Fibroblast growth factor 23 (FGF23), a hormone secreted by osteocytes and osteoblasts, is a major regulator of vitamin D and phosphate homeostasis. FGF23 has been associated with the disturbance of ...mineral homeostasis, and with kidney and cardiovascular diseases. Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect virtually any organ. In the present work, we set out to analyze the relationship of FGF23 with the expression of SLE, including patterns of activity, damage, and severity. A total of 284 well-characterized patients with SLE were recruited. Activity (SLEDAI), severity (Katz), and damage index (SLICC-DI) scores were determined. The serum levels of FGF23 were also assessed. Multivariable linear regression analysis was performed to study the relationship between disease characteristics and FGF23. FGF23 and 25(OH) vitamin D were negatively correlated. Furthermore, prednisone use was associated with higher circulating FGF23 after an adjustment for confounding factors. SLICC-DI was related to higher serum levels of FGF23 after a multivariable analysis. However, when the SLICC-DI index items and domains were analyzed separately, apart from proteinuria ≥3.5 gm/24 h, only the musculoskeletal domain, encompassing arthritis and osteoporosis, was significantly associated with higher serum levels of FGF23. In conclusion, an association is observed between elevated serum FGF23 levels and disease damage, particularly related to musculoskeletal complications and proteinuria, in patients with SLE.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia. Complement system disturbance is ...implicated in the pathogenesis of SLE. In this work, we aim to study how a full assessment of the complement system, which includes the evaluation of its three pathways, relates to blood cell counts in a population of patients with SLE. New-generation functional assays of the classical, alternative, and lectin pathways of the complement system were conducted in 284 patients with SLE. Additionally, serum levels of inactive molecules (C1q, C2, C3, C4, factor D) and activated molecules (C3a), as well as regulators (C1-inhibitor and factor H), were evaluated. Complete blood cell counts were analyzed. Multivariable linear regression analysis was performed to study the relationship of hematological profiles with this full characterization of the complement system. After multivariable adjustments that included age, sex, SLICC-DI (damage), and SLEDAI (activity) scores, as well as the use of aspirin, prednisone, methotrexate, azathioprine, and mycophenolate mofetil, several relationships were observed between the C pathways and the individual products and blood cells profile. Lower values of C1q and C2 were associated with lower hemoglobin levels. Lower leukocyte counts showed significantly lower values of C4, C1 inhibitor, C3, factor D, and alternative pathway functional levels. Neutrophil counts showed significant negative relationships only with the alternative pathway and C1-inh. In the case of lymphocytes, associations were found, especially with functional tests of the classical and alternative pathways, as well as with C2, C4, C3, and C3a. On the contrary, for platelets, significance was only observed, after multivariable adjustment, with lower C2 concentrations. In conclusion, the serum complement system and hematological profile in SLE are independently linked, after adjustment for disease activity and damage. These relationships are basically negative and are predominantly found in lymphocytes.
The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A ...cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.
Osteosarcoma is the most frequent primary bone tumor in the pediatric age group. Its aggressive local growth pattern and its high propensity to metastasize, mainly to the lungs, give the disease an ...unfavorable prognosis that has situated this disease as one of the leading causes of pediatric cancer death. Current protocols for osteosarcoma treatment are based on neo-adjuvant (pre-operatory) chemotherapy followed by surgical resection of the tumor and a new phase of adjuvant chemotherapy. Despite the progress that these protocols have made in improving the outcome of the disease, the limited access of drugs to bone tumor and metastases, their indiscriminate distribution in the organism, the high required doses that cause intolerable toxicity and the development of multidrug resistance, still represent a major challenge. Nanotechnology has emerged as a new strategy to successfully address these problems by the development of nanoscaled drug carriers that present the ability to target the drug to the tumor cells, achieving high drug concentrations in the tumor area, while decreasing its presence in healthy tissues and therefore its potential systemic toxicity. This review summarizes the different lipid nanocarriers developed to deliver first and second-line anti-osteosarcoma drugs as well as emerging agents in the treatment of this disease. Moreover, it also discusses the potential of these nanocarriers for the treatment of osteosarcoma.
Cholesterol efflux capacity (CEC), the ability of high-density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages, has been linked to cardiovascular events. Systemic lupus ...erythematosus (SLE) is characterized by the consumption of complement (C) proteins and has been associated with an increased risk of cardiovascular disease. CEC is reduced in SLE patients compared to controls. In the present work, our objective was to analyze whether the disruption of C influences CEC in patients with SLE. New-generation functional assays of the three pathways of the C system were performed in 207 patients with SLE. Additionally, serum levels of inactive (C1q, C2, C3, C4, and factor D) and activated (C3a) molecules, and regulators (C1-inhibitor and factor H) of C system were measured. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed. Multivariable linear regression analysis was performed to assess the relationship between C system and CEC. After full multivariable analysis, the alternative C cascade functional test showed a significant and negative relationship with CEC. This was also the case for C2 and C3, in which the associations were found to be positive and statistically significant, after adjustment for covariates. In conclusion, C system and CEC are interconnected in patients with SLE.
Purpose
Definitions of acute respiratory distress syndrome (ARDS) include radiographic criteria, but there are concerns about reliability and prognostic relevance. This study aimed to evaluate the ...independent relationship between chest imaging and mortality and examine the inter-rater variability of interpretations of chest radiographs (CXR) in pediatric ARDS (PARDS).
Methods
Prospective, international observational study in children meeting Pediatric Acute Lung Injury Consensus Conference (PALICC) criteria for PARDS, which requires new infiltrate(s) consistent with pulmonary parenchymal disease, without mandating bilateral infiltrates. Mortality analysis focused on the entire cohort, whereas inter-observer variability used a subset of patients with blinded, simultaneous interpretation of CXRs by intensivists and radiologists.
Results
Bilateral infiltrates and four quadrants of alveolar consolidation were associated with mortality on a univariable basis, using CXRs from 708 patients with PARDS. For patients on either invasive (IMV) or non-invasive ventilation (NIV) with PaO
2
/FiO
2
(PF) ratios (or SpO
2
/FiO
2
(SF) ratio equivalent) > 100, neither bilateral infiltrates (OR 1.3 (95% CI 0.68, 2.5),
p
= 0.43), nor 4 quadrants of alveolar consolidation (OR 1.6 (0.85, 3),
p
= 0.14) were associated with mortality. For patients with PF ≤ 100, bilateral infiltrates (OR 3.6 (1.4, 9.4),
p
= 0.01) and four quadrants of consolidation (OR 2.0 (1.14, 3.5),
p
= 0.02) were associated with higher mortality. A subset of 702 CXRs from 233 patients had simultaneous interpretations. Interobserver agreement for bilateral infiltrates and quadrants was “slight” (kappa 0.31 and 0.33). Subgroup analysis showed agreement did not differ when stratified by PARDS severity but was slightly higher for children with chronic respiratory support (kappa 0.62), NIV at PARDS diagnosis (kappa 0.53), age > 10 years (kappa 0.43) and fluid balance > 40 ml/kg (kappa 0.48).
Conclusion
Bilateral infiltrates and quadrants of alveolar consolidation are associated with mortality only for those with PF ratio ≤ 100, although there is high- inter-rater variability in these chest-x ray parameters.
A new method to form a nanoparticle-structured hydrogel is reported; it is based on the drug being loaded into the nanoparticles to form a solid structure. A lipophilic form of gemcitabine (modified ...lauroyl), an anti-cancer drug, was encapsulated in lipid nanocapsules (LNCs), using a phase-inversion temperature process. A gel was formed spontaneously, depending on the LNC concentration. The drug loading, measured with total entrapment efficiency, and the rheological properties of the gel were assessed. Physical studies (surface tension measurements) showed that modified gemcitabine was localised at the oil-water interface of the LNC, and that the gemcitabine moieties of the prodrug were exposed to the water phase. This particular assembly promoted inter-LNC interactions via hydrogen bonds between gemcitabine moieties that led to an LNC gel structure in water, without a matrix, like a tridimensional pearl necklace. Dilution of the gel produced a gemcitabine-loaded LNC suspension in water, and these nanoparticles presented cytotoxic activity to various cancer cell lines to a greater degree than the native drug. Finally, the syringeability of the formulation was successfully tested and perspectives of its use as a nanomedicine (intratumoural or subcutaneous injection) can be foreseen.
Pediatric-specific ventilator liberation guidelines are lacking despite the many studies exploring elements of extubation readiness testing. The lack of clinical practice guidelines has led to ...significant and unnecessary variation in methods used to assess pediatric patients' readiness for extubation.
Twenty-six international experts comprised a multiprofessional panel to establish pediatrics-specific ventilator liberation clinical practice guidelines, focusing on acutely hospitalized children receiving invasive mechanical ventilation for more than 24 hours. Eleven key questions were identified and first prioritized using the Modified Convergence of Opinion on Recommendations and Evidence. A systematic review was conducted for questions that did not meet an
threshold of ⩾80% agreement, with Grading of Recommendations, Assessment, Development, and Evaluation methodologies applied to develop the guidelines. The panel evaluated the evidence and drafted and voted on the recommendations.
Three questions related to systematic screening using an extubation readiness testing bundle and a spontaneous breathing trial as part of the bundle met Modified Convergence of Opinion on Recommendations criteria of ⩾80% agreement. For the remaining eight questions, five systematic reviews yielded 12 recommendations related to the methods and duration of spontaneous breathing trials, measures of respiratory muscle strength, assessment of risk of postextubation upper airway obstruction and its prevention, use of postextubation noninvasive respiratory support, and sedation. Most recommendations were conditional and based on low to very low certainty of evidence.
This clinical practice guideline provides a conceptual framework with evidence-based recommendations for best practices related to pediatric ventilator liberation.
After more than ten years of operation of EU-ETS trading, it is time to analyse the results and draw lessons from the experience. Economic research typically considers emission price as the main ...explanatory variables when measuring the effects of Emission Trading Systems. The novelty of this work is to analyse whether or not trade alone, as an institutional change, is effective in reducing greenhouse gases emissions. The objective of this paper is to analyse to what extent the EU-ETS as a “regulatory” instrument of the supply of allowances is responsible for the effectiveness of the carbon market as a basic tool in the reduction of emissions. The analysis also includes other overlapping policies aimed at fighting climate change, for example, the promotion of renewables. For the empirical analysis, an econometric model is estimated using panel data for the 28 European Union countries between 1990 and 2014. The econometric model include three dummy variables to measure the effectiveness of the three phases of the EU-ETS commerce in reducing emissions. Furthermore, we analyse how effective the phases are when renewables energies are included in the analysis. The results show that the EU-ETS is effective to reduce emissions and each phase has a greater impact on the reduction. Nevertheless, the system should be more flexible to adapt to the fluctuations in the demand for rights.
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