Histology and histopathology Vol.15, nº 3 (2000)

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Open Access
Mechanisms underlying eosinophil trafficking and their relevance in vivo
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Cara, D. C.; Negrao-Correa, D.; Teixeira, M. M.
After their formation in the bone marrow, eosinophils circulate with a short half-life and are distributed throughout the body, especially in mucosal and sub-mucosal regions. Although a small amount of these cells are normally seen in healthy tissue, blood and tissue eosinophilia is a hallmark of helminthic and allergic diseases. The role of eosinophils in the normal physiology of mucosal tissues is not understood, but there is good evidence to demonstrate that these cells protect the host at least against some intestinal helminths, specially those with a lung cycle. In addition, there are now many data that support a role for eosinophils in the pathophysiology of allergic diseases, such as asthma. Because helminthic diseases have been largely controlled in developed countries, there has been much interest in the development of drugs which affect eosinophil migration and/or activation in the tissue and which may, thus, be useful in the treatment of allergic conditions. The understanding of the mechanisms controlling eosinophil trafficking and/or activation are essential in the development of anti-eosinophil-based therapeutic strategies. The present paper reviews aspects of eosinophil biology with emphasis on the role of eosinophils in parasitic infections and allergy, the basic mechanisms underlying the trafficking of eosinophils into tissue and how these can be modulated pharmacologically.
Open Access
Current knowledge of dystrophin and dystrophin-associated proteins in the retina
(Murcia : F. Hernández, 2000) Ueda, H.; Baba, T.; Ohno, S.
Dramatical development of molecular genetics has been disclosing the molecular mechanism of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (RMD). DMD gene product, dystrophin, is a submembranous cytoskeletal protein and many dystrophin-associated proteins (DAPs) have been identified, such as utrophin, dystroglycans, sarcoglycans, syntrophins and dystrobrevins. Dystrophin and DAPs are very important proteins not only for skeletal, cardiac, or smooth muscles but also for peripheral and central nervous systems including the retina. The retina has been extensively examined to demonstrate that dystrophin and B-dystroglycan localize at the photoreceptor terminal, and their deficiency produces the abnormal neurotransmission between photoreceptor cells and ON-bipolar cells. Dystrophin has seven isoforms in variable tissues, and the retina contains fulllength dystrophin (Dp427), Dp260, and Dp71. Recent studies have demonstrated that Dp71 localizes in the inner limiting membrane (INL) and around the blood vessel, and Dp260 is expressed in the outer plexiform layer (OPL). B-dystroglycan is also expressed in the same regions as well as dystrophin, but it remains unclear whether other DAPs are expressed in the retina or not. It is generally assumed that dystrophin functions to stabilize muscle fibers with DAPs by linking the sarcolemma to the basement membrane, but its function in the retina is totally unknown so far.
Open Access
Evaluation of the smooth muscle cell eomponent and apoptosis in the varicose vein wall
(Murcia : F. Hernández, 2000) Buján, J.; Jimenez-Cossio, J.A.; Jurado, F.; Gimeno, M.J.; Pascual, G.; García-Honduvilla, N.; Dominguez, B.; Bellón, J.M.
This study was designed to evaluate the role of the smooth muscle cell and the apoptosis in the pathogenesis of the varicose vein. Segments of saphenous vein were obtained from healthy subjects and from those with varicose veins. The vein specimens were subdivided according to subject age (younger or older than 50 years) and according to the varicose vein source (distal or proximal). Morphological, ultrastructural, cell proliferation (anti- PCNA method) and cell death (TUNEL method) analysis were performed. The walls of healthy, control vein specimens acquired a more collagenous and papilomatous appearance with age. A slight increase in the number of TUNEL-positive cells was also observed in specimens from older subjects. The proportion of apoptotic cells was much greater in the varicose veins than in control specimens. Most cellular alterations were seen in proximal varicose segments obtained from young subjects. These specimens showed hypertrophic areas with a high degree of cellularity (both in the media and in the thickened intima). The highest proportion of apoptotic cells and collagenisation were also observed in these areas. The enhanced number of apoptotic cells in varicose veins observed mainly in proximal/young vein specimens could be responsible, at least in part, for the acceleration of the final fibrosclerotic process characteristic of the varicose vein wall.
Open Access
Changes in the immunoreactivity of substance P and calcitonin gene-related peptide in the laryngeal taste buds of chronically hypoxic rats
(Murcia : F. Hernández, 2000) Kusakabe, T.; Yoshida, T.; Matsuda, H.; Yamamoto, Y.; Hayashida, Y.; Kawakami, T.; Takenaka, T.
The distribution of substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers in the taste buds of the epiglottis and aryepiglottic folds was compared between normoxic control and chronically isocapnic hypoxic rats (10% O2 and 3-4% CO2 for 3 months). In the normoxic laryngeal taste buds, SP- and CGRP-imrnunoreactive fibers were detected within the taste buds, where they appeared as thin processes with many varicosities. Most CGRP fibers showed coexistence with SP, but a few fibers showed the immunoreactivity of CGRP only. The density of intraand subgemmal SP and CGRP fibers penetrating into the laryngeal taste buds was significantly higher in chronically hypoxic rats than in normoxic control rats. Water intake in the hypoxic rats was significantly lower than in the normoxic rats. These results indicate that the increased density of SP- and CGRP-containing nerve fibers within the laryngeal taste buds is a predominant feature of hypoxic adaptation. The altered peptidergic innervation and reduced water intake support the hypothesis that the laryngeal taste buds are involved in water reception, and that the water reception may be under the control of peptidergic innervation.
Open Access
Histopathology and molecular pathology of synovial B-lymphocytes in rheumatoid arthritis
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Krenn, V.; Souto-Carneiro, M. M.; Kim, H.- J.; Berek, C.; Starostik, P.; König, A.; Harms, H.; Müller-Hermelink, H. K.
B-cells of the rheumatoid synovial tissue are a constant part of and, in some histopathological subtypes, the dominant population of the inflammatory infiltrate, located in the region of tissue destruction. The pattern of B-cell distribution and the relationship to the corresponding antigen-presenting cells (follicular dendritic reticulum cells: FOCs) show a great variety. Bcells may exhibit (i) a follicular organization forming secondary follicles; (ii) follicle-like patterns with irregularly formed FOC networks, and (iii) a diffuse pattern of isolated FOCs. Molecular analysis of immunoglobulin YH and YL genes from human synovial B-cell hybridomas and synovial tissue demonstrates somatic mutations due to antigen activation. The FOC formations in the synovial tissue may therefore serve as an environment for B-cell maturation, which is involved in the generation of autoantibodies. An autoantibody is defined as "pathogenic" if it fulfills the Witebsky-Rose-Koch criteria for classical autoimmune diseases: definition of the autoantibody; induction of the disease by transfer of the autoantibody; and isolation of the autoantibody from the disease-specific lesion. B-cells from rheumatoid synovial tissue show specificity for FcIgG, type II collagen, COMP, sONA, tetanus toxoid , mitochondrial antigens (M2), filaggrin and bacterial HSPs. The contributions of these antigens to the pathogenesis of RA are still hypothetical. A possible contribution could derive from crossreactivity and epitope mimicry: due to crossreaction, an antibody directed originally against a foreign infectious agent could react with epitopes from articular tissues, perpetuating the local inflammatory process. The characteristic distribution pattern, the localisation within the area of tissue destruction, the hypermutated IgYH and IgYL genes, and their exclusive function to recognize conformation-dependent antigens suggest a central role for B-cells in the inflammatory Offprint requests to: Dr. Veit Krenn, MD., Institute for Pathology, University of Wurzburg. Josef-Schneider-Str. 2, 0-97080 Wurzburg, Germany. Fax: +49931 2013440. e-mail : path119@mail.uniwuerzburg.de process of rheumatoid arthritis. Therefore, the analysis of synovial B-cell hybridomas and experimental expression of synovial IgYH and IgYL genes will help to characterise the antigens responsible for the pathogenesis of rheumatoid arthritis.
Open Access
Aging, methylation and cancer
(2000) Ahuja, N.; Issa, J.-P.J.
Alterations in methylation are widespread in cancers. DNA methylation of promoter-associated CpG islands is an alternate mechanism to mutation in silencing gene function, and affects tumor-suppressor genes such as p16 and RBl, growth and differentiation controlling genes such as ER and many others. Evidence is now accumulating that some of these methylation changes may initiate in subpopulations of normal cells as a function of age and progressively increase during carcinogenesis. Age-related methylation appears to be widespread and is one of the earliest changes marking the risk for neoplasia. In colon cancer, we have shown a pattern of age-related methylation for several genes, including ER, IGF2, N33 and MyoD, which progresses to full methylation in adenomas and neoplasms . Hypermethylation of these genes is associated with gene silencing. Age-related methylation involves at least 50% of the genes which are hypermethylated in colon cancer, and we propose that such age-related methylation may partly account for the fact that most cancers occur as a function of old age. Age-related methylation, then, may be a fundamental mark of the field defect in patients with neoplasia. The causes of age-related methylation are still unknown at this point, but evidence points to an interplay between local predisposing factors in DNA (methylation centers), levels of gene expression and environmental exposure. The concept that age-related methylation is a predisposing factor for neoplasia implies that it may serve as a diagnostic risk marker in cancer, and as a novel target for chemoprevention. Studies in animal models support this hypothesis and should lead to novel approaches to risk-assessment and chemoprevention in humans.
Open Access
Immunopathology of autoimmune gastritis: Lessons from mouse models
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Alderuccio, F.; Toh, B. H.
Autoimmune gastritis in humans is a chronic inflammatory disease of the stomach accompanied by specific destruction of gastric parietal and zymogenic cells resulting in pernicious anemia. Human gastritis can be accurately reproduced in mice and is characterised by autoantibodies to the a- and B-subunits of the gastric H/K ATPase (the enzyme responsible for gastric acid secretion) and cellular destruction of parietal and zymogenic cells within the gastric gland. Studies with these mouse models have given us our current concepts of the immunopathogenesis of the gastritis. Mouse models have shown that a T cell response is generated to the a- and B-subunits of the H/K ATPase and that an immune response to the B-subunit seems to be required for disease initiation. Using these models, we have defined key events associated with a damaging autoimmune response to the gastric H/K ATPase. The mechanisms associated with the cellular destruction associated with autoimmune gastritis are not know, but may involve signaling through death inducing pathways such as the Fas/FasL and TNF/TNFR pathways. This knowledge should permit us to develop strategies to prevent and treat the gastritis.
Open Access
Stretching molecular springs: elasticity of titin filaments in vertebrate striated muscle
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Linke, W. A.
Titin, the giant protein of striated muscle, provides a continuous link between the Z-disk and the M-line of a sarcomere. The elastic I-band section of titin comprises two main structural elements, stretches of immunoglobulin-like domains and a unique sequence, the PEYK segment. Both elements contribute to the extensibility and passive force development of nonactivated muscle. Extensibility of the titin segments in skeletal muscle has been determined by immunof1uorescence/immunoelectron microscopy of sarcomeres stained with sequence-assigned titin antibodies. The force developed upon stretch of titin has been measured on isolated molecules or recombinant titin fragments with the help of optical tweezers and the atomic force microscope. Force has also been measured in single isolated myofibrils. The force-extension relation of titin could be readily fitted with models of biopolymer elasticity . For physiologically relevant extensions, the elasticity of the titin segments was largely explainable by an entropic-spring mechanism. The modelling explains why during stretch of titin, the Ig-domain regions (with folded modules) extend before the PEYK domain. In cardiac muscle, I-band titin is expressed in different isoforms, termed N2-A and N2-B. The N2-A isoform resembles that of skeletal muscle, whereas N2-B titin is shorter and is distinguished by cardiac-specific Ig-motifs and nonmodular sequences within the central I-band section . Examination of N2-B titin extensibility revealed that this isoform extends by recruiting three distinct elastic elements: poly-Ig regions and the PEYK domain at lower stretch and, in addition , a unique 572- residue sequence insertion at higher physiological stretch. Extension of all three elements allows cardiac titin to stretch fully reversibly at physiological sarcomere lengths, without the need to unfold individual Ig domains. However, unfolding of a very small number of Ig domains remains a possibility.
Open Access
Apoptosis regulating genes in neuroendocrine tumors
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Liu, W.-H.; Wang, D.-G.
Neuroendocrine turnors (NETs) are a heterogeneous group of neoplasms. They are relatively uncommon and characterised by a relatively indolent clinical course. The indolent nature of NETs has long been enigmatic and recent advances in apoptosis research have led to speculation regarding the role of programmed cell death in NET tumorigenesis. It is hoped that a fundamental molecular understanding will help explain these variant behaviors that are so evident to the clinician, and ultimately yield novel and more effecti ve therapies. Recent studies have demonstrated that deregulation of programmed cell death may be a critical component in the multistep tumorigenesis of NETs and that the frequent expression of the BCL-2 oncoprotein in these tumors may contribute to their pathogenesis. The genetic complementation of simultaneously deregulated BCL-2 and c-MYC may be implicated in the multistep tumorigenesis of human NETs. It is also clear that numerous cellular gene products can and will be shown to impact upon apoptosis in NETs; some of these may even be molecules identified as oncoproteins or tumor suppressors. The major challenge will be to ascribe primary pathogenetic significance to tumor-associated derangements in expression of these molecules, and hopefully to then exploit our knowledge toward therapeutic benefit.
Open Access
Metamorphosed fibroblasts and their relation to the histogenesis of malignant fibrous histiocytoma in experimental murine model
(Murcia : F. Hernández, 2000) Osanai, T.; Yamakawa, Mitsunori; Suda, A.; Watanabe, Y.
Malignant fibrous histiocytoma (MFH) is a clinicopathologically established entity, but its histogenesis remains to be clarified. We have reported the existence of a specific cell type, the "fibrohistiocytoid (FH) cells", in various chronic inflammatory tissues. The FH cells are the metamorphosed fibroblasts and we have revealed the morphological resemblance between FH cells and MFH cells. In the present study we carried out some experiments to ascertain whether the FH cells have a possibility of neoplastic potential for the development of MFH in mice. A total of 50 female Balb/c mice treated with a chemical carcinogen, 9,lOdimethyl- 1,2-benzanthracene (DMBA), were examined histopathologically from 8 to 22 weeks after the initial treatment. It was found that 1) the chemically induced tumors in the mice resembled human pleomorphic/ storiform variant of MFH and cells from the tumor were transplantable subcutaneously in the back of another mouse, 2) the tumors were composed mainly of malignant FH cells, and there were many benign FH cells and fibroblasts in granulation tissues obtained at the initial stage of the experiment, 3) all DNA histograms obtained from MFHs were aneuploid and granulation tissues were diploid, and 4) benign FH cells in the granulation tissue appeared to have higher DNA synthesis activity than typical fibroblasts on the basis of bromodeoxyuridine (BrdU) labeling and cytofluorometric studies. From these findings, we suggest that the FH cells are not only a merely morphologically changed fibroblast, but also a biologically ominous cell which may contribute to develop MFH in mice.
Open Access
The distribution of cholinergic neurons in the human central nervous system
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Oda, Y.; Nakanishi, I.
Choline acetyltransferase (ChAT), the enzyme responsible for the biosynthesis of acetylcholine, is presently the most specific marker for identifying cholinergic neurons in the central and peripheral nervous systems. The present article reviews immunohistochemical and in situ hybridization studies on the distribution of neurons ex pressing ChAT in the human central nervous system. Neurons with both immunoreactivity and in situ hybridization signals of ChAT are observed in the basal forebrain (diagonal band of Broca and nucleus basalis of Meynert), striatum (caudate nucleus, putamen and nucleus accumbens), cerebral cortex, mesopontine tegmental nuclei (pedunculopontine tegmental nucleus, laterodorsal tegmental nucleus and parabigeminal nucleus), cranial motor nuclei and spinal motor neurons. The cerebral cortex displays regional and laminal differences in the distribution of neurons with ChAT. The medial seotal nucleus and medial habenular nucleus contain immunoreactive neurons for ChAT, which are devoid of ChAT mRNA signals. This is probably because there is a small number of cholinergic neurons with a low level of ChAT gene expression in these nuclei of human. Possible connections and speculated functions of these neurons are briefly summarized.
Open Access
The SH2 and SH3 adapter Nck: a two-gene family and a linker between tyrosine kinases and multiple signaling networks
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Li, W.; She, H.
SH2 and SH3 adapter proteins connect cell surface tyrosine kinases to intracellular signaling networks. For instance, the SH3-SH2-SH3 adapter Grb2 links receptor tyrosine kinases to the Ras pathway. Nck, composed of three SH3 domains and one SH2 domain, represents a two-gene (alpha and beta) family in mammals. Ncka and Nck13 are expressed in the same cells and appear to have distinct signaling specificity. Studies show that Nck plays a role in cell mitogenesis and morphogenesis. The former uses Ras-dependent and Ras-independent pathways. The latter appears to coordinate with the Cdc42/Rac>PAK lIWASp>actin cytoskeleton pathway. Understanding the specificity of Ncka and NckB signal transduction will provide answers for the previously often conflicting observations.
Open Access
Distribution of T-cell subsets and immunoglobulin-containing cells in nasal-associated lymphoid tissue (NALT) of chickens
(Murcia : F. Hernández, 2000) Ohshima, K.; Hiramatsu, K.
The present study demonstrated the localization of the T-cell subsets (CD4+ and CD8+) and immunoglobulin (1g)-containing cells (IgA, IgM, and IgG) in the nasal mucosa and its accessory structures. These lymphoid structures may be compared with nasalassociated lymphoid tissue (NALT) of rats and mice. In the chicken NALT, T-cell subsets were more widely distributed than Ig-containing cells, especially in large lymphoid accumulations restricted to the respiratory mucosa in the nasal cavity and the nasolacrimal duct. These lymphoid accumulations in the mucosa of the nasal cavity and nasolacrimal duct consisted of widely distributed CD8+ cells and deeply aggregated CD4+ cells adjacent to large germinal centers. In these lymphoid accumulations, IgG-containing cells were more frequently observed than IgM- and IgA-containing cells. T-cell subsets, predominantly CD8+ cells were more widely distributed in the duct epithelium of the lateral nasal glands than Ig-containing cells. Moreover, numerous CD8+ cells and a few Ig-containing cells were found in the chicken salivary glands, especially around the orifice of their ducts into the oral cavity. Therefore, it seems likely that the chicken NALT plays an important part in the upper respiratory tract, with a close relationship to the paraocular immune system.
Open Access
Ethylnitrosourea ENU - induced apoptosis in the rat fetal tissues
(Murcia : F. Hernández, 2000) Katayama, K.; Ishigami, M.; Uetsuka, K.; Nakayama, Hiroyuki; Doi, K.
Ethylnitrosourea (ENU), a well known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues and male reproductive organs. In this study, pregnant rats were treated with 60 mg/kg ENU at day 13 of gestation, and their fetuses were examined from 1 to 48 hours after treatment (HAT) to find a clue for clarifying the mechanisms of the ENU fetotoxicity and teratogenicity. From 3 to 12 HAT, the moderate to marked increase in the number of pyknotic cells was detected in the fetal CNS, craniofacial mesenchymal tissues, gonads and so on. These pyknotic cells had nuclei positively stained by the TUNEL method, which is widely used for the detection of apoptotic nuclei, and they also showed electron microscopic characteristics identical to those of apoptotic cells. The present results strongly suggest that excess cell death by apoptosis in the fetal CNS, craniofacial tissues and gonads may have a close relation to the later occurrence of anomalies reported in these tissues following ENU-administration.
Open Access
Tumor heterogeneity: morphological, molecular and clinical implications
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Lleonart, M. E.; Martin-Duque, P.; Sanchez-Prieto, R.; Moreno, A.; Ramon y Cajal, S.
Malignant tumors are characterized by their great heterogeneity and variability. There are hundreds of different types of malignant tumors that harbour many oncogenic alterations. The tumor heterogeneity has important morphological, molecular and clinical implications. Except for some hematopoietic and lymphoproliferative processes and small cell infant tumors, there are not specific molecular alterations for most human tumors. In this review we summarize the most important aspects of carcinogenesis and chemoradiosensitivity of malignant cells. In this regard, some oncogenes such as neu , ras and bcl-2 have been associated with cellular resistance to treatment with anticancer agents. The knowledge of oncogenic alterations involved in each tumor can be important to correlate the morphological features, the genetic background, the prognosis and the clinical response to treatment with anticancer agents. Based on the molecular background of the tumor there are new cancer gene therapy protocols. For example using adenovirus Ela in tumors with overexpression of neu oncogene, inhibitors of tirosine kinase specific for the PDGF receptor in glioma, inhibitors of farnesil transferase to prevent ras activity in tumors with mutations in the ras gene.
Open Access
Toward a molecular classification of the gliomas: histopathology, molecular genetics, and gene expression profiling
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Caskey, L. S.; Fuller, G. N.; Bruner, J. M.; Yung, W.K.A; Sawaya, R. E.; Holland, E. C.; Zhang, W.
As many as 100 ,000 new cases of brain tumor are diagnosed each year in the United States. About half of these are primary gliomas and the remaining half are metastatic tumors and non-glial primary tumors. Currently, gliomas are classified based on phenotypic characteristics. Recent progress in the elucidation of genetic alterations found in gliomas have raised the exciting possibility of using genetic and molecular analyses to resolve some of the problematic issues currently associated with the histological approach to glioma classification. Recently , immunohistochemical studies using novel proliferation markers have significantly advanced the assessment of tumor growth potential and the grading criteria of some tumor subtypes. Preliminary studies using cDNA array technologies suggest that the profiling of gene expression patterns may provide a novel and meaningful approach to glioma classification and subclassification. Furthermore, cDNA array technologies may also be used to identify candidate genes involved in glioma tumor development, invasion, and progression. This review summarizes current glioma classification schemes that are based on histopathological characteristics and discusses the potential for using cDNA array technology in the molecular classification of gliomas.
Open Access
Telomerase activity in cancer as a diagnostic and therapeutic target
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Kyo, S.; Takakura, M.; Inoue, M.
Major advances have been made in understanding the role of telomerase in cellular immortalization and carcinogenesis. Human telomeres undergo progressive shortening with cell division, and critical shortening of telomeres with cellular aging triggers a signal for cells to stop dividing and senesce. Telomerase is an enzyme that adds telomeric-repeated sequences to the ends of human chromosome DNA. Telomerase is active in the vast majority of tumors, but not in normal somatic tissues, and prevents progressive shortening of telomeres with cell division, probably giving tumor cells a growth advantage over normal cells. Highly-sensitive PCR-based TRAP (telomeric repeat amplification protocol) assay provided the means to analyze telomerase in a wide variety of tissues. Evidence has been accumulated that this assay may be useful as a potential diagnostic tool for cancer. The constituents of telomerase complex have recently been identified, and human telomerase reverse transcriptase (hTERT) has been found to be responsible for the enzymatic activity of telomerase. Detection of hTERT mRNA may therefore be useful for the screening and diagnosis of cancers. The mechanisms regulating hTERT expression have been extensively analyzed, and transcriptional regulation of hTERT has been found to be essential for hTERT expression, in which several nuclear factors including c-Myc play crucial roles. Understanding of such mechanisms might provide insight into molecular basis of human carcinogenesis and contributes to the development of novel cancer gene therapy targeting telomerase.
Open Access
Transient structures of the human fetal brain: Subplate, thalamic reticular complex, ganglionic eminence
(Murcia : F. Hernández, 2000) Ulfig, N.; Neudorfer, F.; Bohl, J.
Morphological features of the subplate, the thalamic reticular complex and the ganglionic eminence, which represent three major transient structures of the human fetal forebrain, are summarized with special reference to their functional roles. The subplate harboring various neuronal types is an outstandingly wide zone subjacent to the cortical plate in the human fetal brain. Within the subplate various cortical afferents establish synaptic contacts for a prolonged period before entering the cortical plate. Therefore, the subplate is regarded as a "waiting compartment" which is required for the formation of mature cortical connections. Next to the thalamic reticular nucleus, within the fibers of internal capsule, the perireticular nucleus is located which has been established as a distinct entity during development. Its various neuronal types express a number of different neuroactive substances. Perinatally, the perireticular nucleus is drastically reduced in size. It is involved in the guidance of corticofugal and thalamocortical fibers. The ganglionic eminence is a conspicuous proliferative area that persists throughout nearly the entire fetal period. In the human fetal brain it extends medially upon the dorsal thalamic nuclei which receive precursor cells from the ganglionic eminence. Postmitotic cells in the marginal zone of the ganglionic eminence serve as an intermediate target for growing axons. On the whole, all three structures establish transient neural circuitries that may be essential for the formation of adult projections. The characteristics of the three transient structures are particularly relevant for developmental neuropathology as these structures may be damaged in disorders that preferentially occur in preterm infants.
Open Access
lmmunohistochemical and in situ hybridization studies of choline acetyltransferase in large motor neurons of the human spinal cord
(Murcia : F. Hernández, 2000) Muroishi, Y.; Kasashima, S.; Nakanishi, I.; Oda, Y.
The localization of choline acetyltransferase (ChAT) protein and mRNA was investigated in large motor neurons of the lumbar spinal cord of 10 autopsied individuals without neurological diseases, by immunohistochemistry and in situ hybridization. In the immunohistochemistry using 20 serial tissue sections with a total thickness of 80 pm, about 58-85% (average 67%) of the large motor neurons (30 pm and more in somal minimal diameter) in the ventral horn were stained with the anti-human ChAT antibody. In the positive neurons, most immunoreactive products were observed focally in the perikarya. Occasionally, the perikarya of some neurons were stained diffusely. In situ hybridization with a single 4 pm-thick tissue section showed that almost all large motor neurons had positive signals (93-loo%, average 98%), which were distributed diffusely in the perikarya. The positivity rate in the in situ hybridization was higher than that in the immunohistochemistry for all 10 cases. These results indicate that ChAT mRNA is transcribed in almost all large motor neurons in the ventral horn of the human spinal cord, but ChAT protein cannot always be detected in the cytoplasm by immunohistochemistry.
Open Access
Neuropeptides bombesin and calcigonin induce resistance to etoposide induced apoptosis in prostate cancer cell lines
(Murcia : F. Hernández, 2000) Salido, M.; Vilches, J.; Lopez, A.
Background: Neuroendocrine differentiation in prostatic carcinoma has been related to regulation of proliferation and metastatic potential and correlated with prognosis. More than 80% of prostate carcinomas initially respond to androgen ablation, but most relapse, due to the heterogeneous presence of androgendependent and independent clones. The pathways of cellular proliferation and apoptosis are inexorabily linked to minimize the ocurrence of neoplasia, and disfunction of apoptosis is proposed as a pathogenic process in malignant tumors. Androgen-dependent prostatic cancer cells undergo apoptosis after androgen deprivation, but not androgen-independent ones due to a defect in the initiation step. Anyway, they retain the basic cellular machinery to undergo apoptosis. We suggest a possible role of neuroendocrine differentiation in the onset and regulation of apoptosis in prostatic neoplasia. Methods: LNCaP, PC-3 and DU 145 prostatic cancer cell lines were induced to undergo apoptosis after treatment with etoposide alone or plus androgen ablation. We tested the role of neuropeptides bombesin and calcitonin at modulating etoposide induced apoptosis. Results: Etoposide-induced apoptosis in all cancer cell lines was achieved. In LNCaP androgen ablation was also required. Apoptosis is prevented in all three lines when bombesin was added. Calcitonin addition prevents apoptosis in PC-3, LNCaP and in an etoposide dose-dependent way in DU 145. Conclusion: Neuropeptides bombesin and calcitonin can modulate the apoptotic response of prostate cancer cells by inducing resistance to etoposide-induced apoptosis, suggesting that neuropeptides can be used as a target of therapeutical approach in prostatic carcinoma.