Preoperative respiratory therapy in patients undergoing surgery for lung cancer: A randomized controlled trial.

BACKGROUND: A preoperative respiratory therapy treatment was performed to analyze the effectiveness, with respect to postoperative air leak and pain, in patients undergoing surgery for lung cancer. OBJECTIVES: To analyze air leakage and postoperative pain. MATERIAL AND METHODS: Seventy one patients were studied, with a mean age of 62.58 years. Descriptive variables of gender, carcinogenic pathology, type of surgical incision and lung resection, use of glue and endostapler, and presence of adhesions were analyzed. Likewise, analysis of the quantitative variables of age, body mass index and forced expiratory volume in 1 s Two homogeneous groups resulted. Differentiated, experimental group (EG) that performed preoperative respiratory therapy and control group (CG). RESULTS: There were statistically significant differences in favor of the EG with respect to postoperative air leak on days 1-2 during the performance of physiotherapy techniques, the food and during the performance of the exercises autonomously. Furthermore, differences in air leakage were observed on days 2-4 during gait. The number of patients decreased to a greater extent in the EG. Regarding pain, there were statistically significant differences in the sample on days 1-4, with greater intensity of pain in the CG and after doing physiotherapy every day except the second. CONCLUSIONS: Preoperative respiratory therapy in patients undergoing surgery for lung cancer was effective in reducing the number of patients who presented postoperative air leak and reducing pain in the EG.

The Chemokine Receptor CCR5 Links Memory CD4+ T Cell Metabolism to T Cell Antigen Receptor Nanoclustering.

The inhibition of anabolic pathways, such as aerobic glycolysis, is a metabolic cornerstone of memory T cell differentiation and function. However, the signals that hamper these anabolic pathways are not completely known. Recent evidence pinpoints the chemokine receptor CCR5 as an important player in CD4+ T cell memory responses by regulating T cell antigen receptor (TCR) nanoclustering in an antigen-independent manner. This paper reports that CCR5 specifically restrains aerobic glycolysis in memory-like CD4+ T cells, but not in effector CD4+ T cells. CCR5-deficient memory CD4+ T cells thus show an abnormally high glycolytic/oxidative metabolism ratio. No CCR5-dependent change in glucose uptake nor in the expression of the main glucose transporters was detected in any of the examined cell types, although CCR5-deficient memory cells did show increased expression of the hexokinase 2 and pyruvate kinase M2 isoforms, plus the concomitant downregulation of Bcl-6, a transcriptional repressor of these key glycolytic enzymes. Further, the TCR nanoclustering defects observed in CCR5-deficient antigen-experienced CD4+ T cells were partially reversed by incubation with 2-deoxyglucose (2-DG), suggesting a link between inhibition of the glycolytic pathway and TCR nanoscopic organization. Indeed, the treatment of CCR5-deficient lymphoblasts with 2-DG enhanced IL-2 production after antigen re-stimulation. These results identify CCR5 as an important regulator of the metabolic fitness of memory CD4+ T cells, and reveal an unexpected link between T cell metabolism and TCR organization with potential influence on the response of memory T cells upon antigen re-encounter.

Suicidal behaviour: emergency department attendance for suicidal recurrence and other psychiatric or medical reasons in the 6 months following the index episode.

The prevention of a complex phenomenon, such as suicide, requires an interdisciplinary approach that provides a comprehensive response to the care needs of people with suicidal behavior (SB). The aim of this study is to investigate the clinical and healthcare features of people presenting thoughts and/or attempts of suicide to define risk factors for recurrence.

Hemoperitoneum secondary to haemocholecyst due to acute cholecystitis.

The haemocholecyst is a rare disease with a low index of suspiction, which is even lower if the patient does not present risk factors. Likewise, the course of this pathology with a haemoperitoneum without vesicular perforation is equally infrequent. We present an unusual case in which the diagnosis of the patient was carried out intraoperatively. We consider that communicating these unusual cases in clinical practice helps to increase clinical suspiction and prompt diagnosis.

El hemocolecisto es una patología poco frecuente y con un índice bajo de sospecha, que todavía es menor si el paciente no presenta factores de riesgo. Asimismo, su curso con clínica de hemoperitoneo sin perforación vesicular es igualmente infrecuente. Presentamos un caso poco habitual en el cual el diagnóstico de la paciente se llevó a cabo intraoperatoriamente. Consideramos que comunicar estos casos poco habituales en la práctica clínica colabora a aumentar la sospecha clínica y el diagnóstico precoz.

Comparing the effect of Cu-based fungicides and pure Cu salts on microbial biomass, microbial community structure and bacterial community tolerance to Cu.

The effect of Cu on three different microbial endpoints was studied using different Cu sources, in order to check the usefulness of pure Cu salts to estimate the toxicity of commercial Cu fungicides on soil microbes. Cu additions caused similar dose-response curves of substrate induced respiration (SIR) decreases regardless of Cu source, i.e. the use of pure Cu salts to estimate the effect of Cu fungicides on microbial biomass using SIR may be useful. Phospholipid fatty acid (PLFA) analysis showed that the Cu source was more important for the microbial community structure than Cu concentration. Thus, the use of Cu salts to infer the effects of Cu fungicides on microbial community structure using PLFA analysis is not recommended, since effects of Cu concentration will be confounded with Cu source. Analyzing pollution induced community tolerance (PICT) to Cu showed that the use of pure Cu salts may overestimate Cu effects if Cu salt additions modified the soil pH. The highest doses of Cu salts increased bacterial community tolerance to Cu between 300 and 600 times, while commercial Cu fungicide increases were between 20 and 160 times. Therefore, the use of pure Cu salts to estimate the Cu fungicides effects on soil microbes is not recommended for PLFAs analyses, not suitable for PICT at high Cu concentrations, while useful for SIR.

Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial.

BACKGROUND: Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. METHODS: Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. RESULTS: Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline-post-bevacizumab-tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. CONCLUSIONS: This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. TRIAL REGISTRATION: (www.clinicaltrials.gov): NCT02802098 . Registered on June 16, 2020.

Coping with Wolf-Hirschhorn syndrome: quality of life and psychosocial features of family carers.

BACKGROUND: Wolf-Hirschhorn Syndrome (WHS) is a rare, congenital disease characterized by a distinctive facial phenotype, seizures, intellectual disability and developmental delay, and pre and postnatal growth requiring lifelong care. The psychosocial status of the family caregivers of children diagnosed with WHS is unknown. This study aims to characterize the sociodemographic and psychosocial profile of WHS caregivers and analyze how these variables impact their quality of life (QoL) and well-being. RESULTS: The sociodemographic and clinical profile of 22 Spanish caregivers of children with WHS and the characteristics of those affected have been described. Significant relationships were found between sociodemographic and psychosocial characteristics among caregivers. The impact on the parents' QoL and negative relationship with the symptomatology were assessed. The use of engagement strategies such as problem focused coping was associated with improved psychological QoL and social support. CONCLUSIONS: WHS caregivers share similarities in their profile and needs with caregivers of children with other rare diseases. Pychosocial support groups involving parents caring for children with the same disease could improve caregivers' well-being and QoL by strengthening their social support network and using positive coping styles.

CCR5 deficiency impairs CD4+ T-cell memory responses and antigenic sensitivity through increased ceramide synthesis.

CCR5 is not only a coreceptor for HIV-1 infection in CD4+ T cells, but also contributes to their functional fitness. Here, we show that by limiting transcription of specific ceramide synthases, CCR5 signaling reduces ceramide levels and thereby increases T-cell antigen receptor (TCR) nanoclustering in antigen-experienced mouse and human CD4+ T cells. This activity is CCR5-specific and independent of CCR5 co-stimulatory activity. CCR5-deficient mice showed reduced production of high-affinity class-switched antibodies, but only after antigen rechallenge, which implies an impaired memory CD4+ T-cell response. This study identifies a CCR5 function in the generation of CD4+ T-cell memory responses and establishes an antigen-independent mechanism that regulates TCR nanoclustering by altering specific lipid species.

Recurrence of suicidal thoughts and behaviors during one year of follow-up: An exploratory study.

Suicidal thoughts and behaviors (STB) include suicidal ideation (SI), suicide attempt (SA) and completed suicide. We aimed to identify recurrence predictors of any type of STB, and separately for SA and SI, and to analyze the time until event. A 108-subject cohort presenting at Emergencies with STB was followed during one year. Recurrence risk factors were investigated by multiple Cox survival regressions. Within one year, 31.5%, 23.1% and 9.3% patients recurred with any STB, SA, and SI respectively. Most recurrences (~70%) occurred within the first 6 months. Seeking emergency psychiatric assistance for problems other than STB during follow-up was a common predictor for recurrence of any STB, and SA and SI specifically. Previous SA history and contact with psychiatry outpatient units during follow-up predicted both STB in general and SA in particular. A specific predictor for SA was hospitalization at index, while SI recurrence was associated to SI at index. These results highlight the importance of early intervention and multidisciplinary follow-up considering concurrent psychosocial or adaptive problems. A careful exploration at Emergencies is needed to target potential predictors.

International meeting on Wolf-Hirschhorn syndrome: Update on the nosology and new insights on the pathogenic mechanisms for seizures and growth delay.

"An International Meeting on Wolf-Hirschhorn Syndrome (WHS)" was held at The University Hospital La Paz in Madrid, Spain (October 13-14, 2017). One hundred and twenty-five people, including physicians, scientists and affected families, attended the meeting. Parent and patient advocates from the Spanish Association of WHS opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes. These proceedings will review the major points of discussion.

Comparison of Cu salts and commercial Cu based fungicides on toxicity towards microorganisms in soil.

Microbial responses to Cu pollution as a function of Cu sources (Cu salts and commercial Cu fungicides) were assessed in a soil using basal soil respiration, and bacterial and fungal community growth, as endpoints. The soil was amended with different concentrations (0-32 mmol Cu kg-1) of Cu nitrate, Cu sulfate, Bordeaux mixture and 3 types of Cu oxychloride. Cu salts decreased soil pH, while this was not found with the other Cu sources. This difference in soil pH effects caused differences in the respiration, bacterial growth and fungal growth response. Basal soil respiration was negatively affected by Cu addition when the soil was spiked with Cu salts, but almost unaffected by commercial Cu fungicides. Bacterial growth was significantly and negatively affected by Cu addition for all the Cu sources, but Cu toxicity was higher for Cu salts than for commercial Cu fungicides. Fungal growth response was also different for Cu salts and commercial Cu fungicides, but only in the long-term. High Cu amendments using Cu salts stimulated fungal growth, whereas for commercial Cu fungicides, these concentrations inhibited fungal growth. Thus, the use of products similar to those used in commercial fungicides is a recommended practice for Cu risk assessments in soil.

A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation.

Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαß transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRß transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active kinases. Only TCRs that spontaneously detached from cholesterol could switch to the active conformation (termed primed TCRs) and then be phosphorylated. Indeed, by modulating cholesterol binding genetically or enzymatically, we could switch the TCR between the resting and primed states. The active conformation was stabilized by binding to peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction.

Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion.

Formation of a regularly branched blood vessel network is crucial in development and physiology. Here we show that the expression of the Notch ligand Dll4 fluctuates in individual endothelial cells within sprouting vessels in the mouse retina in vivo and in correlation with dynamic cell movement in mouse embryonic stem cell-derived sprouting assays. We also find that sprout elongation and branching associates with a highly differential phase pattern of Dll4 between endothelial cells. Stimulation with pathologically high levels of Vegf, or overexpression of Dll4, leads to Notch dependent synchronization of Dll4 fluctuations within clusters, both in vitro and in vivo. Our results demonstrate that the Vegf-Dll4/Notch feedback system normally operates to generate heterogeneity between endothelial cells driving branching, whilst synchronization drives vessel expansion. We propose that this sensitive phase transition in the behaviour of the Vegf-Dll4/Notch feedback loop underlies the morphogen function of Vegfa in vascular patterning.

[EVALUATION OF THE EFFICIENCY OF CLEANING THE AIR BETWEEN TWO METHODS OF MAKING IN PATIENTS WITH AEROSOL CHRONIC OBSTRUCTIVE PULMONARY DISEASE]. / Evaluación de la eficacia en la limpieza de la vía aérea entre dos métodos de toma de aerosolterapia en pacientes con enfermedad pulmonar obstructiva croníca.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is a condition which requires, among others, the administration of bronchodilators and anti-inflammatory drugs to control the disease. They help to keep the airways clear and prevent the buildup of fluid and mucus. Inhalation is the most widely used form of administrating the medication because of its local and rapid action which normally is done by aerosol therapy. The objective of this study is to evaluate the effectiveness of two aerosol methods in clearing the airways of COPD patients, admitted with an exacerbation due to their disease. It also aims to evaluate its effects on the length of stay, oxygen saturation, dyspnea, autonomy and complications. METHODS: Randomized clinical trial. Traditional method (control group) and positive expiratory vibrating device (intervention group): two ways to deliver aerosol were compared. The following outcome variables were considered: length of stay, days of fever, oxygen saturation, need for NIV or VM, the basic activities of daily living index autonomy (Barthel), dyspnea (Borg scale) and peak-flow. RESULTS: 39 patients were included. Regarding hospital stay, patients in the intervention group spend an average of one day less in hospital. Also in this group there were fewer readmissions. No statistically significant differences were found in the remaining variables. CONCLUSIONS: The inhalation treatment with a vibrating device with positive exhalation, appears to reduce the length of stay and prevent readmissions. It is important to continue research on non-pharmacological interventions as to achieve the prevention of relapses.

Conformational changes in the T cell receptor differentially determine T cell subset development in mice.

In the thymus, immature T cells differentiate from common precursors to become T cells expressing either the αß or γδ T cell receptor (TCR) complex. The CD3ε subunit of the TCR complex is thought to transduce ligand-induced conformational changes in the TCR by recruiting the cytosolic adaptor protein Nck. To investigate the role of conformational changes in the TCR in T cell development, we generated mice with a germline mutation (C80G) in the extracellular domain of CD3ε, which prevents the outside-in transmission of conformational changes in the TCR. The development of αß T cells in the C80G mice was blocked at an early stage that depends on signaling by a precursor form of the TCR. In contrast, the C80G mutation did not impair the development of some subsets of γδ T cells, including Vγ1.1(+) cells; however, development of other γδ T cell subsets was blocked. A similar phenotype was observed in mice with a mutation in the cytoplasmic proline-rich sequence (PRS) of CD3ε, the binding site for Nck. In a genetic complementation test, the PRS CD3ε mutant failed to rescue the wild-type phenotype when expressed in heterozygosity with the C80G mutant. These data suggest that Nck may function as an effector of TCR conformational changes during T cell development. Additional experiments showed differential effects of the C80G mutation on the activation of TCR-dependent signaling pathways, which suggests that there are pathways that are either dependent on or independent of the transmission of conformational change in the receptor.

Lack of CCM1 induces hypersprouting and impairs response to flow.

Cerebral cavernous malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1, CCM2 or CCM3. Despite several studies, the mechanism of CCM lesion onset remains unclear. Using a Ccm1 knockout mouse model, we studied the morphogenesis of early lesion formation in the retina in order to provide insight into potential mechanisms. We demonstrate that lesions develop in a stereotypic location and pattern, preceded by endothelial hypersprouting as confirmed in a zebrafish model of disease. The vascular defects seen with loss of Ccm1 suggest a defect in endothelial flow response. Taken together, these results suggest new mechanisms of early CCM disease pathogenesis and provide a framework for further study.

The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis.

Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.

Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo.

On TCR ligation, the adaptor Nck is recruited through its src homology 3.1 domain to a proline-rich sequence (PRS) in CD3ε. We have studied the relevance of this interaction for T cell activation in vitro and in vivo by targeting the interaction sites in both partners. The first approach consisted of studying a knockin (KI) mouse line (KI-PRS) bearing a conservative mutation in the PRS that makes the TCR incompetent to recruit Nck. This deficiency prevents T cell activation by Ag in vitro and inhibited very early TCR signaling events including the tyrosine phosphorylation of CD3ζ. Most important, KI-PRS mice are partly protected against the development of neurological symptoms in an experimental autoimmune encephalitis model, and show a deficient antitumoral response after vaccination. The second approach consisted of using a high-affinity peptide that specifically binds the src homology 3.1 domain and prevents the interaction of Nck with CD3ε. This peptide inhibits T cell proliferation in vitro and in vivo. These data suggest that Nck recruitment to the TCR is fundamental to mount an efficient T cell response in vivo, and that the Nck-CD3ε interaction may represent a target for pharmacological modulation of the immune response.

Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis.

Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities.