or comparing morning to evening administration of antihypertensives were selected. DATA SYNTHESIS: Compared with morning administration, dosing one or more antihypertensive medications at bedtime helps induce a normal circadian blood pressure pattern and reduces the risk of cardiovascular disease morbidity and mortality in individuals with hypertension. Similar results have been reported in high-risk individuals with diabetes, chronic kidney disease, and resistant hypertension. A lack of diversity among studied populations and reliance on subgroup analyses are among the limitations of these data. All antihypertensive medications have not been studied in chronotherapy and do not uniformly achieve desired results. The most substantial evidence exists for medications affecting the renin-angiotensin-aldosterone system. CONCLUSIONS: Despite growing evidence and promise as a cost-effective strategy for reducing cardiovascular risk, chronotherapy is not uniformly recommended in the treatment of hypertension. Careful selection of patients and antihypertensives for chronotherapy is required. Further investigation is needed to evaluate the definitive impact of chronotherapy on cardiovascular outcomes.
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Antihipertensivos/uso terapéutico , Cronoterapia , Hipertensión/tratamiento farmacológico , Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Monitoreo Ambulatorio de la Presión Arterial , Enfermedades Cardiovasculares/tratamiento farmacológico , Esquema de Medicación , Humanos , Estudios Prospectivos , Insuficiencia Renal Crónica/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Factores de RiesgoRESUMEN
Marshes in the urban Jamaica Bay Estuary, New York, USA are disappearing at an average rate of 13 ha/yr, and multiple stressors (e.g., wastewater inputs, dredging activities, groundwater removal, and global warming) may be contributing to marsh losses. Among these stressors, wastewater nutrients are suspected to be an important contributing cause of marsh deterioration. We used census data, radiometric dating, stable nitrogen isotopes, and soil surveys to examine the temporal relationships between human population growth and soil nitrogen; and we evaluated soil structure with computer-aided tomography, surface elevation and sediment accretion trends, carbon dioxide emissions, and soil shear strength to examine differences among disappearing (Black Bank and Big Egg) and stable marshes (JoCo). Radiometric dating and nitrogen isotope analyses suggested a rapid increase in human wastewater nutrients beginning in the late 1840s, and a tapering off beginning in the 1930s when wastewater treatment plants (WWTPs) were first installed. Current WWTPs nutrient loads to Jamaica Bay are approximately 13 995 kg N/d and 2767 kg P/d. At Black Bank, the biomass and abundance of roots and rhizomes and percentage of organic matter on soil were significantly lower, rhizomes larger in diameter, carbon dioxide emission rates and peat particle density significantly greater, and soil strength significantly lower compared to the stable JoCo Marsh, suggesting Black Bank has elevated decomposition rates, more decomposed peat, and highly waterlogged peat. Despite these differences, the rates of accretion and surface elevation change were similar for both marshes, and the rates of elevation change approximated the long-term relative rate of sea level rise estimated from tide gauge data at nearby Sandy Hook, New Jersey. We hypothesize that Black Bank marsh kept pace with sea level rise by the accretion of material on the marsh surface, and the maintenance of soil volume through production of larger diameter rhizomes and swelling (dilation) of waterlogged peat. JoCo Marsh kept pace with sea-level rise through surface accretion and soil organic matter accumulation. Understanding the effects of multiple stressors, including nutrient enrichment, on soil structure, organic matter accumulation, and elevation change will better inform management decisions aimed at maintaining and restoring coastal marshes.
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Conservación de los Recursos Naturales , Estuarios , Nitrógeno/química , Suelo/química , Animales , Ciudades , New York , Poaceae/crecimiento & desarrolloRESUMEN
The COVID-19 pandemic has affected how clinical trials are managed, both within existing portfolios and for the rapidly developed COVID-19 trials. Sponsors or delegated organisations responsible for monitoring trials have needed to consider and implement alternative ways of working due to the national infection risk necessitating restricted movement of staff and public, reduced clinical staff resource as research staff moved to clinical areas, and amended working arrangements for sponsor and sponsor delegates as staff moved to working from home.Organisations have often worked in isolation to fast track mitigations required for the conduct of clinical trials during the pandemic; this paper describes many of the learnings from a group of monitoring leads based in United Kingdom Clinical Research Collaboration (UKCRC) Clinical Trials Unit (CTUs) within the UK.The UKCRC Monitoring Task and Finish Group, comprising monitoring leads from 9 CTUs, met repeatedly to identify how COVID-19 had affected clinical trial monitoring. Informed consent is included as a specific issue within this paper, as review of completed consent documentation is often required within trial monitoring plans (TMPs). Monitoring is defined as involving on-site monitoring, central monitoring or/and remote monitoring.Monitoring, required to protect the safety of the patients and the integrity of the trial and ensure the protocol is followed, is often best done by a combination of central, remote and on-site monitoring. However, if on-site monitoring is not possible, workable solutions can be found using only central or central and remote monitoring. eConsent, consent by a third person, or via remote means is plausible. Minimising datasets to the critical data reduces workload for sites and CTU staff. Home working caused by COVID-19 has made electronic trial master files (TMFs) more inviting. Allowing sites to book and attend protocol training at a time convenient to them has been successful and worth pursuing for trials with many sites in the future.The arrival of COVID-19 in the UK has forced consideration of and changes to how clinical trials are conducted in relation to monitoring. Some developed practices will be useful in other pandemics and others should be incorporated into regular use.
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COVID-19 , Ensayos Clínicos como Asunto , Consentimiento Informado , Humanos , Pandemias , Reino UnidoRESUMEN
TNF-alpha is a pleitropic cytokine that expresses both pro- and anti-inflammatory activity and transgenic mice expressing human tumor necrosis factor-alpha (TNF-alpha) exhibit a progressive polyarthritis that models rheumatoid arthritis (RA). One of the common comorbidities of RA is anemia of chronic disease (ACD). The purpose of these experiments was to study the changes in the bone marrow and peripheral blood that accompany polyarthritis in TNF-alpha transgenic mice in an effort to better understand the pathogenesis of myelodysplasia and ACD. Polychromatic cytometry, hematology and serum cytokine analysis were used to study the pathogenesis of ACD in human TNF-alpha transgenic mice. Our hematological evaluation revealed a mild, compensated, microcytic hypochromic anemia, and monocytosis. In the bone marrow, we observed alterations in cell kinetics, decreased relative expression of transferrin receptor and increased apoptosis and cell death in several late precursor cell populations. Although significant levels of human TNF-alpha were found in the serum, neither change in serum murine erythropoietin nor any significant difference observed in serum levels of murine IL-beta, IL-5, IL-6, IL-10, IL-12(p70), IL-17, TNF-alpha, IFNgamma, GM-CSF, MIP-1alphaJE, MCP-5 was observed. Tg197 mice develop a compensated, microcytic, hypochromic anemia, and a functional iron deficiency by 9 weeks of age. Changes in peripheral blood are reflected in alterations in cell kinetics, transferrin receptor expression and markedly increased apoptosis and cell death in the bone marrow indicating that TNF-alpha may contribute to myelodysplasia in ACD. Moreover, since human TNF-alpha can interact only with murine TNFR1, our data suggest that TNFR1 may play an important role in the development of ACD.
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Anemia Hipocrómica/patología , Artritis/patología , Citocinas/sangre , Síndromes Mielodisplásicos/patología , Factor de Necrosis Tumoral alfa/fisiología , Anemia Hipocrómica/metabolismo , Animales , Apoptosis/fisiología , Artritis/metabolismo , Médula Ósea/metabolismo , Muerte Celular/fisiología , Enfermedad Crónica , Humanos , Cápsula Articular/metabolismo , Cápsula Articular/patología , Ratones , Ratones Transgénicos , Síndromes Mielodisplásicos/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) is a cell surface glycoprotein overexpressed in many solid tumors. In addition to its ability to stimulate stromal MMP expression, tumor-associated EMMPRIN also induces vascular endothelial growth factor (VEGF) expression. To explore the underlying signaling pathways used by EMMPRIN, we studied the involvement of phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), JUN, and p38 kinases in EMMPRIN-mediated VEGF regulation. Overexpression of EMMPRIN in MDA-MB-231 breast cancer cells stimulated the phosphorylation of only Akt and MAPKs but not that of JUN and p38 kinases. Conversely, inhibition of EMMPRIN expression resulted in suppressed Akt and MAPK phosphorylation. Furthermore, the PI3K-specific inhibitor LY294002 inhibited VEGF production by EMMPRIN-overexpressing cells in a dose- and time-dependent manner. On the other hand, the MAPK inhibitor U0126 did not affect VEGF production. In vivo, EMMPRIN-overexpressing tumors with elevated VEGF expression had a high level of phosphorylation of Akt and MAPK. Finally, when fibroblast cells were treated with recombinant EMMPRIN, Akt kinase but not MAPK was phosphorylated concomitant with an increase in VEGF production. Both the activation of Akt kinase and the induction of VEGF were specifically inhibited with a neutralizing antibody to EMMPRIN. Our results show that in both tumor and fibroblast cells EMMPRIN regulates VEGF production via the PI3K-Akt pathway but not via the MAPK, JUN, or p38 kinase pathways.
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Basigina/metabolismo , Proteína Oncogénica v-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Basigina/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Fibroblastos/metabolismo , Humanos , Metaloproteinasas de la Matriz , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Trasplante de Neoplasias , Neoplasias/metabolismo , Neovascularización Patológica , Fosforilación , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Recombinantes/farmacología , Trasplante Heterólogo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by overexpressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.
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Antígenos CD/fisiología , Neoplasias de la Mama/irrigación sanguínea , Metaloproteinasa 2 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/biosíntesis , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Animales , Antígenos CD/biosíntesis , Antígenos CD/genética , Basigina , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Técnicas de Cocultivo , Células Endoteliales/citología , Femenino , Fibroblastos/citología , Humanos , Ratones , Ratones Desnudos , Neovascularización Patológica/enzimología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Trasplante Heterólogo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
An important component of safety assessment of new pharmaceuticals is evaluation of their potential to increase the risk of developing cancer in humans. The traditional 2-year rodent bioassay often is not feasible or scientifically applicable for evaluation of biotherapeutics. Additionally, it has poor predictive value for non-genotoxic immunosuppressive compounds. Thus, there is a need for alternative testing strategies. A novel 3-stage tumor model in syngeneic C3H/HeN mice was evaluated here to study the effects of immunosuppressive drugs on tumor promotion and progression in vivo. The model employed a skin squamous cell carcinoma cell line (SCC VII) due to the increased prevalence of squamous cell carcinoma (SCC) in humans associated with immunosuppression after transplants. Local invasion, colonization and tumor progression were evaluated. The validation set of immunosuppressive drugs included: Cyclosporin (CSA), cyclophosphamide (CTX), azathioprine, etanercept, abatacept and prednisone. Local invasion was evaluated by histological assessment as well as fluorescence trafficking from Qdot(®)-labeled tumor cells from the site of inoculation to the draining lymph node. Colonization was evaluated by lung colony counts following intravenous inoculation. Tumor progression was assessed by morphometric analysis of lesion area, angiogenesis and growth fraction of established metastatic neoplasia. Immunosuppressive drugs in the validation set yielded mixed results, including decreased progression. The methods and results described herein using an in vivo syngeneic mouse tumor model can provide insight about the assessment of immunosuppressive drugs in carcinogenicity risk assessment.
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Antineoplásicos/farmacología , Carcinoma de Células Escamosas , Neoplasias Experimentales , Neoplasias Cutáneas , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patologíaRESUMEN
Many immunosuppressive drugs are associated with an increased risk of neoplasia, principally non-melanoma skin cancers and B-cell lymphomas. However, only 6 of the 13 immunosuppressive drugs tested in 2 year bioassays increased the incidence of neoplasia. For example, the 2-year bioassays conducted with cyclosporine (CSA), an International Agency for Research on Cancer (IARC) Group 1 human carcinogen, were negative. The purpose of these investigations was to use transplanted tumor models in immunocompetent, syngeneic mice to gain insight into the failure of the 2-year bioassay to show an increased incidence of neoplasia with CSA. C3H HeN mice were used in a battery of assays with a transplanted squamous cell carcinoma (SCC VII cells) or a B-cell, lymphoma (38C13 cells) cells to study effects of CSA on local growth and metastases, experimental metastases, and progression of established metastases. Mice received CSA twice weekly by subcutaneous (SC) injection at doses of 0.5, 5, or 50 mg/kg; controls received the CSA vehicle. CSA had a modest inhibitory effect on SC tumors initiated by 38C13 cells and on intramuscular tumors initiated by SCC VII cells. CSA also decreased the number of lung colonies and decreased the size, growth fraction and vascularity of established lung metastases initiated by SCC VII cells. In contrast, CSA increased progressive growth of metastases to the sentinel lymph node from an intramuscular SCC VII tumor, but had no effect cellular traffic to the node. In conclusion, CSA at doses up to 50 mg/kg did not facilitate tumor progression and it partially inhibited tumor growth, suggesting that suppression of tumor progression may partially explain the failure of CSA to act as a carcinogen in 2 year bioassays.
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Carcinoma de Células Escamosas/secundario , Ciclosporina/toxicidad , Inmunosupresores/toxicidad , Neoplasias Pulmonares/secundario , Linfoma de Células B/patología , Neoplasias de los Músculos/patología , Animales , Pruebas de Carcinogenicidad , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/prevención & control , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclosporina/administración & dosificación , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Inmunosupresores/administración & dosificación , Inyecciones Subcutáneas , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/prevención & control , Metástasis Linfática , Linfoma de Células B/inmunología , Linfoma de Células B/prevención & control , Ratones , Ratones Endogámicos C3H , Neoplasias de los Músculos/inmunología , Neoplasias de los Músculos/prevención & control , Invasividad Neoplásica , Medición de Riesgo , Factores de Tiempo , Carga Tumoral/efectos de los fármacosRESUMEN
OBJECTIVE: Emerging evidence suggests a link between innate immunity and development of type 2 diabetes mellitus (T2D); however, the molecular mechanisms linking them are not fully understood. Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that recognizes the double-stranded RNA of microbial or mammalian origin and contributes to immune responses in the context of infections and chronic inflammation. The objective of this study was to determine whether TLR3 activity impacts insulin sensitivity and lipid metabolism. MATERIALS AND METHODS: Wild type (WT) and TLR3 knock-out (TLR3(-/-)) mice were fed a high fat diet (HFD) and submitted to glucose tolerance tests (GTTs) over a period of 33 weeks. In another study, the same group of mice was treated with a neutralizing monoclonal antibody (mAb) against mouse TLR3. RESULTS: TLR3(-/-) mice fed an HFD developed obesity, although they exhibited improved glucose tolerance and lipid profiles compared with WT obese mice. In addition, the increase in liver weight and lipid content normally observed in WT mice on an HFD was significantly ameliorated in TLR3(-/-) mice. These changes were accompanied by up-regulation of genes involved in cholesterol efflux such as PPARδ, LXRα, and LXRα-targeting genes and down-regulation of pro-inflammatory cytokine and chemokine genes in obese TLR3(-/-) mice. Furthermore, global gene expression profiling in liver demonstrated TLR3-specific changes in both lipid biosynthesis and innate immune response pathways. CONCLUSIONS: TLR3 affects glucose and lipid metabolism as well as inflammatory mediators, and findings in this study reveal a new role for TLR3 in metabolic homeostasis. This suggests antagonizing TLR3 may be a beneficial therapeutic approach for the treatment of metabolic diseases.
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Hígado Graso/fisiopatología , Prueba de Tolerancia a la Glucosa , Obesidad/fisiopatología , Receptor Toll-Like 3/fisiología , Animales , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Toll-Like 3/genéticaRESUMEN
INTRODUCTION: Immunosuppressive drugs are associated with an increased risk of infections and in some cases neoplasia, particularly non-melanoma skin cancers. This paper describes the development of a model to test the effects of immunosuppressive drugs on local invasion and metastases of a squamous cell carcinoma in syngeneic, immunocompetent mice. METHODS: SCC VII cells were labeled with 655 quantum dots (QDs), injected intramuscularly into C3H HEN mice and traffic and progressive growth in the draining popliteal lymph node were evaluated. RESULTS: SCC VII cells express RAE-1, an NKG2D ligand, and were sensitive to natural killer (NK) cells in vitro. QDs were stable in SCC VII cells and showed no evidence of toxicity to the cells. In vivo, confocal microscopy showed that QD-labeled SCC VII cells could migrate to the draining node and microfluorimetry showed progressive traffic of QDs to the node. There was no evidence of systemic toxicity of QDs. Primary immunosuppression in SCID and SCID-beige mice and treatment of normal mice with immunosuppressive agents (anti-asialoGM1 and cyclophosphamide) can enhance traffic of QDs and/or metastases to the draining lymph node. In contrast, cyclosporine had no effect on traffic or metastases. CONCLUSION: This model of local invasion and metastases may be useful in immunotoxicology for identifying and characterizing the hazard posed by selective immunosuppressive drugs.
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Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/secundario , Inmunosupresores/toxicidad , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/secundario , Animales , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Citometría de Flujo , Inmunohistoquímica , Metástasis Linfática , Ratones , Ratones Endogámicos C3H , Ratones SCID , Trasplante de NeoplasiasRESUMEN
In vivo models have demonstrated that interleukin-13 (IL-13) plays an important role in asthma; however, few studies have evaluated the effect of inhibition of IL-13 on established and persistent disease. In the present study, we have investigated the effect of a therapeutic dosing regimen with an anti-IL-13 monoclonal antibody (mAb) in a chronic mouse model of persistent asthma. BALB/c mice were sensitized to allergen [ovalbumin (OVA); on days 1 and 8] and challenged with OVA weekly from day 22. Anti-IL-13 mAb or vehicle dosing was initiated following two OVA challenges when disease was established. At this time, mice exhibited airway hyperresponsiveness (AHR), increased mucus production, inflammation, and initiation of subepithelial fibrosis compared with saline-challenged mice. Mice received four additional OVA challenges. Treatment with anti-IL-13 mAb inhibited AHR and prevented the further development of subepithelial fibrosis and progression of inflammation. Furthermore, mAb treatment reversed the mucus hyperplasia to basal levels. These effects were associated with an inhibition of cytokines, chemokines, and matrix metalloproteinase-9. These data demonstrate that neutralization of IL-13 can inhibit the progression of established disease in the presence of repeated allergen exposures.