Visfatin/eNampt induces endothelial dysfunction in vivo: a role for Toll-Like Receptor 4 and NLRP3 inflammasome.

Visfatin/extracellular-nicotinamide-phosphoribosyltranferase-(eNampt) is a multifaceted adipokine enhanced in type-2-diabetes and obesity. Visfatin/eNampt cause in vitro endothelial dysfunction and vascular inflammation, although whether the same effects are achieved in vivo is unknown. Toll-like receptor-4 (TLR4), a main surface pattern recognition receptor of innate immune system is a potential target for visfatin/eNampt. We studied its capacity to generate vascular dysfunction in vivo, focusing on TLR4 role and downstream activation of nod-like-receptor-protein-3 (NLRP3)-inflammasome. 4 month-old C57BL/6 mice were exposed to 7 days infusion of visfatin/eNampt, alone or together with FK 866 (Nampt enzymatic inhibitor), CLI 095 (TLR4 blocker), MCC 950 (NLRP3-inflammasome inhibitor), or anakinra (interleukin(IL)-1-receptor antagonist). Endothelial dysfunction was tested in isolated microvessels. In human umbilical endothelial cells (HUVEC), proteins related to the NLRP3-inflammasome phosphorylated p-65, NLRP3, caspase-1, pro-IL-1ß, and mature IL-1ß were determined by Western blot, while the inflammasome related apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC-specks) was studied by immunofluorescence. Impaired endothelium-dependent relaxations were observed in isolated mesenteric microvessels from visfatin/eNampt-infused mice. This effect was attenuated by co-treatment with FK 866 or CLI 095, supporting a role for Nampt enzymatic activity and TLR4 activation. Moreover, cultured HUVEC exposed to visfatin/eNampt showed higher expression and activation of NLRP3-inflammasome. Again, this effect relied on Nampt enzymatic activity and TLR4 activation, and it was abrogated by the inflammasome assembly blockade with MCC 950. The endothelial dysfunction evoked by visfatin/eNampt infusion in vivo was also sensitive to both MCC 950 and anakinra treatments, suggesting that the NLRP3-inflammasome-driven tissular release of IL-1ß is the final mediator of endothelial damage. We conclude that Visfatin/eNampt produces in vivo vascular dysfunction in mice by a Nampt-dependent TLR4-mediated pathway, involving NLRP3-inflammasome and paracrine IL-1ß. Thus, those targets may become therapeutic strategies for attenuating the adipokine-mediated vascular dysfunction associated to obesity and/or type-2-diabetes.

Evaluación de las complicaciones clínicas de los pacientes con fractura de cadera y sus factores asociados en una Unidad de Agudos de Ortogeriatría / Assessment of clinical complications and their associated factors in hip-fracture patients in an Acute Geriatric Orthopaedic Unit

Introducción. Las complicaciones clínicas en pacientes con fractura de cadera (FC) son elevadas y variables por su heterogéneo registro. El objetivo del estudio fue evaluar las complicaciones clínicas y sus factores asociados en pacientes con FC ingresados en la Unidad de Ortogeriatría de un hospital universitario de 283 camas que atiende un promedio de 200 FC/año. Material y métodos. Se incluyó a 383 pacientes ingresados consecutivamente en 2013 y en 2014 en un estudio analítico observacional prospectivo. Las complicaciones clínicas se definieron según recomendaciones avaladas por la AOTrauma Network (Red de Trabajo de la Asociación Internacional de Traumatólogos para el estudio de la osteosíntesis). Resultados. Doscientos setenta y tres pacientes (71,28%) presentaron alguna complicación. Las principales fueron el delirium (55,4%), la insuficiencia renal (15,4%) y las complicaciones cardiacas (12,3%). Se asociaron a la presencia de alguna complicación la clasificación ASA III-IV (OR=1,962; IC del 95%, 1,040-3,704; p = 0,038), un índice de Barthel al alta inferior (b = -3,572;IC del 95%, -0,866 a -0,104; p = 0,01), el incremento en la estancia media (b = 2,683; IC del 95%, 3,522-0,325; p < 0,001) y preoperatoria (OR = 1,165; IC del 95%, 1,050-1,294; p = 0,004). Conclusiones. Las complicaciones clínicas más frecuentes son el delirium, la insuficiencia renal y las complicaciones cardiacas. Una puntuación en la escala de ASA III-IV, una peor situación funcional al alta, así como una estancia preoperatoria y media prolongada, son factores asociados a la presencia de alguna complicación clínica. Las complicaciones cardiacas, pulmonares y digestivas son las principales causas de mortalidad en la unidad

Introduction. The incidence of clinical complications in hip fracture (HF) patients is high and variable due to their heterogeneous nature. The aim of the study was to assess the clinical complications and their associated factors in HF patients admitted to the Orthopaedic Geriatric Unit of a 283 bed University Hospital. An average of 200 HF patients is attended yearly. Material and methods. A prospective, observational and analytical study was conducted on 383 consecutive patients admitted to the unit during the years 2013 and 2014. Clinical complications were defined according to recommendations supported by the AOTrauma Network (International Network of Traumatologists for the Study of Osteosynthesis). Results. A total of 273 patients (71.28%) showed some clinical complication. The main ones were, delirium (55.4%), renal failure (15.4%), and cardiac complications (12.3%). An ASA III-IV score of OR = 1.962 (95% CI; 1.040-3.704, P=.038), lower Barthel index at discharge (b = -3.572, 95% CI -0.866 to -0.104, P=.01), the increase in pre-operative stay (OR = 1.165, 95% CI 1.050-1.294, P=.004) and an increased length of stay (b = 2.663, 95% CI 3.522-0.325; P<.001) were factors associated with clinical complications. Conclusions. Delirium, renal failure, and cardiac complications were the most frequent complications according the new recommendations. An ASA III-IV score, worse functional status at discharge, prolonged pre-operative period, and increased length of stay, were risk factors associated with clinical complications. Cardiac, pulmonary, and gastrointestinal complications were the main causes of mortality in the unit

[Assessment of clinical complications and their associated factors in hip-fracture patients in an Acute Geriatric Orthopaedic Unit]. / Evaluación de las complicaciones clínicas de los pacientes con fractura de cadera y sus factores asociados en una Unidad de Agudos de Ortogeriatría.

INTRODUCTION: The incidence of clinical complications in hip fracture (HF) patients is high and variable due to their heterogeneous nature. The aim of the study was to assess the clinical complications and their associated factors in HF patients admitted to the Orthopaedic Geriatric Unit of a 283 bed University Hospital. An average of 200 HF patients is attended yearly. MATERIAL AND METHODS: A prospective, observational and analytical study was conducted on 383 consecutive patients admitted to the unit during the years 2013 and 2014. Clinical complications were defined according to recommendations supported by the AOTrauma Network (International Network of Traumatologists for the Study of Osteosynthesis). RESULTS: A total of 273 patients (71.28%) showed some clinical complication. The main ones were, delirium (55.4%), renal failure (15.4%), and cardiac complications (12.3%). An ASA III-IV score of OR = 1.962 (95% CI; 1.040-3.704, P=.038), lower Barthel index at discharge (b = -3.572, 95% CI -0.866 to -0.104, P=.01), the increase in pre-operative stay (OR = 1.165, 95% CI 1.050-1.294, P=.004) and an increased length of stay (b = 2.663, 95% CI 3.522-0.325; P<.001) were factors associated with clinical complications. CONCLUSIONS: Delirium, renal failure, and cardiac complications were the most frequent complications according the new recommendations. An ASA III-IV score, worse functional status at discharge, prolonged pre-operative period, and increased length of stay, were risk factors associated with clinical complications. Cardiac, pulmonary, and gastrointestinal complications were the main causes of mortality in the unit.

Impacto presupuestario para el Sistema Nacional de Salud de la prevención del tromboembolismo venoso con Apixaban en pacientes sometidos a artroplastia total de rodilla o cadera / Budgetary impact for the National Health System of Apixaban prophylaxis of venous thromboembolism in patients undergoing total knee or hip replacement

Fundamentos: Debido al elevado coste sanitario del tromboembolismo venoso (TEV) es necesario realizar análisis económicos que determinen la eficiencia de sus diferentes tratamientos farmacológicos. El objetivo del trabajo es estimar el impacto presupuestario para el Sistema Nacional de Salud (SNS) de la prevención del tromboembolismo venoso (TEV) con apixaban en artroplastia total de cadera (ATC) o rodilla (ATR). Métodos: Se consideraron los costes de los diferentes fármacos para la prevención del TEV (apixaban, dabigatrán, enoxaparina, fondaparinux, otras heparinas, rivaroxaban y warfarina) y los de las complicaciones del TEV a corto plazo (90 días) y a 5 años (trombosis venosa profunda, embolismo pulmonar, sangrados y síndrome postrombótico). La eficacia de la prevención se estimó mediante un metaanálisis. Las tasas de TEV y muerte con apixaban fueron inferiores en ATC y ATR a las observadas con enoxaparina (-3,5% y -10,0%, respectivamente) y tuvo menos acontecimientos hemorrágicos (-0,7% y -1,6%, respectivamente). Los datos poblacionales y los costes se obtuvieron de fuentes españolas. Horizonte temporal: 5 años. Todos los costes se descontaron anualmente un 3,5%. Se estimó que a los cinco años de su comercialización el consumo de apixaban supondría el 23% de la prevención del TEV y el de enoxaparina descendería del 60% hasta el 33%. Resultados: La introducción de apixaban para la prevención del TEV produciría un ahorro para el SNS de 547.422 euros en un periodo de 5 años. En el caso de considerar sin coste la administración ambulatoria de las heparinas, el ahorro quinquenal para el SNS ascendería a 270.068 euros. Conclusiones: La introducción de apixaban podría reducir la tasa de TEV y sangrados en comparación con enoxaparina, reduciéndose el gasto del SNS en la prevención del TEV(AU)

Background: Due to high health care costs of venous thromboembolism (VTE), economic analyses are needed to determine the efficiency of different drug treatments. Consequently, a study was conducted to estimate the budgetary impact for the National Health System (NHS) with apixaban for prevention of venous thromboembolism (VTE) in total hip (THR) or knee (TKR) replacement. Methods: Cost considered: the drugs for the prevention of VTE (apixaban, dabigatran, enoxaparin, fondaparinux, other heparins, rivaroxaban and warfarin) and the complications of VTE in the short term and in 5 years (deep vein thrombosis, pulmonary embolism, bleedings and the post-thrombotic syndrome). The effectiveness of prophylaxis was estimated using a meta-analysis. The VTE rates and death with apixaban are lower in THR and TKR than enoxaparin (-3.5% and -10.0%, respectively) with less bleeding events (-0.7% and -1.6%, respectively). Population data and unit costs were obtained from Spanish sources. Time horizon: 5 years. All costs were discounted by 3.5% annually. Five years after commercialization, the use of apixaban was estimated to account for 23% of the prophylaxis of VTE and the use of enoxaparin decrease from the 60% to 33%. Results: Apixaban's introduction for the prophylaxis of VTE would have a significant impact for the NHS, resulting in a saving of euros 547,422 over a period of 5 years. In the case of outpatient administration of heparin did not have a cost, the savings for the NHS five years amount to euros 270,068. Conclusions: According to this study, the introduction of apixaban may reduce the rate of VTE and bleeding compared with enoxaparin, decreasing the expenditure of NHS in VTE prophylaxis(AU)

[Budgetary impact for the National Health System of apixaban prophylaxis of venous thromboembolism in patients undergoing total knee or hip replacement]. / Impacto presupuestario para el Sistema Nacional de Salud de la prevención del trombolismo venoso con apixaban en pacientes sometidos a artroplastia total de rodilla o cadera.

BACKGROUND: Due to high health care costs of venous thromboembolism (VTE), economic analyses are needed to determine the efficiency of different drug treatments. Consequently, a study was conducted to estimate the budgetary impact for the National Health System (NHS) with apixaban for prevention of venous thromboembolism (VTE) in total hip (THR) or knee (TKR) replacement. METHODS: Cost considered: the drugs for the prevention of VTE (apixaban, dabigatran, enoxaparin, fondaparinux, other heparins, rivaroxaban and warfarin) and the complications of VTE in the short term and in 5 years (deep vein thrombosis, pulmonary embolism, bleedings and the post-thrombotic syndrome). The effectiveness of prophylaxis was estimated using a meta-analysis. The VTE rates and death with apixaban are lower in THR and TKR than enoxaparin (-3.5% and -10.0%, respectively) with less bleeding events (-0.7% and -1.6%, respectively). Population data and unit costs were obtained from Spanish sources. TIME HORIZON: 5 years. All costs were discounted by 3.5% annually. Five years after commercialization, the use of apixaban was estimated to account for 23% of the prophylaxis of VTE and the use of enoxaparin decrease from the 60% to 33%. RESULTS: Apixaban´s introduction for the prophylaxis of VTE would have a significant impact for the NHS, resulting in a saving of 547,422 Euro over a period of 5 years. In the case of outpatient administration of heparin did not have a cost, the savings for the NHS five years amount to 270,068 Euro. CONCLUSIONS: According to this study, the introduction of apixaban may reduce the rate of VTE and bleeding compared with enoxaparin, decreasing the expenditure of NHS in VTE prophylaxis.