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Biomedical subjects

A Aguzzi

Publications and source records attributed to A Aguzzi.

At least 217 records · Page 12Linked to original sources
PubMed1994

Prognostic significance of Ki-67 proliferation index in supratentorial fibrillary astrocytic neoplasms.

Histological grading of fibrillary astrocytic neoplasms has proved to be a valuable prognostic tool, but potentially could benefit from more objective data, such as estimates of proliferative rate. The authors have investigated the prognostic utility of quantitative Ki-67 immunoreactivity in a prospective survival analysis of 36 adult patients with astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme diagnosed between 1987 and 1992. A digital image analyzer was used to assay proliferation indices (PIs) in surgical biopsy specimens obtained at first diagnosis (32 of 36) or at a second biopsy of histologically unchanged high-grade disease (4 of 36). A Ki-67 PI of > or = 7.5% was associated with higher histological grade and poorer survival, and the Ki-67 PI was more significantly related to survival (P < 0.001) than histological grade as determined by a modified Ringertz grading system (P = 0.002). Survival analysis within histological grades suggested that astrocytoma patients with PI > or = 3% may be at increased risk for shorter survival than those with PI < 3%.

Adult↗
PubMed1994

Open brain, a new mouse mutant with severe neural tube defects, shows altered gene expression patterns in the developing spinal cord.

We describe a new mouse mutation, designated open brain (opb), which results in severe defects in the developing neural tube. Homozygous opb embryos exhibited an exencephalic malformation involving the forebrain, midbrain and hindbrain regions. The primary defect of the exencephaly could be traced back to a failure to initiate neural tube closure at the midbrain-forebrain boundary. Severe malformations in the spinal cord and dorsal root ganglia were observed in the thoracic region. The spinal cord of opb mutant embryos exhibited an abnormal circular to oval shape and showed defects in both ventral and dorsal regions. In severely affected spinal cord regions, a dorsalmost region of cells negative for Wnt-3a, Msx-2, Pax-3 and Pax-6 gene expression was detected and dorsal expression of Pax-6 was increased. In ventral regions, the area of Shh and HNF-3 beta expression was enlarged and the future motor neuron horns appeared to be reduced in size. These observations indicate that opb embryos exhibit defects in the specification of cells along the dorsoventral axis of the developing spinal cord. Although small dorsal root ganglia were formed in opb mutants, their metameric organization was lost. In addition, defects in eye development and malformations in the axial skeleton and developing limbs were observed. The implications of these findings are discussed in the context of dorsoventral patterning of the developing neural tube and compared with known mouse mutants exhibiting similar defects.

Animals↗
PubMed1994

Developmental expression of nicein adhesion protein (laminin-5) subunits suggests multiple morphogenic roles.

Nicein/kalinin (laminin-5) is a heterotrimeric laminin-like adhesion protein, which is secreted at the basement membrane of subsets of epithelia and is involved in the etiology of junctional epidermolysis bullosa, a severe human blistering disease characterized by disadhesion of epidermis from dermis. cDNA clones encoding the three chains of mouse nicein and antibodies specific to each polypeptide were used to examine the expression of the protein in the developing mouse embryo from 10.5 day post coitum to 7 days after birth. At various stages of development, co-expression of the three chains of nicein was observed in amnion, skin, and in epithelia of respiratory, urinary and digestive systems. High level expression of nicein was seen in enamel-secreting ameloblasts in developing teeth. Cell-specific distribution of nicein was also detected in other specialized tissues representative of the three primary embryonic germ layers with prominent secretory or protective functions. Differential and focal expression of nicein subunits was observed in the choroid plexus and the floor plate of the neural tube. Messenger for the heavy chain of nicein was detected in the floor plate, where mouse s-laminin messengers were also found. This suggests that nicein genes may play a role in the migration and polarization of motor neurons in the developing spinal cord.

Amino Acid Sequence↗
PubMed1994

[Neurotoxicity of human foamy virus in transgenic mice].

Human foamy virus (HFV) is a human retrovirus originally isolated from patients with various neoplastic and degenerative diseases. Similarly to other human retroviruses, HFV encodes the three structural retroviral genes, gag, pol and env, and an additional region containing three open reading frames, bel-1 to bel-3. Bel-1 activates transcription of the long terminal repeat of HFV and also of HIV. Until today it has not been possible to identify HFV as the causative agent of any disease. In order to identify a possible pathogenic potential of HFV, we have introduced parts of the HFV genome into the germ line of mice. Our studies with transgenic mice have shown that HFV transgenes encompassing the bel region are transiently transcribed between midgestation and birth at moderate levels in various tissues. Expression is then suppressed, but resumes after a latency of several weeks in a restricted range of tissues and accumulate extensively in single cells. This is associated with a progressive degenerative disease of the central nervous system and of striated muscle. These findings provide the first evidence of a disease induced by HFV and suggest that HFV might also act as a human pathogen in neurological diseases. Moreover, the transgenic mouse model will be useful for studying the molecular basis of HFV-induced neurotoxicity, the role of individual disease-associated HFV genes, and the regulation of retroviral latency.

Animals↗
PubMed1994

[Morphology and development of neural transplants of AMOG-deficient mice].

The adhesion molecule on glia (AMOG) has been reported to function as cell adhesion molecule and also to constitute the beta 2-subunit of the murine Na,K-ATPase. In order to elucidate these functions in vivo, Magyar et al. have generated mice carrying a targeted deletion of the AMOG gene. These mice exhibit behaviourally normal development till postnatal day P16. At this time, they develop muscular weakness, incoordination, and tremor. Death invariably occurs 24-36 hours after onset of the symptoms. Histological and ultrastructural examination of brain sections show enlarged ventricles, brain edema, and swelling of astrocyte end feet. However, no disturbances of the architecture or cell migration in the brain can be detected. In order to identify long-term consequences of AMOG deficiency which might not yet be detectable at the time of death, we have established a CNS grafting model. The embryonal brain anlage (E10.5-E13.5) was grafted into the caudoputamen of wild type mice. The graft recipients are sacrificed up to 7 months after the procedure. Both wild type and AMOG deficient grafts develop and form solid neural tissue with neurons, myelinated axons, glial cells, and ventricular structures, as shown by histological and immunocytochemical analysis. However, no differences in grafts derived from wild type, heterozygous, and AMOG-deficient donors can be detected. Proliferation has been examined by BrdU immunocytochemistry. The blood-brain barrier as examined by repeated magnetic resonance imaging after injection of Gadolinium-DTPA has been shown to be largely reconstituted five weeks after grafting.

Adenosine Triphosphatases↗
PubMed1994

High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene.

BACKGROUND: It has been proposed that the prion, the infectious agent of transmissible spongiform encephalopathies, is PrPSc, a post-translationally modified form of the normal host protein PrPC. We showed previously that mice devoid of PrPC (Prn-p0/0) are completely resistant to scrapie. We now report on the unexpected response of heterozygous (Prn-p0/+) mice to scrapie infection. MATERIALS AND METHODS: Prn-p0/+, Prn-p0/0 and Prn-p+/+ mice were obtained from crosses of Prn-p0/+ mice. Mice were inoculated intracerebrally with mouse-adapted scrapie agent and the clinical progression of the disease recorded. Mice were sacrificed at intervals, PrPSc was determined as protease-resistant PrP and the prion titer by the incubation time assay. RESULTS: Prn-p0/+ mice, which have about half the normal level of PrPC in their brains, show enhanced resistance to scrapie, as manifested by a significant delay in onset and progression of clinical disease. However, while in wild type animals an increase in prion titer and PrPSc levels is followed within weeks by scrapie symptoms and death, heterozygous Prn-p0/+ mice remain free of symptoms for many months despite similar levels of scrapie infectivity and PrPSc. CONCLUSIONS: Our findings extend previous reports showing an inverse relationship between PrP expression level and incubation time for scrapie. However, contrary to expectation, overall accumulation of PrPSc and prions to a high level do not necessarily lead to clinical disease. These findings raise the question whether high titers of prion infectivity could also persist for long periods under natural circumstances in the absence of clinical symptoms.

Animals↗
PubMed1993

c-jun is essential for normal mouse development and hepatogenesis.

The proto-oncogene c-jun is the cellular homologue of v-jun, the transforming oncogene of the avian sarcoma virus 17 (ref. 1). c-jun encodes one major component of the AP-1 transcription factor complex and is expressed in many organs during mouse development and in the adult. Because of its rapid induction in cells following growth stimulation and the presence of AP-1 binding sites in the promoter regions of many genes, the c-Jun protein is thought to have important functions in cell proliferation and differentiation. But embryonic stem (ES) cells lacking c-Jun are viable and have a normal in vitro differentiation capacity, although c-Jun appears to be important for growth of teratocarcinomas in vivo. To define the function of c-jun better, targeted ES cells were used to generate mice lacking c-Jun. Here we report that heterozygous mutant mice appear normal, but embryos lacking c-Jun die at mid- to late-gestation and exhibit impaired hepatogenesis, altered fetal liver erythropoiesis and generalized oedema. Interestingly, c-jun-/- ES cells can participate efficiently in the development of all somatic cells in chimaeric mice except liver cells, further suggesting an essential function of c-Jun in hepatogenesis.

Animals↗
PubMed1993

Mice devoid of PrP are resistant to scrapie.

S.B. Prusiner proposed that the infectious agent of scraple, the prion, is PrPSc, a modified form of the normal host protein PrPC. Prn-p0/0 mice devoid of PrPC showed normal development and behavior. When inoculated with mouse scrapie prions, they remained free of scrapie symptoms for at least 13 months while wild-type controls all died within 6 months. Surprisingly, heterozygous Prn-p0/+ mice also showed enhanced resistance to scrapie. After introduction of Syrian hamster PrP transgenes, Prn-p0/0 mice became highly susceptible to hamster but not to mouse prions. These experiments show that PrPC, possibly at close to normal levels, is required for the usual susceptibility to scrapie and that lack of homology between incoming prions and the host's PrP genes retards disease.

Animals↗
PubMed1993

The foamy virus family: molecular biology, epidemiology and neuropathology.

The family of foamy viruses designates a group of retroviruses which share a specific morphology and provoke characteristic cytopathic effects in cultured cells. Like HTLV and HIV, foamy viruses are complex viruses encoding a number of ancillary genes in addition to gag, pol and env, including a transcriptional transactivator. Foamy viruses are endemic in various primate species, and human foamy viruses (HFV) have been isolated from patients with various neoplastic and degenerative diseases. Despite a growing body of knowledge on the biology of foamy viruses, it has not yet been possible to identify a disease specifically caused by foamy virus infection. After reviewing the epidemiology and molecular biology of the various animal foamy viruses, this article focuses on the pathogenic properties of HFV in transgenic mouse systems. HFV transgenes exhibit a striking neurotropism and elicit a progressive degenerative disease of the central nervous system and striated muscle. Similarly to patients with HIV-associated encephalopathy, HFV transgenic mice develop accumulations of syncytial giant cells in their brains. The relevance of these findings for human neuropathology is discussed.

Amino Acid Sequence↗
PubMed1993

Identification of pol-related gene products of human foamy virus.

Human foamy virus pol gene fragments were molecularly cloned into a procaryotic expression vector. The expression pattern of the cloned fragments and nucleotide sequence analysis of the 5' pol gene region revealed that in HFV the protease (PR) is located in the pol open reading frame. Purified recombinant proteins were used to generate antibodies in rats. In immunoblot assay, using infected cells as antigen, a precursor protein with an apparent molecular mass (M(r)) of 127K was identified by antibodies directed against the reverse transcriptase (RT), RNaseH, or integrase (IN) domains of pol. With concentrated virus as antigen, the RT and RNaseH antibodies recognized a protein of 80K, the IN antiserum recognized a protein of 40K, and the PR antiserum detected a protein of approximately 10K.

Base Sequence↗
PubMed1993

Differential transcription and translation of immediate early genes in the gerbil hippocampus after transient global ischemia.

Excitotoxic activation of glutamate receptors is thought to be a key event for the molecular pathogenesis of postischemic delayed neuronal death of CA-1 neurons in the gerbil hippocampus. Glutamate receptor stimulation also causes induction of transcription factors that belong to the class of immediate early genes. We examined the expression of six different immediate early genes in the gerbil hippocampus after transient global ischemia. Comparative analysis of c-fos and Krox-24 expression was carried out in the same animals at the transcriptional and translational level by in situ hybridization and immunocytochemistry. Postischemic synthesis of four additional immediate early gene (IEG)-encoded proteins (FOS-B, c-JUN, JUN-B, and JUN-D) was investigated by immunocytochemistry at recirculation intervals between 1 and 48 h. After 5 min of ischemia, transcription of c-fos and Krox-24 mRNA was induced in all hippocampal subpopulations with peak expression at 1 h after recirculation. In vulnerable CA-1 neurons, increased transcription of c-fos and Krox-24 was not followed by translation into protein. Induction of immediate early gene-encoded proteins was restricted to neuronal populations less vulnerable to brief ischemia and identified neurons that are targets of glutamate receptor-mediated neurotoxicity but that are destined to survive. Our data indicate an asynchronous synthesis and persistence of individual IEG-encoded proteins in these neurons. The staggered induction implies that combinatorial changes of transcription factors allow a differential postischemic regulation of target gene expression both spatially and over time.

Animals↗
PubMed1993

Coronary thrombosis in non-cardiac death.

BACKGROUND: Coronary thrombosis is the major cause of acute myocardial ischaemia but can be, albeit rarely, clinically silent. We investigated a series of autopsy hearts from hospitalized patients who died from non-cardiac causes, to detect and study coronary thrombosis. METHODS: The series consisted of 132 autopsy cases (81 men and 51 women, age range 32-39 years, mean 63 +/- 14), in whom cause of death was confirmed as extracardiac. Major epicardial coronary arteries were isolated from the hearts and routinely processed for histopathological study. We evaluated the presence of coronary atherosclerosis and thrombosis. Plaque size was histologically graded with low magnification lenses. RESULTS: Coronary atherosclerosis, which was found in 110 hearts, caused critical stenosis or occlusion of at least one major vessel in 55 (41.6%) cases. Coronary thrombosis was found in 10 vessels from nine different hearts. One coronary tree presented two thrombi in two different vessels. Thrombi were mural in all but one vessel. We did not observe either deep sub-thrombotic ulceration or atheromatous material mixed with thrombus. Deep thrombus layers often presented organizing features. There was no correlation between thrombosis and degree of vessel stenosis, which was only mildly increased by thrombus. Plaque rupture without thrombus was found in five coronary arteries of five different cases. CONCLUSIONS: Coronary thrombus may overlay the intima of a diseased vessel independently of plaque type and severity. Moreover, thrombosis is more frequent than expected, although it is rare when compared with the spread of coronary atherosclerosis. It may represent a plaque progression mechanism in the natural history of coronary atherosclerosis.

Adult↗
PubMed1993

Possible role of human foamy virus in Graves' disease.

Human foamy virus (HFV) is a member of the retroviral family of Spumaretrovirinae. In addition to the three retroviral structural genes, gag, pol and env, HFV also contains regulatory sequences, called bel. Foamy viruses have been previously associated with human thyroid disease, notably DeQuervain's thyroiditis. In indirect immunofluorescence tests we have demonstrated the reactivity of the thyroid glands of 7/7 patients with Graves' disease and antibodies to HFV gag proteins. No reactivity was observed with antibodies to pol, env and bel proteins. Nine thyroids of patients with struma parenchymatosa, 4 with follicular carcinoma and 2 normal thyroids were negative throughout. From the thyroids of 5 patients with Hashimoto's disease, 4 were negative and 1 showed a single small focus of anti-gag antibody reactivity. The uniform immunofluorescent staining was restricted to the basal and lateral intercellular areas between the thyroid epithelial cells. Extension of these studies to the retrobulbar tissue of 1 Graves' disease patient with malignant exophthalmus revealed positive staining with anti-gag antibodies of fibroblasts and fat cells but not eye muscles. Furthermore, we were successful in establishing several T-cell lines derived from the retrobulbar tissue of this patient. They were CD8+ and proliferated, in contrast to peripheral blood cells, upon cocultivation with autologous retroorbital fibroblasts. It remains to be determined whether these observations are of relevance in the pathogenesis of Graves' disease.

Graves Disease↗
PubMed1993

Induction of tumor formation and cell transformation by polyoma middle T antigen in the absence of Src.

In polyomavirus-transformed cells, middle T antigen binds to and activates the protein tyrosine kinase, Src. To determine whether this interaction is critical for middle T transformation, we examined the ability of middle T to transform cells that lack endogenous Src (because of a targeted disruption of both Src alleles). Infection of newborn or 2-week-old Src-negative mice with a retrovirus encoding middle T led to the induction of visceral hemangiomas that were indistinguishable from tumors in wild-type mice with respect to their morphology, frequency or latency period. In addition, middle T was able to induce foci formation on cell monolayers and colony formation in soft agar in Src-negative immortalized fibroblasts. These results indicated that Src is not essential for middle T-induced transformation of the cells targeted in these assays. To examine the protein tyrosine kinases that interact with middle T in the absence of Src, we compared the level of middle T phosphorylation in immune complex kinase assays from Src-negative and Src-positive cell lysates, and identified the middle T-associated kinases in these cells. In Src-positive cell lysates, there was a similar level of middle T phosphorylation in Src and Yes immunoprecipitates, suggesting that middle T can bind to Src and Yes to a similar extent in this cell type. Fyn immunoprecipitates displayed fourfold lower levels of middle T phosphorylation than that detected in the Src and Yes immunoprecipitates. In Src-negative cells, the level of middle T phosphorylation in Yes and Fyn immunoprecipitates was not significantly different from that detected in the Src-positive cells, suggesting that the absence of Src does not lead to a compensating increase in the proportion of middle T associated with these kinases. The level of middle T-associated phosphatidylinositol 3'-kinase was also examined since this kinase is known to interact with middle T-kinase complexes. Phosphatidylinositol 3'-kinase activity associated with middle T was reduced 30-60% in Src-negative cells, suggesting that Src contributes at least one-third of the total middle T associated in wild-type cells. Taken together, these results indicate that Src is not required for middle T-induced hemangiomas in mice or for focus induction in immortalized fibroblasts, and that the residual level of Yes, Fyn and phosphatidylinositol kinase activity associated with middle T in Src-negative cells may compensate for the absence of Src.

Animals↗
PubMed1993

Human foamy virus proteins accumulate in neurons and induce multinucleated giant cells in the brain of transgenic mice.

Human foamy virus (HFV) is a retrovirus encoding structural genes and, like human immunodeficiency virus and human T cell leukemia virus I, several ancillary reading frames collectively termed the be1 genes. We have previously shown that HFV transgenic mice develop an encephalopathy with neuronal loss in hippocampus and cerebral cortex. We have now raised and characterized rabbit antisera to various recombinant portions of gag, pol, env, and bel-1, the viral trans-activator. Immunoreactivity for gag and bel-1 was observed in nuclei and processes of hippocampal and cortical neurons before the onset of morphological lesions and correlated with the appearance of HFV mRNA. Astrocyte-derived multinucleated giant cells containing HFV proteins were present in the brain of transgenic mice coexpressing full-length HFV genes but not in mice expressing truncated gag and env, suggesting that these genes contain a fusogenic domain. Expression of full-length structural genes decreased the life expectancy of transgenic mice, implying an adjuvant role for these proteins in HFV-induced brain damage.

Animals↗
PubMed1992

Oncogene complementation in fetal brain transplants.

Using a neural transplantation model and retrovirus-mediated gene transfer, we have introduced the oncogenes v-Ha-ras and v-myc into the developing rat brain. Upon insertion of a construct encoding v-Ha-ras and the Escherichia coli beta-galactosidase marker gene, the retroviral vector was found to be expressed in neurons, astrocytes, and endothelial cells of the graft. After latency periods of several months, fascicular neoplasms with expression of S-100 protein were observed in 50% of the transplants. The foreign genes were shown to be highly expressed in the tumors and in intact donor cells, by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside histochemistry, indicating that an activated Ha-ras oncogene has the potential to initiate neoplastic transformation of glial cells. Introduction of the v-myc oncogene into 15 grafts resulted in only a single primitive neuroectodermal tumor. However, simultaneous expression of the v-Ha-ras and v-myc genes yielded highly malignant, polyclonal neoplasms in all recipient animals, as early as 13 days after transplantation, from which cell lines could be easily derived. In addition, neoplastic transformation was also observed in vitro following introduction of ras and myc into embryonic forebrain cultures and into newborn cerebellar cultures. These data indicate a powerful complementary transforming effect of ras and myc on neural progenitors in vivo and in vitro. Coexpression of ras and myc may, therefore, provide a highly efficient tool for transforming neural precursor cells in distinct segments of the central nervous system at different stages of development.

Animals↗
PubMed1992

Ovarian mucinous tumors frequently express markers of gastric, intestinal, and pancreatobiliary epithelial cells.

In 100 mucinous tumors of the ovary (37 benign, 24 borderline, and 39 malignant), the authors determined by histochemical and immunohistochemical techniques the frequencies and patterns of expression of a total of nine markers of gastric, intestinal, and pancreatobiliary duct epithelial cells. M1, a mucin antigen, and cathepsin E (CaE), an aspartic proteinase, two markers of normal gastric superficial/foveolar epithelial cells, were expressed in 95 and 92 tumors, respectively. Periodic acid-concanavalin A-reactive mucin or pepsinogen (PG) II, markers of gastric mucus neck and pyloric gland cells, were found in 79 tumors. All of these tumors also expressed M1 or CaE. DU-PAN-2 and the N-terminal epitope of gastrin-releasing peptide, markers of normal pancreatobiliary duct cells, were found in 70 and 49 tumors, respectively, and CAR-5 and M3SI, markers of intestinal mucin, were expressed in 51 and 30 tumors, respectively. All tumors expressed at least two of the nine markers studied; none expressed PG I, a marker of gastric chief cells. The mucopeptic cell marker, PG II, was significantly more common in benign and borderline than in malignant tumors (P less than 0.005), whereas CAR-5 and M3SI, markers of intestinal mucin, were expressed significantly more often in malignant than in benign and borderline tumors (P less than 0.001). By electron microscopic examination, many tumor cells had fine structural features characteristic of gastric superficial/foveolar and pyloric gland cells, intestinal columnar or goblet cells, and endocervical cells. The results indicate that gastroenteropancreatic cell differentiation--and, in particular, gastric type differentiation--is a prominent feature of ovarian mucinous tumors.

Adenocarcinoma, Mucinous↗