Histology and histopathology Vol.23, nº1 (2008)

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Open Access
Effects of sediment sorbed linear alkylbenzene sulphonate on juveniles of the Senegal sole, Solea senegalensis, Toxicity and histological indicators
(Murcia : F. Hernández, 2008) Hampel, M.; Ortiz-Delgado, J.B.; Sarasquete, C.; Blasco, J.
Many synthetic organic substances, including surfactants, tend to be sorbed on suspended solids and to accumulate finally on bottom sediments, where benthic communities may be exposed to them. Concentrations of Linear Alkylbenzene Sulphonates (LAS) have been detected in estuarine and coastal sediments, presenting wide concentration ranges depending on the presence of treatment facilities, hydrodynamic conditions, organic matter content, etc. Senegal sole, Solea senegalensis, larvae (40 days posthatching; dph) were exposed to increasing concentrations of LAS spiked sediments, comprised between 0.37 and 880.78 mg LAS·kg-1 during 30 days. The obtained results showed that survival of exposed larvae was not significantly affected at environmentally relevant concentrations, the LC50 value being obtained after 30 days 876.46 mg·kg-1. However, the histological and histopathological analyses carried out in target organs revealed, that first alterations from the normal pattern were observed at concentrations of 222.66 mg·kg-1, presenting effects such as blood extravasation and hyperplasy of the lamellar epithelium in gills, increase of inter-myotomal spaces of the skeletal musculature and edematous separation of the skin from epidermis. At the highest exposure concentrations (755.27 and 880.78 mg LAS·kg-1), shrinkage of hepatocytes, nuclear pycnosis and blood stagnation are observed in the liver, degeneration of pancreatic cells, reduction of hemocytopoietic tissue in the kidney and vacuolisation of intestinal enterocytes was observed at histological level, as well as severe separation of the epidermis from the underlying tissues. Simultaneously, a significant increase of the wet weight with exposure concentration was observed in the test organisms.
Open Access
AB deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer s disease
(Murcia : F. Hernández, 2008) Howlett, D.R.; Bowler, K.; Soden, P.E.; Riddell, D.; Davis, J.B.; Richardson, J.C.; Burbidge, S.A.; Gonzalez, M.I.; Irving, E.A.; Lawman, A.; Miglio, G.; Dawson, E.L.; Howlett, E.R.; Hussain, I.
Summary. A transgenic mouse bearing mutant transgenes linked to familial forms of Alzheimer’s disease (AD) for the amyloid precursor protein and presenilin-1 (TASTPM) showed Aß plaque deposition and age-related histological changes in associated brain pathology. The Aß present was of multiple forms, including species with a C-terminus at position 40 or 42, as well as an N-terminus at position 1 or truncated in a pyro-3-glutamate form. Endogenous rodent Aß was also present in the deposits. Laser capture microdissection extracts showed that multimeric forms of Aß were present in both plaque and tissue surrounding plaques. Associated with the Aß deposits was evidence of an inflammatory response characterised by the presence of astrocytes. Also present in close association with the deposits was phosphorylated tau and cathepsin D immunolabelling. The incidence of astrocytes and of phosphorylated tau and cathepsin D load showed that both of these potential disease markers increased in parallel to the age of the mice and with Aß deposition. Immunohistochemical labelling of neurons in the cortex and hippocampus of TASTPM mice suggested that the areas of Aß deposition were associated with the loss of neurons. TASTPM mice, therefore, exhibit a number of the pathological characteristics of disease progression in AD and may provide a means for assessment of novel therapeutic agents directed towards modifying or halting disease progression.
Open Access
Desmoid tumor: a disease opportune for molecular insights
(Murcia : F. Hernández, 2008) Kotiligam, D.; Lazar, A.J.F.; Pollock, R.; Lev, D.
Summary. Desmoid tumors are monoclonal proliferations that fall within a broad histologic spectrum of fibrous mesenchymal tumors that ranges from benign proliferations of scar tissue to high-grade fibrosarcomas. These low-grade tumors are extremely infiltrative locally, but lack the ability to metastasize systemically. While they are only rarely a direct cause of mortality, using current therapeutic modalities, these tumors have a high rate of local recurrence that can result in significant treatment related morbidity. Sporadic desmoids are usually associated with somatic mutations in codons 41 or 45 of exon 3 of ß-catenin (CTNNB1). Desmoid tumors occurring in the background of familial adenomatous polyposis (FAP) usually contain inactivating germline mutations in the adenomatous polyposis coli (APC) gene. CTNNB1 and APC are part of the Wnt signaling pathway and mutations in either gene result in stabilization of the ß-catenin protein and allow nuclear translocation and binding of ß-catenin to the T-cell factor/lymphoid enhancer factor (TCF/Lef) family of transcription factors, resulting in activation of target genes which may underlie desmoid tumor biology and clinical behavior. In an era of molecularly targeted therapeutics there is a real need to better grasp the molecular mechanisms behind desmoid tumorigenesis and progression. This knowledge will eventually result in the development of patient and tumor tailored therapies and assist in the control and eradication of this disease.
Open Access
Blood-borne cells involved in arterial repair upon experimental incision injury
(Murcia : F. Hernández, 2008) Pieri, L.; Rinaldi, B; Domenici Lombardo, L.; Bacci, S.; Filippelli, A.; Capuano, A.; Rossi, F.; Romagnoli, P.
Summary. We had previously shown that microscopically detectable infiltration of dendritic cells and expression of Hsp47 in tissue lysates occur during repair upon experimental arterial injury. We have further analysed here the cell types involved in the repair process by histology, electron microscopy and immunofluorescence. Rat carotid arteries were subjected to brief crushing and full thickness incision and were analysed up to 21 d thereafter. Adhesion and activation of platelets occurred 3 h after surgery. A neointima had formed 7 d after surgery, where immature cells entered from the lumen and gave rise to cells rich in organelles of the secretory pathway and endowed with bundles of phalloidin-binding microfilaments. Alpha smooth muscle-positive, secretory and contractile smooth muscle cells were found in the neointima 14 and 21 d after injury. Seven to 21 d after surgery, endothelial cells appeared immature and the newly formed tissue contained MHC-II positive, CD43 positive dendritic cells which clustered with lymphocytes, a few macrophages containing apoptotic remnants and cells labelled for Hsp47. Thin elastic fibrils appeared in the neointima 21 d after injury. The results suggest that the response to acute arterial incision injury is mediated by blood borne cells which differentiate along multiple pathways; the process evolves without reaching stabilization within the observed time lapse; the secretion of extracellular matrix is marked by the expression of Hsp47; and the constant presence of dendritic cells clustered with lymphocytes makes these cells candidate to a pivotal role in the tissue response to injury.
Open Access
Gold complexes as prospective metal-based anticancer drugs
(Murcia : F. Hernández, 2008) Milacic, Vesna; Fregona, D.; Dou, Q.P.
Medical and therapeutic value of gold has been recognized thousands of years ago, but its rational use in medicine has not begun until the early 1920s. Cisplatin is one of the first metal-containing compounds with anti-cancer activity discovered in the 1960s. Despite the fact that cisplatin treatment is efficient for several types of solid tumors, its effectiveness is limited by toxic side effects and tumor resistance that often leads to the occurrence of secondary malignancies. Since gold(III) is isoelectronic with platinum(II) and tetracoordinate gold(III) complexes have the same square-planar geometries as cisplatin, the anticancer activity of gold(III) compounds has been investigated. Previous studies suggested that, in contrast to cisplatin, gold complexes target proteins but not DNA. Recently, we have investigated gold(III) dithiocarbamates for their anticancer activity and showed that their primary target is the proteasome. Treatment of human breast tumorbearing nude mice with a gold(III) dithiocarbamate complex resulted in significant inhibition of tumor growth, associated with proteasome inhibition and massive apoptosis induction in vivo. Better understanding of physiological processing of gold compounds will provide a rational basis for their further development into novel anticancer drugs.
Open Access
Glucocorticoid receptor changes its cellular location with breast cancer development
(Murcia : F. Hernández, 2008) Conde, Isabel; Paniagua, Ricardo; Fraile, Benito; Lucio, Javier; Arenas, María I.
Glucocorticoids play a major role in attenuation of the inflammatory response and they are useful in the primary combination chemotherapy of breast cancer, since in vitro studies have demonstrated an antiproliferative effect in human breast cancer cells. In contrast, it was recently shown that glucocorticoids protect against apoptotic signals evoked by cytokines, cAMP, tumour suppressors, and death genes in mammary gland epithelia. Their actions are mediated by intracellular receptor (GR) that functions as a hormonedependent transcription factor; however, no previous studies have been focused on GR expression in different pathologies of the human breast, and the possible relationship with that of mineralocorticoid receptor (MR) and COX-2. Also, the role of these proteins on tumoral breast epithelial cells remains unclear. Therefore, we examined GR, MR and COX-2 expression by immunohistochemistry and Western blot techniques in 142 samples of human breast obtained by total or partial mastectomy. We found that the percentage of positive patients presenting nuclear immunoreaction to GR decreased with tumor development, while all samples analyzed showed cytoplasmic immunoreactions to MR. All positive samples to COX-2 antibody showed cytoplasmic location, a higher immunoreaction being observed in benign breast diseases than in carcinomatous lesions. Thus, breast cancer progression is associated with the accumulation of GR in the cytoplasm of tumoral cells and the decrease of COX-2 expression.
Open Access
Protein markers in the microcyst of the posteroventral cochlear nucleus of the gerbil
(Murcia : F. Hernández, 2008) Yu, S. M.; Lin, K. H.; Lai, Y.L.
Microcysts are most evident in the posteroventral and anteroventral cochlear nuclei (PVCN and AVCN) of the Mongolian gerbil. The origin and contents of the microcyst are not elucidated at present. The present study investigated the possible inclusions in the microcyst by employing immunocytochemical labeling to localize the existence of various protein markers. Thirty and 100 μm thick sections were used to substitute and reconstruct between 6 and 20 paraffin serial sections, respectively. In 30-μm-thick slice sections, immunoreactivity of glial fibrillary acidic protein (GFAP-IR), mitochondria inner membrane (MCA-In-IR), S-100 (S-100-IR), serotonin (5-HT-IR), myelin proteolipid protein (PLP-IR) and substance P (SP-IR) abutted on the perimeter of the microcyst. The immunolabeled SP-positive cells were adjacent to the evagination of the microcyst. In 100-μm-thick slice sections, immunoreactivity of nitric oxide synthase (NOS-IR) and somatostatin (SOM-IR) mainly precipitated as flocculent structures in the small to medium-sized microcysts. 5-HT-IR also precipitated as an elongated flocculent stalk adjacent to the large microcyst or randomly distributed in the neuropil. The findings suggest that GFAP, MCA-In, S-100, 5-HT, PLP, SP, NOS and SOM may be involved in modulating the physiological functions and maintaining microenvironmental homeostasis of the microcyst in the cochlear nucleus of the gerbil.
Open Access
Intraductal papillary neoplasms of bile duct. A distinct entity like its counterpart in pancreas
(Murcia : F. Hernández, 2008) Ji, Y.; Fan, J.; Zhou, J.; Wang, B.S.; Liu, H.B.; Wu, Z.W.; Tan, Y.S.
To recognize the new entity-intraductal papillary neoplasia of bile duct in liver, the authors reviewed the clinical records of sixteen patients, analyzed the microscopic features, and selected immunohistochemical reactivity (cytokeratins and mucins) that might correlate with classification. Ten patients were male and six were female, with a mean age of 58 years (range, 21-73 years). According to their cell phenotypes, these papillary tumors were classified as intestinal type (6 cases), pancratobiliary type (4 cases), gastric type (5 cases) and oncocytic type (1 case). Most were located in the left hepatic duct and accompanied with bile duct dilatation (10 cases). Eight showed minimal expansile invasion into the ductal wall and eight were noninvasive. Five patients were treated with a hepatectomy, three underwent segmental resections, and one underwent a left hepatic lobectomy. One patient died of unrelated causes 6 years after operation, and another died of postoperative complications. The remaining 7 patients are alive and disease free 1-5 years after surgery. Because of its distinct clinical, pathological features and a favorable prognosis can be expected after complete surgical resection, we suggested that intraductal papillary neoplasia should be distinguished from other types of peripheral cholangiocarcinoma, as a distinct entity, like its counterparts in the pancreas. Neoexpressed and overexpressed mucins are of clinical value as a marker for supportive diagnosis, prognosis or monitoring therapy
Open Access
Skin homeostasis during inflammation, a role for nerve growth factor
(Murcia : F. Hernández, 2008) Sivilia, S.; Paradisi, M.; D’Intino, G.; Fernandez, M.; Pirondi, S.; Lorenzini, L.; Calzà, L.
The skin is a neuroendocrine immune organ in which many different molecules operate in autocrineparacrine manner to guarantee tissue homeostatsis in physiological and pathophysiological conditions. In this paper we examined NGF and p75 receptor expression in the skin, during CFA induced inflammation, in a timecourse study. We also examined cutaneus innervation and proliferation, by means of immunohistochemistry and quantitative image analysis, RT-PCR and Western blot. Spontaneous and evoked pain-behavior was also measured in experimental rats. The main results can be summarized as follows: 1). a peripheral sensory neuropathy develops in this condition, as indicated by thermal hyperalgesia, thus leading to a sensory denervation of the hind-paw skin as indicated by disappearance of CGRP and PGP9.5-IR fibers; 2). NGF and p75 expression (mRNA and protein) increases in the skin (keratinocytes) in the acute phase of CFA inflammation; 3). at this stage, a higher proliferative activity is observed in the skin, as defined by the expression of cell cycle-associated protein Ki67; 4). in the long-lasting chronic phase there is a further upregulation of NFG and p75 expression in the skin; 5). trkA mRNA expression inversely correlates with p75 and NGF mRNA expression. These results suggest that CFA chronic inflammation evolves from inflammation to a small fibers sensory neuropathy and NGF seems to play a role in both events.
Open Access
Ghrelin localization in the medulla of rat and human adrenal gland and in pheochromocytomas
(Murcia : F. Hernández, 2008) Raghay, K.; Garcia-Caballero, Tomas; Bravo, S.; Alvárez, C.V.; González, R.; Diéguez, C.; Beiras, Andres; Fraga, M.; Gallego, R.
Objective: Ghrelin is predominantly produced by neuroendocrine cells of stomach and has been expressed in several normal and tumour endocrine tissues. It has been reported that the localization of ghrelin is exclusively in the cortex of human and rat adrenal gland and in adrenocortical tumours. This prompted us to analyze the expression of this peptide in medulla of human and rat adrenal glands and in human pheochromocytomas. Design and methods: Analysis of ghrelin mRNA expression in rat adrenal gland was conducted by means of semi-quantitative RT-PCR. Ghrelin localization was studied in medulla of human and rat adrenal gland by immunohistochemistry. In addition, we have carried out a double immunofluorescence with chromogranin A to determine the specific cell type expressing ghrelin immunoreactivity. Ghrelin expression was also analyzed in five cases of pheochromocytoma by immunohistochemistry. Finally, Western blotting analysis was performed with goat ghrelin antibody in the cortex and in the medulla of rat adrenal gland. Results: RT-PCR demonstrated expression of ghrelin mRNA in rat adrenal gland. We also detected ghrelin expression in virtually all rat pheochromocytes by immunohistochemistry and double immunofluorescence. Furthermore, we showed ghrelin immunoreactivity in the medulla of human adrenal gland and in pheochromocytomas. By Western blotting, we found the expression of ghrelin precursor, proghrelin and mature ghrelin in the medulla of rat adrenals. However, the cortex of rat adrenal gland only expressed ghrelin precursor. Conclusions: Our study is the first to demonstrate a medullar expression of ghrelin in human and rat adrenal gland; we also showed ghrelin expression in pheochromocytomas.
Open Access
Molecular characterization of small peripheral lung tumors based on the analysis of fine needle aspirates
(Murcia : F. Hernández, 2008) Zudaire, I.; Lozano, M.D.; Vazquez, M.F.; Pajares, M.J.; Agorreta, J.; Pio, R.; Zulueta, J.J.; Yankelevitz, D.F.; Henschke, C.I.; Montuenga, L.M.
The computed tomography (CT)-based early lung cancer diagnostic technologies allow the detection of very small stage I lung tumors. As part of these screening protocols any suspicious nodule has to be diagnosed morphologically, which requires CT-guided Fine Needle Aspiration, open biopsy or surgery. Fine Needle Aspiration (FNA) cytology is a well-recognised method for a rapid and accurate diagnosis of small lung tumors. Molecular analysis of the FNA specimens could complement cytology diagnosis by the characterization of the biological traits at the preoperative stage. In this study, we aimed to characterize the biological profile of 33 paraffin-embedded transthoracic FNA samples obtained from three groups of lung cancer patients: two groups of small early-detected lung adenocarcinomas (radiologically subsolid and solid nodules) and a third group of small metastatic adenocarcinomas. Genetic analysis was performed by fluorescence in situ hybridization using the four-color LAVysion probe. p53 and Ki-67 protein expression was also evaluated by immunocytochemistry. The samples showed gains for all targets analyzed; two cases had EGFR gene amplification and two cases had MYC amplification. There were no significant differences in the percentage of genetically malignant cells and the expression of Ki- 67 among the three groups. However, p53 accumulation was significantly higher in the metastatic group compared to the subsolid early-detected group (P = 0.001). In conclusion, molecular analysis of FNA specimens may provide useful information at preoperative stages. In our series, a good prognostic profile in subsolid early detected adenocarcinomas is suggested.
Open Access
Molecular mechanisms of medullary thyroid carcinoma, current approaches in diagnosis and treatment
(Murcia : F. Hernández, 2008) Boikos, S.A.; Stratakis, C.A.
Medullary thyroid carcinoma is the most common cause of death among patients with multiple endocrine neoplasia (MEN) 2. Dominant-activating mutations in the RET proto-oncogene have been shown to have a central role in the development of MEN 2 and sporadic medullary thyroid cancer (MTC): about half of sporadic MTCs are caused by somatic genetic changes of the RET oncogene. Inactivating mutations of the same gene lead to Hirschprung disease and other developmental defects. Thus, RET genetic changes lead to phenotypes that largely depend on their location in the gene and the function and timing of developmental expression of the RET protein. The reproducibility of the phenotype caused by each RET genotype led to MEN 2/MTC being among the first conditions in Medicine where a drastic measure is applied to prevent cancer, following genetic testing: thyroidectomy is currently routinely done in young children that are carriers of MTC-predisposing RET mutations. RET inhibitors have been also developed recently and are used in various types of thyroid and other cancers. This report reviews the RET involvement in the etiology of MEN 2 and MTC and updates the therapeutic approach in preclinical and clinical studies.
Open Access
Adrenomedullin expression in pituitary adenomas and nontumoral adenohypophyses
(Murcia : F. Hernández, 2008) Lombardero, M.; Kovacs, K.; Horvath, E.; Scheithauer, B.W.; Rotondo, F.; Salehi. F; Lloyd, R.V.
Summary. Adrenomedullin (ADM) is a novel peptide originally identified in extracts of human pheochromocytoma. It is produced by several tissues, including the pituitary gland. The presence of ADM has been immunohistochemically demonstrated in pathologic pituitary glands, but no systematic study of ADM expression in human pituitary adenomas has been reported. Thus, we investigated ADM immunoexpression in 88 various hormone-secreting and clinically nonfunctioning pituitary adenoma types as well as 30 nontumoral adenohypophyses. Furthermore, ADM immunoreactivity was assessed on a 0 to +3 scale in all samples. We found strong immunoreativity for ADM in normal gonadotrophs also expressing FSH and LH whereas in the other adenohypophysial cell types expression of ADM was mild. Results showed that normal adenohypophyses were strongly immunopositive for ADM (2.18±0.11). Our findings demonstrate that ADM expression in the anterior pituitary is diminished in tumors as compared to the normal gland. The physiologic function of ADM is unknown, but it could act as a paracrine or autocrine factor in the adenohypophysis.
Open Access
Indices 1,2,3
(Murcia : F. Hernández, 2013-01-18)
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