Marcadores bioquímicos e hipertensión gestacional : utilidad del ácido ùrico como marcador de riesgo de las enfermedades de hipertensión inducidas por el embarazo

It is well known that preeclampsia is associated to high uric acid levels, but the clinical assessment of this relationship is still under consideration.\nOur aim was to describe the behavior of serum uric acid in pregnant woman and its possible role as an early predictor of gestational hypertensive pathologies to contribute to the care of pregnancy and childbirth.\nIn a retrospective study performed at the National Hospital "Dr. Prof. Alejandro Posadas ", we found that in the first half of gestation, uric acid levels were similar in normotensive pregnant women and in those who developed preeclampsia. However, after the 20th weeks of gestation, uric acid increases 1.5-fold in preeclamptic pregnant women, with no changes in uremia and creatininemia, confirming that these patients had no renal complications.\nIn a prospective approach, we found that the ratio of uricemia (after 20 weeks of gestation / before 20 weeks of gestation) has a high predictive negative value excluding these pathologies if the result is negative (<1,5) and high sensitivity if it is positive.\nOur findings suggest that uric acid is a candidate molecule for monitoring the risk of this group of pathologies.Fil: Corominas, Ana Irene. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, ArgentinaAunque se conoce que existe una asociación entre los niveles elevados de ácido úrico y preeclampsia, el debate sobre su aplicación clínica aún está abierto.\nNuestro objetivo fue describir el comportamiento del ácido úrico sérico en la mujer embarazada y su eventual rol como predictor precoz de las patologías hipertensivas gestacionales con el fin de contribuir al cuidado del embarazo y el parto.\nEn un estudio retrospectivo realizado en el Hospital Nacional ?Dr. Prof. Alejandro Posadas?, encontramos que en la primera mitad de la gestación los niveles de ácido úrico fueron similares en embarazadas normotensas y en aquellas que desarrollaron preeclampsia. Sin embargo, a partir de la semana 20, el ácido úrico aumenta 1,5 veces en gestantes preeclámpticas, sin cambios en la uremia y creatininemia, descartándose así el compromiso renal.\nEn un abordaje prospectivo, encontramos que la razón de uricemias (después de las 20 semanas de gestación/ antes de las 20 semanas de gestación) presenta un alto valor predictivo negativo si es que el resultado es negativo (<1,5) y alta sensibilidad si el mismo da positivo.\nNuestros hallazgos sugieren que el ácido úrico es una molécula candidata para el monitoreo de riesgo de este grupo de patologías

Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer

NF-кB has been linked to doxorubicin resistance in breast cancer patients. NF- кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB -dependent genes and the biological consequences are unclear. We studied NF-кB -dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-кB –dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKβ-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-кB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF NF- кB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-кB –dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDAMB- 231 cells impaired NF-кB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-кB /p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-кB -response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.Financial support: This work was supported by RD12/0036/0051 (J.A.), RD09/0076/0101, RD09/0076/0036, RD12/0036/0054 (A.B), RD12/0036/0070 (A. Ll), PI12/00680 (J.A.), PI12/01552 (F.R.), PI12/01421 (A.Ll.), 2009 SGR 321 (J.A.), FMM 9757/002 (F.R.), and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC). J.A. and F.R. are recipients of intensification program ISCIII/FEDER. We thank Fundació Cellex (Barcelona) for a generous donation to the Hospital del Mar Medical Oncology Service. We thank Millenium for generously providing MLN120B

Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

Uric acid levels in gestational hypertensive disorders and fetal growth restriction

Objectives: To evaluate the levels of serum uric acid in pregnant womenwith fetal growth restriction associated or not with hypertensivedisorders.Methods: A retrospective descriptive-quantitative study was carried out inall women who attended their pregnancy at the Hospital Posadas during2014. Newborn of singleton pregnancies with fetal growth restriction(IUGR) and more than 22 weeks were studied. Uricemia ratio (uricemiaafter 20th week /uricemia before 20th week) was calculated in women whopresented IUGR associated or not to preeclampsia (PE) and gestationalhypertension (PIH).Results: In 3589 simple gestations analyzed, 100 presented PE (24 withIUGR), 208 PIH (19 with IUGR) and 3281 were normotensive (203 withIUGR).In the hypertensive group, the relative risk (RR) of having a newbornunder percentile 10 was 4.09(2.82-5.94) for PE and 1.72(1.12-2.64) for PIH.Regarding the evolution of pregnancy and birth, PE women have thehighest RR of prematurity, pathological Doppler, newborn weight <2500and requirement for neonatal intensive care at birth, while the RR foroligohydramnios was higher in PIH than in PE [2.1(1.02-3.94) vs 2.58 (1.45-4.60)]. Uricemia ratio was significantly increased in women with preeclampsia(1.77±0.28 in PE, 1.26±0.31 in PIH, 1.20±0.28 in normotensivewomen). The association between hypertension and IUGR increased theselevels (2.18±0.68 in PE and 1.6±0.50 in PIH). Uricemia ratio in normotensivewomen with IUGR was unchanged (1.21±0.29).Conclusion: Our results showed that normotensive pregnancies with orwithout growth restriction are not associated with an increase in uricemialevels. However, in gestational hypertensive disorders accompanying withfetal growth restriction the high increase in uricemia seems to be related toa more severe presentation of the maternal endothelial dysfunction. Thesefindings suggest that the etiology of the insufficient placentation in thesesyndromes may be different.Fil: Corominas, Ana Irene. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Balconi, Silvia. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Ortiz, Maria. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Maskin, Bernardo. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Damiano, Alicia Ermelinda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Biología Celular y Molecular; ArgentinaInternational Federation of Placenta Association MeetingCiudad Autonoma de Buenos AiresArgentinaInternational Federation of Placenta Association

Lactic Acid Transport Mediated by Aquaporin-9: Implications on the Pathophysiology of Preeclampsia

Aquaporin-9 (AQP9) expression is significantly increased in preeclamptic placentas. Since feto-maternal water transfer is not altered in preeclampsia, the main role of AQP9 in human placenta is unclear. Given that AQP9 is also a metabolite channel, we aimed to evaluate the participation of AQP9 in lactate transfer across the human placenta. Explants from normal term placentas were cultured in low glucose medium with or without L-lactic acid and in the presence and absence of AQP9 blockers (0.3 mM HgCl2 or 0.5 mM Phloretin). Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release. Apoptotic indexes were analyzed by Bax/Bcl-2 ratio and Terminal Deoxynucleotidyltransferase-Mediated dUTP Nick-End Labeling assay. Heavy/large and light/small mitochondrial subpopulations were obtained by differential centrifugation, and AQP9 expression was detected by Western blot. We found that apoptosis was induced when placental explants were cultured in low glucose medium while the addition of L-lactic acid prevented cell death. In this condition, AQP9 blocking increased the apoptotic indexes. We also confirmed the presence of two mitochondrial subpopulations which exhibit different morphologic and metabolic states. Western blot revealed AQP9 expression only in the heavy/large mitochondrial subpopulation. This is the first report that shows that AQP9 is expressed in the heavy/large mitochondrial subpopulation of trophoblasts. Thus, AQP9 may mediate not only the lactic acid entrance into the cytosol but also into the mitochondria. Consequently, its lack of functionality in preeclamptic placentas may impair lactic acid utilization by the placenta, adversely affecting the survival of the trophoblast cells and enhancing the systemic endothelial dysfunction.Fil: Medina Mora, Yollyseth Astrid. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Acosta, Lucas. Universidad Abierta Interamericana; ArgentinaFil: Reppetti, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Corominas, Ana Irene. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Bustamante, Juanita. Universidad Abierta Interamericana; ArgentinaFil: Szpilbarg, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Damiano, Alicia Ermelinda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentin

Assessing the Role of Uric Acid as a Predictor of Preeclampsia

We assessed the diagnostic utility of uric acid for the prediction of preeclampsia. An observational prospective approach was carried out during 2014. Preeclamptic women were classified into 4 groups accordingly to the onset of preeclampsia and the presence of intrauterine growth restriction (IUGR). Serum uric acid levels, urea, and creatinine were measured. Receiver operating curves (ROC) of the uric acid levels ratio (UAr) between a dosage before and after the 20th week of gestation were performed. One thousand two hundred and ninety-third pregnant women were enrolled in this study. Eight hundred ten had non-complicated pregnancies, 40 preeclampsia, 33 gestational hypertension, and 20 IUGR without preeclampsia. Uric acid significantly raised after 20 weeks of gestation in women who develop preeclampsia before 34 weeks (Group A) or in those who develop preeclampsia after 37 weeks associated with IUGR (Group C). In women who develop preeclampsia after 34 weeks without IUGR (Groups B and D), uric acid increased after the 30th week of gestation. In all groups, UAr was greater than 1.5. In gestational hypertension, UAr was superior to 1.5 toward the end of gestation, while in IUGR without preeclampsia, the behavior of serum uric acid was similar to non-complicated pregnancies. In all cases, urea and creatinine showed normal values, confirming that patients had no renal compromise. ROC area was 0.918 [95% confidence interval (CI): 0.858–0.979) for the preeclampsia group and 0.955 (95% CI: 0.908–1.000) for Group A. UAr at a cut-off point ≥1.5 had a very low positive predictive value, but a high negative predictive value of 99.5% for preeclampsia and it reached 100% for Group A. Thus, a UAr less than 1.5 may be a helpful parameter with a strong exclusion value and high sensitivity for those women who are not expected to develop preeclampsia. Additionally, this low-cost test would allow for better use of resources in developing countries.Fil: Corominas, Ana Irene. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Medina Mora, Yollyseth Astrid. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Balconi, Silvia. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Casale, Roberto. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Farina, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Martínez, Nora Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Damiano, Alicia Ermelinda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentin

Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer

NF-кB has been linked to doxorubicin resistance in breast cancer patients. NF-кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB-dependent genes and the biological consequences are unclear. We studied NF-кB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-кB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKβ-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-кB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-кB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-кB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-кB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-кB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-кB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.This work was supported by RD12/0036/0051 (J.A.), RD09/0076/0101, RD09/0076/0036, RD12/0036/0054 (A.B), RD12/0036/0070 (A. Ll), PI12/00680 (J.A.), PI12/01552 (F.R.), PI12/01421 (A.Ll.), 2009 SGR 321 (J.A.), FMM 9757/002 (F.R.), and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC). J.A. and F.R. are recipients of intensification program ISCIII/FEDER. We thank Fundació Cellex (Barcelona) for a generous donation to the Hospital del Mar Medical Oncology Service. We thank Millenium for generously providing MLN120

Influence of the length of hospitalisation in post-discharge outcomes in patients with acute heart failure: Results of the LOHRCA study.

To investigate the relationship between length of hospitalisation (LOH) and post-discharge outcomes in acute heart failure (AHF) patients and to ascertain whether there are different patterns according to department of initial hospitalisation. Consecutive AHF patients hospitalised in 41 Spanish centres were grouped based on the LOH (15 days). Outcomes were defined as 90-day post-discharge all-cause mortality, AHF readmissions, and the combination of both. Hazard ratios (HRs), adjusted by chronic conditions and severity of decompensation, were calculated for groups with LOH >6 days vs. LOH 6 days vs. LOH We included 8563 patients (mean age: 80 (SD = 10) years, 55.5% women), with a median LOH of 7 days (IQR 4-11): 2934 (34.3%) had a LOH 15 days. The 90-day post-discharge mortality was 11.4%, readmission 32.2%, and combined endpoint 37.4%. Mortality was increased by 36.5% (95%CI = 13.0-64.9) when LOH was 11-15 days, and by 72.0% (95%CI = 42.6-107.5) when >15 days. Conversely, no differences were found in readmission risk, and the combined endpoint only increased 21.6% (95%CI = 8.4-36.4) for LOH >15 days. Stratified analysis by hospitalisation departments rendered similar post-discharge outcomes, with all exhibiting increased mortality for LOH >15 days and no significant increments in readmission risk. Short hospitalisations are not associated with worse outcomes. While post-discharge readmissions are not affected by LOH, mortality risk increases as the LOH lengthens. These findings were similar across hospitalisation departments