[Long-acting reversible contraception methods in women under 26 years of age]. / Métodos anticonceptivos de larga duración en mujeres menores de 26 años.

OBJECTIVES: Long-acting reversible contraception (LARC) methods have proven their high safety and efficacy for pregnancy prevention and they are specially indicated in young and vulnerable population, but their use encounter barriers both between providers and users due to lack of information or to the economic cost. The aim of this study was to assess the use of two LARC methods, intrauterine device (IUD) and implant, in minors under 26 years old after giving an adequate contraceptive advice and subsidizing them in vulnerability situations. To analyze the population that chooses them, the side effects, the reasons for abandoning and the permanence time. MATERIAL AND METHODS: Retrospective descriptive study of IUD and implants inserted to minors under 26 years old from January 2016 to December 2019 at the Municipal Health Center of Usera belonging to Madrid Salud. Data is collected from n=266 women who started using IUD or implant. 87 copper IUD, 37 medicated IUD and 142 implants have been placed. RESULTS: Increased prescription of both methods, with significant implant use in the last year of the study. There has been vulnerability in 91.7% of women. The average age of IUD users is about 21.4 years, almost 2 years older than that of the implant and they have more children. The side effects frequency has been similar with both methods, being abnormal bleeding as the most frequent side effect. 31% of copper IUD, 32% of medicated IUD and 12% of implants have been removed early. The average permanence time was 19.3 months (SD=13.3), 89.1% remained at the end of the first year, 81.2% at two years and 77.4% at three years. CONCLUSIONS: An adequate contraceptive advice and free access are essential keys for increasing the LARC methods use in this particularly vulnerable population. Few and minor side effects and high continuity rate have been found, especially for the implant.

Exploring the radiosensitizing potential of magnetotherapy: a pilot study in breast cancer cells.

Aim: To explore the influence of electromagnetic fields (EMFs) on the cell cycle progression of MDA-MB-231 and MCF-7 breast cancer cell lines and to evaluate the radiosensitizing effect of magnetotherapy during therapeutic co-exposure to EMFs and radiotherapy. Material and methods: Cells were exposed to EMFs (25, 50 and 100 Hz; 8 and 10 mT). In the co-treatment, cells were first exposed to EMFs (50 Hz/10 mT) for 30 min and then to ionizing radiation (IR) (2 Gy) 4 h later. Cell cycle progression and free radical production were evaluated by flow cytometry, while radiosensitivity was explored by colony formation assay. Results: Generalized G1-phase arrest was found in both cell lines several hours after EMF exposure. Interestingly, a marked G1-phase delay was observed at 4 h after exposure to 50 Hz/10 mT EMFs. No cell cycle perturbation was observed after repeated exposure to EMFs. IR-derived ROS production was enhanced in EMF-exposed MCF-7 cells at 24 h post-exposure. EMF-exposed cells were more radiosensitive in comparison to sham-exposed cells. Conclusions: These results highlight the potential benefits of concomitant treatment with magnetotherapy before radiotherapy sessions to enhance the effectiveness of breast cancer therapy. Further studies are warranted to identify the subset(s) of patients who would benefit from this multimodal treatment.

Radiofrequency exposure in the Neonatal Medium Care Unit.

The aims of this study were to characterize electromagnetic fields of radiofrequency (RF-EMF) levels generated in a Neonatal Medium Care Unit and to analyze RF-EMF levels inside unit's incubators. Spot and long-term measurements were made with a dosimeter. The spot measurement mean was 1.51±0.48V/m. Higher values were found in the proximity to the window and to the incubator evaluated. Mean field strength for the entire period of 17h was 0.81 (±0.07)V/m and the maximum value was 1.58V/m for long-term RF-EMF measurements in the incubator. Values found during the night period were higher than those found during the day period. It is important to consider RF-EMF exposure levels in neonatal care units, due to some evidence of adverse health effects found in children and adults. Characterization of RF-EMF exposure may be important to further investigate the mechanisms and underlying effects of electromagnetic fields (EMF) on infant health. A prudent avoidance strategy should be adopted because newborns are at a vulnerable stage of development and the actual impact of EMF on premature infants is unknown.

Comparative study of the effect of PTH (1-84) and strontium ranelate in an experimental model of atrophic nonunion.

UNLABELLED: This study aimed to set up an experimental model of long bone atrophic nonunion and to explore the potential role of PTH-1-84 (PTH 1-84) and strontium ranelate (SrR). A model of atrophic nonunion was created in Sprague-Dawley rats at the femoral midshaft level. The animals were randomised into four groups. Group A1: control rodents, fracture without bone gap; Group A2: rodents with subtraction osteotomy (non-union model control) treated with saline; Group B: rodents with subtraction osteotomy treated with human-PTH (PTH 1-84); and Group C: rodents with subtraction osteotomy treated with strontium ranelate (SrR). The groups were followed for 12 weeks. X-rays were be obtained at weeks 1, 6 and 12. After sacrificing the animals, we proceeded to the biomechanical study and four point bending tests to evaluate the resistance of the callus and histological study. In second phase, the expression of genes related to osteoblast function was analysed by reverse transcription-quantitative PCR in rats subjected to substraction osteotomy and treated for 2 weeks. The animals were randomised into three groups: Group A2: rodents treated with saline; Group B: rodents treated with PTH 1-84 and Group C: rodents treated with SrR. RESULTS: No significant histological differences were found between animals subjected to subtraction osteotomy and treated with either saline or PTH (p=0.628), but significant difference existed between animals receiving saline or SrR (p=0.005). There were no significant differences in X-ray score between the saline and PTH groups at either 6 or 12 weeks (p=0.33 and 0.36, respectively). On the other hand, better X-ray scores were found in the SrR group (p=0.047 and 0.006 in comparison with saline, at 6 and 12 weeks, respectively). In line with this, biomechanical tests revealed improved results in the SrR group. Gene expression analysis revealed a slightly decreased levels of DKK1, a Wnt pathway inhibitor, in rats treated with SrR. CONCLUSIONS: SrR increases has a beneficial effect in this atrophic non-union model in rats. This suggests that it might have a role may have important implications for the potential clinical role in the treatment of fracture nonunion.

[Treatment of proximal humeral fractures by reverse shoulder arthroplasty: mid-term evaluation of functional results and Notching]. / Evaluación de resultados funcionales y Notching tras el tratamiento de fracturas de húmero mediante artroplastia total invertida a medio plazo.

OBJECTIVE: An analysis was made on relationship between Notching and functional and radiographic parameters after treatment of acute proximal humeral fractures with reverse total shoulder arthroplasty. METHODS: A retrospective evaluation was performed on 37 patients with acute proximal humeral fracture treated by reversed shoulder arthroplasty. The mean follow-up was 24 months. Range of motion, intraoperative and postoperative complications were recorded. Nerot's classification was used to evaluate Notching. Patient satisfaction was evaluated with the Constant Score (CS). Statistical analysis was performed to evaluate the relationship between Notching and glenosphere position, or functional outcomes. RESULTS: Mean range of elevation, abduction, external and internal rotation were 106.22°, 104.46°, 46.08° and 40.27°, respectively. Mean CS was 63. Notching was present at 12 months in 29% of patients. Statistical analysis showed significance differences between age and CS, age and notching development, and tilt with notching. No statistical significance differences were found between elevation, abduction, internal and external rotation and CS either with scapular or glenosphere-neck angle. CONCLUSION: Reverse shoulder arthroplasty is a valuable option for acute humeral fractures in patients with osteoporosis and cuff-tear arthropathy. It leads to early pain relief and shoulder motion. Nevertheless, it is not exempt from complications, and long-term studies are needed to determine the importance of notching.

Outdoor characterization of radio frequency electromagnetic fields in a Spanish birth cohort.

There is considerable public concern in many countries about the possible adverse effects of exposure to non-ionizing radiation electromagnetic fields, especially in vulnerable populations such as children. The aim of this study was to characterize environmental exposure profiles within the frequency range 100kHz-6GHz in the immediate surrounds of the dwellings of 123 families from the INMA-Granada birth cohort in Southern Spain, using spot measurements. The arithmetic mean root mean-square electric field (ERMS) and power density (SRMS) values were, respectively, 195.79mV/m (42.3% of data were above this mean) and 799.01µW/m(2) (30% of values were above this mean); median values were 148.80mV/m and 285.94µW/m(2), respectively. Exposure levels below the quantification limit were assigned a value of 0.01V/m. Incident field strength levels varied widely among different areas or towns/villages, demonstrating spatial variability in the distribution of exposure values related to the surface area population size and also among seasons. Although recorded values were well below International Commission for Non-Ionizing Radiation Protection reference levels, there is a particular need to characterize incident field strength levels in vulnerable populations (e.g., children) because of their chronic and ever-increasing exposure. The effects of incident field strength have not been fully elucidated; however, it may be appropriate to apply the precautionary principle in order to reduce exposure in susceptible groups.

Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown. MATERIALS AND METHODS: We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors. RESULTS: Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines. CONCLUSIONS: Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.

Missense polymorphisms of the WNT16 gene are associated with bone mass, hip geometry and fractures.

UNLABELLED: Two missense polymorphisms of WNT16 were associated with hip bone mineral density (BMD), the buckling ratio of the femoral neck, calcaneal ultrasound and hip fractures in individuals under 80 years of age. These results confirm the association of the WNT16 gene with bone mass and osteoporotic fractures. INTRODUCTION: Osteoporosis has a strong genetic component. Wnt ligands stimulate the differentiation of osteoblast precursors and play a major role in skeletal homeostasis. Therefore, the aim of this study was to explore the association of allelic variants of the WNT16 gene with BMD, other structural parameters of bone and osteoporotic hip fractures. METHODS: Six single nucleotide polymorphisms were analysed in 1,083 Caucasian individuals over 49 years of age. RESULTS: Two missense polymorphisms (rs2908004 and rs2707466) were associated with femoral neck BMD, with average differences across genotypes of 35 mg/cm(2) (p = 0.00037 and 0.0015, respectively). Likewise, the polymorphisms were associated with calcaneal quantitative ultrasound parameters (p = 0.00004 and 0.0014, respectively) and the buckling ratio, an index of cortical instability of the femoral neck (p = 0.0007 and 0.0029, respectively). Although there were no significant differences in the genotype frequency distributions between 294 patients with hip fractures and 670 controls, among the subgroup under 80 years of age, TT genotypes were underrepresented in patients with fractures (odds ratio 0.50; CI 0.27-0.94). CONCLUSION: Common missense polymorphisms of the WNT16 gene are associated with BMD at the hip, calcaneal ultrasound and the buckling ratio of the femoral neck, as well as with hip fractures in individuals under 80 years of age. Overall, these results confirm the association of the WNT16 locus with BMD identified in genome-wide association studies and support its role in determining the risk of osteoporotic fractures.

Matrix metalloproteinases: potential therapy to prevent the development of second malignancies after breast radiotherapy.

Radiotherapy is widely used in the treatment of patients with breast cancer, but ionizing radiation-induced carcinogenesis has been described in several studies. Matrix metalloproteinases (MMPs) are a wide family of proteases secreted by tumour and microenvironmental cells that are directly linked with invasion and metastasis through complete extracellular matrix (ECM) breakage. In the past decade, MMPs have been associated with other carcinogenesis steps, including tumour growth and angiogenesis promotion. Moreover, in vitro studies have demonstrated an enhanced migration, invasiveness, and angiogenic ability of cancer cells after radiation exposure through an increase in MMP activity. These findings are consistent with clinical observations of breast cancer metastases raised in bone, lung and brain tissues after radiotherapy. The aim of this review was to analyse the current state of research on MMPs and report new insights into the potential of MMP-targeted therapy in combination with radiotherapy to decrease the risk of radiation-induced second malignancies and to improve the overall survival of breast cancer patients.

Exposure to electromagnetic fields (non-ionizing radiation) and its relationship with childhood leukemia: a systematic review.

Childhood exposure to physical contamination, including non-ionizing radiation, has been implicated in numerous diseases, raising concerns about the widespread and increasing sources of exposure to this type of radiation. The primary objective of this review was to analyze the current state of knowledge on the association between environmental exposure to non-ionizing radiation and the risk of childhood leukemia. Scientific publications between 1979 and 2008 that include examination of this association have been reviewed using the MEDLINE/PubMed database. Studies to date have not convincingly confirmed or ruled out an association between non-ionizing radiation and the risk of childhood leukemia. Discrepancies among the conclusions of the studies may also be influenced by confounding factors, selection bias, and misclassification. Childhood defects can result from genetic or epigenetic damage and from effects on the embryo or fetus, which may both be related to environmental exposure of the parent before conception or during the pregnancy. It is therefore critical for researchers to define a priori the type and "window" of exposure to be assessed. Methodological problems to be solved include the proper diagnostic classification of individuals and the estimated exposure to non-ionizing radiation, which may act through various mechanisms of action. There appears to be an urgent need to reconsider exposure limits for low frequency and static magnetic fields, based on combined experimental and epidemiological research into the relationship between exposure to non-ionizing radiation and adverse human health effects.

Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study.

UNLABELLED: In comparison with hip fractures, increased expression of genes in the Wnt pathway and increased Wnt activity were found in bone samples and osteoblast cultures from patients with osteoarthritis, suggesting the involvement of this pathway in subchondral bone changes. No consistent differences were found in the genetic association study. INTRODUCTION: This study aims to explore the allelic variations and expression of Wnt pathway genes in patients with osteoporosis and osteoarthritis. METHODS: The expression of 86 genes was studied in bone samples and osteoblast primary cultures from patients with hip fractures and hip or knee osteoarthritis. The Wnt-related activity was assessed by measuring AXIN2 and in transfection experiments. Fifty-five SNPs of the LRP5, LRP6, FRZB, and SOST genes were analyzed in 1,128 patients. RESULTS: Several genes were differentially expressed in bone tissue, with the lowest values usually found in hip fracture and the highest in knee osteoarthritis. Overall, seven genes were consistently upregulated both in tissue samples and in cell cultures from patients with knee osteoarthritis (BCL9, FZD5, DVL2, EP300, FRZB, LRP5, and TCF7L1). The increased expression of AXIN2 and experiments of transient transfection of osteoblasts with the TOP-Flash construct confirmed the activation of Wnt signaling. Three SNPs of the LRP5 gene and one in the LRP6 gene showed marginally significant differences in allelic frequencies across the patient groups, but they did not resist multiple-test adjustment. CONCLUSIONS: Genes in the Wnt pathway are upregulated in the osteoarthritic bone, suggesting their involvement not only in cartilage distortion but also in subchondral bone changes.

Rhomboid domain containing 2 (RHBDD2): a novel cancer-related gene over-expressed in breast cancer.

In the course of breast cancer global gene expression studies, we identified an uncharacterized gene known as RHBDD2 (Rhomboid domain containing 2) to be markedly over-expressed in primary tumors from patients with recurrent disease. In this study, we identified RHBDD2 mRNA and protein expression significantly elevated in breast carcinomas compared with normal breast samples as analyzed by SAGE (n=46) and immunohistochemistry (n=213). Interestingly, specimens displaying RHBDD2 over-expression were predominantly advanced stage III breast carcinomas (p=0.001). Western-blot, RT-PCR and cDNA sequencing analyses allowed us to identify two RHBDD2 alternatively spliced mRNA isoforms expressed in breast cancer cell lines. We further investigated the occurrence and frequency of gene amplification and over-expression affecting RHBDD2 in 131 breast samples. RHBDD2 gene amplification was detected in 21% of 98 invasive breast carcinomas analyzed. However, no RHBDD2 amplification was detected in normal breast tissues (n=17) or breast benign lesions (n=16) (p=0.014). Interestingly, siRNA-mediated silencing of RHBDD2 expression results in a decrease of MCF7 breast cancer cells proliferation compared with the corresponding controls (p=0.001). In addition, analysis of publicly available gene expression data showed a strong association between high RHBDD2 expression and decreased overall survival (p=0.0023), relapse-free survival (p=0.0013), and metastasis-free interval (p=0.006) in patients with primary ER-negative breast carcinomas. In conclusion, our findings suggest that RHBDD2 over-expression behaves as an indicator of poor prognosis and may play a role facilitating breast cancer progression.

PARP-1-dependent 3-nitrotyrosine protein modification after DNA damage.

3-nitrotyrosine (NO2-Tyr) is thought to be a specific marker of cell injury during oxidative damage. We have evaluated the role of poly(ADP-ribose)polymerase-1 (PARP-1) in protein nitration after treatment of immortalized fibroblasts parp-1+/+ and parp-1-/- with the alkylating agent 2'-methyl-2'-nitroso-urea (MNU). Both cell lines showed increased iNOS expression following MNU treatment in parallel with a selective induction of tyrosine nitration of different proteins. PARP-1 deficient cells displayed a delayed iNOS accumulation, reduced number of nitrated proteins, and a lower global nitrotyrosine "footprint." We have identified the mitochondrial compartment as the major site of oxidative stress during DNA damage, being MnSOD one of the NO2-Tyr-modified proteins, but not in parp-1-/- cells. These results suggest that NO-derived injury can be modulated by proteins involved in the response to genotoxic damage, such as PARP-1, and may account for the limited oxidative injury in parp-1 knockout mice during carcinogenesis and inflammation.

[CA125 cytosolic levels in lung adenocarcinomas. New biological aspects]. / El CA125 citosólico en adenocarcinomas pulmonares. Nuevos aspectos biológicos.

INTRODUCTION: CA125 is a useful serum tumor marker in patients with non-mucinous ovarian cancer, but there may be high serum levels in other malignant tumors, among them the non-small cell lung cancers. We decided to study the cytosolic levels of CA125 in lung adenocarcinomas and compare them with pS2, CD44s, CD44v5 and CD44v6, all of them with biological interest in this subtype of lung carcinomas. SUBJECTS AND METHODS: The study group included 55 patients (33 males) having lung adenocarcinomas. CA125 and cytostolic pS2 were measured by both IRMAS methods (CIS. Biointernational. France). The concentrations of CD44 standard (CD44s), CD44v5 and CD44v6 on cell surfaces were dosed by EIAS (Bender Diagnostics. Austria). Clinical stage, ploidy and S-phase cellular fraction were also taken into account. RESULTS: In the 55 lung adenocarcinomas, cytosolic CA125 levels ranged between 1 and 225 U/mg prot. (median 80.5) and were higher (p:0.002) than those observed in 16 normal lung tissues from the same patients (r: 1-32.5; median 6.7 U/mg prot.). When the 25th (7.2 U/mg prot.) and 75th (320 U/mg prot.) percentiles were used as clinical cut-offs, we found that the cases with high antigenic levels showed a greater positivity for CD44v6 (p:0.002) and a reduced positivity for CD44 standard (p:0.053). Likewise, they showed a tendency towards being pS2 + (p:0.09) more frequently. CONCLUSIONS: Our results lead us to draw the following conclusions: 1) Cytosolic CA125 levels in lung adenocarcinomas were higher than those observed in normal tissues from the same patients. 2) Lung adenocarcinomas with high cytosolic CA125 concentrations had a greater positivity for CD44v6, a reduced positivity for CD44s and were more frequently pS2 +. These associations support the usefulness of the cytosolic CA125 levels as an indicator of poor outcome in this subtype of lung carcinomas.

Cytosolic levels of neuron-specific enolase in squamous cell carcinomas of the lung.

To study the behavior and possible correlations of neuron-specific enolase (NSE) with other clinicobiological parameters, we measured the cytosolic levels of this marker by means of an immunoradiometric assay (IRMA) in 95 squamous cell lung carcinoma samples. We also analyzed the levels of pS2, tissue-type plasminogen activator (t-PA), hyaluronic acid (HA), free beta subunit of human chorionic gonadotropin (beta-HCG), CYFRA 21.1 and CA 125 in cytosol. On the cell surface we analyzed the concentrations of epidermal growth factor receptor (EGFR), HA, erbB-2 oncoprotein, CD44s, CD44v5 and CD44v6. Other parameters considered were clinical stage, lymph node involvement, histological grade (HG), ploidy and the cellular S-phase fraction measured by flow cytometry on nuclei obtained from fresh tissues. In the 95 squamous cell carcinomas the cytosolic levels of NSE varied from 4.5 to 2235 ng/mg protein (median: 267) and were significantly higher (p < 0.001) than those observed in 38 samples of normal pulmonary tissue obtained from the same patients (range: 56-657; median: 141.5). When classifying tumors according to the different parameters analyzed, we observed that the levels of NSE were higher in aneuploid than in diploid cases (p = 0.046) and in those that were HG3 than in those that were HG2 (p < 0.001). Tumors with high NSE levels (> 422 ng/mg protein; 75th percentile) were more likely to have high S-phase values (p = 0.012) and were more frequently aneuploid (p = 0.038) and HG3 (p < 0.001) than those with low levels of NSE (< 180 ng/mg protein; 25th percentile). These results lead us to the following conclusions: 1) the cytosolic concentrations of NSE are significantly higher in squamous cell carcinomas than in healthy pulmonary tissue, and 2) the cytosolic concentrations of NSE are not correlated with clinical stage or nodal involvement. However, in our study higher levels of the enzyme were statistically correlated with aneuploidy, histological grade 3 and S-phase. This may explain its association with poorer outcome and progression, but also the more favorable response of tumors with elevated NSE to chemotherapy, as suggested by other groups.

[CD44s Cell surface expression in 55 lung adenocarcinomas. Negative correlation with tumor size and CA125 cytosolic levels]. / Estudio de la expresión de CD44s en 55 adenocarcinomas pulmonares. Correlación inversa con el tamaño y las concentraciones citosólicas de CA125.

INTRODUCTION: CD44s belongs to a family of cell adhesion molecules involved in cell adhesion, migration and cell-extracellular matrix interactions. In this work we attempt to study CD44s expression in lung adenocarcinomas and its possible correlation with other clinicobiological parameters. MATERIAL AND METHODS: Using an EIA, cell surface CD44s levels were determined in 55 lung adenocarcinomas, classified according to clinical stage, histological grade, ploidy and cellular S-phase fraction. CA125 cytosolic concentrations were also assayed. RESULTS: Forty two adenocarcinomas (76.4%) showed CD44s concentrations > 80 ng/mg prot, and did not differ significantly from those observed in 16 normal samples (93.7%). There were no differences in CD44s expression when clinical stage (I: 24/28, II: 6/9 and III: 12/17), lymph node involvement (N = 245/29, N+: 18/26), ploidy (diploid: 3/5, aneuploid: 32/39), histological grade (I: 6/7, III: 18/26) and cellular S-phase (> 8.8%: 24/31, < or = 8.8%: 17/24) were considered. Positive CD44s tumors had lower CA125 (p: 0.0072) cytosolic levels and a reduced tumor size (p: 0.0093). CONCLUSIONS: CD44s expressions in lung adenocarcinomas did not correlate with any clinicobiological parameters, but there was a negative correlation between this and reduced tumor size and lower CA125 cytosolic levels.