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Biomedical subjects

A Fontana

Publications and source records attributed to A Fontana.

At least 91 records · Page 5Linked to original sources
PubMed1999

Treatment of experimental glioma by administration of adenoviral vectors expressing Fas ligand.

Fas ligand (FasL) is a cytokine, produced by activated T cells and NK cells, that triggers apoptosis of Fas-positive target cells including human glioma cells. As shown here, in vitro infection of rat F98 and human LN18 glioma cell lines with recombinant adenovirus (rAd) expressing FasL cDNA under control of the cytomegalovirus promoter (rAd-CMV-FasL) induced striking cytotoxicity in Fas-positive glioma cell lines but not in the Fas-negative F98 glioma subline F98/ZH. The extent of FasL-mediated cytotoxic effects outranged the expectations based on expression of beta-galactosidase (beta-Gal) by F98 cells infected with a control virus expressing the lacZ gene (rAd-CMV-lacZ). The detection of FasL bioactivity in supernatants of infected cells provides evidence of a bystander mechanism involving the cytotoxic action of FasL on uninfected cells. In F98 tumor-bearing rats, infection with rAd-CMV-FasL increased the mean survival time by 50% compared with infection with rAd-CMV-lacZ or untreated controls. These data suggest that viral vector transduction of the FasL gene could be part of a successful glioma gene therapy.

Adenoviruses, Human↗
PubMed1999

Induction of antitumor immunity with Fas/APO-1 ligand (CD95L)-transfected neuroblastoma neuro-2a cells.

Fas/Apo-1 (CD95)-Fas ligand (FasL) system has been implicated in the suppression and stimulation of immune responses. We examined the induction of antitumor immunity with neuroblastoma Neuro-2a cells transfected with FasL cDNA (Neuro-2a+FasL). Neuro-2a+FasL cells expressed FasL on the cell surface and secreted soluble FasL. Histologic and flow cytometric analyses revealed that Neuro-2a+FasL cells caused neutrophils to infiltrate into the injected site, resulting in strong inflammation. Neutrophil infiltration was inhibited by treatment with anti-FasL mAb and did not occur in Fas-deficient lpr mice. Normal syngeneic mice rejected Neuro-2a+FasL cells after the inflammation and acquired tumor-specific protective immunity. CD8+ T cells were responsible for the antitumor immunity. Neuro-2a+FasL cells formed tumors after far longer latency compared with mock-transfected Neuro-2a+Neo cells in nude mice, and immune competent mice rejected Neuro-2a cells but not sarcoma S713a cells when they were injected with Neuro-2a+FasL cells in a mixture. These results suggest that neutrophils attracted through the Fas-FasL system may impair tumor cells by inflammation at the initial step, followed by development of CD8+ T cell-dependent tumor-specific antitumor immunity, leading to complete eradication of tumor cells. Importantly, the treatment with Neuro-2a+FasL cells exhibited therapeutic efficacy against growing tumors.

Animals↗
PubMed1999

Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase.

The gene encoding the human puromycin-sensitive aminopeptidase (PSA) has been cloned and characterized. The human PSA gene is composed of 23 exons and 22 introns and spans approximately 40 kb of chromosome 17 at the interval 17q12-21. An analysis of the 5' end of the human PSA transcript reveals that the translational start site corresponds to nt 210 of the human PSA cDNA, as suggested by RT-PCR, 5' RACE, and computer analysis of expressed sequence tags. A comparison of the exon/exon boundaries of the human PSA gene with those of the human aminopeptidase N (APN) gene shows little conservation, suggesting that the two genes, which are closely related in protein sequence, diverged early during evolution.

Amino Acid Sequence↗
PubMed1999

[Bone and hormones. Estrogens and antiestrogens: action on osteoporosis].

ESTROGEN INSUFFICIENCY: Estrogens play a cardinal role in bone tissue in women. Estrogen insufficiency leads to accelerated bone loss within 5 to 8 years after menopause. HORMONE SUBSTITUTION THERAPY: Substitution therapy prevents postmenopausic bone loss (lumbar vertebrae, hip, radius) and reduces the risk of osteoporotic fracture. Cohort studies have demonstrated that women given hormone substitution therapy for at least 7 years have a significantly higher bone density than untreated women. Although still controversial, it would appear that the risk of breast cancer increases with prolonged use of hormone substitution therapy. SERM: Observations in patients given tamoxifen, an antiestrogen used in the treatment of breast cancer, have led to the concept of selective estrogen receptor modulators (SERM), a new class of compounds with estrogen agonistic or antagonistic activity, depending on the tissue. Among these molecules, raloxifen has reached advanced clinical testing phases. Phase III trials have demonstrated that raloxifen can prevent bone loss and reduce the risk of vertebral fractures while reducing total cholesterol and LDL-cholesterol in menopaused women without stimulating the endometrium. SERMs are a promising alternative to hormone substitution therapy for the treatment of menopaused women.

Aged↗
PubMed1999

Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon-gamma inducible protein 10.

Central nervous system (CNS) involvement is a prominent feature of human immunodeficiency virus (HIV-1) infection. Monocytes and CD4+ T cells traverse the blood brain barrier (BBB), and serve as vehicles for the virus and perpetrators for brain pathology by their production of neurotoxins. In the present study cerebrospinal fluid (CSF) samples from HIV-1-infected patients were analyzed for the presence of chemotactic factors. All 36 CSF samples from the patients were positive for the CXC chemokine interferon-gamma inducible protein (IP-10), which was not detected in CSF samples of 14 controls. The IP-10 concentrations were higher in HIV-1-infected patients with HIV-1 associated neurologic disorders than in those without neurological deficits. In contrast to IP-10, other chemotactic factors including the CC chemokines MCP-1, MIP-1alpha, MIP-1beta and RANTES and the cytokines IL-15 and IL-16 were either not detected or increased in only less than 30% of the patients. Unlike the CSF samples of controls, all CSF samples from HIV-1-infected patients induced chemotaxis of T cells activated with IL-2. The significance of IP-10 as a T cell chemotactic cytokine in HIV-1-infected CSF is shown by (1) the correlation of the IP-10 levels with the extent of T cell chemotaxis, (2) the neutralization of T cell chemotaxis by anti-IP-10 antibodies and (3) the correlation of the chemotactic response of CSF samples on activated T cells and the CSF white cell count in the patients. Our data provide evidence that IP-10 contributes to the accumulation of activated T cells in the CSF compartment in HIV-1-infected individuals.

AIDS Dementia Complex↗
PubMed1999

Occupational, environmental, and life-style factors associated with the risk of hematolymphopoietic malignancies in women.

BACKGROUND: The etiology of lymphomas, leukemias, and multiple myeloma is still largely unknown. The known risk factors (ionizing radiation, solvent exposure, pesticide exposure, immunosuppression) explain only a small proportion of the cases that occur. METHODS: We conducted a multicenter population-based case-control study on hematolymphopoietic malignancies in Italy and interviewed 2,011 women (1,183 cases and 828 controls). RESULTS: There was a suggestion of a positive association between smoking and the risk of non-Hodgkin's lymphoma + chronic lymphocytic leukemia. A slight increased risk of leukemias was observed among women using permanent hair dye. Housewives were at increased risk for leukemia and multiple myeloma. The risk of non-Hodgkin's lymphomas + chronic lymphocytic leukemia, leukemias, multiple myeloma, and Hodgkin's disease increased among women employed as hairdressers and textile workers. Teachers were at increased risk for non-Hodgkin's lymphomas + chronic lymphocytic leukemia, leukemias, and Hodgkin's disease. CONCLUSIONS: These results confirm previous associations and may provide additional clues to some determinants of hematolymphopoietic malignancies in women.

Adult↗
PubMed1999

Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1.

The individual role of tumor necrosis factor receptor 1 (TNFR1) and TNFR2 signaling in experimental autoimmune encephalomeylitis (EAE) was investigated using mice lacking TNFR1 (TNFR1-/-), TNFR2 (TNFR2-/-) as well as double receptor (TNFR1/2-/-) and double ligand (TNF/LT alpha-/-) knockout mice. In wild-type (wt) mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 the clinical course is characterized by an acute disease onset with peak disease scores and a consecutive chronic phase lasting up to 60 days. Compared to control mice, TNF/LT alpha-deficient mice showed a significant delay in disease onset and a remarkable reduction in demyelination which was, however, associated with increased inflammation. In TNFR1-/- and TNFR1/2-/- mice, the disease course was comparable to TNF/LT alpha-deficient mice but rather monophasic and less severe at late time points. Likewise only minimal spinal cord demyelination became apparent. In contrast, the course of EAE in TNFR2-/- mice was severe and associated with remarkable demyelination. Taken together these findings define TNFR1 as crucial mediator in MOG-induced EAE and suggest a protective role for TNFR2 signaling in the clinical course of EAE.

Animals↗
PubMed1999

Involvement of the N-methyl-D-aspartate receptor in neuronal cell death induced by cytotoxic T cell-derived secretory granules.

The mechanisms underlying neurotoxicity mediated by cytotoxic T lymphocytes (CTL) and their secretory granule proteins perforin and granzymes remain unclear. We evaluated the possible role of the neurotransmitter glutamate in cell death observed in differentiated neurons exposed to CTL-derived granules. Excitotoxicity induced by excessive concentrations of extracellular glutamate is associated with a rise in intracellular calcium and can lead to generation of NO through the activation of glutamatergic N-methyl-D-aspartate (NMDA) receptors. Consistent with an involvement of glutamate, we found that cell death in mature cerebral granule cells was inhibited by 65-80% by two NMDA receptor blockers (MK-801 and D-2-amino-5-phosphonovaleric acid) or a NO synthase blocker (N(G)-nitro-L-arginine methylester). Furthermore, neurons treated with secretory granules responded with a biphasic rise in the intracellular calcium concentration ([Ca2+]i). Whereas MK-801 did not interfere with the immediate rise of [Ca2+]i, the second wave of calcium accumulation starting at 40 min was delayed by 20 min and reduced in amplitude in the presence of MK-801. In immature, NMDA receptor-negative neurons, MK-801 prevented neither the cytotoxicity nor the calcium influx observed 5 min after addition of cytotoxic granules. The demonstration that NMDA receptors and NO are involved in granule-mediated killing of mature neurons opens new avenues in the treatment of neuronal cell death in CTL-mediated diseases such as viral encephalitis.

2-Amino-5-phosphonovalerate↗
PubMed1999

Impairment of TNF-receptor-1 signaling but not fas signaling diminishes T-cell apoptosis in myelin oligodendrocyte glycoprotein peptide-induced chronic demyelinating autoimmune encephalomyelitis in mice.

T-cell apoptosis in inflammatory demyelinating lesions of chronic myelin oligodendrocyte glycoprotein peptide35-55 induced autoimmune encephalomyelitis was studied in several different gene knockout mice as well as their wild-type counterparts. The gene deletions included tumor necrosis factor (TNF) alpha, lymphotoxin, TNF receptor 1 or 2, Fas-L, inducible nitric oxide synthase, perforin, and interleukin1beta-converting enzyme. Impairment of the TNF receptor 1 pathway led to a 50% reduction of T-cell apoptosis in the central nervous system lesions, whereas the other genetic deletions showed no significant effect. Our study thus identified the TNF receptor 1 signaling pathway as one mechanism responsible for the removal of T lymphocytes from inflammatory demyelinating lesions of the central nervous system.

Animals↗
PubMed1999

Volvatellin, caulerpenyne-related product from the sacoglossan volvatella sp

Volvatellin (4) is a highly unstable terpene isolated from the extracts of the Indian opisthobranch mollusk Volvatella sp. The structure and the relative stereochemistry of 4 were determined by NMR methods. The paper also describes a hypothetical biosynthesis of 4 starting from the alga-derived caulerpenyne.

Journal Article↗
PubMed1999

A model of war zone stressors and posttraumatic stress disorder.

We present a theoretical model of field placement, war zone stressors (fighting, death and injury of others, threat of death or injury to oneself, killing others, participating in atrocities, harsh physical conditions and insufficiency of resources in the environment) and posttraumatic stress disorder (PTSD). Theater veterans from the National Vietnam Veterans Readjustment Study were divided randomly into two subsamples of 599 each. The model was developed on the first subsample and cross-validated on the second using structural equation modeling. The model provides a theoretically and empirically satisfactory description of the anatomy of war zone stressors and their role in the etiology of PTSD, but it leaves unanswered important questions regarding the etiological role of insufficiency of resources in the environment.

Adult↗
PubMed1999

Analysis of violent behavior in Vietnam combat veteran psychiatric inpatients with posttraumatic stress disorder.

This study tested the hypothesis that male Vietnam veterans seeking inpatient treatment for PTSD (n = 228) exhibit more violent behavior compared with a mixed diagnostic group of male psychiatric inpatients without PTSD (n = 64) and a community sample of Vietnam veterans with PTSD not undergoing inpatient treatment (n = 273). Violent acts assessed included property destruction, threats without a weapon, physical fighting, and threats with a weapon. PTSD inpatients engaged in more types of violent behavior than both comparison conditions. Correlates of violence among PTSD inpatients included PTSD symptom severity and, to a lesser degree, measures of substance abuse. These findings justify routine assessment of violent behavior among inpatient with PTSD, as well as application of specialized interventions for anger dyscontrol and aggression.

Case-Control Studies↗
PubMed1999

The structural basis for the regulation of tissue transglutaminase by calcium ions.

The role of calcium ions in the regulation of tissue transglutaminase is investigated by experimental approaches and computer modeling. A three-dimensional model of the transglutaminase is computed by homology building on crystallized human factor XIII and is used to interpret structural and functional results. The molecule is a prolate ellipsoid (6.2 x 4.2 x 11 nm) and comprises four domains, assembled pairwise into N-terminal and C-terminal regions. The active site is hidden in a cleft between these regions and is inaccessible to macromolecular substrates in the calcium-free form. Protein dynamics simulation indicates that these regions move apart upon addition of calcium ions, revealing the active site for catalysis. The protein dimensions are consistent with results obtained with small-angle neutron and X-ray scattering. The gyration radius of the protein (3 nm) increases in the presence of calcium ions (3.9 nm), but it is virtually unaffected in the presence of GTP, suggesting that only calcium ions can promote major structural changes in the native protein. Proteolysis of an exposed loop connecting the N-terminal and C-terminal regions is linearly correlated with enzyme inactivation and prevents the calcium-induced conformational changes.

Amino Acid Sequence↗
PubMed1999

Hematopoietic cancer and peptic ulcer: a multicenter case-control study.

Helicobacter pylori has been suggested as a cause of gastric carcinoma and gastric non-Hodgkin's lymphoma (NHL). In a previous cohort study, a relative risk of six for gastric NHL was reported among subjects who tested positive for anti-H.pylori antibodies. The association between peptic ulcer and NHL has been studied in a population-based case-control investigation on hemato-lymphopoietic malignancies in Italy, based on face-to-face interviews to 2671 cases and 1718 controls (refusal rates 10 and 19%, respectively). Subjects who reported a diagnosis of peptic ulcer had a relative risk of 5.6 [95% confidence interval (CI) 3.8-8.0] for gastric NHL, whereas the estimate for non-gastric NHL was 1.3 (1.0-1.6). The association with recent diagnosis of ulcer was stronger, but the odds ratio (OR) was as high as 2.1 (95% CI 1.1-4.2) after >/=20 years since such diagnosis. After exclusion of the last 2 years before the diagnosis of NHL, and of ulcers diagnosed before 1978 (when gastroscopy became common in Italy), the OR was still 5.3 (95% CI 3.0-9.2). We found a strong effect modification by educational level, with ORs for ulcer more elevated in higher social groups. Gender was an effect modifier (OR = 4.1 in males, 9.2 in females; P = 0.03 for heterogeneity). The association with other gastrointestinal pathologies was much lower and statistically not significant. Almost all gastric lymphomas were B-cell NHLs of intermediate grade according to the working formulation; the majority belonged to the mucosa-associated lymphoid tissue (MALT) type. The association with ulcer was much stronger among MALT lymphomas, but only for recent ulcer diagnoses (2-10 years). Our study shows an increased risk for gastric NHL, very similar to the estimate reported in a previous cohort study. The risk was higher among more educated subjects.

Adult↗
PubMed1999

Comparison of outcome between homogeneous and heterogeneous treatment environments in combat-related posttraumatic stress disorder.

This study compared treatment outcome at discharge, and 4, 8, and 12 month follow-up between an inpatient program consisting of a mixture of Vietnam combat veterans with posttraumatic stress disorder (PTSD) and general psychiatric patients (N = 42), and the same program at a later period, consisting of only Vietnam combat veterans with PTSD (N = 33). Veterans rated the homogeneous environment higher in satisfaction, support, order, clarity, and amount of discussion of combat, and lower in hostility, than the heterogeneous condition. However, veterans showed no improvement in condition at 12 month follow-up, with the exception of decreased violence, replicating earlier studies. No differences in outcome were found between homogeneous or heterogeneous treatment environments. This study underscores the enduring nature of chronic posttraumatic stress disorder in the veteran population.

Adult↗
PubMed1999

Assessing quality of care: administrative indicators and clinical outcomes in posttraumatic stress disorder.

BACKGROUND: Although the use of quality of care indicators based on data collected for administrative purposes has become widespread, the relationship between those measures and clinical outcomes has yet to be evaluated. RESEARCH DESIGN: This study used hierarchical linear modeling to examine the relationship between 12 performance indicators derived from administrative data sets and 6 clinical outcome measures addressing symptoms, substance abuse, and social functions. SUBJECTS: Patient interviews were conducted with 4,165 veterans 4 months after their discharge from 62 specialized VA inpatient programs for treatment of Posttraumatic Stress disorder. RESULTS: Five of twelve administrative measures were significantly associated with at least one of the clinical outcome measures, which was all in the expected directions. The number of hospital readmissions during the 6 months after the index discharge was significantly related to poor outcomes on all 5 of 6 measures. Measures of readmission and post-discharge hospital use were more strongly and consistently related to outcome than to measures of access, intensity, or continuity of outpatient care. CONCLUSION: Administrative data, especially measures of hospital readmission, are significantly related to clinical outcomes. Correlations, however, are small to modest in magnitude indicating that these 2 types of performance measures assess different aspects of quality and can not be substituted for one another.

Adult↗
PubMed1999

Neuronal and glial cell type-specific promoters within adenovirus recombinants restrict the expression of the apoptosis-inducing molecule Fas ligand to predetermined brain cell types, and abolish peripheral liver toxicity.

Gene therapy using Fas ligand (FasL) for treatment of tumours and protection of transplant rejection is hampered because of the systemic toxicity of FasL. In the present study, recombinant replication-defective adenovirus vectors (RAds) encoding FasL under the control of either the neuronal-specific neuronal-specific enolase (NSE) promoter or the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter have been constructed. The cell type-specific expression of FasL in both neurons and glial cells in primary cultures, and in neuronal and glial cell lines is demonstrated. Furthermore, transgene expression driven by the neuronal and glial promoter was not detected in fibroblastic or epithelial cell lines. Expression of FasL driven by a major immediate early human cytomegalovirus promoter (MIEhCMV) was, however, achieved in all cells tested. As a final test of the stringency of transgene-specific expression, the RAds were injected directly into the bloodstream of mice. The RAds encoding FasL under the control of the non-cell type-specific MIEhCMV promoter induced acute generalized liver haemorrhage with hepatocyte apoptosis, while the RAds containing the NSE or GFAP promoter sequences were completely non-toxic. This demonstrates the specificity of transgene expression, enhanced safety during systemic administration, and tightly regulated control of transgene expression of highly cytotoxic gene products, encoded within transcriptionally targeted RAds.

Adenoviridae↗