Changes in objectively measured physical activity in adolescents with Down syndrome: the UP&DOWN longitudinal study.

BACKGROUND: It is a priority to understand that physical activity behaviour over time is a priority in Down syndrome population in order to design and promote succesfull interventions to maintain or increase levels of physical activity. We aimed to study 1 and 2-year changes in objectively measured physical activity among a relatively large sample of adolescents with Down syndrome. METHODS: This study comprised a total of 99 adolescents with Down syndrome (38 girls) aged from 11 to 20 years old at baseline. Participants with valid accelerometer data at baseline and at least one of the follow-up visits were included in the analysis. RESULTS: Overall, levels of physical activity observed in adolescents with Down syndrome declined from baseline to follow-ups, but these changes were not significant (all P > 0.05). Moderate-to-moderately high tracking of physical activity was observed in adolescents with Down syndrome (all P < 0.001). Youths who met physical activity guidelines at baseline demonstrated a greater decline in physical activity in 1 and 2-year changes (P < 0.05), although they were also more likely to meet physical activity guidelines at 1 and 2-year follow-ups (P < 0.05). CONCLUSIONS: Adolescents with Down syndrome do not change their levels of physical activity at 2-year follow-ups, but those who met physical activity guidelines presented stronger declines in physical activity over time.

Role of HDAC6-STAT3 in immunomodulatory pathways in Colorectal cancer cells.

Colorectal cancer (CRC) is one of the most common malignant neoplasms and the second leading cause of death from tumors worldwide. Therefore, there is a great need to study new therapeutical strategies, such as effective immunotherapies against these malignancies. Unfortunately, many CRC patients do not respond to current standard immunotherapies, making it necessary to search for adjuvant treatments. Histone deacetylase 6 (HDAC6) is involved in several processes, including immune response and tumor progression. Specifically, it has been observed that HDAC6 is required to activate the Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor involved in immunogenicity, by activating different genes in these pathways, such as PD-L1. Over-expression of immunosuppressive pathways in cancer cells deregulates T-cell activation. Therefore, we focused on the pharmacological inhibition of HDAC6 in CRC cells because of its potential as an adjuvant to avoid immunotolerance in immunotherapy. We investigated whether HDAC6 inhibitors (HDAC6is), such as Nexturastat A (NextA), affected STAT3 activation in CRC cells. First, we found that NextA is less cytotoxic than the non-selective HDACis panobinostat. Then, NextA modified STAT3 and decreased the mRNA and protein expression levels of PD-L1. Importantly, transcriptomic analysis showed that NextA treatment affected the expression of critical genes involved in immunomodulatory pathways in CRC malignancies. These results suggest that treatments with NextA reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulatory genes involved in the inflammatory and immune responses. Therefore, targeting HDAC6 may represent an interesting adjuvant strategy in combination with immunotherapy.

[Interpretation of ventilator curves in patients with acute respiratory failure]. / Interpretación de las curvas del respirador en pacientes con insuficiencia respiratoria aguda.

Mechanical ventilation is a therapeutic intervention involving the temporary replacement of ventilatory function with the purpose of improving symptoms in patients with acute respiratory failure. Technological advances have facilitated the development of sophisticated ventilators for viewing and recording the respiratory waveforms, which are a valuable source of information for the clinician. The correct interpretation of these curves is crucial for the correct diagnosis and early detection of anomalies, and for understanding physiological aspects related to mechanical ventilation and patient-ventilator interaction. The present study offers a guide for the interpretation of the airway pressure and flow and volume curves of the ventilator, through the analysis of different clinical scenarios.

Evaluation of sludge from paper recycling as bedding material for broilers.

Several materials have been used as bedding substrates in broiler production. In this work, the sludge from paper recycling was tested for its potential use as litter material and was compared with wood shavings. Moisture content, apparent density, and water-holding capacity were measured and characterized in both materials. Later, 192 male broiler chickens were distributed among 16 experimental pens, 8 of which contained wood shavings as bedding material and 8 of which contained the sludge. Growth rate, consumption, tonic immobility, gait score, breast lesions, foot pad dermatitis, hock burn, tibial dyschondroplasia, and metatarsal thickness were determined in the birds. Although the moisture content of the sludge was high, it decreased strongly after 7 d of drying, reaching lower values than those of wood shavings. In general, few differences were found between the materials in terms of bird performance and welfare and only the incidence of hock burn was higher in the sludge than in the wood shavings. Although further research is needed, sludge from paper recycling is a possible alternative to traditional bedding materials because it achieves most of the requirements for broiler bedding materials and does not show negative effects on the birds.

Reduction in catheter-related bloodstream infections in critically ill patients through a multiple system intervention.

In this study, we aimed to determine the utility of a multiple system intervention to reduce catheter-related bloodstream infections (CR-BSI) in our intensive care unit (ICU). A prospective cohort study was undertaken in the medical and surgical ICU at a university hospital. We applied five measures: educational sessions about inserting and maintaining central venous catheters, skin cleaning with chlorhexidine, a checklist during catheter insertion, subclavian vein insertion and avoiding femoral insertion whenever possible, and removing unnecessary catheters. We determined the rate of CR-BSI per 1,000 catheter-days during the intervention (March to December 2007) and compared it with the rate during the same period in 2006 in which we applied only conventional preventive measures. CR-BSI was defined as the recovery of the same organism (same species, same antibiotic susceptibility profile) from catheter tip and blood cultures. We registered 4,289 patient-days and 3,572 catheter-days in the control period and 4,174 patient-days and 3,296 catheter-days in the intervention period. No significant differences in the number of patients with central venous catheters during the two periods were observed: catheters were used in 81.5% of patients during the control period and in 80.6% of patients during the intervention period. During the control period, 24 CR-BSI were diagnosed (6.7/1,000 catheter-days); during the intervention period, 8 CR-BSI were diagnosed (2.4/1,000 catheter-days) (relative risk 0.36; 95% confidence interval [CI] 0.16 to 0.80; p = 0.015). Nurses interrupted the procedure to correct at least one aspect when completing the checklist in 17.7% of insertions. In conclusion, a multiple system intervention applying evidence-based measures reduced the incidence of CR-BSI in our ICU.

The dynamic of antibiotic resistance in commensal Escherichia coli throughout the growing period in broiler chickens: fast-growing vs. slow-growing breeds.

Antimicrobial resistance (AMR) is an important threat to public health worldwide. Furthermore, different studies have demonstrated a close association between antibiotic use in animal production and AMR in humans. It is well known that it is necessary to reduce antibiotic administration in farms by finding effective alternative treatments, using more resistant breeds and improving animal welfare. However, to be able to assess the alternatives proposed, it is essential to study the epidemiology of AMR under production conditions. Hence, the aim of this study was to investigate the AMR dynamic in 2 genetic poultry breeds during the growing period. The study was performed in 2 experimental poultry houses to simulate real production conditions, and no antibiotics were administered during the growing period. In addition, 2 poultry breeds were used, fast-growing and slow-growing. To evaluate AMR evolution, Escherichia coli was selected as indicator bacterium. To this end, animals from each experimental group were sampled at different times: on day of arrival, at mid-period, and at slaughter day. In the laboratory, cecal content was removed and inoculated in selective media. Then, biochemical tests were performed to confirm E. coli. Finally, antibiotic susceptibility was assessed according to Decision 2013/653. At the onset of the cycle, significant differences were observed between breeds, as the E. coli strains isolated from fast-growing 1-day-old-chicks showed higher AMR rates. However, at the end of the period, no significant differences were found between breeds and their presence of resistant bacteria (above 95%). Therefore, although no antibiotics were administered during the growing period, a high level of AMR at slaughter day was demonstrated. Further studies are necessary to determine the main risk factors that increase the level of AMR throughout the productive cycle in broiler chickens. In conclusion, it is important to highlight that although it is crucial to control both antibiotic use and animal welfare during the growing period, measures should be taken at all levels of the production chain.

Effect of different housing systems (single and group penning) on the health and welfare of commercial female rabbits.

In recent decades, concern about rabbit welfare and sustainability has increased. The housing system is a very important factor for animal welfare. However, information about how different available housing types for female rabbits affect their health status is scarce, but this is an important factor for their welfare. Hence, the objective of this study was to evaluate the health status of female rabbits in five common housing systems: three different single-housing systems with distinct available surfaces and heights; a single-housing system with a platform; a collective system. Female rabbits in the collective and platform cages had greater cortisol concentrations in hair than those in the single-housing system with no platform. Haptoglobin concentrations and kit mortality rates during lactation were greater for the collective-cage female rabbits. The collective group had more culled females and more lesions than in the other groups. The main reasons for culling in all the groups were reproduction problems and presence of abscesses, and the collective group of females was the most affected. In conclusion, it appears that keeping females together in collective systems negatively affects their health status and welfare, while single-housing systems imply lower kit mortality rates during lactation and cortisol concentrations, and fewer lesions in female rabbits.

Preparation and Biochemical Analysis of Classical Histone Deacetylases.

Histone deacetylase assays were first developed in the 1970s, and subsequently refined in the 1990s with the cloning of HDAC enzymes. Most of these early assays, relying on traditional in vitro chemical methodologies, are still applicable today. More recently, however, cell-based HDAC assays that measure HDAC activities in physiological conditions are emerging. Also, there is a continuing development of assays that can measure an isolated HDAC in the absence of other HDAC activities. This chapter reviews some of the older established methods for assaying HDAC activities, as well as introduces more recently developed nontraditional assays.

Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation.

The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.

Non-invasive mechanical ventilation in status asthmaticus.

OBJECTIVE: To evaluate our clinical experience with the use of non-invasive mechanical ventilation (NIMV) in patients with an acute asthmatic attack. DESIGN: Seven-year period retrospective observational study. SETTING: General intensive care department (ICU) of a county hospital. PATIENTS: From 1992 to 1998, we documented clinical data, gas exchange and outcome of every asthmatic patient admitted to our ICU because of status asthmaticus (SA) refractory to initial medical therapy. INTERVENTIONS: Clinical charts were reviewed and patients were allocated to two groups according to their suitability as participants in an NIMV trial. Patients who arrived in respiratory arrest and those who ultimately improved with medical management alone were not considered candidates for NIMV. For the present analysis, the rest of the patients were considered candidates for NIMV, while the decision to start a NIMV trial or to perform endotracheal intubation (ETI) remained at the discretion of the attending physician. When patients failed to improve with NIMV, standard mechanical ventilation (MV) with ETI was initiated. MEASUREMENTS AND RESULTS: Fifty-eight patients were included in the study. Twenty-five patients (43%) were not eligible for NIMV: 11 patients (19%) because of respiratory arrest on their arrival at the Emergency Room and 14 patients (24%) because of improvement with medical management (bronchodilators, corticoids and oxygen). The remaining 33 patients were eligible for NIMV (57%): 11 patients (33%) received invasive MV and 22 patients (67%) were treated with NIMV. Three NIMV patients (14%) needed ETI. We compared data at baseline, 30 min, 2-6 h and 6-12 h after the onset of ventilatory support. Significant differences were observed in arterial blood gases on admission to the Emergency Room between MV and NIMV: PaCO2 (89 +/- 29 mmHg vs 53 +/- 13 mmHg, p < 0.05), pH (7.05 +/- 0.21 vs 7.28 +/- 0.008, p < 0.05) and HCO3- level (22 +/- 5 mmol/l vs 26 +/- 6 mmol/l, p < 0.05). No differences were found in the median length of ICU stay (4.5 vs 3 days), median hospital stay (15 vs 12 days) and mortality (0 vs 4%). CONCLUSION: Face mask NIMV appears to be a suitable method for improving alveolar ventilation and can reduce the need for intubation in a selected group of patients with SA.

Improvement in oxygenation by prone position and nitric oxide in patients with acute respiratory distress syndrome.

OBJECTIVE: Inhaled nitric oxide (NO) and prone position improve arterial oxygenation in patients with the acute respiratory distress syndrome. This study was undertaken to assess the combined effects of NO and prone position in these patients. DESIGN: Prospective clinical study. SETTING: General intensive care service in a community teaching hospital. PATIENTS: 14 mechanically ventilated adult patients with the acute respiratory distress syndrome (mean lung injury score 3.23+/-0.27). MEASUREMENTS AND RESULTS: We measured hemodynamic and oxygenation parameters in the supine position and 2 h later in the prone position, before and during inhalation of 10 ppm NO. A positive response in oxygenation was defined as a > or =20% increment in the arterial oxygen tension/fractional inspired oxygen ratio (PaO2/FIO2). In the prone position PaO2/FIO2 increased significantly (from 110+/-55 to 161+/-89 mm Hg, p<0.01) and venous admixture decreased (from 38+/-12 to 30+/-7%, p<0.01) compared to the supine position. Ten of the 14 patients were responders in the prone position. In the supine position, inhalation of NO improved oxygenation to a lesser extent, increasing PaO2/FIO2 to 134+/-64 mm Hg (p<0.01) and decreasing venous admixture to 35+/-12%, (p<0.01). Five of the 14 patients responded to NO inhalation supine and 8 of 14 responded prone (p = 0.22). The combination of NO therapy and prone positioning was additive in increasing PaO2/FIO2 (197+/-92 mm Hg) and decreasing venous admixture (27+/-8%) (p<0.01). This combination also showed a positive oxygenation response on compared to the supine value without NO in 13 of the 14 patients (93 %). NO-induced changes in PaO2/FIO2 were correlated to changes in pulmonary vascular resistance only in the prone position. CONCLUSIONS: In patients with the acute respiratory distress syndrome, the combination of NO and prone position is a valuable adjunct to mechanical ventilation.

Neural system states and networks.

A neural circuit at the human cerebellar cortex and nuclei is interpreted in terms of an optimized code and a reliable network.

Paracoccidioidomycosis associated with acquired immunodeficiency syndrome. Report of seven cases.

We report the clinical findings and evolution of seven patients (five men and two women), the majority of them intravenous drug users, with paracoccidioidomycosis associated to acquired immunodeficiency syndrome (AIDS). In four of the patients the paracoccidioidomycosis was restricted to the lung and in the three others was generalized with cutaneous involvement. Only two of them had lived recently in rural area, an indication of the possible reactivation of latent focal infection in the other five patients. The recognition of the role of cell-mediated immunity in host defense against Paracoccidioides brasiliensis leds to the prediction of a growing occurrence of the paracoccidioidomycosis-AIDS association in areas that are endemic for these diseases.

Development of a pododermatitis score in breeding does using clustering methods.

Pododermatitis in rabbit production is an important welfare problem and there is less information on this type of lesion in rabbits than in many other species. The aim of this work was to develop a scoring system to assess the presence and severity of pododermatitis through observation of 1367 photos of rabbit feet by two observers. Different groups of lesions were established according to color, size, presence of chaps, presence of ulcers, shape, appearance and presence of blood in each observed foot. A two-step cluster methodology was used to gather the results in homogenous and objective units. The inter-rater agreement was moderate, and after the cluster analysis four main clusters were obtained. These clusters were later comprehensively described in terms of pododermatitis severity. Finally, attending to cluster description, a five-level score was defined and this scale resulted in a practical and objective way to assess pododermatitis in rabbit does. Cluster analysis provided a detailed characterization of this type of lesions and helped to obtain uniform scores.

Patient-ventilator dyssynchrony during assisted invasive mechanical ventilation.

Patient-ventilator dyssynchrony is common during mechanical ventilation. Dyssynchrony decreases comfort, prolongs mechanical ventilation and intensive care unit stays, and might lead to worse outcome. Dyssynchrony can occur during the triggering of the ventilator, the inspiration period after triggering, the transition from inspiration to expiration, and the expiratory phase. The most common dyssynchronies are delayed triggering, autotriggering, ineffective inspiratory efforts (which can occur at any point in the respiratory cycle), mismatch between the patient's and ventilator's inspiratory times, and double triggering. At present, the detection of dyssynchronies usually depends on healthcare staff observing ventilator waveforms; however, performance is suboptimal and many events go undetected. To date, technological complexity has made it impossible to evaluate patient-ventilator synchrony throughout the course of mechanical ventilation. Studies have shown that a high index of dyssynchrony may increase the duration of mechanical ventilation. Better training, better ventilatory modes, and/or computerized systems that permit better synchronization of patients' demands and ventilator outputs are necessary to improve patient-ventilator synchrony.

Histone deacetylases and the immunological network: implications in cancer and inflammation.

The initiation, magnitude and duration of an immune response against antigens are a tightly regulated process involving a dynamic, orchestrated balance of pro- and anti-inflammatory pathways in immune cells. Such a delicate balance is critical for allowing efficient immune response against foreign antigens while preventing autoimmune attack against self-antigens. In recent years, much effort has been devoted to understanding immune evasion by cancer cells. Also, significant advances have been made in mechanistically understanding the role of pro- and anti-inflammatory cytokines in the regulation of immune responses against antigens, including those expressed by tumors. However, we still know very little about the regulation of inflammatory/anti-inflammatory genes in their natural setting, the chromatin substrate. Several mechanisms have been identified to influence chromatin flexibility and allow dynamic changes in gene expression. Among those, chromatin modifications induced by acetylation and deacetylation of histone tails have gained wide attention. In this study, we discuss the role of histone deacetylases in the transcriptional regulation of genes involved in the inflammatory response and how these enzymes coordinate the dynamic expression of these genes during an immune response. This emerging knowledge is opening new avenues to better understand epigenetic regulation of inflammatory responses and providing new molecular targets for either amplifying or ameliorating immune responses.