Ambulatory surgery in orthopedics: experience of over 10,000 patients

PurposeThe concept of day surgery is becoming an increasingly important part of elective surgery worldwide. Relentless pressure to cut costs may constrain clinical judgment regarding the most appropriate location for a patient’s surgical care. The aim of this study was to determine clinical and quality indicators relating to our experience in orthopedic day durgery, mainly in relation to unplanned overnight admission and readmission rates. Additionally, we focused on describing the main characteristics of the patients that experienced complications, and compared the patient satisfaction rates following ambulatory and non-ambulatory procedures.MethodsWe evaluated 10,032 patients who underwent surgical orthopedic procedures according to the protocols of our Ambulatory Surgery Unit. All complications that occurred were noted. A quality-of-life assessment (SF-36 test) was carried out both pre- and postoperatively. Ambulatory substitution rates and quality indicators for orthopedic procedures were also determined.ResultsThe major complication rate was minimal, with no mortal cases, and there was a high rate of ambulatory substitution for the procedures studied. Outcomes of the SF-36 questionnaire showed significant improvement postoperatively. An unplanned overnight admission rate of 0.14 % was achieved.ConclusionsOur institution has shown that it is possible to provide good-quality ambulatory orthopedic surgery. There still appears to be the potential to increase the proportion of these procedures. Surgeons and anesthesiologists must strongly adhere to strict patient selection criteria for ambulatory orthopedic surgery in order to reduce complications in the immediate postoperative term

Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis.

The sympathetic nervous system has been evolutionary selected to respond to stress and activates haematopoietic stem cells via noradrenergic signals. However, the pathways preserving haematopoietic stem cell quiescence and maintenance under proliferative stress remain largely unknown. Here we found that cholinergic signals preserve haematopoietic stem cell quiescence in bone-associated (endosteal) bone marrow niches. Bone marrow cholinergic neural signals increase during stress haematopoiesis and are amplified through cholinergic osteoprogenitors. Lack of cholinergic innervation impairs balanced responses to chemotherapy or irradiation and reduces haematopoietic stem cell quiescence and self-renewal. Cholinergic signals activate α7 nicotinic receptor in bone marrow mesenchymal stromal cells leading to increased CXCL12 expression and haematopoietic stem cell quiescence. Consequently, nicotine exposure increases endosteal haematopoietic stem cell quiescence in vivo and impairs hematopoietic regeneration after haematopoietic stem cell transplantation in mice. In humans, smoking history is associated with delayed normalisation of platelet counts after allogeneic haematopoietic stem cell transplantation. These results suggest that cholinergic signals preserve stem cell quiescence under proliferative stress

Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes.

Hematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3-adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes

LIGHT/HVEM/LTβR Interaction as a Target for the Modulation of the Allogeneic Immune Response in Transplantation

[EN] The exchange of information during interactions of T cells with dendritic cells, B cells or other T cells regulates the course of T, B and DC-cell activation and their differentiation into effector cells. The tumor necrosis factor superfamily member LIGHT (homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) is transiently expressed upon T cell activation and modulates CD8 T cell-mediated alloreactive responses upon herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR) engagement. LIGHT-deficient mice, or WT mice treated with LIGHT-targeting decoy receptors HVEM-Ig, LTβR-Ig or sDcR3-Ig, exhibit prolonged graft survival compared to untreated controls, suggesting that LIGHT modulates the course and severity of graft rejection. Therefore, targeting the interaction of LIGHT with HVEM and/or LTβR using recombinant soluble decoy receptors or monoclonal antibodies represent an innovative therapeutic strategy for the prevention and treatment of allograft rejection and for the promotion of donor-specific tolerance. This review discusses how targeting the interaction of LIGHT with HVEM and/or LTbR using recombinant soluble decoy receptors or monoclonal antibodies may represent an innovative therapeutic intervention for the prevention and treatment of allograft rejection and promotion of donor-specific tolerance. © 2013 The American Society of Transplantation and the American Society of Transplant SurgeonsSIThis work has been supported by grants FIS reference # PI10/01039 from Ministry of Health and Department of Education from Junta of Castilla and Leon reference # LE007A10-2 (to JIRB), and by the Swiss National Science Foundation (to PS

Manifiesto: geología para una nueva cultura de la tierra

Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEpu

RIPK1 is a critical modulator of both tonic and TLR-responsive inflammatory and cell death pathways in human macrophage differentiation

In this study, we took advantage of human-induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 technology to investigate the potential roles of RIPK1 in regulating hematopoiesis and macrophage differentiation, proinflammatory activation, and cell death pathways. Knock-out of RIPK1 in hiPSCs demonstrated that this protein is not required for erythro-myeloid differentiation. Using a well-established macrophage differentiation protocol, knock-out of RIPK1 did not block the differentiation of iPSC-derived macrophages, which displayed a similar phenotype to WT hiPSC-derived macrophages. However, knock-out of RIPK1 leads to a TNFα-dependent apoptotic death of differentiated hiPSC-derived macrophages (iPS-MΦ) and progressive loss of iPS-MΦ production irrespective of external pro-inflammatory stimuli. Live video analysis demonstrated that TLR3/4 activation of RIPK1 KO hiPSC-derived macrophages triggered TRIF and RIPK3-dependent necroptosis irrespective of caspase-8 activation. In contrast, TLR3/4 activation of WT macrophages-induced necroptosis only when caspases were inhibited, confirming the modulating effect of RIPK1 on RIPK3-mediated necroptosis through the FADD, Caspase-8 pathway. Activation of these inflammatory pathways required RIPK3 kinase activity while RIPK1 was dispensable. However, loss of RIPK1 sensitizes macrophages to activate RIPK3 in response to inflammatory stimuli, thereby exacerbating a potentially pathological inflammatory response. Taken together, these results reveal that RIPK1 has an important role in regulating the potent inflammatory pathways in authentic human macrophages that are poised to respond to external stimuli. Consequently, RIPK1 activity might be a valid target in the development of novel therapies for chronic inflammatory diseases.España, MINECO/FEDER SAF2015-64171

Sarcomas de partes blandas. Análisis de 42 casos

El objetivo de este estudio es valorar el pronóstico a largo plazo de una serie de pacientes tratados en nuestro hospital en relación con diversos factores clínicos, diagnósticos y terapéuticos que podrían condicionarlo. Se revisaron 123 pacientes tratado por tumores malignos de partes blandas entre los años 1979 y 1999, de estos solo 42 cumplieron las características para incluirles en nuestro estudio. Se valoró su evolución teniendo en cuenta las variables pronosticas identificadas en trabajos previamente publicados y nuestra propia experiencia y se realizó el estudio estadístico de las mismas. En el análisis estadístico del estudio se utilizó el programa SPSS versión 8.0WIN y se realizó el análisis de supervivencia mediante el método de Kaplan-Meier. El tiempo de supervivencia total descrito según este método para el total de los casos estudiados presenta una mediana de 33 meses con un error estándar de 8 y un intervalo de confianza del 95% de (17,49), el tiempo libre de enfermedad presenta una mediana de 9 meses con un error estándar de 2 y un intervalo de confianza del 95% de (6,12) y el tiempo de aparición de metástasis presenta una mediana de 26 meses con un error estándar de 5 y un intervalo de confianza del 95% de (17,35). A su vez se realizó el análisis bivariante de las múltiples variables pronosticas. El gran número de variables y la dispersión de la muestra hacen aconsejable estudios multicéntricos prospectivos más numerosos para obtener conclusiones definitivas sobre este tipo de tumores.The aim of this study is to evaluate the long-term prognosis of a series of patients treated in our hospital with regard to various clinical, diagnostic and therapeutic factors. A total of 123 patients who had been treated for malignant soft tissue tumours between 1979 and 1999 were reviewed. Of these, only 42 fulfilled the requirements to be included in our study. The outcome was evaluated taking into account prognostic variables identified in previously published studies and our own experience, and a statistical study of these factors as carried out with the Kaplan-Meier survival analysis method. The total survival time for all the cases studied was 33+8 (median + SE) months with a 95% confidence interval of 17.49 months. The time free of illness was 9+2 (median + SE) months with a 95% confidence interval of 6.12 months. The time-period until metastasis appeared was 26+5 (median + SE) months with a 95% confidence interval of 17.35 months. At the same time, the bivariant analysis of the many prognostic variables was performed. The high number of variables and the dispersion of the sample group suggest that it would be advisable to carry out more prospective, multicentric studies to reach definitive conclusions about this type of tumour

Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395– 1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation

[EN]Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells in transplantation. The administration of an NK cell depleting antibody to either CD8 T cell replete or CD8 T cell-depleted naïve C57BL/6 immunocompetent mice accelerated graft rejection. This accelerated rejection response was associated with an in vivo increased cytotoxic activity of CD8 T cells against bm1 allogeneic hematopoietic cells and bm1 skin allografts. These findings show that NK cells were impli-cated in the control host anti-donor cytotoxic responses, likely by competing for common cell growth factors in both CD8 T cell replete and CD8 T cell-depleted mice, the latter reconstituting in response to lymphopenia. Our data calls for precaution in solid organ transplantation under tolerogenic protocols involving extensive depletion of lymphocytes. These pharmacological biologics with depleting proper-ties over NK cells may accelerate graft rejection and promote aggressive CD8 T cell cytotoxic allore-sponses refractory to current immunosuppression.SIThis work has been supported by grant FIS PI# 1300029 (Fondo de Investigaciones Sanitarias, Ministry of Health, Spanish Government and co-funded by European Union ERDF/ESF, “Investing in your future”), LE093U13 and Unit of Excellence Research UIC #012 (Department of Education of the Regional Government, Junta de Castilla y Leon) and Gerencia Regional de Salud (BIO/01/15) to JIRB, and by Miguel Servet National Grant (Health National Organization Research) CP12/03063, CPII17/00002 and FIS PI16/00002 (Instituto de Salud Carlos III and co-funded by European Union ERDF/ESF, “Investing in your future”), and Gerencia Regional de Salud GRS963/A/2014, GRS1142/A/2015 and GRS 1505/A/2017 to M.L.R.G.This work has been partially funded by the National Network CIBER-ONC (oncology research) CB16/12/00480. P.S. is funded by grant 31003A-17-6256 of the Swiss National Science Foundation. We thank University of Leon for providing funding to cover publication expenses

CD4+ and CD8+ T-cell responses in bone marrow to fatty acids in high-fat diets

13 Páginas.-- 5 Figuras.--3 TablasObesity is associated with disruptions in the adaptive immune system; however, dietary fatty acids in high-fat diets (HFDs) that induce obesity have consequences that are currently unclear regarding T-cell maintenance in bone marrow (BM). C57BL/6J mice were randomly assigned to isocaloric HFDs formulated with dietary fats rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), or MUFAs supplemented with eicosapentaenoic and docosahexaenoic acids for 20 weeks, followed by an analysis of the immunophenotypic feature of lymphocytes (CD3+) T and their subsets CD4+ and CD8+ T cells in spleen and BM, identification of fatty acids in BM extracellular fluid and analysis of the correspondence between fatty acids with the frequency of T-cell subsets in BM. Splenic CD3+ T cells were reduced irrespective of HFDs. In BM, CD3+ T cells were reduced after HFD-SFAs, while CD4+ T cells were increased after HFDs enriched in MUFAs and CD8+ T cells were reduced irrespective of HFDs. In BM extracellular fluid, the content of palmitic and myristic acids increased after HFD-SFAs and that of oleic acid increased after HFDs enriched in MUFAs. There was a statistical correspondence between HFD-induced changes in fatty acids in BM extracellular fluid and HFD-induced changes in the frequency of CD3+ and CD4+ T cells in BM. These findings reveal an undervalued critical role for dietary fatty acids in the selective acquisition of T-cell subsets in BM, highlighting that oleic acid existing in the surroundings of T-cell niches during HFD-induced obesity could be instrumental in the maintenance of CD4+ T cells.This work was supported by a grant AGL2016-80852-R funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe.”Peer reviewe