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Biomedical subjects

S Normann

Publications and source records attributed to S Normann.

At least 19 recordsLinked to original sources
PubMed2004

The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation and expression analysis.

Focal epilepsies in young patients are frequently associated with differentiated glioneuronal tumours. Dysplastic neurones represent a characteristic neuropathological feature of gangliogliomas, the most common entity encountered in this group. Here, we have analysed two major components of the reelin pathway involved in neuronal migration and cortical development, that is, p35 and disabled-1 (dab1), in gangliogliomas. Genomic structures of human dab1 and p35 were identified 'in silico' using the HTGS databank, NCBI BLAST 2.1. DNA sequence analysis was carried out in gangliogliomas obtained from 29 epilepsy patients vs. peripheral blood DNA from non-affected control individuals (n = 100). Gene expression of dab1 and p35 was determined by real-time RT-PCR (reverse transcriptase polymerase chain reaction) in gangliogliomas (n = 14) vs. non-neoplastic central nervous system tissue (n = 20). The human dab1 gene contains 13 coding exons and is located on chromosome 1p31-32. A single coding exon constitutes the human p35 gene, which is located on chromosome 17q11.2. A novel homologueous genomic region on chromosome 2 has to be taken into account for future studies on p35. One ganglioglioma patient showed a unique polymorphism in the p35 gene. The single base exchange (C to A) at nucleotide 904 of the p35 cDNA (GenBank X80343, start ATG, codon 302) results in a leucine-isoleucine amino acid substitution. No mutations of the dab1 and p35 genes in gangliogliomas were observed. However, significantly lower levels of dab1 and p35 gene transcripts were detected in gangliogliomas compared to controls (dab1 28.24%, t-test P < 0.001; p35 21.28%, t-test P < 0.001, in gangliogliomas vs. controls). Our data suggest that mutational events of dab1 and p35 are not involved in the molecular pathogenesis of gangliogliomas. A potential functional role of these developmentally regulated genes for the formation of epileptogenic glioneuronal lesions remains to be elucidated.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy.

A considerable potential for neurogenesis has been identified in the epileptic rat hippocampus. Here, we explore this feature in human patients suffering from chronic mesial temporal lobe epilepsy. Immunohistochemical detection of the neurodevelopmental antigen nestin was used to detect neural precursor cells, and cell-type specific markers were employed to study their histogenetic origin and potential for neuronal or glial differentiation. The ontogenetic regulation of nestin-positive precursors was established in human control brains (week 19 of gestation-15 years of age). A striking increase of nestin-immunoreactive cells within the hilus and dentate gyrus could be observed in a group of young patients with temporal lobe epilepsy (TLE) and surgical treatment before age 2 years compared to adult TLE patients and controls. The cellular morphology and regional distribution closely resembled nestin-immunoreactive granule-cell progenitors transiently expressed during prenatal human hippocampus development. An increased Ki-67 proliferation index and clusters of supragranular nestin-immunoreactive cells within the molecular layer of the dentate gyrus were also noted in the group of young TLE patients. Confocal studies revealed colocalization of nestin and the betaIII isoform of tubulin, indicating a neuronal fate for some of these cells. Vimentin was consistently expressed in nestin-immunoreactive cells, whereas cell lineage-specific markers, i.e., glial fibrillary acidic protein, MAP2, neurofilament protein, NeuN, or calbindin D-28k failed to colocalize. These findings provide evidence for increased neurogenesis in pediatric patients with early onset of temporal lobe epilepsy and/or point towards a delay in hippocampal maturation in a subgroup of patients with TLE.

Adolescent↗
PubMed2001

Mutational analysis of TSC1 and TSC2 genes in gangliogliomas.

Gangliogliomas constitute the most frequent tumour entity in patients with temporal lobe epilepsy. The characteristic histopathological admixture of glial and neuronal elements, the focal nature and their differentiated phenotype and benign biological behaviour suggest an origin from a developmentally compromised or dysplastic precursor lesion. The present study analysed TSC1 and TSC2 genes as potential candidates involved in the pathogenesis of this intriguing neoplasm. Recent data suggest that both genes play a role in cortical differentiation and growth control. DNA sequence analysis of TSC1 and TSC2 was studied in 20 patients with gangliogliomas. Fifteen of these tumours (75%) carried polymorphisms in the TSC2 gene. The frequency of these polymorphisms was significantly increased in intron 4 (12.5%) and exon 41 (15%) compared to control individuals (8.1 and 6.5%, respectively, n = 100). A somatic mutation in intron 32 of the TSC2 gene was encountered in one patient. In the TSC1 gene, seven polymorphisms occurred as a combination of base exchanges in exon 14 and intron 13. No mutations were observed in this gene. Laser microdissection and harvesting of individual neuronal and glial elements identified the intron 32 mutation within the glial portion but not in dysplastic neurones of the tumour. The data demonstrate numerous polymorphisms as well as a novel TSC2 mutation in gangliogliomas from patients with chronic epilepsies. The selective detection of the TSC2 mutation within the glial component of a ganglioglioma suggests that the glioma portion has undergone clonal evolution in this case.

Brain Neoplasms↗
PubMed2001

Distinct expression pattern of microtubule-associated protein-2 in human oligodendrogliomas and glial precursor cells.

Microtubule-associated protein 2 (MAP2), a protein linked to the neuronal cytoskeleton in the mature central nervous system (CNS), has recently been identified in glial precursors indicating a potential role during glial development. In the present study, we systematically analyzed the expression of MAP2 in a series of 237 human neuroepithelial tumors including paraffin-embedded specimens and tumor tissue microarrays from oligodendrogliomas, mixed gliomas, astrocytomas, glioblastomas, ependymomas, as well as dysembryoplastic neuroepithelial tumors (DNT), and central neurocytomas. In addition, MAP2-immunoreactive precursor cells were studied in the developing human brain. Three monoclonal antibodies generated against MAP2A-B or MAP2A-D isoforms were used. Variable immunoreactivity for MAP2 could be observed in all gliomas with the exception of ependymomas. Oligodendrogliomas exhibited a consistently strong and distinct pattern of expression characterized by perinuclear cytoplasmic staining without significant process labeling. Tumor cells with immunoreactive bi- or multi-polar processes were mostly encountered in astroglial neoplasms, whereas the small cell component in neurocytomas and DNT was not labeled. These features render MAP2 immunoreactivity a helpful diagnostic tool for the distinction of oligodendrogliomas and other neuroepithelial neoplasms. RT-PCR, Western blot analysis, and in situ hybridization confirmed the expression of MAP2A-C (including the novel MAP2+ 13 transcript) in both oligodendrogliomas and astrocytomas. Double fluorescent laser scanning microscopy showed that GFAP and MAP2 labeled different tumor cell populations. In embryonic human brains, MAP2-immunoreactive glial precursor cells were identified within the subventricular or intermediate zones. These precursors exhibit morphology closely resembling the immunolabeled neoplastic cells observed in glial tumors. Our findings demonstrate MAP2 expression in astrocytic and oligodendroglial neoplasms. The distinct pattern of immunoreactivity in oligodendrogliomas may be useful as a diagnostic tool. Since MAP2 expression occurs transiently in migrating immature glial cells, our findings are in line with an assumed origin of diffuse gliomas from glial precursors.

Adult↗
PubMed2000

Endocrine host responses during early and late phases of tumor development.

It is well established that hormones affect tumor growth. Conversely, inoculation of cells obtained from tumors that had been transplanted for many generations causes changes in the concentration of different hormones before and after tumor detection. We aimed at answering the question of whether hormonal alterations also occur during the development of primary tumors and following transplantation of tumors from early generations. Primary tumors were induced in mice by either the carcinogenic agent 3-methylcholanthrene, which produces fibrosarcomas, or the milk-transmitted mammary tumor virus, which induces adenocarcinomas. The results showed that (i) in both models, an early reduction in plasma insulin and prolactin levels occurred, and in the case of insulin, this reduction was sustained for a prolong period prior to tumor detection, indicating that recognition by the host of emergent tumor cells triggers an endocrine response; (ii) in contrast with multiply transplanted tumors, cells from early transplant generations produced no significant endocrine changes during latency; (iii) irrespective of whether they were primary or transplanted, large tumor burdens caused similar hormonal alterations, consisting of increased corticosterone and growth hormone and decreased insulin, thyroxin, prolactin and sex steroid levels in blood. Our comprehensive longitudinal study demonstrates host endocrine responses during different stages of neoplastic development.

Animals↗
PubMed2000

A reduction in blood insulin levels as a host endocrine response during tumor development.

It has been previously reported that endogenous insulin levels decrease during tumor growth. We have now studied whether this host endocrine response is independent of the way in which the tumor is induced. For this purpose, animals transplanted with tumor cells induced by 3-methylcholanthrene (MCA) or 7,12-dimethylbenz(a) anthracene (DMBA), or with EL-4 lymphoma cells, and animals that develop autochthonous tumors induced by MCA or the murine mammary tumor virus (MMTV) were used. These procedures result in the induction of tumors of different histologic types: fibrosarcoma, mammary adenocarcinoma and lymphoma. The results obtained showed that a reduction in insulin levels preceded the overt appearance of tumors in all models of syngeneic or autochthonous tumors studied but not when DMBA-induced tumor cells were administered into allogeneic recipients. Reduced levels of insulin before tumor detection appeared to affect the onset of MCA-induced tumors. Indeed, those mice with a late tumor onset were those that had a more pronounced decrease in insulin blood levels during the induction phase of autochthonous MCA-induced tumors. Soluble factors associated with tumor growth seem to mediate the reduction in insulin blood levels in mice transplanted with EL-4 tumor cells. The results obtained indicate that the reduction in insulin levels detected is a consequence of the recognition of tumor cells by the host, and seems to be independent of the histologic type of the neoplastic cells that develop. Pharmacological interventions at the levels of mechanisms that control insulin output should clarify the relevance of decreased levels of this hormone for tumor development.

Animals↗
PubMed1998

Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain.

We have examined the imprinting status of the serotonin-2A (5-HT2A) receptor gene (HTR2A) in a series of 41 tissue samples from human adult brain. Using a HpaII RFLP polymorphism in the coding region, we obtained evidence of monoallelic expression of HTR2A in 4 out of 18 informative individuals. However, biallelic expression of HTR2A was observed in other individuals (14/18), suggesting that within the human population HTR2A imprinting in brain is polymorphic.

Alleles↗
PubMed1997

Prevention of postoperative pericardial adhesions using tissue-protective solutions.

Repeat cardiac surgical procedures are associated with increased technical difficulty and risk because of the previous formation of dense adhesions between the heart and the surrounding tissues. Dilute solutions of sodium hyaluronic acid (NaHA) and carboxymethyl cellulose (CMC) have been shown to prevent postoperative abdominal and pelvic adhesions and could therefore potentially inhibit adhesion formation following cardiac surgery. Adhesion prevention using 0.1% NaHA, 0.4% NaHA, or 0.1% CMC solutions was examined in a canine abrasion/desiccation pericardial adhesion model (5 animals/group) and compared to 10 animals treated with Ringer's lactate (RL) solution alone. The pericardium and heart were coated with 25 ml of test or control solution prior to and after pericardiotomy, after controlled gauze abrasion, after 30 min of desiccation, and prior to closure. At 6 weeks, animals were reexplored and adhesions were scored in a blinded manner by three to four surgeons using a 0-4 scale. Scores of 2 or greater were considered clinically significant. Mean adhesion scores from the left epicardium were 0.0 in animals treated with 0.1% NaHA, 0.6 in animals treated with 0.4% NaHA or 1% CMC, and 2.3 in animals treated with RL (P < 0.05 Duncan's ANOVA). In addition, none of the animals treated with 0.1% NaHA, 20% of the animals treated with 0.4% NaHA, and 20% of the animals treated with 1% CMC had clinically significant adhesions, whereas 80% of animals treated with RL had such adhesions. Sodium hyaluronic acid and CMC solutions, used as tissue coatings during cardiac surgery, inhibit the formation of undesired postoperative adhesions. Application of these biocompatible polymer solutions during surgery could reduce the technical difficulty and risk of repeat cardiac surgical procedures.

Animals↗
PubMed1997

Tuberous sclerosis-like lesions in epileptogenic human neocortex lack allelic loss at the TSC1 and TSC2 regions.

Glioneuronal malformations with a striking histological resemblance to cortical tubers of tuberous sclerosis, but no extracerebral stigmata of this phacomatosis, are frequently encountered in patients with chronic pharmacoresistant epilepsies. It is controversial as to whether these lesion represent a forme fruste of tuberous sclerosis or a distinct entity. The recently reported loss of heterozygosity (LOH) at the regions of the TSC1 or TSC2 locus in hamartomas obtained from different organs of patients with established tuberous sclerosis, including cortical tubers, stimulated us to examine epilepsy-associated tuberous sclerosis-like glioneuronal malformations with respect to LOH at the TSC1 and TSC2 loci of chromosomes 9q34 and 16p 13.3, respectively. The analysis was carried out on DNA derived from paraffin-embedded brain tissues of 11 patients. For 5 patients, peripheral blood leukocytes were also available for DNA extraction. We performed microsatellite analysis with five markers on chromosome 9 and four markers on chromosome 16. In addition, polymerase chain reaction-restriction fragment length polymorphism (RFLP) analysis was performed using a polymorphic EcoRV restriction site in exon 40 of the TSC2 gene. No LOH was identified in any of the cases. These findings do not support a relationship between the epilepsy-associated glioneuronal lesions and tuberous sclerosis. However, tuberous sclerosis is genetically heterogeneous and microsatellite and RFLP analysis cannot exclude small deletions or point mutations. Thus, given the histopathological similarity of glioneuronal malformations in epilepsy patients to cortical tubers, further molecular genetic studies will be needed as our understanding of the molecular basis of tuberous sclerosis increases to completely clarify the relationship of these lesions to tuberous sclerosis.

Adolescent↗
PubMed1994

Rotational atherectomy for treatment of occluded prosthetic grafts.

Potentially, percutaneous rotational atherectomy (RA) can be used to open occluded prosthetic arterial bypass grafts with less morbidity than surgical catheter thrombectomy. However, RA could damage prosthetic grafts or produce significant distal emboli. To investigate this, acutely thrombosed and chronically occluded prosthetic grafts, harvested from dogs, were placed in an ex vivo perfusion system and recanalization was attempted using the TRAC-Wright rotational atherectomy system. Urokinase (UK) was delivered through the RA catheter in one-half of the procedures. Graft surface thrombogenicity and graft mechanical integrity after successful recanalization were determined and debris released during recanalization was collected. Results were compared to those from grafts opened by catheter thrombectomy. One hundred percent (22/22) of acute prosthetic graft occlusions and 39% (16/41) of chronic prosthetic graft occlusions were opened using RA, similar to results achieved using catheter thrombectomy. In addition, surface thrombogenicity after recanalization of acute graft occlusion with RA was lower than that after catheter thrombectomy (P < 0.05) and infusion of UK improved RA success in chronically occluded grafts (52% vs 25%). Debris generated during RA averaged 15-18 micrograms, equivalent to debris generated during catheter thrombectomy, and graft mechanical integrity was unaffected by recanalization using RA. Thus, rotational atherectomy is a minimally invasive means of safe and effective prosthetic graft recanalization that produces a less thrombogenic graft than thrombectomy.

Animals↗
PubMed1991

On the mechanism of antiinflammation induced by tumor transplantation, surgery, and irritant injection.

Tumor transplantation, major surgery, and injection of nonspecific irritants elicit inflammation locally while suppressing inflammation induced subsequently and at distant sites. Such systemic antiinflammation in rodents occurs via corticosterone-independent and -dependent pathways. Based upon hormone measurements and the response to adrenalectomy, antiinflammation induced by irritants and certain surgical procedures is corticosterone independent while that which follows tumor transplantation is corticosterone dependent. However, injection of tumorous ascites stimulates both pathways since it contains two antiinflammatory factors: Factor A (molecular weight less than 2,000) does not alter hormone balance while Factor B (molecular weight 30,000-100,000) increases corticosterone levels and is corticosterone dependent. Desensitization of systemic antiinflammation develops rapidly regardless of whether it is corticosterone dependent (Factor B) or independent (Factor A or irritants). However, tumor transplantation resists desensitization possibly by inducing an immune response since lymphocytic mitogens prevent development of and break established desensitization. Nevertheless, abolition of tumor-induced antiinflammation follows injection of tumorous ascites by a mechanism that involves Factor B suppression of the corticosterone response to the tumor while Factor A apparently raises the threshold at which physiological increases in corticosterone inhibit leukocyte emigration. We conclude that systemic antiinflammation is a general consequence of a localized inflammatory reaction and that desensitization of such antiinflammation develops rapidly. Recent evidence indicates that certain mediators of inflammation are proinflammatory when administered intradermally but antiinflammatory when given intravenously. Thus, systemic antiinflammation may arise when chemical mediators of inflammation generated by a local reaction gain access to the circulation.

Adrenalectomy↗
PubMed1991

Radiation-associated valvular disease.

The prevalence of radiation-associated cardiac disease is increasing due to prolonged survival following mediastinal irradiation. Side effects of radiation include pericarditis, accelerated coronary artery disease, myocardial fibrosis and valvular injury. We evaluated the cases of three young patients with evidence of significant valvular disease following mediastinal irradiation. One patient underwent the first reported successful aortic and mitral valve replacement for radiation-associated valvular disease (RAVD) as well as concurrent coronary artery revascularization. A review of the literature revealed 35 reported cases of RAVD, with only one successful case of valve replacement that was limited to the aortic valve. Asymptomatic RAVD is diagnosed 11.5 years after mediastinal irradiation compared with 16.5 years for symptomatic patients, emphasizing that long-term follow-up is important for patients receiving mediastinal irradiation. This study defines a continuum of valvular disease following radiation that begins with mild asymptomatic valvular thickening and progresses to severe valvular fibrosis with hemodynamic compromise requiring surgical intervention.

Adolescent↗
PubMed1988

Hormonal changes following tumor transplantation: factors increasing corticosterone and the relationship of corticosterone to tumor-induced anti-inflammation.

EL-4 lymphoma cells transplanted to syngeneic C57BL/6J mice induced a biphasic decrease in inflammation and a bi-phasic increase in serum levels of corticosterone. In addition, this tumor altered serum levels of 3 other hormones, resulting in a biphasic decrease in insulin, an early decrease in prolactin, and a terminal severe deficiency in thyroxine. Early changes occurred 16 to 48 hr after tumor transplantation and were of variable duration, while late-phase defects developed during the last few days of life. Soluble factors associated with tumor growth may mediate certain hormonal changes since serum levels of corticosterone increased and insulin decreased following injection of tumorous ascites into normal mice. Further, injection of cell-free tumor culture supernatants increased corticosterone levels. Hormonal changes following injection of soluble factors occurred after a delay of 16 hr indicating that the factors acted indirectly. Surgical adrenalectomy blocked the corticosterone increase induced by tumor transplantation or ascites injection and eliminated the anti-inflammatory effect of tumor transplantation while significantly decreasing the effect associated with injection of tumorous ascites. Thus, the physiologically induced increase in serum levels of corticosterone reached anti-inflammatory levels. Further, elevated levels of corticosterone are a major contributing factor to anti-inflammation induced by tumorous ascites injection and constitute the principal mechanism of anti-inflammation following tumor transplantation.

Animals↗
PubMed1988

Interactions between endogenous glucocorticoids and inflammatory responses in normal and tumor-bearing mice: role of T cells.

Appropriately stimulated lymphocytes and macrophages produce factors in vitro that increase serum corticosterone levels when injected in vivo. In this study, we used euthymic and congenitally athymic mice on a BALB/c background to explore the role of T cells in controlling corticosterone levels and the leukocyte response to inflammation. Adult athymic mice had more intense inflammatory reactions than euthymic mice despite higher basal corticosterone levels. This latter condition may be due to interleukin-1 (IL-1) since macrophages from athymic mice when stimulated in vitro by lipopolysaccharide produced more IL-1 than macrophages from euthymic mice. In response to mitogen stimulation, however, splenocytes from athymic mice produced a factor (not IL-1), which, upon injection, increased corticosterone levels and suppressed inflammation. Production of this factor was enhanced by T cells since splenocyte supernatants from euthymic mice were more potent in eliciting both effects. Evidence for in vivo participation of T cells in regulating corticosterone levels was obtained by tumor transplantation. Injection of syngeneic tumor cells or cell-free tumorous ascites rapidly increased corticosterone levels in euthymic but not athymic mice. Anti-inflammation correlated with increased corticosterone levels but was observed also in athymic mice receiving syngeneic tumor transplants. These studies demonstrate that T cells enhance production of a lymphokine that increases corticosterone levels and are required for the corticosterone response to tumor transplantation. In addition, the data suggest two pathways of anti-inflammation in tumor-bearing hosts: a corticosterone-independent, T cell-independent mechanism and a T cell-dependent mechanism that involves a lymphokine-mediated increase in corticosterone blood levels.

Animals↗
PubMed1987

Cancer induced anti-inflammation and its potentiation by tumor excision and rechallenge.

Tumor rechallenge following primary tumor excision elicits systemic anti-inflammation that occurs rapidly, affects granulocytes as well as macrophages and is more severe, longer in duration, and induced by fewer tumor cells than the macrophage specific anti-inflammatory effect sometimes seen after primary tumor challenge. Factors important in the pathogenesis of this abnormality are the following. First, primary tumor excision was required as defects did not occur when a second tumor was transplanted during primary tumor growth. Second, the abnormality was restricted to neoplastic cells since normal cells were unable to substitute for either primary or secondary tumor challenge. Third, the anti-inflammatory effect was not due to surgical trauma or local irritation. Fourth, defective inflammation occurred in syngeneic but not allogeneic rats, suggesting an immunological basis for the anti-inflammation. Fifth, elevated glucocorticoids, such as might be expected from an immunological reaction or release of IL-1, may be a contributing but not sole cause for the phenomenon.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Changes in plasma hormone profiles after tumor transplantation into syngeneic and allogeneic rats.

Transplantation of 2 chemically (DMBA, MCA)-induced tumors into syngeneic female or male DA strain rats elicited hormonal changes during tumor growth. Plasma levels of 7 different hormones were studied. Tumor cells in syngeneic recipients produced a biphasic decrease in insulin, an early increase in prolactin, and a late-phase decrease in thyroxine. Corticosterone decreased in female tumor bearers but increased in males. This difference may reflect differences in the tumors transplanted. Male rats had a decrease in testosterone during the late phase of tumor growth, while females had a biphasic decrease in progesterone and a late-phase increase in growth hormone. The tumors used were moderately immunogenic in syngeneic recipients. However, tumor transplantation to allogeneic recipients produced an early decrease in growth hormone and no change in insulin, corticosterone or thyroxine. Further, transplantation of normal liver cells to syngeneic or allogeneic recipients produced no hormonal abnormalities. This study demonstrates that hormonal changes which are not observed with normal cells or allogeneic tumor transplantation can occur within 2 days of syngeneic tumor transplantation. Progressive tumor growth is characterized by a worsening endocrine imbalance which involves multiple hormone systems.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

A new model for investigation of transluminal recanalization: human atherosclerotic coronary artery xenografts.

A model for testing transluminal recanalization techniques was developed. Human atherosclerotic arteries were transplanted in dogs and evaluated by angiographic and histologic study within a 12-week period. An inflammatory response was most intense within the first 2 weeks. By 12 weeks, no inflammation was noted. The model has several advantages: (1) The pathologic characteristics are those of a human coronary artery. (2) Thrombus formation is frequent, with progression to a well organized dense fibrocellular vascular occlusion within 4 to 12 weeks. (3) The arterial occlusion resembles human vascular disease. (4) The vascular occlusions are readily accessible with standard catheterization technique. (5) The model is easy to produce within a short period. This model has been used to evaluate laser recanalization of vascular obstructions.

Angiography↗