Biomedical subjects

A Fontana

Publications and source records attributed to A Fontana.

At least 73 records · Page 4Linked to original sources

PubMed2000

TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia.

During inflammatory reactions in the central nervous system (CNS), resident macrophages, the microglia, are exposed to Th1 cell-derived cytokines and pro-apoptotic Fas ligand (FasL). Despite the presence of TNF-alpha and IFN-gamma, both being capable of sensitizing microglia to FasL, apoptosis of microglia is not a hallmark of inflammatory diseases of the CNS. In the present study, TGF-beta is found to counteract the effect of TNF-alpha and IFN-gamma to sensitize microglia to FasL-mediated apoptosis. Resistance to Fas-mediated apoptosis by TGF-beta does not correlate with a down-regulation of Fas expression. As a key inhibitor of Fas-mediated apoptosis, we found expression of the cellular FLICE-inhibitory protein (c-FLIP) to be induced by TGF-beta in resting as well as in activated microglia. Induction of FLIP was found to depend on a mitogen-activated protein kinase kinase (MKK)-dependent pathway as shown by the use of the specific MKK-inhibitor PD98059. The presence of FLIP strongly interfered with FasL-induced activation of caspase-8 and caspase-3 preventing subsequent cell death. The presented data provide the first evidence for a TGF-beta-mediated FLIP in macrophage-like cells and suggest a mode of action for the anti-apoptotic role of TGF-beta in the CNS.

Animals↗

PubMed2000

Fas ligand gene transfer combined with low dose cyclosporine A reduces acute lung allograft rejection.

The interaction between Fas and its ligand (FasL) induces apoptosis in the Fas-expressing cell. We hypothesized that liposome-mediated FasL gene transduction to the lung allograft, in addition to low-dose immunosuppression, might reduce acute rejection. Orthotopic left lung allotransplantation was performed in male rats (Brown Norway to Fischer F344). FasL gene transfer was performed by use of the plasmid pBCMGSNeo carrying the gene coding for murine FasL and the cationic liposome GL#67:DOPE. Six hundred and sixty micrograms of DNA in 250 microl H2O and 0.5 micromol GL#67 in 250 microl H2O were diluted to 5 ml with saline solution. This emulsion (20 degrees C) was instilled retrogradely through the left pulmonary vein after flushing with LPD solution (20 ml, at 4 degrees C). Subsequently, the graft was stored at 10 degrees C for 3 h. A single dose of cyclosporine A (CsA; 2.5 mg/kg i.m.) was given to all groups 48 h after the transplantation. In group 1 (n = 6), FasL/GL#67 was instilled as described. In group 2 (n = 5), GL#67 was given without DNA. Group 3 (n = 5) animals received CsA only. Five days after transplantation, gas exchange was assessed after exclusion of the contralateral native lung (FiO2 = 1.0). Grafts were flushed with saline solution and fixed in formaldehyde for histological evaluation. No statistical difference in gas exchange (PaO2) between the two control groups 2 (6.4 +/- 0.4 kPa) and 3 (7.4 +/- 0.4 kPa) could be detected 5 days postoperatively (P = 0.9). In contrast, grafts transduced with FasL (group 1) had significantly better gas exchange on postoperative day 5 (PaO2: group 1 37.0 +/- 10.6 kPa vs group 2 6.4 +/- 0.41 kPa; P = 0.002). Two animals in group 1 revealed no or only minimal improvement in gas exchange. Histologically, all lung specimen of all groups showed signs of acute rejection (A2). Leukocyte infiltrates, rated by two independent observers, were less severe in all group 1 animals. Liposome-mediated FasL gene transfer at the time of harvest in combination with low-dose CsA reduces acute rejection in four out of six animals in this model of rat lung allotransplantation.

Animals↗

PubMed2000

Arthroscopic assessment of total hip replacement and polyethylene wear: a case report.

We report the case of a patient who showed clinical and radiological signs of massive polyethylene wear 3 years after total hip replacement. Arthroscopy was performed to assess the loosening of the acetabular cup. The procedure showed the polyethylene element to be broken into three pieces in the area corresponding to the upper border.

Arthroplasty, Replacement, Hip↗

PubMed2000

Formation of micelles and liposomes from carnitine amphiphiles.

Esterification of the carboxy and/or the hydroxy groups of (R)-carnitine (3-hydroxy-4-trimethylammonium butanoate) produces interesting classes of (cationic or zwitterionic) surfactants whose CMC values are in general predictable from their molecular structure. In fact similar relationships between CMC and the number of carbon atoms, Cn, have been found for three classes of such surfactants. However the sensitivity of CMC to Cn for the diesters is considerably lower than that calculated from literature values for the monoesters (either in their cationic or zwitterionic forms). The CMC values for the diesters have been determined by tensiometric, conductimetric and spectrophotometric methods, both in pure water and in 0.154 M NaCl solutions, at 25 degrees C. In particular the tensiometric results provide evidence that double-chain diesters undergo self assembly into structures more complex than simple micelles if the two chains are of comparable length. EPR and electron microscopy experiments show that the aggregates spontaneously formed by these surfactants are a mixture of multilamellar vescicles.

Carnitine↗

PubMed2000

Scalarane and homoscalarane compounds from the nudibranchs Glossodoris sedna and Glossodoris dalli: chemical and biological properties.

A series of homoscalarane and scalarane compounds (2-7) have been isolated from two distinct species of Pacific Glossodoris nudibranchs. The structure and elucidation of the relative stereochemistry of the new metabolites 2 and 3 were obtained by spectroscopic methods. Compound 2 was ichthyotoxic at 0.1 ppm against Gambusia affinis and showed moderate activity (IC(50) 18 microM) to inhibit mammalian phospholipase A(2).

Animals↗

PubMed2000

The endothelin system in human glioblastoma.

Endothelin-1 (ET-1) is a powerful mitogenic and/or anti-apoptotic peptide produced by many cancer cells. To evaluate the potential role of the endothelin system in glioblastoma we first determined the cellular distribution of the mRNA and proteins of the components of the endothelin system, preproendothelin-1 (PPET-1), endothelin-converting enzyme-1 (ECE-1), and ET(A) and ET(B) receptors in human glioblastoma tissue and glioblastoma cell lines. PPET-1, ECE-1, and ET(A) receptor were highly expressed in glioblastoma vessels and in some scattered glioblastoma areas whereas ET(B) receptor was mainly found in cancer cells. This suggests that glioblastoma vessels constitute an important source of ET-1 that acts on cancer cells via the ET(B) receptor. Four human glioblastoma cell lines expressed mRNA for all of the components of the ET-1 pathway. Bosentan, a mixed ET(A) and ET(B) receptor antagonist, induced apoptosis in these cell lines in a dose-dependent manner. Apoptosis was potentiated by Fas Ligand (APO-1L, CD95L), a pro-apoptotic peptide, only in LNZ308 cells, corresponding to the known functional Fas expression in these cell lines. LNZ308 cells also expressed the long and short forms of the cellular FLICE/caspase-8 inhibitory protein (FLIP). Bosentan and a protein kinase C inhibitor down-regulated short FLIP in these cells. ET-1 induced transient phosphorylation of extracellular signal-regulated kinase but did not induce long-term thymidine incorporation in LNZ308 glioblastoma cells. These results suggest that, in glioblastoma cells, ET-1, mainly acting via the ET(B) receptor, is a survival/antiapoptotic factor produced by tumor vasculature, but not a proliferation factor, involving protein kinase C and extracellular signal-regulated kinase pathways, and stabilization of the short form of FLIP.

Base Sequence↗

PubMed2000

TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease.

In this review we summarize the essential findings about the function of tumour necrosis factor (TNF) and its cognate receptors TNFR1 and TNFR2, and lymphotoxin alpha (LT-alpha) ligands in immune-mediated CNS inflammation and demyelination. The advent of homologous recombination technology in rodents provides a new method which has been used during the last 5 years and has led to insights into the pathophysiology of experimental autoimmune encephalomyelitis (EAE) in an unprecedented way. Studies with knockout mice in which genes of the TNF ligand/receptor superfamily are not expressed and studies with transgenic mice overexpressing TNF and TNFR reveal the critical role of the TNFR1 signalling pathway in the control of CNS demyelination and inflammation. These studies provide novel findings and at the same time shed light on the complex pathophysiology of EAE. Together, these findings may contribute to better understanding of EAE and open new avenues in experimental therapies for multiple sclerosis.

Animals↗

PubMed2000

Impact of combat and sexual harassment on the severity of posttraumatic stress disorder among men and women peacekeepers in Somalia.

The impact of combat and sexual harassment on the severity of posttraumatic stress disorder (PTSD) is compared for 1,307 men and 197 women peacekeepers who served in the same military units. A theoretical model was proposed to express the nature of the impact. Structural equation modeling was used to evaluate the model separately for men and women. Good-fitting, parsimonious models were developed that showed substantial similarity for men and women. For men, severity of PTSD symptoms was impacted by exposure to combat directly and indirectly through fear and sexual harassment. For women, severity of PTSD symptoms was impacted by combat indirectly through the same two influences, although the mechanisms involving fear and sexual harassment were somewhat different. For both genders, moreover, PTSD severity was impacted directly by exposure to the dying of the Somali people. These similarities suggest that in modern stressful overseas military missions, both genders may be susceptible to the same types of risk for the development of PTSD. The incidence and impact of sexual harassment is particularly noteworthy in the case of men and calls for more detailed investigation in future studies.

Adult↗

PubMed2000

Benzodiazepine use in posttraumatic stress disorder among veterans with substance abuse.

Veterans with posttraumatic stress disorder (PTSD) and substance abuse may abuse benzodiazepines and develop violent dyscontrol when using them. A total of 370 veterans were compared by substance abuse diagnosis (50%), benzodiazepine use (36%), and their interaction on 1-year outcomes after inpatient discharge. Substance abusers were less likely to be prescribed benzodiazepines (26% vs. 45%). No outcome showed a differential worsening by substance abuse or benzodiazepines, although some baseline differences were noted. Outpatient health care utilization was lower in benzodiazepine users (47 vs. 33 visits). Among PTSD patients with comorbid substance abuse, benzodiazepine treatment was not associated with adverse effects on outcome, but it may reduce health care utilization.

Ambulatory Care↗

PubMed2000

Delayed infection, family size and malignant lymphomas.

BACKGROUND: The annual incidence of non-Hodgkin's lymphomas (NHL) is increasing by 3%-4% in different parts of the developed world. Excesses of NHL have been observed in populations exposed to immunosuppressants and to HIV, but these causes do not explain the increasing trends. It is suggested that delayed infection could explain NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns. METHODS: In a population-based study on 1388 patients with NHL, 354 with Hodgkin's disease (HD) and 1718 healthy controls, the age of first occurrence of bacterial and viral diseases was investigated. Clinical records were perused in one centre to check the anamnestic data. FINDINGS: The age of occurrence of bacterial and viral diseases was significantly higher among NHL patients than in the controls. The association between later age at first bacterial or viral disease was limited to small families (OR= 1.95; 95% confidence intervals 1.26, 3.00, for age 4-8 at first infection; OR=1.91; 1.19, 3.06, for age 9+, compared with less than 4). The association was more obvious for bacterial diseases (possibly for the lower degree of misclassification). High grade lymphomas showed the strongest association. The later age of occurrence of bacterial or viral diseases in NHL patients is consistent with a higher incidence of lymphomas observed in higher social groups. No clear association was found between HD and age at first bacterial or viral diseases. INTERPRETATION: It is proposed that delayed infection could explain the increasing NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns. The model of delayed infection has been proposed also to explain increasing prevalence rates of asthma.

Adult↗

PubMed2000

Haematopoietic cancer and medical history: a multicentre case control study.

BACKGROUND: Viruses (such as Epstein-Barr virus) and pathological conditions (mainly involving immunosuppression) have been shown to increase the risk of haematolymphopoietic malignancies. Other associations (diabetes, tonsillectomy, autoimmune diseases) have been inconsistently reported. METHODS: The association between different haematolymphopoietic malignancies (lymphomas, myelomas and leukaemias) and the previous medical history has been studied in a population-based case-control investigation conducted in Italy, based on face to face interviews to 2669 cases and 1718 population controls (refusal rates 10% and 19%, respectively). Controls were a random sample of the general population. RESULTS: Previous findings were confirmed concerning the association between non-Hodgkin's lymphoma (NHL) and lupus erythematosus (odds ratio, OR=8.4; 95% CI 1. 6, 45), tuberculosis (OR=1.6; 1.05, 2.5) and hepatitis (1.8; 1.4, 2. 3). An association was found also between NHL and maternal (OR=2.8; 1.1, 6.9) or paternal tuberculosis (OR=1.7; 0.7, 3.9). Odds ratios of 4.0 (1.4, 11.8) and 4.4 (1.1, 6.6) were detected for the association between NHL and Hodgkin's disease, respectively, and previous infectious mononucleosis, but recall bias cannot be ruled out. No association was found with diabetes, tonsillectomy and adenoidectomy. An association with malaria at young age and "low grade" lymphatic malignancies is suggested. One interesting finding was the observation of four cases of poliomyelitis among NHL patients, one among Hodgkin's disease and one among myeloid leukaemia patients, compared with none among the controls (Fisher's exact test for NHL and Hodgkin's disease, p= 0.03, one tail). CONCLUSIONS: Some of these findings are confirmatory of previous evidence. Other observations, such as the putative role of the polio virus and of malaria are new. A unifying theory on the mechanisms by which previous medical history may increase the risk of haematolymphopoietic malignancies is still lacking.

Adult↗

PubMed2000

Effects of an outreach intervention on use of mental health services by veterans with posttraumatic stress disorder.

OBJECTIVE: The study examined the effectiveness of an outreach intervention designed to increase access to mental health treatment among veterans disabled by chronic posttraumatic stress disorder (PTSD) and identified patient-reported barriers to care associated with failure to seek the treatment offered. METHODS: Participants were 594 male Vietnam veterans who were not enrolled in mental health care at a Department of Veterans Affairs (VA) medical center but who were receiving VA disability benefits for PTSD. Half the sample was randomly assigned to an outreach intervention, and the other half was assigned to a control group. Veterans in the intervention group received a mailing that included a brochure describing PTSD treatment available at an urban VA medical center, along with a letter informing them about how to access care. Participants in the intervention group were subsequently telephoned by a study coordinator who encouraged them to enroll in PTSD treatment and who administered a survey assessing barriers to care. RESULTS: Veterans in the intervention group were significantly more likely than those in the control group to schedule an intake appointment (28 percent versus 7 percent), attend the intake (23 percent versus 7 percent), and enroll in treatment (19 percent versus 6 percent). Several patient-identified barriers were associated with failure to seek VA mental health care, such as personal obligations that prevented clinic attendance, inconvenient clinic hours, and current receipt of mental health treatment from a non-VA provider. CONCLUSIONS: Utilization of mental health services among underserved veterans with PTSD can be increased by an inexpensive outreach intervention, which may be useful with other chronically mentally ill populations.

Community-Institutional Relations↗

PubMed2000

Outcomes monitoring and the testing of new psychiatric treatments: work therapy in the treatment of chronic post-traumatic stress disorder.

OBJECTIVE: To evaluate the effectiveness of a work therapy intervention, the Department of Veterans Affairs (VA) Compensated Work Therapy program (CWT), in the treatment of patients suffering from chronic war-related post-traumatic stress disorder (PTSD); and to demonstrate methods for using outcomes monitoring data to screen previously untested treatments. DATA SOURCES/STUDY SETTING: Baseline and four-month follow-up questionnaires administered to 3,076 veterans treated in 52 specialized VA inpatient programs for treatment of PTSD at facilities that also had CWT programs. Altogether 78 (2.5 percent) of these patients participated in CWT during the four months after discharge. STUDY DESIGN: The study used a pre-post nonequivalent control group design. DATA COLLECTION/EXTRACTION METHODS: Questionnaires documented PTSD symptoms, violent behavior, alcohol and drug use, employment status, and medical status at the time of program entry and four months after discharge from the hospital to the community. Administrative databases were used to identify participants in the CWT program. Propensity scores were used to match CWT participants and other patients, and hierarchical linear modeling was used to evaluate differences in outcomes between treatment groups on seven outcomes. PRINCIPAL FINDINGS: The propensity scaling method created groups that were not significantly different on any measure. No greater improvement was observed among CWT participants than among other patients on any of seven outcome measures. CONCLUSIONS: Substantively this study suggests that work therapy, as currently practiced in VA, is not an effective intervention, at least in the short term, for chronic, war-related PTSD. Methodologically it illustrates the use of outcomes monitoring data to screen previously untested treatments and the use of propensity scoring and hierarchical linear modeling to adjust for selection biases in observational studies.

Chronic Disease↗

PubMed2000

[Combination of cisplatin and vinorelbin in the neoadjuvant treatment of locally advanced cervical carcinoma. Phase II study].

BACKGROUND: Aim of this phase II study is to evaluate the cytoreductive efficacy and the toxicity of a regimen consisting of cisplatin and vinorelbine as neoadjuvant chemotherapy for three cycles every 21 days in patients with locally-advanced cervical carcinoma. METHODS: Between April 1996 and December 1998, 33 untreated patients with locally-advanced cervical carcinoma received neoadjuvant chemotherapy with cisplantino 80 mg/m2 (day 1) plus vinorelbine 25 mg/m2 (day 1 and 8). Within 28 days from completion of chemotherapy patients in complete or partial response were submitted to radical hysterectomy plus pelvic lymphadenectomy. RESULTS: Twenty-six patients (79%) were submitted to radical surgery; four patients were not submitted to surgery because of poor response to treatment, two for anesthesiological contraindications and one refused surgery. The combination of cisplatin plus vinorelbine in this phase II study induced a clinical overall response rate of 90%, with 8 pathologic complete response (24%). CONCLUSIONS: The association of cisplatin and vinorelbine as neoadjuvant chemotherapy in locally-advanced cervical carcinoma showed to be safe and effective with a low cost and poor toxicity.

Adult↗

PubMed2000

Splenic involvement in ovarian cancer. Description of three cases.

Metastatic involvement of the spleen in patients with ovarian cancer is unusual. Solitary splenic metastasis in the absence of disseminated disease are rare. Three cases of advanced ovarian cancer with splenic involvement are reported. The splenectomy was adopted in two patients.

Adult↗

PubMed2000

[Reconstructive surgery in oncological gynecology. Our experience].

BACKGROUND: Personal experience in reconstructive surgery for gynecologic oncology is reported. These techniques are playing, during last years, a leading role since it is necessary to assure a good treatment and top quality lifestyle to oncologic patients. METHODS: A retrospective study was made on 357 major surgical treatments for neoplastic disease at the IInd Clinic of Obstetrics and Gynecology, University of Bari. For each disease the technique, the length of surgery and possible complications have been reported. In total 50 reconstructive procedures on 357 surgical interventions for gynecologic neoplastic disease (14%) were made. RESULTS: There was no rate of mortality, and the complications were found only in 5 patients (10%). CONCLUSIONS: Reconstructive surgery can increase surgical radicality, improve the quality of life of the patients and reduce the postoperative complications.

Endometrial Neoplasms↗

PubMed1999

Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-x(L).

Fas activation triggers apoptosis in many cell types. Studies with anti-Fas antibodies have produced conflicting results on Fas signaling, particularly the role of the Bcl-2 family in this process. Comparison between physiological ligand and anti-Fas antibodies revealed that only extensive Fas aggregation, by membrane bound FasL or aggregated soluble FasL consistently triggered apoptosis, whereas antibodies could act as death agonists or antagonists. Studies on Fas signaling in cell lines and primary cells from transgenic mice revealed that FADD/MORT1 and caspase-8 were required for apoptosis. In contrast, Bcl-2 or Bcl-x(L) did not block FasL-induced apoptosis in lymphocytes or hepatocytes, demonstrating that signaling for cell death induced by Fas and the pathways to apoptosis regulated by the Bcl-2 family are distinct.

Adaptor Proteins, Signal Transducing↗

PubMed1999

HIV type 1 Nef protein is a viral factor for leukocyte recruitment into the central nervous system.

Recombinant HIV-1 Nef protein, but not Tat, gp120, and gp160, provoked leukocyte recruitment into the CNS in a rat model. The strong reduction of bioactivity by heat treatment of Nef, and the blocking effect of the mAb 2H12, which recognizes the carboxy-terminal amino acid (aa) residues 171-190 (but not of mAb 3E6, an anti-Nef Ab of the same isotype, which maps the aa sequence 168-175, as well as a mixture of mAbs to CD4) provided evidence for the specificity of the observed Nef effects. Using a modified Boyden chamber technique, Nef exhibited chemotactic activity on mononuclear cells in vitro. Coadministration of the anti-Nef mAb 2H12, as well as treatment of Nef by heat inhibited Nef-induced chemotaxis. Besides soluble Nef, chemotaxis was also induced by a Nef-expressing human astrocytoma cell line, but not by control cells. These data suggest a direct chemotactic activity of soluble Nef. The detection of elevated levels of IL-6, TNF-alpha, and IFN-gamma in rat cerebrospinal fluid 6 h after intracisternal Nef injection hint at the additional involvement of indirect mechanisms in Nef-induced leukocyte migration into rat CNS. These data propose a mechanism by which HIV-1 Nef protein may be essential for AIDS neuropathogenesis, as a mediator of the recruitment of leukocytes that may serve as vehicles of the virus and perpetrators for disease through their production of neurotoxins.

Animals↗