Glioblastomas de larga supervivencia: un análisis sistemático de la literatura a propósito de un caso / Long-term survival of glioblastoma: A systematic analysis of literature about a case

Introducción: A pesar de las modificaciones introducidas en el tratamiento de los glioblastomas a partir del 2005, los pacientes supervivientes de más de 10 años se han mantenido constantes, siendo dicha cifra muy pobre e inferior al 1% en la mayoría de los estudios.Material y métodos: Se realiza un análisis sistemático de la literatura identificando los factores que pueden influir en los pacientes de larga supervivencia. Se identifica un caso en nuestro medio de más de 20 años de supervivencia realizándose un análisis actual del bloque de parafina que se conservaba del paciente.Resultados: La variable que más se asocia a la larga supervivencia en todos los análisis multivariantes es la edad, aunque, cuando se analiza las características genéticas y moleculares de los tumores, parecen existir otras variables como la metilación del promotor MGMT que juegan un papel muy importante. El análisis anatomo-patológico actual de la muestra comprueba la certeza del diagnóstico en nuestro paciente de muy larga supervivencia.Conclusiones: Múltiples variables son encontradas que influencian la larga supervivencia en distintas series, si bien los estudios analizados son muy heterogéneos resultando muy difícil la comparación entre ellos. La mayoría de los estudios referenciados pertenecen a bases de datos nacionales de distintos países que engloban a cientos de pacientes. Sería interesante fomentar el uso de una única base de datos en España que permita, entre otros, el análisis de estos pacientes de larga supervivencia afectos de glioblastoma (AU)

Introduction: In spite of the changes for the treatment of glioblastoma since 2005, we haven’t seen differences between long-survival patients of more than 10 years showing a value minor than 1%.Material and method: We realize a systematic analysis and identify important factors for long survivor patients. We also show an own case with more of 20 years of survival. We make a new pathological study of the old paraffin block of this patient.Results: The most important variable associated with long-survival between all multivariant studies is the age. When we try to find genetic and molecular alterations in glioblastoma associated with prolongated survival, the MGMT promoter methylation play the most important role. We find a correct diagnosis in the current analysis of our patient's sample with very long survival.Conclusions: Multiple variables are found that affect long survival of glioblastoma series but analyzed studies are very heterogeneous and it is very difficult comparation between them. Most articles we review are obtained from databases of different countries with hundreds of patients. It would be very interesting to promote the use of a single database in Spain that allows us to study these long-term glioblastoma survivors (AU)

[How has the Paris System contributed to urine cytology? Evaluating the contribution of the Paris System to urine cytology. A comparative study of the Paris System and the Papanicolaou method in a tertiary centre]. / ¿Qué ha aportado el sistema de París al diagnóstico en citología de orina? Estudio comparativo del sistema de París con el sistema clásico en un centro terciario.

INTRODUCTION AND OBJECTIVES: The Paris System (PS) has replaced the classical Papanicolaou System (PapS) in reporting urine cytology, due to its improved sensitivity and negative predictive value (NPV) without loss of specificity. Furthermore, it has enabled the risk of malignancy to be established in each cytological category. The aim of this study is to compare the Paris System with previous results and determine the changes in sensitivity, specificity, positive predictive value, NPV and risk of malignancy in our centre, MATERIALS AND METHODS: Evaluation of the diagnostic power of urine cytology by means of a retrospective cohort study, comparing two series of 400 cytological studies, one using the Papanicolaou System and the other the Paris System. RESULTS: In the detection of high-grade urothelial carcinoma, Paris System has better specificity (93.82% PapS vs 98.64% PS; P=.001) and PPV (39.5% PapS vs 70.6% PS; P=.044) than Papanicolaou System, without changes in sensitivity (53.5% PapS vs 37.5% PS; P=.299) or NPV (96.4% PapS vs 94.8% PS; P=.183). The risk of malignancy for the atypical category increases from low to high levels (1.6% PapS vs 40.0% PS; P=.001); the other categories showed no significant statistical changes. CONCLUSION: The Paris System improves specificity and positive predictive value and establishes a better indication of risk of malignancy for each category, enabling specific clinical management in each case.

¿Qué ha aportado el sistema de París al diagnóstico en citología de orina? Estudio comparativo del sistema de París con el sistema clásico en un centro terciario / How has the Paris System contributed to urine cytology? Evaluating the contribution of the Paris System to urine cytology. A comparative study of the Paris System and the Papanicolaou method in a tertiary centre

Introducción y objetivos: El sistema de París (SP) ha sustituido al sistema de Papanicolaou (SPap) como sistema de citodiagnóstico de orina. La evidencia indica que el SP ha logrado aumentar la sensibilidad y el valor predictivo negativo (VPN) sin perder especificidad, y establecer un riesgo de malignidad para cada categoría diagnóstica. El objetivo de este estudio es conocer los cambios que han experimentado la sensibilidad, especificidad, valor predictivo positivo (VPP), VPN y el riesgo de malignidad en la transición en nuestro centro. Materiales y métodos: Evaluación de prueba diagnóstica a través de una cohorte retrospectiva en la que se comparan dos series de 400 citologías de orina, una diagnosticada mediante el SPap y otra con SP. Resultados: Para la detección de carcinoma urotelial de alto grado describimos con el SP mejor especificidad (93,82 SPap vs. 98,64% SP; p=0,001) y VPP (39,5 SPap vs. 70,6% SP; p=0,044), sin observar cambios significativos en la sensibilidad (53,5 SPap vs. 37,5% SP; p=0,299) y VPN (96,4 SPap vs. 94,8% SP; p=0,183), respecto al SPap. El riesgo de malignidad en el SP experimenta un cambio estadísticamente significativo para la categoría atipia con respecto a la atipia en el SPap (1,6 SPap vs. 40,0% SP; p=0.001), manteniéndose el resto de las categorías sin cambios estadísticamente significativos. Conclusiones: El SP ha conseguido mejorar la especificidad y el VPP de la citología de orina y establece un riesgo de malignidad propio para la categoría de atipia, permitiendo establecer un manejo específico para cada resultado.(AU)

Introduction and objectives: The Paris System (PS) has replaced the classical Papanicolaou System (PapS) in reporting urine cytology, due to its improved sensitivity and negative predictive value (NPV) without loss of specificity. Furthermore, it has enabled the risk of malignancy to be established in each cytological category. The aim of this study is to compare the Paris System with previous results and determine the changes in sensitivity, specificity, positive predictive value, NPV and risk of malignancy in our centre. Materials and methods: Evaluation of the diagnostic power of urine cytology by means of a retrospective cohort study, comparing two series of 400 cytological studies, one using the Papanicolaou System and the other the Paris System. Results: In the detection of high-grade urothelial carcinoma, Paris System has better specificity (93.82% PapS vs 98.64% PS; P=.001) and PPV (39.5% PapS vs 70.6% PS; P=.044) than Papanicolaou System, without changes in sensitivity (53.5% PapS vs 37.5% PS; P=.299) or NPV (96.4% PapS vs 94.8% PS; P=.183). The risk of malignancy for the atypical category increases from low to high levels (1.6% PapS vs 40.0% PS; P=.001); the other categories showed no significant statistical changes. Conclusion: The Paris System improves specificity and positive predictive value and establishes a better indication of risk of malignancy for each category, enabling specific clinical management in each case.(AU)

Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo.

Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE-/- mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE-/- mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.

Long-term survival of glioblastoma: A systematic analysis of literature about a case.

INTRODUCTION: In spite of the changes for the treatment of glioblastoma since 2005, we have not seen differences between long-survival patients of more than 10 years showing a value minor than 1%. MATERIAL AND METHOD: We realize a systematic analysis and identify important factors for long survivor patients. We also show an own case with more of 20 years of survival. We make a new pathological study of the old paraffin block of this patient. RESULTS: The most important variable associated with long-survival between all multivariant studies is the age. When we try to find genetic and molecular alterations in glioblastoma associated with prolongated survival, the MGMT promoter methylation play the most important role. We find a correct diagnosis in the current analysis of our patient's sample with very long survival. CONCLUSIONS: Multiple variables are found that affect long survival of glioblastoma series but analyzed studies are very heterogeneous and it is very difficult comparation between them. Most articles we review are obtained from databases of different countries with hundreds of patients. It would be very interesting to promote the use of a single database in Spain that allows us to study these long-term glioblastoma survivors.

Hepatic Encephalopathy-Associated Cerebral Vasculopathy in Acute-on-Chronic Liver Failure: Alterations on Endothelial Factor Release and Influence on Cerebrovascular Function.

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F1α releases were increased, whereas thromboxane (TX) B2 was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI2 synthase, and TXA2S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE.

Acute-on-chronic liver disease enhances phenylephrine-induced endothelial nitric oxide release in rat mesenteric resistance arteries through enhanced PKA, PI3K/AKT and cGMP signalling pathways.

Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks. Phe-induced vasoconstriction (in the presence/absence of the NO synthase -NOS- inhibitor L-NAME) and vasodilator response to NO donor DEA-NO were analysed. Phe-induced NO release was determined in the presence/absence of either H89 (protein kinase -PK- A inhibitor) or LY 294002 (PI3K inhibitor). PKA and PKG activities, alpha-1 adrenoceptor, endothelial NOS (eNOS), PI3K, AKT and soluble guanylate cyclase (sGC) subunit expressions, as well as eNOS and AKT phosphorylation, were determined. The results show that LC blunted Phe-induced vasoconstriction, and enhanced DEA-NO-induced vasodilation. L-NAME increased the Phe-induced contraction largely in LC animals. The Phe-induced NO release was greater in MRA from LC animals. Both H89 and LY 294002 reduced NO release in LC. Alpha-1 adrenoceptor, eNOS, PI3K and AKT expressions were unchanged, but sGC subunit expression, eNOS and AKT phosphorylation and the activities of PKA and PKG were higher in MRA from LC animals. In summary, these mechanisms may help maintaining splanchnic vasodilation and hypotension observed in decompensated LC.

Protocolo para la valoración anatomopatológica de las piezas de cirugía de carcinomatosis peritoneal de origen ovárico, tubárico y peritoneal / Protocol for the examination of surgical specimens from patients with peritoneal carcinomatosis originating in ovary, fallopian tube and peritoneum

La carcinomatosis peritoneal (CP) es una entidad tumoral con una alta tasa de morbimortalidad, considerada la evolución común de varias neoplasias abdominopélvicas, entre ellas, el carcinoma de ovario, trompa uterina y peritoneo. Aunque muchos de estos tumores son sensibles a quimioterapia sistémica, el pronóstico es desfavorable por la elevada tasa de recurrencia. La cirugía de citorreducción (CC) se emplea como tratamiento de primera línea en los estadios avanzados, ya que aumenta la supervivencia de los pacientes cuando la CC es óptima. El procedimiento terapéutico descrito por Sugarbaker para el carcinoma de colon en la década de los 80, que incluye CC y quimioterapia intraperitoneal ha sido adaptado a la CP de origen ginecológico. El estudio anatomopatológico de esta cirugía empieza a ser una práctica habitual en algunos de nuestros servicios. Es un procedimiento complejo, que requiere especialización y sistematización para valorar un gran número de piezas quirúrgicas, cuantificando de forma lo más objetiva posible la carga tumoral. El objetivo de este trabajo es mostrar la experiencia inicial en nuestro servicio de anatomía patológica con pacientes diagnosticadas de CP de origen ovárico, tubárico y peritoneal y sometidas a cirugía citorreductora, destacando el papel del patólogo. Mostramos el esquema de trabajo utilizado en nuestro servicio y resumimos los resultados iniciales de 31 pacientes intervenidas entre enero de 2013 y julio de 2014

Peritoneal carcinomatosis (PC) is a malignant entity with a high rate of morbimortality. It is considered an end-stage common to several abdominal and pelvic malignant tumours, such as epithelial ovarian, fallopian tubal and peritoneal cancer. Although many of these tumors have a good response to chemotherapy, prognosis is poor due to the high rate of recurrence. Surgeons, gynecologists and oncologists are increasingly concerned with improving the survival. The surgical technique described by Sugarbaker in the eighties is a plausible option. It aims for a complete resection of macroscopic carcinomatosis (cytoreductive surgery) followed by intraoperative or perioperative intraperitoneal chemotherapy. This therapeutic option necessarily involves specific multidisciplinary units; histopathology of specimens from this surgical technique is now more frequent in our department. We describe our initial experience with PC originating from epithelial ovarian, tubal and peritoneal cancer treated with the modified Sugarbaker surgery employed in our hospital. We outline our protocol designed to achieve uniformity in procedure, and summarize the initial results

[Protocol for the examination of surgical specimens from patients with peritoneal carcinomatosis originating in ovary, fallopian tube and peritoneum]. / Protocolo para la valoración anatomopatológica de las piezas de cirugía de carcinomatosis peritoneal de origen ovárico, tubárico y peritoneal.

Peritoneal carcinomatosis (PC) is a malignant entity with a high rate of morbimortality. It is considered an end-stage common to several abdominal and pelvic malignant tumours, such as epithelial ovarian, fallopian tubal and peritoneal cancer. Although many of these tumors have a good response to chemotherapy, prognosis is poor due to the high rate of recurrence. Surgeons, gynecologists and oncologists are increasingly concerned with improving the survival. The surgical technique described by Sugarbaker in the eighties is a plausible option. It aims for a complete resection of macroscopic carcinomatosis (cytoreductive surgery) followed by intraoperative or perioperative intraperitoneal chemotherapy. This therapeutic option necessarily involves specific multidisciplinary units; histopathology of specimens from this surgical technique is now more frequent in our department. We describe our initial experience with PC originating from epithelial ovarian, tubal and peritoneal cancer treated with the modified Sugarbaker surgery employed in our hospital. We outline our protocol designed to achieve uniformity in procedure, and summarize the initial results.

Decompensated liver cirrhosis and neural regulation of mesenteric vascular tone in rats: role of sympathetic, nitrergic and sensory innervations.

We evaluated the possible alterations produced by liver cholestasis (LC), a model of decompensated liver cirrhosis in sympathetic, sensory and nitrergic nerve function in rat superior mesenteric arteries (SMA). The vasoconstrictor response to electrical field stimulation (EFS) was greater in LC animals. Alpha-adrenoceptor antagonist phentolamine and P2 purinoceptor antagonist suramin decreased this response in LC animals more than in control animals. Both non-specific nitric oxide synthase (NOS) L-NAME and calcitonin gene related peptide (CGRP) (8-37) increased the vasoconstrictor response to EFS more strongly in LC than in control segments. Vasomotor responses to noradrenaline (NA) or CGRP were greater in LC segments, while NO analogue DEA-NO induced a similar vasodilation in both experimental groups. The release of NA was not modified, while those of ATP, nitrite and CGRP were increased in segments from LC. Alpha 1 adrenoceptor, Rho kinase (ROCK) 1 and 2 and total myosin phosphatase (MYPT) expressions were not modified, while alpha 2B adrenoceptor, nNOS expression and nNOS and MYPT phosphorylation were increased by LC. Together, these alterations might counteract the increased splanchnic vasodilation observed in the last phases of decompensated liver cirrhosis.

Biphasic Effect of Diabetes on Neuronal Nitric Oxide Release in Rat Mesenteric Arteries.

INTRODUCTION: We analysed possible time-dependent changes in nitrergic perivascular innervation function from diabetic rats and mechanisms implicated. MATERIALS AND METHODS: In endothelium-denuded mesenteric arteries from control and four- (4W) and eight-week (8W) streptozotocin-induced diabetic rats the vasoconstriction to EFS (electrical field stimulation) was analysed before and after preincubation with L-NAME. Neuronal NO release was analysed in the absence and presence of L-arginine, tetrahydrobiopterine (BH4) and L-arginine plus BH4. Superoxide anion (O2-), peroxynitrite (ONOO-) and superoxide dismutase (SOD) activity were measured. Expressions of Cu-Zn SOD, nNOS, p-nNOS Ser1417, p-nNOS Ser847, and Arginase (Arg) I and II were analysed. RESULTS: EFS response was enhanced at 4W, and to a lesser extent at 8W. L-NAME increased EFS response in control rats and at 8W, but not at 4W. NO release was decreased at 4W and restored at 8W. L-arginine or BH4 increased NO release at 4W, but not 8W. SOD activity and O2- generation were increased at both 4W and 8W. ONOO- decreased at 4W while increased at 8W. Cu-Zn SOD, nNOS and p-NOS Ser1417 expressions remained unmodified at 4W and 8W, whereas p-nNOS Ser847 was increased at 4W. ArgI was overexpressed at 4W, remaining unmodified at 8W. ArgII expression was similar in all groups. CONCLUSIONS: Our results show a time-dependent effect of diabetes on neuronal NO release. At 4W, diabetes induced increased O2- generation, nNOS uncoupling and overexpression of ArgI and p-nNOS Ser847, resulting in decreased NO release. At 8W, NO release was restored, involving normalisation of ArgI and p-nNOS Ser847 expressions.

Factores histopatológicos con valor pronóstico en el cordoma sacro. Estudio de 10 casos del Hospital Universitario Doctor Peset y el Hospital Clínico Universitario de Valencia / Histopathological factors of prognositic value in sacral chordoma. A 10 case study from the University Hospital «Doctor Peset» and the University Clinical Hospital of Valencia

El cordoma es una neoplasia de la línea media espinal que tiene su origen en derivados normales o en remanentes de la notocorda. Representa entre 1 y 4% de todos los tumores de hueso y suele afectar los extremos del esqueleto axial. Se considera una neoplasia de bajo grado con crecimiento lento e infrecuentes metástasis, sin embargo su gran capacidad de invasión local y su alto índice de recurrencia causan una considerable mortalidad tardía. Varios autores han propuesto múltiples factores clínicos y biológicos para predecir el pronóstico de la enfermedad, sin embargo la utilidad de la evaluación histopatológica pronóstica no está aún bien definida en estos casos. El objetivo de este estudio es evaluar las características histopatológicas de 10 casos de cordomas y correlacionar dichos datos con la evolución de la enfermedad (AU)

Chordomas are rare midline neoplasms arising from notochord tissue remnants. They account for 1-4% of all bone malignancies. Although considered to be slow growing, low grade neoplasms which rarely metastasize, their tendency for local invasion and frequent recurrence mean that they have a considerable late mortality rate. Several clinical and biological factors have been proposed as prognostic indicators, however, histopathological characteristics have not yet been considered. Our aim is to evaluate the histopathological features of ten cases of chordoma in relation to the clinical outcome (AU)

Classical Hodgkin's lymphoma of the thyroid / Linfoma de Hodgkin clásico del tiroides

Hodgkin's lymphoma is characterized by the presence of Reed–Sternberg cells. The majority of cases originate at nodal sites and only rarely does it occur in extranodal locations. Here we report a case of a woman with a classical Hodgkin's lymphoma of the thyroid developed from a Hashimoto thyroiditis. She presented with a mass in her thyroid which was surgically removed. Biopsy showed a nodular sclerosis classical Hodgkin's lymphoma. Our results were similar to previously reported cases. It would appear that the lesions grew over a MALT tissue created by the lymphoid proliferation of the thyroiditis. Differential diagnosis was made between the different types of lymphomas considering those most commonly occurring in extranodal lymphoid tissues. A final diagnosis was reached after consideration of the histopathology, immunophenotyping and molecular biology (AU)

El linfoma de Hodgkin se caracteriza por la presencia de células de Reed–Sternberg. La mayor parte de los casos se originan en ganglios linfáticos y raramente en localizaciones extranodales. Comunicamos un caso de una paciente con un linfoma de Hodgkin clásico desarrollado sobre una tiroiditis de Hashimoto. Se presentó como una masa tiroidea que fue extirpada. Histológicamente mostró un linfoma de Hodgkin clásico de tipo esclerosis nodular. Nuestros resultados concuerdan con casos publicados anteriormente. La lesión posiblemente se originó sobre un tejido MALT creado por la proliferación linfoide relacionada con la tiroiditis. Realizamos diagnósticos diferenciales entre diferentes tipos de linfoma que tienen lugar en tejido linfoide extranodal. El diagnóstico final fue realizado tras considerar su histopatología, inmunofenotipo y genética molecular (AU)

Aerobic exercise training increases nitrergic innervation function and decreases sympathetic innervation function in mesenteric artery from rats fed a high-fat diet.

INTRODUCTION: We investigated whether high-fat diet (HFD)-induced obesity was associated with modifications in mesenteric innervation function, the mechanisms involved, and the possible effects of aerobic exercise training on these changes. MATERIALS AND METHODS: Male Wistar rats were divided into three groups: rats fed a standard diet (control group); rats fed a HFD (35% fat) for 8 weeks; and HFD rats submitted to aerobic exercise training (8 weeks, 5 times per week for 50  min). Segments of isolated mesenteric arteries were exposed to electric field stimulation (EFS) with or without phentolamine, suramin, or Nω nitro-L-arginine methyl ester. Noradrenaline, ATP, and nitric oxide release, and total and phosphorylated neuronal nitric oxide synthase (nNOS, P-nNOS) expression were also measured. RESULTS: EFS contraction was greater in sedentary HFD than in control rats. Phentolamine reduced EFS contractions more markedly in HFD rats. Suramin decreased EFS contractions only in control rats. Phentolamine + suramin practically abolished EFS-induced contraction in control rats, whereas it did not modify it in the HFD rats. Noradrenaline release was greater and ATP was lower in HFD rats. Nω nitro-L-arginine methyl ester increased contractions to EFS only in segments from control rats. Nitric oxide release and nNOS and P-nNOS expressions were lower in arterial segments from HFD rats than from control rats. None of these changes in sedentary HFD rats was present in the trained HFD rats. CONCLUSIONS: Enhanced sympathetic and diminished nitrergic components contributed to increased vasoconstrictor responses to EFS in sedentary HFD rats. All these changes were avoided by aerobic exercise training, suggesting that aerobic exercise could reduce peripheral vascular resistance in obesity.

Alterations in perivascular sympathetic and nitrergic innervation function induced by late pregnancy in rat mesenteric arteries.

BACKGROUND AND PURPOSE: We investigated whether pregnancy was associated with changed function in components of perivascular mesenteric innervation and the mechanism/s involved. EXPERIMENTAL APPROACH: We used superior mesenteric arteries from female Sprague-Dawley rats divided into two groups: control rats (in oestrous phase) and pregnant rats (20 days of pregnancy). Modifications in the vasoconstrictor response to electrical field stimulation (EFS) were analysed in the presence/absence of phentolamine (alpha-adrenoceptor antagonist) or L-NAME (nitric oxide synthase-NOS- non-specific inhibitor). Vasomotor responses to noradrenaline (NA), and to NO donor DEA-NO were studied, NA and NO release measured and neuronal NOS (nNOS) expression/activation analysed. KEY RESULTS: EFS induced a lower frequency-dependent contraction in pregnant than in control rats. Phentolamine decreased EFS-induced vasoconstriction in segments from both experimental groups, but to a greater extent in control rats. EFS-induced vasoconstriction was increased by L-NAME in arteries from both experimental groups. This increase was greater in segments from pregnant rats. Pregnancy decreased NA release while increasing NO release. nNOS expression was not modified but nNOS activation was increased by pregnancy. Pregnancy decreased NA-induced vasoconstriction response and did not modify DEA-NO-induced vasodilation response. CONCLUSIONS AND IMPLICATIONS: Neural control of mesenteric vasomotor tone was altered by pregnancy. Diminished sympathetic and enhanced nitrergic components both contributed to the decreased vasoconstriction response to EFS during pregnancy. All these changes indicate the selective participation of sympathetic and nitrergic innervations in vascular adaptations produced during pregnancy.

Tranilast increases vasodilator response to acetylcholine in rat mesenteric resistance arteries through increased EDHF participation.

BACKGROUND AND PURPOSE: Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA). EXPERIMENTAL APPROACH: Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholine-induced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619. KEY RESULTS: Acetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilast-incubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast. CONCLUSIONS AND IMPLICATIONS: Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channels.

Opposite effect of mast cell stabilizers ketotifen and tranilast on the vasoconstrictor response to electrical field stimulation in rat mesenteric artery.

OBJECTIVES: We analyzed whether mast cell stabilization by either ketotifen or tranilast could alter either sympathetic or nitrergic innervation function in rat mesenteric arteries. METHODS: Electrical field stimulation (EFS)-induced contraction was analyzed in mesenteric segments from 6-month-old Wistar rats in three experimental groups: control, 3-hour ketotifen incubated (0.1 αmol/L), and 3-hour tranilast incubated (0.1 mmol/L). To assess the possible participation of nitrergic or sympathetic innervation, EFS contraction was analyzed in the presence of non-selective nitric oxide synthase (NOS) inhibitor L-NAME (0.1 mmol/L), α-adrenergic receptor antagonist phentolamine (0.1 µmol/L), or the neurotoxin 6-hydroxydopamine (6-OHDA, 1.46 mmol/L). Nitric oxide (NO) and superoxide anion (O2.(-) levels were measured, as were vasomotor responses to noradrenaline (NA) and to NO donor DEA-NO, in the presence and absence of 0.1 mmol/L tempol. Phosphorylated neuronal NOS (P-nNOS) expression was also analyzed. RESULTS: EFS-induced contraction was increased by ketotifen and decreased by tranilast. L-NAME increased the vasoconstrictor response to EFS only in control segments. The vasodilator response to DEA-NO was higher in ketotifen- and tranilast-incubated segments, while tempol increased vasodilator response to DEA-NO only in control segments. Both NO and O2(-) release, and P-nNOS expression were diminished by ketotifen and by tranilast treatment. The decrease in EFS-induced contraction produced by phentolamine was lower in tranilast-incubated segments. NA vasomotor response was decreased only by tranilast. The remnant vasoconstriction observed in control and ketotifen-incubated segments was abolished by 6-OHDA. CONCLUSION: While both ketotifen and tranilast diminish nitrergic innervation function, only tranilast diminishes sympathetic innnervation function, thus they alter the vasoconstrictor response to EFS in opposing manners.

Defectos congénitos en recién nacidos y fetos procedentes de interrupción del embarazo tras diagnóstico prenatal en el período 1982-2009 / Evolution of the frequency of congenital defects in newborn infants and fetuses from terminations of pregnancy after prenatal diagnosis in the period 1982-2009

Fundamento y objetivo: El estudio de la frecuencia de los defectos congénitos (DC) requiere incluir interrupciones voluntarias del embarazo (IVE) por DC y evaluar los factores que influyen en aquella. Pacientes y método: Serie consecutiva de 517 recién nacidos (RN) y 202 IVE con DC en 38.191 nacimientos entre 1982-2009. Resultados: La frecuencia media de RN con DC es 13,54‰ y la de RN + IVE por DC de 18,73‰. Los DC aislados suponen el 61,12% en RN y el 52,17% en IVE. El 18,37% de los DC en RN y el 40,58% en IVE son sindrómicos. La media de edad gestacional en IVE es 17,92 semanas. La frecuencia global de anencefalia es 2,62 y 6,77 por 10.000, respectivamente, en RN y en RN + IVE. La de la espina bífida es 3,14 y 5,99 por 10.000, respectivamente. La frecuencia global de síndrome de Down es 10,74 por 10.000 RN y 22,14 por 10.000 RN + IVE. El porcentaje de madres extranjeras en nuestra maternidad alcanza el 35,9% en 2009. La media de edad materna asciende significativamente a lo largo del tiempo. Conclusiones: Observamos una disminución estadísticamente significativa de DC en RN, pero no en su concepción. No detectamos prevención primaria de anencefalia ni espina bífida. El descenso de síndrome de Down en RN no alcanza significación estadística. La diversidad étnica y la mayor edad materna pueden estar modificando la frecuencia. El 53% de los casos (RN + IVE) con DC del trienio 2007-2009 fueron IVE. Se precisa el estudio completo de IVE por DC para ofrecer consejo reproductivo (AU)

Background and objective: The study of congenital defects (CD) must include termination of pregnancy (TOP) for CD and evaluate risk factors that modify their frequency. Patients and methods: Consecutive series of 517 newborn and 202 TOP with CD among 38,191 childbirths, between 1982-2009 years. Results: The mean frequency for newborns with CD is 13.54‰ and for newborn and TOP with CD is 18.73‰. Single CD are 61.12% in newborns and 52.17% in TOP. The 18.37% of CD in newborn and 40.58% of TOP are syndromic. Mean gestational age for TOP is 17.92 weeks. Overall frequency of anencephaly is 2.62‰ for newborns and 6.77 for 10,000 for newborns and TOP. Spina bifida is 3.14 for 10,000 newborns and 5.99 for 10,000 newborns and TOP. Overall frequency of Down syndrome (DS) is 10.74 for 10,000 newborns and 22.14 for 10,000 newborns and TOP. The percentage of foreign mothers was 35.9% in 2009 and the mean maternal age significantly increased in this period. Conclusion: We observe a significant decrease of CD in newborns but not in their conception. We have not detected primary prevention for neural tube defects. The decrease in DS in newborns is not statistically relevant but ethnic diversity and maternal aging may be modifying the frequency. The 53% of CD were TOP in the period 2007-2009. It is mandatory a complete study for CD in TOP in order to offer serious reproductive counseling (AU)

Aerobic exercise training increases neuronal nitric oxide release and bioavailability and decreases noradrenaline release in mesenteric artery from spontaneously hypertensive rats.

OBJECTIVE: To study the effect of aerobic exercise training on sympathetic, nitrergic and sensory innervation function in superior mesenteric artery from spontaneously hypertensive rats (SHRs). METHODS: De-endothelized vascular rings from sedentary and trained SHRs (treadmill 12 weeks) were used. Vasomotor responses to electrical field stimulation (EFS), noradrenaline, nitric oxide donor DEA-NO and calcitonin gene-related peptide (CGRP) were studied. Neuronal nitric oxide synthase (nNOS) expression and nitric oxide, superoxide anions (O(2.-)), noradrenaline and CGRP levels were also determined. RESULTS: Aerobic exercise training decreased vasoconstrictor response to EFS but increased noradrenaline response. Phentolamine decreased while N(ω)-nitro-(L)-arginine methyl ester ((L)-NAME) increased the response to EFS; the effect of both drugs was greater in trained animals. Training also decreased noradrenaline release and O(2.-) production and increased nNOS expression, nitric oxide release and the vasodilator response to DEA-NO. The O(2.-) scavenger tempol increased DEA-NO-induced vasodilation only in sedentary rats. The EFS-induced contraction was increased to a similar extent in both experimental groups by preincubation with CGRP (8-37). CGRP release and vasodilator response were not modified by training. CONCLUSION: Aerobic exercise training decreases contractile response to EFS in mesenteric artery from SHRs. This effect is the net result of decreased noradrenaline release, increased sensitivity to the vasoconstrictive effects of noradrenaline and increased neuronal nitric oxide release and bioavailability. These modifications might contribute to the beneficial effects of aerobic exercise training on blood pressure.

Breast feeding increases vasoconstriction induced by electrical field stimulation in rat mesenteric artery. Role of neuronal nitric oxide and ATP.

OBJECTIVES: The aim of this study was to investigate in rat mesenteric artery whether breast feeding (BF) affects the vasomotor response induced by electrical field stimulation (EFS), participation by different innervations in the EFS-induced response and the mechanism/s underlying these possible modifications. METHODS: Experiments were performed in female Sprague-Dawley rats (3 months old), divided into three groups: Control (in oestrous phase), mothers after 21 days of BF, and mothers that had recovered their oestral cycle (After BF, in oestrous phase). Vasomotor response to EFS, noradrenaline (NA) and nitric oxide (NO) donor DEA-NO were studied. Neuronal NO synthase (nNOS) and phosphorylated nNOS (P-nNOS) protein expression were analysed and NO, superoxide anion (O(2)(.-)), NA and ATP releases were also determined. RESULTS: EFS-induced contraction was higher in the BF group, and was recovered after BF. 1 µmol/L phentolamine decreased the response to EFS similarly in control and BF rats. NA vasoconstriction and release were similar in both experimental groups. ATP release was higher in segments from BF rats. 0.1 mmol/L L-NAME increased the response to EFS in both control and BF rats, but more so in control animals. BF decreased NO release and did not modify O(2)(.-) production. Vasodilator response to DEA-NO was similar in both groups, while nNOS and P-nNOS expressions were decreased in segments from BF animals. CONCLUSION: Breast feeding increases EFS-induced contraction in mesenteric arteries, mainly through the decrease of neuronal NO release mediated by decreased nNOS and P-nNOS expression. Sympathetic function is increased through the increased ATP release in BF rats.