Pardo-Mindan, F.J. (Francisco Javier)
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- Jejunal microvilli atrophy and reduced nutrient transport in rats with advanced liver cirrhosis: improvement by Insulin-like Growth Factor I(BioMed Central, 2004) Varela-Nieto, I. (Isabel); Urdaneta, E. (Elena); Castilla-Cortazar, I. (Inma); Gonzalez-Baron, S. (Salvador); Puche, J.E. (Juan Enrique); Diaz-Casares, A. (Amalia); Castilla, A. (Alberto); Diaz-Sanchez, M. (Matías); Garcia, M. (María); Pardo-Mindan, F.J. (Francisco Javier); Pascual, M. (María); Vivas, B. (Bárbara)Previous results have shown that in rats with non-ascitic cirrhosis there is an altered transport of sugars and amino acids associated with elongated microvilli. These alterations returned to normal with the administration of Insulin-Like Growth Factor-I (IGF-I). The aims of this study were to explore the evolution of these alterations and analyse the effect of IGF-I in rats with advanced cirrhosis and ascites. Thus, jejunal structure and nutrient transport (D-galactose, L-leucine, L-proline, L-glutamic acid and L-cystine) were studied in rats with ascitic cirrhosis. METHODS: Advanced cirrhosis was induced by CCl4 inhalation and Phenobarbital administration for 30 weeks. Cirrhotic animals were divided into two groups which received IGF-I or saline during two weeks. Control group was studied in parallel. Jejunal microvilli were studied by electron microscopy. Nutrient transport was assessed in brush border membrane vesicles using 14C or 35S-labelled subtracts in the three experimental groups. RESULTS: Intestinal active Na+-dependent transport was significantly reduced in untreated cirrhotic rats. Kinetic studies showed a decreased Vmax and a reduced affinity for sugar and four amino acids transporters (expressed as an increased Kt) in the brush border membrane vesicles from untreated cirrhotic rats as compared with controls. Both parameters were normalised in the IGF-I-treated cirrhotic group. Electron microscopy showed elongation and fusion of microvilli with degenerative membrane lesions and/or notable atrophy. CONCLUSIONS: The initial microvilli elongation reported in non ascitic cirrhosis develops into atrophy in rats with advanced cirrhosis and nutrient transports (monosaccharides and amino acids) are progressively reduced. Both morphological and functional alterations improved significantly with low doses of IGF-I.
- Susceptibility to apoptosis measured by MYC, BCL-2, and BAX expression in arterioles and capillaries of adult spontaneously hypertensive rats(Nature publishing group, 1999) Diez-Martinez, J. (Javier); Vega, F. (Francisco); Panizo, A. (Ángel); Pardo-Mindan, F.J. (Francisco Javier)Hypertension results in microvascular rarefaction or disappearance of microvessels. In the present study, we investigated the pathogenic role of apoptosis in hypertension-induced rarefaction of heart arterioles and capillaries of spontaneously hypertensive rats (SHR). Experiments were performed on hearts from 6-week-old, 16-week-old, and 30-week-old SHR (n = 30 rats) (SHR6, SHR16, SHR30). We used as controls 6-week-old, 16-week-old, and 30-week-old normotensive rats (WKY) (n = 30 rats) (WKY6, WKY16, WKY30). We analyzed the expression of c-myc, bcl-2, and bax and in situ end-labeling DNA fragmentation in vascular smooth muscle cells of arterioles and endothelial cells of arterioles and capillaries. Endothelial cells of capillaries and endothelial and smooth muscle cells of arterioles of hypertensive animals (SHR) express more Bax protein and Myc protein than their respective normotensive controls by margins that were statistically significant. The SHR30 group expressed the lowest levels of Bcl-2 protein by a margin that was statistically significantly different from WKY30. We did not find evidence of apoptosis in arterioles or capillaries on the basis of in situ end-labeling. However, our results indicated that alterations in the expression of members of the Bcl-2 family of proteins and Myc protein occurred in smooth muscle cells and endothelial cells of arterioles and capillaries of SHR. In conclusion, although evidence of apoptosis in arterioles and capillaries was not found by in situ end-labeling, our findings suggest that in hypertension they may have a higher susceptibility to apoptosis, and therefore rarefaction may be a consequence of apoptosis.
- Association of EWS-FLI1 Type 1 Fusion with Lower Proliferative Rate in Ewing’s Sarcoma(Elsevier, 2000) Alava, E. (Enrique) de; Barr, F.G. (Frederic G.); Huvos, A.G. (Andrew G.); Panizo, A. (Ángel); Pardo-Mindan, F.J. (Francisco Javier); Antonescu, C.R. (Cristina R.); Ladanyi, M. (Marc)The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway.
- Plasma levels of leukotriene B4 during hepatic allograft rejection(Elsevier, 1992) Diaz, M.C. (M. C.); Pardo, F. (Fernando); Álvarez-Cienfuegos, J. (Javier); Hernandez-Lizoain, J.L. (Jose Luis); Torramade, J. (J.); Ortigosa, C.R. (C.R.); Pardo-Mindan, F.J. (Francisco Javier); Villa, V. (V.) de; Gonzalez, J. (J.)At the present time, rejection is the most frequent cause of graft dysfunction in liver transplantation. Differential diagnosis between this and other possible causes of dysfunction—preservation injury, vascular, biliary, viral—may well be difficult, as the clinical and analytical findings are often similar; moreover, no markers specific to rejection are available, and histological studies are necessary for a definitive diagnosis. For this reason, markers indicating activity within the immune system need to be established so as to provide a more specific means of distinguishing rejection from other causes of graft dysfunction. The immune response to an allograft is complex, and the intricate mechanisms regulating it are still not entirely understood. Nevertheless, several specialists have drawn connections among changes in the lymphocyte subpopulations, rises in the interleukin-2 levels, expression of the interleukin-2 receptor, and alteration in the expression of antigens belonging to class II in the greater complex of histocompatibility, with rejection of the allograft. Leukotriene B4 (LTB4) is a derivative of the metabolism of arachidonic acid via 5- lipoxygenase, whose in vitro behaviour is to encourage rejection by favoring leukocyte aggregation, proliferation of T lymphocytes, interleukin-1 and -2 secretion, and the development of "natural killer" cell subpopulations. This study examines the role of LTB4 in mediating the immune response to the hepatic allograft in order to assess its usefulness in early diagnosis of rejection.
- Quinapril inhibits c-Myc expression and normalizes smooth muscle cell proliferation in spontaneously hypertensive rats(Nature publishing group, 1997) Hernandez, M. (Marta); Diez-Martinez, J. (Javier); Panizo, A. (Ángel); Pardo-Mindan, F.J. (Francisco Javier); Galindo, M.F. (María F.); Cenarruzabeitia, E. (Edurne)A number of data suggest that angiotensin II-dependent activation of the protooncogene c-myc participates in the proliferative response of smooth muscle cells (SMC) of rats with spontaneous hypertension (SHR). We therefore investigated the effects of chronic treatment with the angiotensin converting enzyme (ACE) inhibitor quinapril on the oncoprotein c-Myc and the proliferating cell nuclear antigen cyclin A in SMC of small intramyocardial arteries from the left ventricle of SHR. The expression of c-Myc and cyclin A was assessed by immunocytochemical analysis. The number of smooth muscle cells was assessed by morphometrical analysis. As compared to normotensive Wistar-Kyoto (WKY) rats, untreated SHR exhibited an increased percentages of cells expressing c-Myc (33% +/- 4% v 19% +/- 2%, mean +/- SEM, P < .005) and cyclin A (25 +/- 2 v 11% +/- 1%, P < .001). In quinapril-treated SHR compared with untreated SHR, we found decreased expression of c-Myc (22% +/- 2%, P < .005) and cyclin A (13% +/- 1%, P < .001). No significant differences were found between WKY rats and quinapril-treated SHR in the above parameters. Cyclin A was directly correlated with the number of SMCs in each group of rats. These results suggest that an enhanced expression of c-Myc may be involved in the increased proliferation seen in SMCs from small arteries of SHR. Quinapril administration normalizes proliferation in the SMCs of SHR, possibly by inhibiting the expression of the oncoprotein c-Myc and its effects on the cell cycle.
- Sarcoma cordoide de fémur. Estudio a microscopio óptico y electrónico de un caso(Universidad de Navarra, 1975) Herranz, P. (Pilar); Cañadell, J.M. (J. M.); Pardo-Mindan, F.J. (Francisco Javier); Imizcoz, J.L. (J. L.); Vazquez, J.J. (Jesús Jaime)Areas of chordoma and chondrosarcoma have been reported extensively in the same tumoral mass located in espheno-palatine region. The same association in long bones of the extremities have been reported recently, with the name of "chordoide sarcoma", "parachordoma" or "chondroid chordoma". We present a case of "chordoid sarcoma". The cells of this tumor have morphologic features of chordoma and chondrosarcoma in both the optical and ultrastructural study. However some morphological, radiological and clinical aspects, suggest that this tumor possesses characteristics that define it as a separate entity.
- Incidencia y mortalidad por cáncer en Navarra, 1998-2002. Evolución en los últimos 30 años(2007) Moreno-Iribas, C. (Conchi); Ezponda, C. (C.); Lizarraga, J. (J.); Valerdi, J.J. (J.J.); Ortigosa, C. (C.); Resano, J. (J.); Pérez de Rada, M.E. (M.E.); Puras, A. (Ana); Pardo-Mindan, F.J. (Francisco Javier); Santamaría, M. (Mercedes); Ezpeleta, I. (I.); Ardanaz, E. (Eva); Floristan-Floristan, M.Y. (María Yugo); Monzón-Muñoz, F.J. (Francisco José); Barricarte, A. (Aurelio); Navaridas, N. (N.); Martinez-Peñuela, J.M. (J.M.)Entre 1998-2002 se registraron 16.952 nuevos casos de cáncer en Navarra. En los hombres, los cánceres más frecuentemente diagnosticados fueron, por este orden próstata, pulmón, colon y recto, vejiga y estómago, que sumaron el 63,2% de todos los casos de cáncer. En mujeres las localizaciones de mama, colon y recto, cuerpo de útero, estómago y ovario sumaron el 57,6 % del total de los casos. En el mismo periodo, 1998-2002, fallecieron por cáncer 4.127 hombres y 2.470 mujeres. El 60 % de todas las muertes producidas por tumores malignos en hombres se debieron a las localizaciones de pulmón, próstata, colón y recto, estómago y vejiga. En las mujeres las localizaciones de colon y recto, mama, estómago, páncreas y pulmón, sumaron el 49% de las defunciones por cáncer. En los hombres de Navarra han aumentado las tasas de incidencia del cáncer de próstata, riñón y linfoma no Hodgkin. Cánceres evitables, como los relacionados con el hábito de fumar (pulmón, cavidad oral y faringe o páncreas), continúan en ascenso, y representan mayor riesgo global de morir por cáncer en el último periodo estudiado que en las décadas de los años 1970 y 1980. A partir de 1995 y hasta la actualidad, la mortalidad por cáncer pasó de ocupar el segundo lugar a ser la primera causa de muerte entre los hombres de Navarra. El riesgo global de muerte por cáncer en hombres se ha igualado al primer periodo estudiado 1975-77. Entre las mujeres el riesgo global de muerte por cáncer descendió un 25% entre 1975 y 2002, a costa fundamentalmente del cáncer de mama y de estómago. Los tumores relacionados con el hábito de fumar muestran incrementos tanto en la mortalidad como en la incidencia y emerge como un problema importante de salud entre las mujeres de Navarra. Ha aumentado la incidencia de cáncer de mama, en cambio en la mortalidad se sitúa en cifras inferiores a las del primer periodo 1975-77. El cáncer invasivo de cérvix se mantiene en tasas muy bajas respecto a muchos países europeos, incluida España. En ambos sexos han aumentado el cáncer colorrectal y el melanoma mientras que continúa el descenso de la incidencia y mortalidad por cáncer de estómago.
- A Comparative Ultrastructural Study of Chondrosarcoma, Chordoid Sarcoma, and Chordoma(Wiley-Blackwell, 1981) Guillen, F.J. (F. J.); Pardo-Mindan, F.J. (Francisco Javier); Vazquez, J.J. (Jesús Jaime); Villas-Tome, C. (Carlos)A morphologic and electron microscopic study was made of two chordoid sarcomas. These lesions were compared with two classical chondrosarcomas and two chordomas. These chondrosarcoma cells showed many features common to chondrocytes, such as abundant RER, well-developed Golgi complexes, and microvillous cytoplasmatic membranes. The chordoid sarcomas bore a close morphologic resemblance to the chordomas but the ultrastructural features revealed a close relationship to the chondrosarcomas. The chordoid sarcoma and chondrosarcoma cells had scalloped cytoplasmatic membranes, variable amounts of glycogen, round or oval nuclei and microfibrils, collagen, and electron-dense granules in the ground substance. The chordoma was characterized by the presence of stellate and physalipherous cells, as well as many transitional cells, with varying nuclear morphology; dilated and irregular RER in contact with mitochondria and morphologically varied vacuoles are the main features in the cytoplasm. This study suggests that chordoid sarcoma represents a variety of the chondrosarcoma rather than a form of chordoma. These findings also support the suggestion of Weiss that chordoid sarcoma is an extraskeletal myxoid chondrosarcoma
- Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease(American Heart Association, 2000) Martinez-Ubago, J.L. (José L.); Gutierrez-Stampa, M. (M.); Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Etayo, J.C. (Juan Carlos); Pardo-Mindan, F.J. (Francisco Javier); Larman, M. (Mariano); Gil, M.J. (María José); Monreal, J.I. (José Ignacio); Emparanza, J.I. (J. I.); Artiñano, E. (E.); Varo-Cenarruzabeitia, M.N. (Miren Nerea)BACKGROUND: This study was designed to investigate whether the serum concentration of the carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, is related to myocardial fibrosis in hypertensive patients. METHODS AND RESULTS: The study was performed in 26 patients with essential hypertension in which ischemic cardiomyopathy was excluded after a complete medical workup. Right septal endomyocardial biopsies were performed in hypertensive patients to quantify collagen content. Collagen volume fraction (CVF) was determined on picrosirius red-stained sections with an automated image analysis system. The serum concentration of PIP was measured by specific radioimmunoassay. Compared with normotensives, both serum PIP and CVF were increased (P<0.001) in hypertensives. A direct correlation was found between CVF and serum PIP (r=0.471, P<0.02) in all hypertensives. Histological analysis revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 18 with nonsevere fibrosis. Serum PIP was higher (P<0.05) in patients with severe fibrosis than in patients with nonsevere fibrosis. Using receiver operating characteristic curves, we observed that a cutoff of 127 microg/L for PIP provided 78% specificity and 75% sensitivity for predicting severe fibrosis with a relative risk of 4.80 (95% CI, 1.19 to 19.30). CONCLUSIONS: These results show a strong correlation between myocardial collagen content and the serum concentration of PIP in essential hypertension. Although preliminary, these findings suggest that the determination of PIP may be an easy and reliable method for the screening and diagnosis of severe myocardial fibrosis associated with arterial hypertension.
- Adenoma de las glándulas de Brunner(The Spanish Society of Digestive Pathology, 1991) Contreras-Mejuto, F. (F.); Robledo-Arribas, M. (M.); Pardo-Mindan, F.J. (Francisco Javier); Sola-Gallego, I. (I.)El adenoma de glándulas de Brunner representa el 10% de los tumores benignos del duodeno. Su localización más frecuente es en la primera porción del duodeno y es extremadamente raro por debajo de la ampolla de Vater. Presentamos dos casos, uno de ellos asociado a adenocarcinoma de la ampolla de Vater. Esta asociación no está descrita en la literatura. No existe ningún caso en que se demuestre una transformación de adenoma a adenocarcinoma. Para estas lesiones nodulares solitarias es más correcto el término de adenoma que el de hiperplasia, debiéndose reservar este último para las proliferaciones más difusas.