GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes.

Gasdermin-D (GsdmD) is a critical mediator of innate immune defense because its cleavage by the inflammatory caspases 1, 4, 5, and 11 yields an N-terminal p30 fragment that induces pyroptosis, a death program important for the elimination of intracellular bacteria. Precisely how GsdmD p30 triggers pyroptosis has not been established. Here we show that human GsdmD p30 forms functional pores within membranes. When liberated from the corresponding C-terminal GsdmD p20 fragment in the presence of liposomes, GsdmD p30 localized to the lipid bilayer, whereas p20 remained in the aqueous environment. Within liposomes, p30 existed as higher-order oligomers and formed ring-like structures that were visualized by negative stain electron microscopy. These structures appeared within minutes of GsdmD cleavage and released Ca(2+) from preloaded liposomes. Consistent with GsdmD p30 favoring association with membranes, p30 was only detected in the membrane-containing fraction of immortalized macrophages after caspase-11 activation by lipopolysaccharide. We found that the mouse I105N/human I104N mutation, which has been shown to prevent macrophage pyroptosis, attenuated both cell killing by p30 in a 293T transient overexpression system and membrane permeabilization in vitro, suggesting that the mutants are actually hypomorphs, but must be above certain concentration to exhibit activity. Collectively, our data suggest that GsdmD p30 kills cells by forming pores that compromise the integrity of the cell membrane.

Treatment outcomes of obstructive sleep apnoea in obese community-dwelling children: the NANOS study.

The first line of treatment of obstructive sleep apnoea syndrome (OSAS) in children consists of adenotonsillectomy (T&A). The aim of the present study was to evaluate treatment outcomes of OSAS among obese children recruited from the community.A cross-sectional, prospective, multicentre study of Spanish obese children aged 3-14 years, with four groups available for follow-up: group 1: non-OSAS with no treatment; group 2: dietary treatment; group 3: surgical treatment; and group 4: continuous positive airway pressure treatment.117 obese children (60 boys, 57 girls) with a mean age of 11.3±2.9 years completed the initial (T0) and follow-up (T1) assessments. Their mean body mass index (BMI) at T1 was 27.6±4.7 kg·m(-2), corresponding to a BMI Z-score of 1.34±0.59. Mean respiratory disturbance index (RDI) at follow-up was 3.3±3.9 events·h(-1). Among group 1 children, 21.2% had an RDI ≥3 events·h(-1) at T1, the latter being present in 50% of group 2, and 43.5% in group 3. In the binary logistic regression model, age emerged as a significant risk factor for residual OSAS (odds ratio 1.49, 95% confidence interval 1.01-2.23; p<0.05) in obese children surgically treated, and RDI at T0 as well as an increase in BMI emerged as significant risk factors for persistent OSAS in obese children with dietary treatment (OR 1.82, 95% CI 1.09-3.02 (p<0.03) and OR 8.71, 95% CI 1.24-61.17 (p=0.03)).Age, RDI at diagnosis and obesity are risk factors for relatively unfavourable OSAS treatment outcomes at follow-up.

Inflammatory markers and obstructive sleep apnea in obese children: the NANOS study.

INTRODUCTION: Obesity and obstructive sleep apnea syndrome (OSA) are common coexisting conditions associated with a chronic low-grade inflammatory state underlying some of the cognitive, metabolic, and cardiovascular morbidities. AIM: To examine the levels of inflammatory markers in obese community-dwelling children with OSA, as compared to no-OSA, and their association with clinical and polysomnographic (PSG) variables. Methods. In this cross-sectional, prospective multicenter study, healthy obese Spanish children (ages 4-15 years) were randomly selected and underwent nocturnal PSG followed by a morning fasting blood draw. Plasma samples were assayed for multiple inflammatory markers. RESULTS: 204 children were enrolled in the study; 75 had OSA, defined by an obstructive respiratory disturbance index (RDI) of 3 events/hour total sleep time (TST). BMI, gender, and age were similar in OSA and no-OSA children. Monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in OSA children, with interleukin-6 concentrations being higher in moderate-severe OSA (i.e., AHI > 5/hrTST; P < 0.01), while MCP-1 levels were associated with more prolonged nocturnal hypercapnia (P < 0.001). CONCLUSION: IL-6, MCP-1, and PAI-1 are altered in the context of OSA among community-based obese children further reinforcing the proinflammatory effects of sleep disorders such as OSA. This trial is registered with ClinicalTrials.gov NCT01322763.

Accelerated partial breast irradiation in a single 18 Gy fraction with high-dose-rate brachytherapy: preliminary results.

PURPOSE: To evaluate the feasibility of acute and chronic toxicity in patients suitable for accelerated partial breast irradiation (APBI) in a single 18 Gy fraction with multicatheter high-dose-rate (HDR) brachytherapy, as well as cosmetic and oncological outcomes. MATERIAL AND METHODS: Between September 2014 and March 2016, twenty consecutive patients with low-risk invasive and ductal carcinoma in situ were treated with interstitial multicatheter HDR brachytherapy in a single 18 Gy fraction. RESULTS: Median age was 63.5 years (range, 51-79). Acute toxicity was observed in seven patients, while the pain during following days and hematoma were seen in four patients. With a median follow-up of 24 months, late toxicity was found in one patient with fat necrosis g2 and fibrosis g2 in another patient. The overall survival (OS) and locoregional control (LC) was 100%. Disease-free survival (DFS) and distant control was 95%. Good to excellent cosmetic outcomes were noted in 80% of patients and fair in 4 patients (20%). CONCLUSIONS: This is the first report in the medical literature that focuses on feasibility and acute and chronic toxicity, with a median follow-up of 24 months (range, 20-40). The protocol is viable and convenient. However, a longer follow-up is needed to know chronic toxicity and oncologic outcomes.

Representaciones sociales asociadas al VIH/Sida en universitarios colombianos / Social representations associated with HIV/AIDS in Colombian university students

Resumen El objetivo de esta investigación fue comprender las representaciones sociales asociadas al VIH y al Sida en un grupo de adolescentes y jóvenes universitarios colombianos. Para ello, se realizó un estudio cualitativo de diseño fenomenológico interpretativo en el que participaron 18 estudiantes universitarios. Las técnicas de recolección empleadas fueron las redes semánticas naturales (RSN) y los grupos de discusión. Las narrativas evidenciaron que existe desconocimiento sobre aspectos generales del VIH y del Sida. También dieron cuenta de la creencia de que el riesgo de contraer VIH recae únicamente en grupos etiquetados en riesgo. Se identificaron, además, actitudes que denotan estigma hacia personas con la enfermedad. Los pares, los padres, la familia y el internet se reportaron como los principales agentes de socialización sobre la enfermedad. En conclusión, se destaca la necesidad de empoderar a los diferentes agentes de socialización y de fortalecer los procesos educativos desde el reconocimiento de los derechos humanos de todas las personas. Se requiere, por tanto, un trabajo articulado, integral y transversal de los diferentes agentes, no solo para la deconstrucción de las creencias y actitudes negativas hacia la enfermedad, sino para la construcción de una sexualidad responsable y saludable que esté centrada en el autocuidado.

Abstract This research aimed to understand the social representations associated with HIV and AIDS in a group of adolescents and university students from Colombia. For this, a qualitative study of phenomenological interpretative design was carried out with 18 university students. The collection techniques used were natural semantic networks (NSN) and discussion groups. The narratives showed that there is lack of knowledge about general aspects of HIV and AIDS. They also reported a belief that the risk of contracting HIV relapses only into at-risk groups. In addition, attitudes that denote stigma towards people with the disease were identified. Partners, parents, family and internet were reported as the main agents of socialization about the disease. In conclusion, the need to empower the different socialization agents and to strengthen educational processes from the recognition of the human rights of all people is highlighted. Therefore, it is required an articulated, integral and transversal work of the different agents, not only for the deconstruction of the negative beliefs and attitudes towards the disease, but for the construction of a responsible and healthy sexuality that is centered in the self-care.

Effectiveness of home single-channel nasal pressure for sleep apnea diagnosis.

INTRODUCTION: Home single-channel nasal pressure (HNP) may be an alternative to polysomnography (PSG) for obstructive sleep apnea (OSA) diagnosis, but no cost studies have yet been carried out. Automatic scoring is simpler but generally less effective than manual scoring. OBJECTIVES: To determine the diagnostic efficacy and cost of both scorings (automatic and manual) compared with PSG, taking as a polysomnographic OSA diagnosis several apnea-hypopnea index (AHI) cutoff points. METHODS: We included suspected OSA patients in a multicenter study. They were randomized to home and hospital protocols. We constructed receiver operating characteristic (ROC) curves for both scorings. Diagnostic efficacy was explored for several HNP AHI cutoff points, and costs were calculated for equally effective alternatives. RESULTS: Of 787 randomized patients, 752 underwent HNP. Manual scoring produced better ROC curves than automatic for AHI < 15; similar curves were obtained for AHI ≥ 15. A valid HNP with manual scoring would determine the presence of OSA (or otherwise) in 90% of patients with a polysomnographic AHI ≥ 5 cutoff point, in 74% of patients with a polysomnographic AHI ≥ 10 cutoff point, and in 61% of patients with a polysomnographic AHI ≥ 15 cutoff point. In the same way, a valid HNP with automatic scoring would determine the presence of OSA (or otherwise) in 73% of patients with a polysomnographic AHI ≥ 5 cutoff point, in 64% of patients with a polysomnographic AHI ≥ 10 cutoff point, and in 57% of patients with a polysomnographic AHI ≥ 15 cutoff point. The costs of either HNP approaches were 40% to 70% lower than those of PSG at the same level of diagnostic efficacy. Manual HNP had the lowest cost for low polysomnographic AHI levels (≥ 5 and ≥ 10), and manual and automatic scorings had similar costs for higher polysomnographic cutoff points (AHI ≥ 15) of diagnosis. CONCLUSION: Home single-channel nasal pressure (HNP) is a cheaper alternative than polysomnography for obstructive sleep apnea diagnosis. HNP with manual scoring seems to have better diagnostic accuracy and a lower cost than automatic scoring for patients with low apnea-hypopnea index (AHI) levels, although automatic scoring has similar diagnostic accuracy and cost as manual scoring for intermediate and high AHI levels. Therefore, automatic scoring can be appropriately used, although diagnostic efficacy could improve if we carried out manual scoring on patients with AHI < 15. CLINICAL TRIALS INFORMATION: Clinicaltrials.gov identifier: NCT01347398.