Publications by authors named "Maria Angeles Martínez"

50 Publications

Human biomonitoring of bisphenol A along pregnancy: An exposure reconstruction of the EXHES-Spain cohort.

Environ Res 2021 05 26;196:110941. Epub 2021 Feb 26.

Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira i Virgili, Sant Llorenç 21, 43201, Reus, Catalonia, Spain.

This study was aimed at reconstructing the exposure to bisphenol (BPA) of 60 pregnant women from the EXHES-Spain cohort. A biomonitoring study was conducted by determining BPA levels in urine samples over the three trimesters of pregnancy. Moreover, the correlations between BPA levels and the role of different potential exposure sources, with special emphasis on the dietary intake, were also studied. Urine samples were subjected to dispersive liquid-liquid microextraction and the subsequent analysis via gas chromatography-mass spectrometry. BPA was detected in 76% of the urine samples. A significant decrease of urinary BPA levels was observed along pregnancy, as mean concentrations of creatinine-adjusted BPA were 4.64, 4.84 and 2.51 μg/g in the first, second and third trimester, respectively. This decrease was essentially associated with changes in the dietary habits of the pregnant women, including a lower intake of canned food and drinks. However, the potential role of other pregnancy-related biochemical or physiological factors should not be disregarded. Very interestingly, significant differences in urine BPA levels were found according to the fruit consumption pattern, as women who ate more citrus fruits showed lower BPA concentrations in urine. The reconstructed exposure to BPA was estimated in 0.072, 0.069 and 0.038 μg BPA/kg of body weight/day in the first, second and third trimesters, respectively. These values are far below the temporary tolerable daily intake (t-TDI) established by the EFSA.
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http://dx.doi.org/10.1016/j.envres.2021.110941DOI Listing
May 2021

Anti-TIF-1γ Antibody Detection Using a Commercial Kit vs In-House Immunoblot: Usefulness in Clinical Practice.

Front Immunol 2020 1;11:625896. Epub 2021 Feb 1.

Internal Medicine Department, Hospital Vall d'Hebrón, Barcelona, Spain.

Objectives: Anti-TIF-1γ autoantibody detection is important for cancer screening in patients with dermatomyositis. The gold standard for anti-TIF-1γ detection, immunoprecipitation, is only available from a few specialized laboratories worldwide, so commercial ELISA/immunoblot tests have emerged in recent years. To analyze their usefulness in diagnosing cancer-associated dermatomyositis, we compared Euroimmun Euroline profile with our previously validated in-house immunoblot assay with human recombinant TIF-1γ.

Methods: We included 308 adult patients from Hospital de la Santa Creu I Sant Pau and Vall Hebrón Hospital (Barcelona, Spain) tested for anti-TIF-1γ autoantibodies using the Euroline profile and an in-house immunoblot assay.

Results: A total of 27 anti-TIF-1γ were detected by the Euroline and 12 by the in-house assay. Fair agreement was observed between Euroline and the in-house immunoblot Cohen's kappa 0.3163. Expected prevalence of anti-TIF-1γ autoantibodies was observed for the two methods for dermatomyositis and undifferentiated connective tissue diseases, but unexpectedly high prevalence of anti-TIF-1γ autoantibodies was detected by Euroline compared to the in-house immunoblot for other diseases (16.5% Euroline vs 0.8% in-house immunoblot, p<0.01). The in-house IB compared to Euroline more reliably detected cancer in patients with DM with anti-TIF-1γ antibodies (p=0.0014 vs p=0.0502 for in-house immunoblot vs Euroline).

Conclusion: We recommend using a second validated method to confirm Euroline-detected anti-TIF-1γ antibodies when the dermatomyositis diagnosis is not definitive. Furthermore, in the context of definite DM diagnosis with negative anti-TIF-1γ antibodies by Euroline and no other myositis specific antibody, is also recommendable to confirm by a second validated method.
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http://dx.doi.org/10.3389/fimmu.2020.625896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894254PMC
February 2021

A nucleus-directed bombesin derivative for targeted delivery of metallodrugs to cancer cells.

J Inorg Biochem 2020 11 10;212:111214. Epub 2020 Aug 10.

Departament de Biologia, Universitat de Girona, Maria Aurèlia Capmany 40, 17003 Girona, Spain. Electronic address:

We have synthesized a set of bombesin derivatives with the aim of exploring their tumor targeting properties to deliver metal-based chemotherapeutics into cancer cells. Peptide QRLGNQWAVGHLL-NH (BN3) was selected based on its high internalization in gastrin-releasing peptide receptor (GRPR)-overexpressing PC-3 cells. Three metallopeptides were prepared by incorporating the terpyridine Pt(II) complex [PtCl(cptpy)]Cl (1) (cptpy = 4'-(4-carboxyphenyl)-2,2':6,2″-terpyridine) at the N-terminus of BN3 or at the N- or N-amino group of an additional Lys residue (1-BN3, Lys-1-BN3 and 1-Lys-BN3, respectively). 1-Lys-BN3 displayed the best cytotoxic activity (IC: 19.2 ± 1.7 μM) and similar ability to intercalate into DNA than complex 1. Moreover, the polypyridine Ru(II) complex [Ru(bpy))(cmbpy)](PF) (2) (bpy = 2,2'-bipyridine; cmbpy = 4-methyl-2,2'-bipyridine-4'-carboxylic acid), with proven activity as photosensitizer, was coupled to BN3 leading to metallopeptide 2-Lys-BN3. Upon photoactivation, 2-Lys-BN3 displayed 2.5-fold higher cytotoxicity against PC-3 cells (IC: 7.6 ± 1.0 μM) than complex 2. To enhance the accumulation of the drugs into the cell nucleus, the nuclear localization signal (NLS) PKKKRKV was incorporated at the N-terminus of BN3. NLS-BN3 displayed higher cellular internalization along with nuclear biodistribution. Accordingly, metallopeptides 1-NLS-BN3 and 2-NLS-BN3 showed increased cytotoxicity (IC: 12.0 ± 1.1 μM and 2.3 ± 1.1 μM). Interestingly, the phototoxic index of 2-NLS-BN3 was 8-fold higher than that of complex 2. Next, the selectivity towards cancer cells was explored using 1BR3.G fibroblasts. Higher selectivity indexes were obtained for 1-NLS-BN3 and 2-NLS-BN3 than for the unconjugated complexes. These results prove NLS-BN3 effective for targeted delivery of metallodrugs to GRPR-overexpressing cells and for enhancing the cytotoxic efficacy of metal-based photosensitizers.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111214DOI Listing
November 2020

Anti-HMGCR Specificity of HALIP: A Confirmatory Study.

J Immunol Res 2020 16;2020:6292631. Epub 2020 Jul 16.

Systemic Autoimmune Diseases Unit, Hospital Vall d'Hebrón, Medicine Department, Universidad Autónoma de Barcelona, Barcelona, Spain.

A distinctive new indirect immunofluorescence pattern in liver tissue has been associated with anti-HMGCR autoantibodies. It is known as HALIP (HMGCR Associated Liver Immunofluorescence Pattern). In this study, we furthered the original studies to demonstrate the association of anti-HMGCR antibodies with the HALIP. Human anti-HMGCR antibodies from patients' sera were purified and incubated with rat triple tissue (kidney/stomach/liver). A characteristic HALIP was observed. Additionally, a colocalization assay of human anti-HMGCR antibodies with rabbit polyclonal anti-HMGCR antibodies showed colocalization of both immunofluorescence patterns. This study confirms that the HALIP is due to human anti-HMGCR antibodies.
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http://dx.doi.org/10.1155/2020/6292631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388648PMC
June 2021

Human biomonitoring to evaluate exposure to toxic and essential trace elements during pregnancy. Part B: Predictors of exposure.

Environ Res 2020 03 1;182:109108. Epub 2020 Jan 1.

Environmental Engineering Laboratory, Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain.

Maternal exposure to toxic and essential trace elements represents a surrogate of exposure to the unborn child. Variables of exposure as sociodemographic, lifestyles and diet may contribute to different exposure of pregnant women to specific trace elements. Blood, urine and cord blood samples of 53 pregnant women of the HEALS-EXHES cohort, recruited in Reus (Catalonia, Spain) between 2016 and 2017, were analysed for the concentrations of As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Se and Zn. Univariate and multivariate models were built in order to assess associations between element concentrations in each matrix, and variables obtained by questionnaires on mothers' characteristics and dietary habits. Results showed several significant associations between various variables and essential trace and toxic elements. Age was associated with higher levels of Cd and Pb in cord blood samples. Multiparous women showed lower levels of Cd in maternal blood and Pb in both maternal and cord blood than nulliparous women. Hispanic mothers presented higher levels of blood As and lower levels of blood Se compared to mothers of different ethnicity. Higher education level was associated with higher As and Hg concentrations in both maternal and cord blood samples. Higher annual income diminished the level of Pb in maternal blood. Smoking in pregnancy incremented the levels of Cd in mothers' blood. Alcohol consumption may affect the absorption of Cu, Mn and Zn. Supplementations with multivitamins, folic acid and iron showed effects on elements as Cr, Mn, Se and Zn. Regarding food group intake, bluefish incremented Pb levels, while canned fish and seafood affected levels of some elements as As, Hg, Cu and Se. Other elements such as Mn and Pb were influenced by the intake of different kinds of foods. The present results showed that some modifiable lifestyles and food intakes could be the target of interventions to help pregnant women to maintain suitable concentrations of essential elements and lower levels of toxic ones, and to improve consequently neonatal health outcomes.
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http://dx.doi.org/10.1016/j.envres.2019.109108DOI Listing
March 2020

Changes of organochlorine compound concentrations in maternal serum during pregnancy and comparison to serum cord blood composition.

Environ Res 2020 03 3;182:108994. Epub 2019 Dec 3.

Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona, Catalonia, Spain. Electronic address:

The concentrations of organochlorine compounds (OCs), including pentachlorobenzene, hexachlorobenzene (HCB), hexachlorocyclohexanes (α-, β-, γ- and δ-HCH), polychlorobiphenyls (PCBs 28, 52, 101, 118, 138, 153 and 180), DDT and metabolites, were measured in maternal serum samples collected at the first trimester of pregnancy, at delivery and in umbilical cord from a cohort of mother-newborn pairs from Tarragona (Spain) (n = 50), representing general population of a Mediterranean area from Southern Europe. The observed concentrations were generally low in comparison with previous studies in other world areas. Higher OC concentrations were observed in the maternal serum collected at delivery than in the first trimester and the cord blood concentrations were lower than the maternal levels. These results show for the first time a small but statistically significant increase in maternal venous concentration of OCs between the first trimester and delivery when measured in ng/ml. HCB, β-HCH and the PCB congeners in cord blood were significantly correlated with the concentrations of these compounds in maternal venous blood and the coefficients were stronger for the samples collected at delivery which was consistent with OC transfer from mother to foetus. In the case of DDT compounds, only 4,4'-DDT showed maternal-cord blood correlation which documented the low metabolic capacity of newborns for OC transformation, e.g. DDT into DDE. Maternal age was the most significant driver of the observed maternal venous OC concentrations in both periods, older ages involving higher concentrations. Higher body mass index was only significantly correlated with higher 4,4'-DDE concentrations in maternal venous blood and cord blood. In some cases, social class and education level were significantly correlated with OC concentrations, e.g. 4,4'-DDE in maternal venous blood from the first trimester and cord blood and PCB153 in maternal venous blood at delivery. In these cases, highest concentrations were found in the women with highest education level and most affluent social class. Comparison of the maternal OC concentrations of this cohort with those observed in 2002 in population of the same geographic area and age range shows decreases between two and ten times over this fourteen-year period.
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http://dx.doi.org/10.1016/j.envres.2019.108994DOI Listing
March 2020

Organophosphate metabolite concentrations in maternal urine during pregnancy.

Environ Res 2020 03 5;182:109003. Epub 2019 Dec 5.

Environmental Engineering Laboratory, Departament d'Enginyeria Química, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain.

The burden of organophosphate (OP) pesticides in pregnant women from Tarragona (n = 157), a Mediterranean area of intense agricultural activity, has been assessed from the study of hydroxylated organic metabolites in urine samples in the three trimesters of pregnancy. 2-Diethylamino-6-methylpyrimidin-4-ol (DEAMPY), a metabolite of pirimiphos, was the compound found in higher concentration, medians 0.66-2.8 μg/g creatinine. 4-Nitrophenol (PNP), a metabolite of parathion, medians 0.24-0.41 μg/g creatinine, was the second most abundant compound. 2-Isopropyl-6-methyl-4-pyrimidol (IMPY), a metabolite of diazinon, was also present but in lower concentrations. Except for DEAMPY, the concentrations found in this cohort were lower than those reported in studies from other countries. Intraclass correlation coefficients (ICCs) were calculated for the compounds found in more than the 35% of the samples, the reliability between trimesters was poor (<0.40) to fair (0.40-0.60). Statistically significant differences were observed for the creatinine adjusted concentrations of the most abundant OP metabolites in these trimesters when examined with the Wilcoxon signed rank test for paired data. In general, no association was found between urinary OP metabolites and most demographic and lifestyle predictors. However, a positive significant association was observed for women with vegetarian diet and for women of higher economic status and eventual consumption of organic food which showed higher PNP concentrations. These results suggest that higher fruit and vegetable consumption may involve higher OP pesticide ingestion but the overall association was weak.
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http://dx.doi.org/10.1016/j.envres.2019.109003DOI Listing
March 2020

Conservative surgical approach of a synchronous malignant ovarian struma and papillary thyroid carcinoma in a postmenopausal woman.

J Obstet Gynaecol 2021 Jan 2;41(1):160-161. Epub 2019 Dec 2.

Department of Gynaecology, Hospital Universitario Virgen del Rocio, Seville, Spain.

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http://dx.doi.org/10.1080/01443615.2019.1677582DOI Listing
January 2021

Human biomonitoring to evaluate exposure to toxic and essential trace elements during pregnancy. Part A. concentrations in maternal blood, urine and cord blood.

Environ Res 2019 10 22;177:108599. Epub 2019 Jul 22.

Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira I Virgili, Sant Llorenç 21, 43201, Reus, Catalonia, Spain; Environmental Engineering Laboratory, Departament D'Enginyeria Quimica, Universitat Rovira I Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain.

Exposures to toxic elements or deficiencies of essential elements during pregnancy may be associated to various birth complications or even diseases in early life. The aim of this paper was to assess the concentrations of selected toxic (As, Cd, Cr, Hg, Ni, Pb) and essential trace elements (Co, Cu, Mn, Se and Zn) in blood and urine samples of delivering women at different periods of gestation and cord blood, as well as to evaluate the placental permeability for these elements. A total of 53 women participating in the HEALS-EXHES study were enrolled. In particular, 48 blood samples from 1st trimester of pregnancy, 40 blood samples at delivery, and 31 cord blood at delivery were collected. Moreover, mothers' urine were sampled at the 1st (53 samples), 2nd (53 samples) and 3rd trimester (49 samples) of pregnancy. Results showed that Hg and Mn levels in cord blood were about 2.0 times higher than in maternal blood, suggesting that these elements may be transferred from mother to fetus. The cord blood levels of As and Pb were lower (ca. the 65%) than those in maternal blood, showing that the placenta modulates the rate of transfer for these elements. Essential elements as Cu and Zn showed significantly lower levels in cord than in maternal blood suggesting that the transplacental transfer of these nutrients was very limited. In addition, correlation between paired maternal and cord blood samples for As, Hg and Pb was statistically significant indicating that the fetal body burden may reflect the maternal exposure. Cadmium, Co, Cr, Ni and Se levels did not show significant correlations between maternal and cord blood. Maternal urinary concentrations of trace elements, including As, Cr, Cu, Hg, Se and Zn decreased along pregnancy, which may cause variations in fetal exposure. The levels of toxic and essential elements in maternal blood and urine, as well as in cord blood, were for most elements at the lower end of the ranges found in the scientific literature not being of special concern for pregnant women and the unborn.
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http://dx.doi.org/10.1016/j.envres.2019.108599DOI Listing
October 2019

Anti-transcriptional intermediary factor 1 gamma antibodies in cancer-associated myositis: a longitudinal study.

Clin Exp Rheumatol 2020 Jan-Feb;38(1):67-73. Epub 2019 Jul 30.

Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.

Objectives: To investigate anti-TIF1-γ antibodies in longitudinally followed patients with myositis and cancer.

Methods: Serum levels of anti-TIF1-γ antibodies at different time-points in relation to myositis and cancer diagnosis were analysed by ELISA in 79 patients from a Swedish cohort with polymyositis (PM) and dermatomyositis (DM) and a Spanish cohort restricted to DM patients. Anti-TIF1-γ positive and negative patients were compared with Fisher's exact test, student t-tests and Wilcoxon test.

Results: Thirty-six patients (17 from cohort 1 and 19 from cohort 2) with myositis and cancer were anti-TIF1-γ antibody positive; all had DM. In 88% of anti-TIF1-γ positive patients, cancer was diagnosed within 3 years from DM diagnosis compared to 63% in anti-TIF1-γ negative. Four DM patients, anti-TIF1-γ positive at cancer diagnosis had positive serum samples even antedating cancer diagnosis up to five years. In cohort 1 the median (interquartile range) antibody level was higher, 2.13 au (1.82-2.15), in the seven patients who died <1 year after cancer diagnosis, compared to the seven that died >1 year after cancer diagnosis, 1.34 au (0.92-1.59), (p=0.004). Three patients were still alive and in remission from cancer and DM 14-16 years after cancer treatment of whom two became negative for anti-TIF1-γ antibodies. In the second cohort remission of cancer coincided with remission of DM and low or negative serum levels of autoantibodies.

Conclusions: Anti-TIF1-γ antibodies may be detected before clinical symptoms of cancer and may disappear after successful treatment of cancer with remission of DM supporting DM being a paramalignant phenomenon.
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March 2020

Prenatal exposure to PFOS and PFOA in a pregnant women cohort of Catalonia, Spain.

Environ Res 2019 08 26;175:384-392. Epub 2019 May 26.

Environmental Engineering Laboratory, Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007, Tarragona, Catalonia, Spain; Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira i Virgili, Sant Llorenç 21, 43201, Reus, Catalonia, Spain. Electronic address:

This study was aimed at assessing the prenatal exposure to perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in a cohort of pregnant women living in Reus (Tarragona County, Catalonia, Spain). These chemicals were biomonitored in maternal plasma during the first trimester of pregnancy, at delivery, and in cord blood. The dietary exposure of PFOS and PFOA was estimated by using questionnaires of food frequency and water intake, as well as data on food levels previously reported in the same area. In addition, the exposure through air inhalation and indoor dust ingestion was also calculated. Finally, a physiologically-based pharmacokinetic (PBPK) model was applied in order to establish the prenatal exposure of the fetus/child and to adjust exposure assessment vs. biomonitoring results. Probabilistic calculations of fetal exposure were performed by forward internal dosimetry and Monte-Carlo simulation. Mean plasma levels of PFOA were 0.45, 0.13 and 0.12 ng/mL at the first trimester, at delivery and in cord plasma, while those of PFOS were 2.93, 2.21, and 1.17 ng/mL, respectively. Traces of PFOS were found in all samples in the trimester and at delivery, and almost in all cord blood samples. Transplacental transfers of PFOS and PFOA were estimated to be around 70% and 60%, respectively. A temporal decrease trend in plasma levels of PFOS and PFOA was noticed, when comparing current values with data obtained 10 years ago in the same area. In agreement with many other studies, dietary intake was the main route of exposure to PFOS and PFOA in our cohort of pregnant women. It is an important issue to establish the exposure in critical windows periods such as fetal development to perfluoroalkylated substances, but also to other endocrine disrupting chemicals.
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http://dx.doi.org/10.1016/j.envres.2019.05.040DOI Listing
August 2019

Occurrence of legacy and emerging organic pollutants in whitemouth croakers from Southeastern Brazil.

Sci Total Environ 2019 Sep 17;682:719-728. Epub 2019 May 17.

Persistent Organic Pollutants Group, Environmental Department, CIEMAT, Madrid, Spain.

The whitemouth croaker (Micropogonias furnieri) is one of the most commercially important species along the Atlantic coast of South America. Moreover, some of its biological traits (long life span, inshore feeding, high trophic position) make this species a suitable sentinel of coastal pollution. Here, we investigated contamination by multiple legacy and emerging organic pollutants, such as brominated and chlorinated flame retardants, polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), in whitemouth croakers from two estuaries (Guanabara and Sepetiba Bays) located in industrialized and urbanized areas in Rio de Janeiro State, Southeastern Brazil. Furthermore, we assessed how biological and ecological features could explain the observed contamination patterns. Regarding brominated flame retardants, concentrations of polybrominated diphenyl ethers (PBDEs) varied from 7.6 to 879.7 pg g wet weight (w.w.), with high contribution of tetra-, penta-, hexa- and deca-BDEs. The sum of chlorinated flame retardants (dechlorane-related compounds, ΣDRC) ranged from
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http://dx.doi.org/10.1016/j.scitotenv.2019.05.213DOI Listing
September 2019

Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations.

Expert Rev Clin Immunol 2018 03 23;14(3):215-224. Epub 2018 Feb 23.

e Internal Medicine Department, Hospital Clinic , Universitat de Barcelona , CIBERER , Barcelona , Spain.

Introduction: Musculoskeletal manifestations are well-recognized side effects of treatment with statins. New advances in this field have appeared in recent years. This review focuses on the diagnosis of these conditions and their underlying pathogenesis, in particular immune-mediated necrotizing myopathy. Areas covered: Clinical phenotypes including rhabdomyolysis, myalgia and/or mild hyperCKemia, self-limited toxin statin myopathy, and immune-mediated necrotizing myopathy are herein described. Therapeutic recommendations and a diagnostic algorithm in statin-associated myopathy are also proposed. The etiology and pathogenesis of statin-induced myopathy has mainly focused on the anti-HMGCR antibodies and the responsibility of the immune-mediated necrotizing myopathy is discussed. The fact that patients who have not been exposed to statins may develop statin-associated autoimmune myopathy with anti-HMGCR antibodies is also addressed. The literature search strategy included terms identified by searches of PubMed between 1969 and December 2017. The search terms 'myositis', 'statin-induced autoimmune myopathy', 'immune-mediate necrotizing myopathy', 'statins', 'muscular manifestations', and 'anti-HMGCR antibodies' were used. Expert commentary: Full characterization of the known phenotypes of statin toxicity and the specific role of the anti-HMGCR in those exposed and not exposed (i.e. juvenile forms) to statins and in some types of neoplasms is of paramount relevance.
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http://dx.doi.org/10.1080/1744666X.2018.1440206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019601PMC
March 2018

Tumour TIF1 mutations and loss of heterozygosity related to cancer-associated myositis.

Rheumatology (Oxford) 2018 02;57(2):388-396

Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Objectives: To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM).

Methods: Paired blood and tumour DNA samples from patients with anti-TIF1γ-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1γ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score.

Results: From seven patients with anti-TIF1γ-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1γ-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1γ staining was more intense in tumours from anti-TIF1γ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1γ staining in muscle was slightly more intense in anti-TIF1γ-positive than in anti-TIF1γ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1γ staining was detected in the skin of both myositis and control patients.

Conclusion: Tumours from paraneoplastic anti-TIF1γ-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1γ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.
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http://dx.doi.org/10.1093/rheumatology/kex413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850766PMC
February 2018

Diagnostic utility of cortactin antibodies in myasthenia gravis.

Ann N Y Acad Sci 2018 01 25;1412(1):90-94. Epub 2017 Oct 25.

Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau - IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Patients with myasthenia gravis (MG) without antibodies to the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) have been classified as having double-seronegative myasthenia gravis (dSNMG). We used the sera from six dSNMG patients with positive immunohistochemistry assays in a protein array to screen reactivity with 9000 human proteins. We identified cortactin, an intracellular protein that interacts with agrin/MuSK favoring AChR aggregation, as a new antigen in dSNMG. We then designed an in-house enzyme-linked immunosorbent assay as a screening assay and confirmed these results by western blot. We found that 19.7% of dSNMG patients had anti-cortactin antibodies. In contrast, patients with AChR MG or other autoimmune disorders and healthy controls were positive at significantly lower rates. Five percent of healthy controls were positive. In a recent study, we screened sera from 250 patients (AChR MG, MuSK MG, dSNMG) and 29 healthy controls. Cortactin antibodies were identified in 23.7% of dSNMG and 9.5% AChR MG patients (P = 0.02). None of the MuSK MG patients, patients with other autoimmune disorders, or healthy controls had antibodies against cortactin. Patients with dSNMG cortactin MG were negative for anti-striated muscle and anti-LRP4 antibodies. Patients with dSNMG cortactin MG presented ocular or mild generalized MG without bulbar symptoms. We conclude that cortactin autoantibodies are biomarkers of MG that, when present, suggest that the disease will be mild.
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http://dx.doi.org/10.1111/nyas.13502DOI Listing
January 2018

Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin.

JAMA Neurol 2016 09;73(9):1099-104

Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.

Importance: Double-seronegative myasthenia gravis (dSNMG) includes patients with myasthenia gravis (MG) without detectable antibodies to the nicotinic acetylcholine receptor (AChR) or to muscle-specific tyrosine kinase (MuSK). The lack of a biomarker hinders the diagnosis and clinical management in these patients. Cortactin, a protein acting downstream from agrin/low-density lipoprotein receptor-related protein 4 (LRP4)/MuSK, has been described as an antigen in dSNMG.

Objective: To describe the frequency and clinical features of patients with dSNMG who have cortactin antibodies.

Design, Setting, And Participants: A retrospective cross-sectional study was conducted at Hospital de la Santa Creu i Sant Pau, an institutional practice referral center in Barcelona, Spain, between May 1, 2015, and November 30, 2015. We included 250 patients with a definitive diagnosis of MG with available serum samples at the time of diagnosis. Descriptive and comparative data analyses were performed.

Exposures: Cortactin antibodies were measured by enzyme-linked immunosorbent assay and Western blot; AChR, MuSK, and anti-striated muscle antibodies were detected using a standard method; and LRP4 antibodies were tested using a cell-based assay.

Main Outcomes And Measures: The primary outcome was the frequency of patients with dSNMG who have cortactin antibodies. Secondary outcomes were demographic, clinical, neurophysiological, and laboratory data.

Results: Of 250 patients (mean [SD] age at onset, 49.7 [21.2] years; 56% female), 38 (15.2%) had dSNMG, 201 (80.4%) had MG with AChR antibodies, and 11 (4.4%) had MG with MuSK antibodies. Cortactin antibodies were identified in 28 patients with MG: 9 of 38 (23.7%) who had dSNMG, 19 of 201 (9.5%) who had MG with AChR antibodies (significantly lower than those with dSNMG: 9.5% vs 23.7%; P = .02), and 0 of 11 who had MG with MuSK antibodies; 0 of 29 controls had cortactin antibodies. At onset, among the 9 patients with dSNMG and cortactin antibodies, 6 had ocular MG and 3 had Myasthenia Gravis Foundation of America clinical classification IIA. Two patients with ocular MG developed generalized MG. The group with dSNMG and cortactin antibodies, compared with those who had MG with AChR antibodies, more frequently had mild forms at onset (100.0% vs 62.7%; P = .03), had fewer bulbar signs at maximal worsening (0% vs 41.3%; P = .01), and were younger at onset (median [interquartile range], 34.9 [9.5] vs 53.9 [38.5] years; P = .03); the group with dSNMG and cortactin antibodies also more frequently had ocular MG at onset than those with MG and AChR antibodies, although the difference was not statistically significant (66.7% vs 40.8%; P = .17). Of 17 patients with ocular dSNMG, 4 (23.5%) had antibodies to cortactin.

Conclusions And Relevance: In this study, patients with cortactin antibodies and dSNMG had an ocular or mild generalized phenotype of MG. Including the detection of cortactin antibodies in the routine diagnosis of dSNMG may be helpful in ocular MG.
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http://dx.doi.org/10.1001/jamaneurol.2016.2032DOI Listing
September 2016

Effect on quality of life of switching to combined oral contraception based on natural estrogen: an observational, multicentre, prospective phase IV study (ZOCAL Study).

Eur J Contracept Reprod Health Care 2016 Aug 25;21(4):276-84. Epub 2016 May 25.

f DIATROS, Clínica de Atención a la Mujer , Barcelona , Spain.

Objectives: This observational, multicentre, prospective phase IV study examined change in health-related quality of life (QOL) from baseline to 6 months in women initiating combined oral contraception (COC) based on natural estrogen.

Methods: Eligible women attending a baseline and 6-month gynaecology appointment belonged to one of three groups: group 1 used barrier contraception (condoms) and elected to continue this method; group 2 used condoms and elected to switch to COC based on natural estrogen; group 3 used COC based on ethinylestradiol and elected to switch to COC based on natural estrogen. The Spanish Society of Contraception (SEC)-QOL scale assessed health-related QOL. Secondary outcomes included symptoms of premenstrual syndrome, intermenstrual bleeding, duration and intensity of menstrual bleeding, contraception continuation rate, and tolerability.

Results: A total of 857 women were enrolled and 785 completed the study. Group 2 (n = 224 completed) had significantly lower SEC-QOL global and dimension scores at baseline and significantly greater increases in SEC-QOL from baseline to 6 months compared with groups 1 (n = 72) and 3 (n = 489). Group 3 reported a similar SEC-QOL score to that of group 1 at baseline but showed significantly greater improvement in SEC-QOL global and psychological scores from baseline to 6 months. Among women receiving COC based on natural estrogen, the contraception continuation rate was 713/780 (91.4%); treatment-related adverse events were reported by 13/780 (1.7%).

Conclusions: Improved SEC-QOL after 6 months was found in women who were dissatisfied with their current contraception at baseline and chose to switch to COC based on natural estrogen.
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http://dx.doi.org/10.3109/13625187.2016.1174206DOI Listing
August 2016

Usefulness of Integrase resistance testing in proviral HIV-1 DNA in patients with Raltegravir prior failure.

BMC Infect Dis 2016 May 13;16:197. Epub 2016 May 13.

Complejo Hospitalario Universitario Granada. Servicio de Microbiología, Hospital Universitario San Cecilio. Instituto de Investigación Ibs. Granada, Av. Del Conocimiento s/n, 18016, Granada (Andalucía), Spain.

Background: In our study, we have hypothesized that proviral DNA may show the history of mutations that emerged at previous failures to a Raltegravir containing regimen, in patients who are currently undetectable and candidates to simplification to a Dolutegravir containing regimen, in order to decide on once a day or twice a day dosing.

Methods: We have performed a pilot, observational, retrospective, non interventional study, including 7 patients infected by HIV-1, all with a history of previous failure to a RAL containing regimen, that were successfully salvaged and had reached viral suppression. A genotypic viral Integrase region study was available for each patient at the moment of RAL failure. After an average (IQR) time of 48 months (29-53) Integrase resistance mutations in proviral DNA were studied.

Results: All the patients were infected by HIV-1 B subtypes, with a mean age of 55 (range 43 to 56), originating from Spain, and 4 were women. Median viral load (log) and CD4 count at the moment of the study on proviral DNA was of 1.3 log cp/ml (range 0-1.47) and 765.5 cells/μL (range; 436.75-1023.75). The median time (IQR) between previous failure to RAL and the study on proviral DNA was 48 (29-53) months. At Raltegravir failure, N155H was detected in four patients, and other secondary mutations were detected in five patients (71.4 %). In proviral DNA, N155H was detected by population sequencing in three patients (42.8 %), and UDS demonstrated a 9.77 % relative abundance of N155H in the remaining patient. Sanger sequencing correctly identified all the secondary mutations.

Conclusion: This is a pilot study that demonstrates the possibility of properly identifying N155H and some secondary mutations 29-53 months after failure.
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http://dx.doi.org/10.1186/s12879-016-1545-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866296PMC
May 2016

Time trends of persistent organic pollutants in spanish air.

Environ Pollut 2016 Oct 1;217:26-32. Epub 2016 Feb 1.

Persistent Organic Pollutants Group, Environmental Department. CIEMAT, Avda. Complutense 40, 28040 Madrid, Spain.

Passive air samplers consisting of polyurethane foam (PUF) disks were deployed in seven remote points and four urban locations to assess levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and some organochlorine pesticides including: 1,1'-(2,2,2-trichloroethane-1,1-diyl)bis(4-chlorobenzene) (DDT) and their metabolites (1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (DDE) and 1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl)ethyl]benzene (DDD)), hexaclorobenzene (HCB) and hexachlorocyclohexanes (HCHs), in the Spanish ambient air. Results revealed HCB (49 pg m(-3); median) as the major pollutant, followed in decreasing order by HCHs (21 pg m(-3)), ∑DDT/E/Ds (20 pg m(-3)), PCBs (20 pg m(-3)), PBDEs (3.3 pg m(-3)) and PCDD/Fs (0.04 pg m(-3)), when urban and remote locations are evaluated together. Urban areas presented statistically significant (p < 0.05, Mann-Whitney U test) higher levels for all families studied, except for HCB, compared to remote locations revealing anthropogenic activities as potential sources for these chemicals. On the contrary, HCB concentrations seem to reflect background levels. Interestingly, results reveal a decreasing trend for PCBs, PBDEs and DDTs levels in remote areas, while this behaviour is only statistically significant in the case of the former chemicals in urban locations. The present study is framed in the Spanish air monitoring plan and represents the first complete analysis related to POP presence in Spanish air coming from inner sites.
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http://dx.doi.org/10.1016/j.envpol.2016.01.040DOI Listing
October 2016

Inflammatory myopathy: diagnosis and clinical course, specific clinical scenarios and new complementary tools.

Expert Rev Clin Immunol 2015 Jun 30;11(6):737-47. Epub 2015 Apr 30.

1 Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.

Idiopathic inflammatory myopathies are a heterogeneous group of rare autoimmune diseases characterized by symmetric proximal muscle weakness and inflammatory infiltrates on muscle biopsy. A meticulously collected combination of clinical, serological, and pathological data is essential to correctly diagnose and classify myositis patients, often a considerable challenge for clinicians. This article provides a comprehensive overview of the most useful tools for the diagnosis and follow-up of patients with myositis. Capillaroscopy, serological biomarkers (particularly the autoantibody profile) and imaging techniques, such as muscle magnetic resonance and chest ultrasound, are of great aid in diagnosing, classifying and managing these patients. Relevant clinical scenarios, such as interstitial lung disease, associated cancer and pregnancy are also addressed in this review. Myositis registries, identification of new autoantibodies, and genetic studies will enhance our understanding of the pathogenesis of these conditions and help to define new diagnostic and therapeutic approaches.
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http://dx.doi.org/10.1586/1744666X.2015.1035258DOI Listing
June 2015

Cortactin autoantibodies in myasthenia gravis.

Autoimmun Rev 2014 Oct 3;13(10):1003-7. Epub 2014 Sep 3.

Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain. Electronic address:

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness, fatigability, and autoantibodies against protein antigens of the muscle endplate. Antibodies against acetylcholine receptor (AChR), and less frequently against muscle-Specific Kinase (MuSK) or lipoprotein related protein 4 (LRP4) occur in patients with seropositive MG (SPMG). However, about 10% of patients do not have detectable autoantibodies despite evidence suggesting that the disorder is immune mediated; this disorder is known as seronegative MG (SNMG). Using a protein array approach we identified cortactin (a protein that acts downstream from agrin/MuSK promoting AChR clustering) as potential new target antigen in SNMG. We set up an ELISA assay and screened sera from patients with SPMG, SNMG, other autoimmune diseases and controls. Results were validated by immunoblot. We found that 19.7% of patients with SNMG had antibodies against cortactin whereas only 4.8% of patients with SPMG were positive. Cortactin antibodies were also found in 12.5% of patients with other autoimmune disorders but only in 5.2% of healthy controls. We conclude that the finding of cortactin antibodies in patients with SNMG, suggests an underlying autoimmune mechanism, supporting the use of immune therapy.
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http://dx.doi.org/10.1016/j.autrev.2014.08.039DOI Listing
October 2014

Identification of a novel myositis-associated antibody directed against cortactin.

Autoimmun Rev 2014 Oct 27;13(10):1008-12. Epub 2014 Aug 27.

Immunology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain.

Objective: The aim of this study is to describe a novel myositis-associated autoantibody (anti-cortactin antibody) and assess related clinical and immunological manifestations and its clinical significance.

Methods: Adult patients with myositis (dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and inclusion body myositis), as well as patients with other autoimmune diseases and non-inflammatory myopathies were analyzed for the presence of anti-cortactin antibody using in-house developed ELISA and immunoblotting techniques with a commercial source of purified cortactin. The cut-off for positive status was determined in a group of healthy volunteers.

Results: Antibody against cortactin was positive in 7/34 (20%) polymyositis patients, 9/117 (7.6%) dermatomyositis, 2/7 (26%) immune-mediated necrotizing myopathy, and none of the 4 patients with inclusion body myositis. The antibody also tested positive in 3/101 patients with other autoimmune diseases (2 systemic sclerosis and 1 systemic lupus erythematosus), and in 1/29 patients with non-inflammatory myopathy. No relevant association with specific clinical features was found in patients with these antibodies. Anti-cortactin antibody was more frequently positive in patients with polymyositis and immune-mediated necrotizing myopathy than in the remaining myositis patients, and was the only myositis autoantibody found in sera of 3 patients from these groups.

Conclusions: Our data indicate that cortactin is a novel target antigen in patients with autoimmune diseases, especially patients with polymyositis or immune-mediated necrotizing myopathy. Anti-cortactin can be considered a new myositis-associated antibody.
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http://dx.doi.org/10.1016/j.autrev.2014.08.038DOI Listing
October 2014

Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis.

J Immunol Res 2014 4;2014:290797. Epub 2014 Feb 4.

Immunology Department, Hospital de La Santa Creu I Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.

A new myositis-specific autoantibody directed against melanoma differentiation-associated gene 5 (anti-MDA5) has been described in patients with dermatomyositis (DM). We report the clinical characteristics of patients with anti-MDA5 in a large Mediterranean cohort of DM patients from a single center, and analyze the feasibility of detecting this autoantibody in patient sera using new assays with commercially available recombinant MDA5. The study included 117 white adult patients with DM, 15 (13%) of them classified as clinically amyopathic dermatomyositis (CADM). Clinical manifestations were analyzed, with special focus on interstitial lung disease and its severity. Determination of anti-MDA5 antibodies was performed by a new ELISA and immunoblot technique. In sera, from 14 (12%) DM patients (8 CADM), MDA5 was recognized by ELISA, and confirmed by immunoblot. Eight of the 14 anti-MDA5-positive patients (57.14%) presented rapidly-progressive interstitial lung disease (RP-ILD) versus 3 of 103 anti-MDA5-negative patients (2.91%) (P < 0.05; OR: 44.4, 95% CI 9.3-212). The cumulative survival rate was significantly lower in anti-MDA5-positive patients than in the remainder of the series (P < 0.05). Patients with anti-MDA5-associated ILD presented significantly lower 70-month cumulative survival than antisynthetase-associated ILD patients. Among the cutaneous manifestations, only panniculitis was significantly associated with the presence of anti-MDA5 antibodies (P < 0.05; OR: 3.85, 95% CI 1.11-13.27). These findings support the reliability of using commercially available recombinant MDA5 for detecting anti-MDA5 antibodies and confirm the association of these antibodies with RP-ILD in a large series of Mediterranean patients with DM.
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http://dx.doi.org/10.1155/2014/290797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987881PMC
January 2015

[Is it necessary to know which workers are carriers of MRSA in contact with cancer patients?].

Rev Esp Quimioter 2012 Dec;25(4):252-5

Laboratorio de Análisis Clínicos y Microbiología, Servicio de Análisis Clínicos y Microbiología, Fundación Instituto Valenciano de Oncología, C/Gregorio Gea, 31, 46009, Valencia, Spain.

Our objective was to determine the prevalence of methicillin-resistant Staphylococcus aureus in workers who had direct contact with oncologic patients infected with MRSA and admitted to the intensive care unit of the Valencian Institute of Oncology. A study of prevalence of MRSA colonization of 62 workers was performed. Samples were taken from nose and pharynx in each of the workers. After 24 hours of incubation in Amies transport medium Viscose (Eurotubo®), 124 samples were seeded (N = 124) in chocolate agar agar, MRSA II and BHI broth (Brain Heart Infusion). Those colonies that were identified by Gram stain gram-positive cocci in clusters available, catalase positive and coagulase positive were processed for study of sensitivity by Kirby-Bauer method and screening test for methicillin (10μg of Oxoid®) on Mueller-Hinton (Becton-Dickinson®, BD), supplemented with NaCl (2%). Those confirmed MRSA isolates, he returned to perform sensitivity study by microdilution (MicroScan®, Siemens) to determine the MIC (mg/L). The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) was 1.61% (1) and 12.90% (8) for methicillin-sensitive Staphylococcus aureus (MSSA), from nostrils. The measures implemented were: nasal application of mupirocin to the worker colonized control isolation measures in infected patients and indoctrination of the personnel involved.
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December 2012

Anti-TIF1γ antibodies (anti-p155) in adult patients with dermatomyositis: comparison of different diagnostic assays.

Ann Rheum Dis 2012 Jun 30;71(6):993-6. Epub 2012 Jan 30.

Department of Internal Medicine, Vall d’Hebron General Hospital. Universitat Autonoma de Barcelona, Barcelona, Spain.

Background: A new myositis-specific autoantibody (anti-p155) directed against transcriptional intermediary factor 1 γ (TIF1γ) has been described as a good marker of cancer-associated myositis (CAM).

Objective: To analyse the feasibility of detecting this autoantibody in patient serum samples using new assays with commercially available recombinant TIF1γ.

Methods: The study included 90 Spanish patients with dermatomyositis (DM), classified as clinically amyopathic DM, CAM, or DM without cancer. Anti-TIF1γ antibodies were detected by ELISA and immunoblot techniques and compared with anti-p155 antibody detection by protein immunoprecipitation assays with radiolabelled HeLa cells. The κ coefficient was used to compare the agreement between the different tests.

Results: Serum samples from 23 (25.6%) and 20 (22.2%) patients with DM recognised TIF1γ by ELISA and immunoblot, respectively. ELISA (κ=0.91) and immunoblot (κ=0.88) showed excellent agreement with immunoprecipitation analysis (anti-p155). Good concordance (κ=0.91) was also seen between ELISA and immunoblot.

Conclusions: Excellent agreement was found between anti-p155 detected by immunoprecipitation and anti-TIF1γ detected by ELISA or immunoblot. These data indicate that identification of this autoantibody can be reliably performed in a standard laboratory setting, with potential application in clinical practice for cancer screening in adult patients with DM.
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http://dx.doi.org/10.1136/annrheumdis-2011-200871DOI Listing
June 2012

Laparoscopic distal pancreatectomy: feasibility study of radiofrequency-assisted transection in a porcine model.

J Laparoendosc Adv Surg Tech A 2012 Apr 30;22(3):242-8. Epub 2012 Jan 30.

General Surgery Department, Hospital del Mar, Barcelona, Spain.

Background And Aim: Despite technological improvements in pancreatic surgery, the incidence and morbidity of pancreatic leak after resection of distal pancreas are persistently high in most series. Laparoscopic distal pancreatectomy (LDP) is today the gold standard procedure for benign and certain malignant neoplasms of the pancreatic body and tail in specialized centers. This study evaluated safety and feasibility of a radiofrequency (RF)-assisted transection device in a porcine model of LDP.

Materials And Methods: LDP was performed on 10 pigs (median weight, 39.6 kg) using a new device based on an internally cooled RF-assisted electrode (Coolinside(®), Apeiron Medical, Valencia, Spain). The animals were subjected to daily observation and then sacrificed and necropsied at 4 weeks postoperatively. Primary end points were the development of postoperative pancreatic fistula using the Pancreatic Anastomotic Leak Study Group definition and/or the presence of abdominal amylase-rich fluid collections or abscesses during necropsy and pathological study and/or dye extravasation from the pancreatic remnant duct. Secondary end points were intra- or postoperative complications, surgery, and transection duration.

Results: No clinically relevant postoperative pancreatic fistulas were observed. In one case a grade A postoperative fistula was diagnosed due to amylase drain concentration of more than 6200 IU/mL on postoperative day 4. Median peritoneal liquid amylase concentration on postoperative day 4 was 2399.0 IU/L (range, 819.2-7122.0 IU/L), similar to the median plasma amylase level of 1520.8 IU/L (range, 1015.3-4056.6 IU/L). Median surgery time was 93.5 minutes (range, 46.0-140.0 minutes), and median transection time was 4.5 minutes (range, 2.0-26.0 minutes). There was one postoperative wound infection. There were no postoperative deaths or major complications. During the histopathological study, the surgical margin of the remaining pancreas showed a common pattern with a central area of necrosis surrounded by granulomatous infiltrate and fibrosis. Ductal obliteration was observed. No purulent inflammatory infiltrate or abscesses were present.

Conclusion: Experimental findings suggest that performing pancreatic transection with Coolinside in a animal model of LDP is feasible and safe.
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http://dx.doi.org/10.1089/lap.2011.0417DOI Listing
April 2012

Lymphohistiocytoid mesothelioma of the pleura: a case report with cytological findings.

Diagn Cytopathol 2013 Jun 24;41(6):546-9. Epub 2011 Oct 24.

Laboratory of Cytology, Department of Obstetrics, Gynecology and Reproduction, USP-Institut Universitari Dexeus, Barcelona, Spain.

Lymphohistiocytoid malignant mesothelioma is an infrequent variant of sarcomatoid mesothelioma representing approximately 0.5-3.3% of malignant mesotheliomas. It has been related to asbestos exposure. The tumor is characterized by a diffuse large histiocyte-like cells proliferation mixed with an inflammatory infiltrate of lymphocytes and plasma cells. Its cytological diagnosis is difficult. We present a case of a 67-year-old female with lymphohistiocytoid mesothelioma involving the left pleura. The cytological, histological, and immunohistochemical features are discussed.
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http://dx.doi.org/10.1002/dc.21824DOI Listing
June 2013

Analysis of perfluorinated alkyl substances in Spanish sewage sludge by liquid chromatography-tandem mass spectrometry.

Anal Bioanal Chem 2011 May 22;400(5):1277-86. Epub 2011 Jan 22.

Persistent Organic Pollutant Group, Environment Department, CIEMAT, Avda. Complutense 22, 28040 Madrid, Spain.

The present article describes the development of an analytical method for the determination of 13 perfluorinated alkyl substances (PFAS), as well as its application to real sewage sludge samples to confirm the presence of these compounds. The isolation of the analytes was performed by agitation, sonication and centrifugation techniques, followed by EnviCarb cleanup and weak anion exchange solid-phase extraction. Sensitive and selective determination was carried out by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Six mass-labelled internal standards were used to ensure the accuracy of the analytical results following isotopic dilution method. Several mobile phases (acetonitrile, methanol, mixtures of both and water with ammonium acetate or acetic acid) have been tested to reach the best resolution and reproducibility results. Other parameters related to MS/MS conditions were optimized. The reliability of the method was confirmed by the evaluation of linearity (R(2) = 0.995-0.999), accuracy (84-99%) and injection repeatability and reproducibility (relative standard deviation below 19 and 23%, respectively). Limits of detection ranged from 0.007 to 2.217 pg. Recoveries show values higher than 80% for most of the target compounds. The application of this method to twenty real samples demonstrates its efficiency and accuracy, as well as provides for the first time to our knowledge, PFAS levels in sewage sludges from Spain.
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http://dx.doi.org/10.1007/s00216-011-4655-6DOI Listing
May 2011

Concentrations and sources of Dechlorane Plus in sewage sludge.

Chemosphere 2011 Jan 30;82(5):692-7. Epub 2010 Nov 30.

Persistent Organic Pollutants Group, Environment Department, CIEMAT, Avd. Complutense 22, Madrid 28040, Spain.

Sewage sludge from 31 urban Spanish wastewater treatment plants (WWTP) was analyzed for the emerging halogenated flame retardant Dechlorane Plus (DP). Concentrations of the two major isomers in the technical mixture, syn and anti, ranged between 0.903-19.2 and 1.55-75.1ngg(-1) dry weight, respectively. Overall, concentrations of DP were lower than those of polybrominated diphenyl ethers (PBDEs) (9.10-995ngg(-1) dry weight) and this is likely related to the higher usage of brominated flame retardants. The average ratio of the syn isomer to total DP (f(syn)) was 0.28±0.05, which is similar to that of the commercial mixture. Comparing different wastewater treatment methods, we found lower concentrations in those using biological nitrogen and phosphorous elimination, suggesting that DP is susceptible to microbial degradation and that anti-DP is more so, given the enrichment of syn-DP in the sewage sludge. Principal components analysis revealed significant positive correlation (r=0.619, p<0.05) between total DP concentrations with the contribution of industrial input to waste streams. This implies release of DP is related to industrial activity, likely stemming from the use of the technical product during manufacture of consumer goods. However, use and disposal of products containing DP could not be dismissed. According to our knowledge, this is the first report on DP in WWTP sludge.
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http://dx.doi.org/10.1016/j.chemosphere.2010.10.097DOI Listing
January 2011

In vitro cellular responses in the RTG-2 cell line to complex mixtures of dioxins and dioxin-like PCDDs, PCDFs and PCBs.

J Appl Toxicol 2010 Aug;30(6):603-10

INIA, Department of Environment, Crta de La Coruña Km 7, 28040 Madrid, Spain.

High-resolution gas chromatography/mass spectrometry (HRGC/MS) is the standard method for analysing dioxin, furan and polybrominated retardants in hazardous waste. Determination of dioxin-like compounds using in vitro bioassays such as ethoxyresorufin-O-deethylase (EROD) is an important tool to evaluate their Ah receptor-mediated toxic effects, because it detects all arylhydrocarbon receptor ligands in a variety of sample matrices. In the present work, we compared RTG-2 cell line EROD bioassay with HRGC/MS for assessing waste samples (liquid and solid) contaminated with polychlorinated dibenzo-p-dioxins and dibenzofurans, polychlorinated biphenyls (dioxin-like PCBs) and other xenobiotics. For liquid samples, HRGC/MS-toxic equivalent (HRGC/MS-TEQ) values ranged from 273.26 to 5.84 ng TEQ l(-1) and correlated well (correlation coefficient 0.99) with values obtained by EROD-TEQ, which ranged from 128 to 2.5 ng TEQ l(-1). For solid samples, HRGC/MS-TEQ values ranged from 3.44 to 0.49 ng TEQ g(-1) and correlated less well than liquid samples (correlation coefficient 0.64) with values obtained by EROD-TEQ ranging from 2.27 to 0.93 ng TEQ g(-1). The overestimation of RTG-2 EROD-TEQ (1.2 +/- 0.92 of values established by HRGC/MS) and the absence of false-negative results may limit analytical costs by eliminating the need for follow-up GC/MS analysis on the negative samples. We suggest that RTG-2 EROD bioassay is an inexpensive means for preliminary dioxin and furan positive screenings of waste samples.
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http://dx.doi.org/10.1002/jat.1532DOI Listing
August 2010