International immune tolerance registry, 1997 update.
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Age Factors↗
Biomedical subjects
G Mariani
Publications and source records attributed to G Mariani.
Oral contraceptives highlight the genotype-specific association between serum phospholipids and activated factor VII.
The present analysis was undertaken to study the effect of oral contraceptive (OC) use on activated factor VII (FVIIa) in subjects characterized by FVII genotypes, with the further aim of evaluating the role of lipids in this pharmacological interaction. In OC users (n=42) and nonusers (n=130) of comparable age, we examined the FVII phenotypic variables (FVII coagulant activity [FVIIc], FVII antigen, and FVIIa), FVII genotypes (the 353R/Q and 5'F7 polymorphisms analyzed in combination; alleles M1/M2 and A1/A2, respectively), and a number of lipid and lipoprotein parameters: serum concentrations of total cholesterol (chol), low density lipoprotein and high density lipoprotein-chol, triglycerides, phospholipids (PhLs), apolipoprotein A1, and lipoprotein(a). PhLs, triglycerides, apolipoprotein A1, chol, FVII antigen, FVIIc, and high density lipoprotein-chol levels were shown to be statistically higher in users than nonusers. FVII levels, particularly those of FVIIa and FVIIc, were much higher in homozygotes for the A1 and M1 alleles (A11 M11), especially in OC users. A strong association was found between PhL and FVIIa: in the multiple regression analysis, women taking OCs who had elevated PhL concentrations also had very high levels of FVIIa, but only if their genotype was A11 M11. These results indicate that the increased FVII levels in OC users depend on the FVII genotype and that high PhL concentrations predict very high levels of FVIIa and FVIIc.
Cardiovascular Diseases↗
Randomized trial of permissive hypercapnia in preterm infants.
OBJECTIVE: To determine whether a ventilatory strategy of permissive hypercapnia (PHC) reduces the duration of assisted ventilation in surfactant-treated neonates weighing 601 to 1250 g at birth. DESIGN: Forty-nine surfactant-treated preterm infants (birth weight: 854 +/- 163 g; gestational age: 26 +/- 1.4 weeks) receiving assisted ventilation were randomized during the first 24 hours of age to a PHC group (PaCO(2): 45-55 mm Hg) or to a normocapnia group (NC; PaCO(2): 35-45 mm Hg). The primary outcome measure was the total number of days on assisted ventilation. Uniform extubation and reintubation criteria were used for both groups. All patients received aminophylline before extubation. RESULTS: The total number of days on assisted ventilation expressed as median (25th-75th percentiles) was 2.5 (1.5-11.5) in the PHC group and 9.5 (2.0-22.5) in the NC group (Mann-Whitney U test). The number of patients on assisted ventilation throughout the first 96 hours after randomization was lower in the PHC group (log rank test). During that period, the ventilated patients in the PHC group had a higher PaCO(2) and lower peak inspiratory pressure, mean airway pressure, and ventilator rate than did those in the NC group. The percentage of patients requiring reintubation within 24 hours postextubation (PHC 17% vs NC 28%) and supplemental oxygen at 28 days of life (PHC 43% vs NC 64%) and the total days of oxygen supplementation (PHC 15 [4-53] vs NC 32 [17-50]) did not differ between the groups. There were no differences in mortality, air leaks, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or patent ductus arteriosus. CONCLUSION: A ventilatory strategy of PHC in preterm infants who receive assisted ventilation is feasible, seems safe, and may reduce the duration of assisted ventilation. assisted ventilation, respiratory distress syndrome, gentle ventilation, lung injury.
Biological Products↗
99mTc-HMPAO regional cerebral blood flow and quantitative electroencephalography in Alzheimer's disease: a correlative study.
UNLABELLED: In this study the neuropsychological status of patients with Alzheimer's disease (AD) was correlated with quantitative electroencephalography (qEEG) and regional cerebral blood flow (rCBF) both in the cortex and in deep gray matter structures. METHODS: Forty-three outpatients (mean age 72.4 +/- 7.5 y) with probable AD underwent 99mTc-hexamethyl propyleneamine oxime SPECT with a brain-dedicated gamma camera and qEEG (relative values) within 1 mo. Preliminary factorial analysis with promax rotation identified four qEEG bands (2-5.5, 6-7.5, 8-11.5 and 12-22.5 Hz, with no distinction as to topography) and six SPECT regions (the two thalami together, the two parietal cortices together, the right temporal cortex, the right hippocampus, the left hippocampus and the remaining cortical areas together) as the variables with highest statistical power. All these variables and the Mini-Mental Status Examination score (MMSE, a sensitive marker of neuropsychological deficit) were processed by a final factorial analysis and multivariate analysis of variance. RESULTS: Both the 2-5.5 Hz and the 8-11.5 Hz powers were correlated with the perfusion level in the parietal regions of interest (ROls) (P = 0.0009), whereas the 2-5.5 Hz power was correlated with the right hippocampal perfusion level (P = 0.007). The MMSE score was significantly correlated with the perfusion level, both in the right (P = 0.006) and in the left (P = 0.004) hippocampal ROls and in the parietal ROls (P = 0.01); moreover, it was correlated with both the 2-5.5 Hz (P = 0.0005) and the 8-11.5 Hz (P = 0.004) power. CONCLUSION: rCBF (bilateral parietal perfusion) and qEEG (especially the slowest frequencies, i.e., 2-5.5 Hz) are confirmed to be good descriptors of AD severity. It is especially noteworthy that bilateral hippocampal CBF was the perfusional index best correlated with the MMSE as well as being significantly correlated to qEEG. Hippocampal SPECT imaging appears to be a promising index to improve characterization of AD in respect to other forms of primary degenerative dementia and may be proposed as a marker for evaluating the effects of pharmacotherapy of AD at the neuronal level.
Aged↗
Serum phospholipids are the main environmental determinants of activated factor VII in the most common FVII genotype. European Union Concerted Action "Clotart".
BACKGROUND AND OBJECTIVE: Numerous studies have emphasized the role of triglyceride-rich lipoproteins and of Factor VII (FVII) polymorphisms in determining levels of FVII activity. DESIGN AND METHODS: This study was undertaken to evaluate the role of other lipid fractions and the interaction between lipids and FVII in subjects with recognised genotypes. Volunteer subjects (n=459) from 5 European countries were studied. Blood samples were drawn irrespective of the time of day or fasting status. Levels of FVII activity (FVIIc), activated FVII (FVIIa) and FVII antigen (FVIIAg) were evaluated with reference to a number of lipid parameters (HDL-, LDL- and total cholesterol, triglycerides, phospholipids, lipoprotein(a), and apoliproptein A1). The two most common FVII polymorphisms were analyzed in combination (353R/Q and 5'F7; alleles M1/M2 and A1/A2, respectively). RESULTS: Homozygotes for the A1 and M1 alleles (M11/A11) had significantly higher FVII levels. At multiple regression analysis the strongest predictor of FVIIa and FVIIc was the concentration of phospholipids. This interaction was confined to the A11M11 genotype subjects. INTERPRETATION AND CONCLUSIONS: These data indicate that lipids contribute mainly to FVIIa levels through their phospholipid content, and that the degree of this contribution is strictly dependent on FVII genotypes.
Adult↗
Imaging of pancreatic adenocarcinoma with radiolabeled monoclonal antibodies.
This review focuses on the potential of immunoscintigraphy with radiolabeled monoclonal antibodies in patients with pancreatic cancer. The general limitations of tumor immunoscintigraphy are particularly important in the case of pancreatic cancer, because of the particular anatomic location, that is in close proximity with sites of physiologic high accumulation of radioactivity during such examinations (bone marrow in the spine, liver, spleen, and most of all kidneys). Thus, the role of immunoscintigraphy in patients with pancreatic cancer appears limited (except in peritoneal carcinosis), or not fully explored given the small cumulative number of patients evaluated so far with such scintigraphic procedure. Perspectives for development of the radiolabeled monoclonal antibody technology in patients with pancreatic cancer might be seen in the field of radioimmunotherapy and possibly radioimmuno-guided surgery.
Adenocarcinoma↗
Detection of acute myocardial infarction by 99mTc-labeled D-glucaric acid imaging in patients with acute chest pain.
UNLABELLED: Definitive diagnosis of acute myocardial infarction early in the process is often difficult. An imaging agent that localized quickly and specifically in areas of acute necrosis could provide this critical diagnostic information. To determine whether imaging with 99mTc-labeled D-glucaric acid (GLA) could provide this information, we imaged a group of patients presenting with symptoms suggestive of acute infarction. METHODS: Twenty-eight patients presenting to the emergency department with symptoms highly suggestive of acute infarction were injected with 99mTC-GLA and imaged about 3 h later. RESULTS: The sensitivity of lesion detection was remarkably time dependent. Fourteen patients with acute infarction injected within 9 h of onset of chest pain had positive scans, even in the presence of persistent occlusion. The remaining 14 patients had negative scans. Nine patients with negative scans had acute infarction but were injected more than 9 h after onset of chest pain. The final diagnosis in the remaining 5 patients was unstable angina (3 injected <9 h and 2 injected >9 h after onset of chest pain). Six patients were reinjected with 99mTc-GLA 4-6 wk after their initial study to determine whether persistent positive scans occurred with this agent. All 6 had negative scans. CONCLUSION: This study suggests that 99mTc-GLA localizes in zones of acute myocardial necrosis when injected within 9 h of onset of infarction.
Aged↗
HIV-1 Tat protein mimicry of chemokines.
The HIV-1 Tat protein is a potent chemoattractant for monocytes. We observed that Tat shows conserved amino acids corresponding to critical sequences of the chemokines, a family of molecules known for their potent ability to attract monocytes. Synthetic Tat and a peptide (CysL24-51) encompassing the "chemokine-like" region of Tat induced a rapid and transient Ca2+ influx in monocytes and macrophages, analogous to beta-chemokines. Both monocyte migration and Ca2+ mobilization were pertussis toxin sensitive and cholera toxin insensitive. Cross-desensitization studies indicated that Tat shares receptors with MCP-1, MCP-3, and eotaxin. Tat was able to displace binding of beta-chemokines from the beta-chemokine receptors CCR2 and CCR3, but not CCR1, CCR4, and CCR5. Direct receptor binding experiments with the CysL24-51 peptide confirmed binding to cells transfected with CCR2 and CCR3. HIV-1 Tat appears to mimic beta-chemokine features, which may serve to locally recruit chemokine receptor-expressing monocytes/macrophages toward HIV producing cells and facilitate activation and infection.
Amino Acid Sequence↗
Identification of a novel domain of HIV tat involved in monocyte chemotaxis.
Human immunodeficiency virus (HIV) Tat is chemotactic for monocytes and dendritic cells, an activity that could play a key role in the expansion of HIV infection of accessory cells. To date, domains of Tat previously found to interact with cell surface molecules have shown only partial chemotactic activity toward monocytes. Using overlapping Tat peptides, we identify a novel region of Tat with a potent chemotactic activity for monocytes, reaching levels equal to Tat itself. This peptide also provokes monocyte polarization similar to Tat and is able to compete with Tat for induction of monocyte migration. Specific high affinity (kd = 3 x 10(-9) M) cell surface binding sites on monocyte cell surfaces for this region of Tat are demonstrated. These data indicate that the majority of Tat effects on monocytes are mediated by a novel region in the cysteine-rich and core domains. These domains are highly conserved among different HIV isolates, suggesting an important role in the establishment of HIV infection.
Cell Polarity↗
Productive human immunodeficiency virus-1 infection of purified megakaryocytic progenitors/precursors and maturing megakaryocytes.
We have evaluated the susceptibility to human immunodeficiency virus (HIV)-1 infection of in vitro grown megakaryopoietic progenitors/precursors and maturing megakaryocytes (MKs), based on the following approach: (1) human hematopoietic progenitor cells (HPCs), stringently purified from peripheral blood and grown in serum-free liquid suspension culture supplemented with thrombopoietin (Tpo), generated a relatively large number of >/= 98% to 99% pure megakaryocytic precursors and then mature-terminal MKs; (2) at different days of culture (ie, 0, 5, 8, 10) the cells were inoculated with 0.1 to 1.0 multiplicity of infection (m.o.i.) of the lymphotropic NL4-3 or 0.1 m.o.i. of the monocytotropic BaL-1 HIV-1 strain; (3) finally, the presence of viral mRNA and proteins was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR)/in situ hybridization and antigen capture assays, respectively, on day 2 to 12 of culture. MKs derived from day 0 and day 5 BaL-1-challenged cells do not support viral replication as assessed by p24 enzyme-linked immunosorbent assay (ELISA) and RT-PCR. On the contrary, HIV transcripts and proteins were clearly detected in all NL4-3 infection experiments by RT-PCR and p24 assay, respectively, with the highest viral expression in day 5 to 8 challenged MKs. In situ hibridization studies indicate that the percentage of HIV+ MKs varies from at least 1% and 5% for day 0 and day 5 infected cells, respectively. Production of an infectious viral progeny, evaluated by the capability of culture supernatants from day 5 NL4-3-challenged MKs to infect C8166 T-lymphoblastoid cell line, was consistently observed (viral titer, approximately 5 x 10(3) tissue culture infectious dose50/mL/10(6) cells). Exposure of MKs to saturating concentration of anti-CD4 OKT4A monoclonal antibody (MoAb), which recognizes the CD4 region binding with the gp120 envelope glycoprotein, markedly inhibited HIV infection, as indicated by a reduction of p24 content in the supernatants: because the inhibitory effect was incomplete, it is apparent that the infection is only partially CD4-dependent, suggesting that an alternative mechanism of viral entry may exist. Morphologic analysis of day 12 MKs derived from HPCs infected at day 0 showed an impaired megakaryocytic differentiation/maturation: the percentage of mature MKs was markedly reduced, in that approximately 80% of cells showed only one nuclear lobe and a pale cytoplasm with few granules. Conversely, megakaryocytic precursors challenged at day 5 to 8 generated fully mature day 10 to 12 MKs showing multiple nuclear segmentation. Thus, the inhibitory effect of HIV on the megakaryopoietic gene program relates to the differentiation stage of cells subjected to the viral challenge. Finally, HPCs treated with 20 or 200 ng/mL of recombinant Tat protein, analyzed at different days of culture, showed an impaired megakaryocytopoiesis comparable to that observed in HIV-infected cells, thus suggesting that Tat is a major mediator in the above described phenomena. These results shed light on the pathogenesis of HIV-related thrombocytopenia; furthermore, they provide a model to investigate the effects of HIV on megakaryocytic differentiation and function.
Adult↗
Use of radioimmunoguided surgery after induction chemotherapy in locally advanced breast cancer.
Twenty-one patients with histologically proven locally advanced breast cancer (LABC) were treated with a combined modality approach based on primary chemotherapy and radical modified mastectomy followed by adjuvant chemotherapy. Surgery was performed by using radioimmunoguided surgery (RIGS) technique with the preoperative injection of Iodine-125 labeled monoclonal antibodies (MoAbs) B72.3 anti-TAG (11 patients, Group A) and FO23C5 anti-carcinoembryonic antigen (CEA; 10 patients, Group B). The role of RIGS was defined at surgery by using an intraoperative hand-held gamma-detecting probe (GDP) to locate the primary tumor, possible clinically occult multicentric foci and ipsilateral lymph node metastases. In Group A, RIGS correctly defined the primary tumor in seven out of 11 patients (63.3%) and was able to find multicentric tumors in two out of four patients (50%). Positive lymph nodes were identified by RIGS in three out of eight patients (37.5%). In Group B, patients RIGS correctly located the primary in 4/10 cases (40%); in two RIGS-positive cases, the tumor was clinically not evident after primary chemotherapy (yT0). RIGS correctly identified multicentric foci of tumor in one out of two cases (50%). Correct lymph nodal RIGS assessment was observed in three out of nine patients (33.3%). No RIGS false-positive findings occurred in the 21 patients included in the study. RIGS appears to be a reliable technique for the intraoperative diagnosis and staging of breast cancer with a potential role especially when conservative surgery is planned after primary chemotherapy in LABC.
Aged↗
Feasibility in the clinical setting of perfusion brain SPECT imaging employing a brain-dedicated gamma camera and the conjugate gradients with modified matrix reconstruction method.
In the present study, we compared Tc-99m HMPAO single photon emission computed tomography (SPECT) brain images obtained using the conventional filtered backprojection (FBP) reconstruction method with the new reconstruction method of conjugate gradients with modified matrix (CGMM). The two methods were employed to generate SPECT images of a brain perfusion study in a 41-year-old patient who had suffered from multiple embolisation of the right hemisphere. Marked improvement in spatial resolution was achieved by CGMM reconstruction as compared to FBP reconstruction; this considerably helped in defining grey matter structures and low-uptake white-matter areas, both in the normal cerebral areas and in the hemisphere that had been affected by stroke. Although the relatively long time still required by the CGMM procedure might be considered as a significant drawback to date, with the increasing diffusion of the new computer facilities the CGMM method can be proposed as a valuable alternative to the standard FBP technique in order to better recognise cerebral areas with different tracer uptake.
Adult↗
Only association of low concentrations of idarubicin plus idarubicinol induced apoptosis on leukaemic cells.
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Antineoplastic Combined Chemotherapy Protocols↗
PBSC mobilization, collection and positive selection in patients with chronic lymphocytic leukemia.
We report the results of PBSC mobilization and immune selection in 17 patients with advanced chronic lymphocytic leukemia (CLL) enrolled in a multicenter Italian study of autologous transplantation with peripheral CD34+ selected cells. Mobilization was achieved by cyclophosphamide (CY) 4 g/m2 + G-CSF 5 microg/kg. CD34+ cells were positively selected by means of avidin-biotin immunoaffinity columns (Ceprate SC) or immunomagnetic beads (Isolex 300i) systems. Evaluation of minimal residual disease was performed by PCR analysis of the IgH gene rearrangment on the apheresis product before and after selection. Our results showed that after CY a median of 3.6 x 10(6)/kg (0.5-12.8) CD34+ cells were collected with a median of two aphereses in 14 out of 17 patients; three failed to mobilize a number of CD34+ cells adequate for subsequent manipulation. We found that in CR patients CD34+ cell yield per apheresis was significantly higher than in PR patients (P < 0.05). Sixteen selection procedures were performed in 13 patients. CD34+ cell recovery was 33.5% (10-85) with a median final yield of 1 x 10(6)/kg CD34+. Two patients underwent marrow collection due to the low number of CD34+ cells recovered. Final purity was 59% (range 22-94) and CD5/20+ cell depletion was 2.7 log (1.6-4.4). Our data showed a statistically higher CD34+ cell recovery and purity with the Isolex device compared to Ceprate (P < 0.01 and 0.01, respectively). All the evaluable samples remained PCR positive after selection. The main issues to be addressed in the future are the identification of patients who fail mobilization and the improvement of purging methods.
Adult↗
Terminal megakaryocytic differentiation of TF-1 cells is induced by phorbol esters and thrombopoietin and is blocked by expression of PML/RARalpha fusion protein.
We have analyzed the differentiation program of growth factor-dependent TF-1 erythroleukemia cells as well as clones with inducible expression of the APL-specific PML/RARalpha protein. We have shown that TF-1 cells may be induced to megakaryocytic differentiation by phorbol ester (phorbol dibutyrate, PDB) addition, particularly when combined with thrombopoietin (Tpo). RT-PCR studies showed that Tpo induces Tpo receptor (TpoR or c-mpl), whose expression was further potentiated by PDB addition. When the cells are induced with both PDB and Tpo erythropoietin receptor (EpoR) expression was inhibited. In the absence of Zn2+-induced PML/RARalpha expression, PDB and Tpo induced megakaryocytic differentiation of TF-1 MTPR clones as observed in 'wild-type' TF-1 cells. Conversely, when PML/RARalpha expression was induced by Zn2+, PDB and Tpo treatment of these clones caused only a reduced level of megakaryocytic differentiation. These observations indicate that: (1) TF-1 cells as well as other erythroleukemic cells, possess the capacity to differentiate to megakaryocytic cells when grown in the presence of protein kinase (PKC) activators and more efficiently when combined with Tpo; (2) the PML/RARalpha gene has a wide capacity to interfere with the program of hematopoietic differentiation, including megakaryocytic differentiation. Finally, we also observed that PML/RARalpha expression in TF-1 cells induces an up-modulation of interleukin-3 receptor, c-kit and c-mpl, a phenomenon which may offer these cells a growth advantage.
Carcinogens↗
Local immunotherapy: pharmacokinetics and efficacy.
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Animals↗
Accumulation of oncofetal fibronectin in the vessels of anaplastic meningiomas.
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Adjuvants, Immunologic↗
Autologous peripheral blood stem and progenitor (CD34+) cell transplantation for systemic lupus erythematosus complicated by Evans syndrome.
Immunoablation followed by allogeneic stem cell (SC) transplantation has been shown to be capable of curing a large spectrum of experimental autoimmune disorders, hereditary and/or induced. Superimposable results, albeit with some exceptions, have been obtained in human patients affected by coincidental autoimmune and blood diseases. However, both because of encouragine experimental results and of the procedure's greater safety, autologous SC are being increasingly utilized worldwide. Case reports are being collected in the registry of the European Group for Blood and Marrow Transplantation (EBMT)/European League against Rheumatism (EULAR) Autoimmune Disease Stem Cell Project. Among the severe autoimmune diseases (SADs), which are the target of autologous transplantation, severe refractory systemic lupus erythematosus (SLE) is a condition which may benefit from this procedure. We report here the case of a 19 year old female patient with a six year history of SLE with secondary antiphospholipid syndrome (APS), who later developed refractory Evans syndrome. She was transplanted with autologous mobilized CD34+ SC and progenitor cells after conditioning with cyclosphosphamide, anti-T lymphocyte globulin and prednisone. Eight months after transplant, the patient is alive and well, with normal blood counts and persistent low-titre direct antiglobulin (DAT, Coombs) and anti-nuclear antibody (ANA) tests. Anti-double stranded DNA antibody (Anti-dsDNA), lupus anticoagulant tests and anti-cardiolipin antibody (ACA) test are negative.
Adolescent↗