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Biomedical subjects

D Conti

Publications and source records attributed to D Conti.

At least 19 recordsLinked to original sources
PubMed2000

Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics.

An intravenous (i.v.) formulation of mycophenolate mofetil (MMF; CellCept, Roche Pharmaceuticals, Inc., Palo Alto, CA) that will enable its administration to patients unable to tolerate oral medication is available. Two separate studies, an open-labeled pharmacokinetic (PK) study and a double-blind safety study, were performed. Within 24 h after transplant, 153 (safety study) and 45 (PK study) first or second renal transplant recipients were started on i.v. MMF 1 g Q12h or placebo (used in the safety study only, 2:1 MMF:placebo), given over 2 h via a dedicated peripheral venous catheter. In the safety study, per os (p.o.) MMF (1g Q12h) or placebo was administered, starting within 72 h after transplant, whereas in the PK study, p.o. MMF was started on the evening of day 5. Sequential blood samples obtained on study days 5 (i.v. MMF) and 6 (p.o. MMF) before and up to 12 h after the AM dose were analyzed for mycophenolic acid (MPA) and MPA glucuronide (MPAG) concentrations by high-performance liquid chromatography. The area under the concentration curve (AUC) was calculated using the linear trapezoidal rule. The MPA AUC(0-12) was higher for i.v. MMF than p.o. MMF (40.8 +/- 11.4 microg x h/ mL vs. 32.9 +/- 15, p < 0.001). There were no other significant PK differences for plasma MPA or MPAG. In the safety study (n = 98 i.v. MMF vs. n = 55 placebo), 11 patients (11%, i.v. MMF) and 4 patients (7%, placebo) discontinued their use of the drug because of an adverse event (AE). Overall, AEs were similar between i.v. MMF and placebo. Injection site phlebitis (4%) and thrombosis (4%) were observed only with i.v. MMF. MMF i.v. 1 g twice daily (b.i.d.) should provide efficacy at least equivalent to p.o. MMF without increased toxicity, and it provides an acceptable alternative dose form in the immediate period after transplant.

Administration, Oral↗
PubMed2000

Micronucleus yield and colorimetric test as indicators of damage in patients' lymphocytes after 131I therapy.

UNLABELLED: To estimate the absorbed dose received by patients who underwent 131I therapy, a modified compartmental model of the International Commission on Radiological Protection (ICRP) was used. The activity in plasma and micronucleus (MN) frequency (MN test) were measured before and after therapy. To evaluate whether a correlation exists between lymphocytes and absorbed dose, a colorimetric test, based on the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT test), was used. METHODS: Twenty patients who underwent 131I therapy were studied. Activity was measured in plasma, and isolated lymphocytes were collected to perform the MN and MTT tests. RESULTS: The mean MN frequency observed in unexposed patient lymphocytes was comparable with that of healthy subjects. 131I therapy induces a small increase in MN, and a good correlation with the bone marrow absorbed dose was obtained (P = 0.040). A consistent decrease in phytostimulation observed after therapy (MTT test) correlated significantly with bone marrow absorbed dose (P = 0.0085). CONCLUSION: The MTT test appears to be more reliable than the MN test for evaluating lymphocyte damage induced by 131I therapy.

Bone Marrow↗
PubMed1997

Dose-response of X-irradiated human and equine lymphocytes.

We have investigated and compared DNA damage and cell killing induced in human and equine lymphocytes after in vitro X-irradiation. Our data show that the cytogenetic and the lethality effects are both greater in equine lymphocytes, but that the difference is wider for lethality. The ratios between doses inducing the same effect are 1.3, 1.7 and 9.4 for the number of binucleated cells with micronuclei, micronucleus frequency in binucleated cells and DNA synthesis inhibition, respectively. The very different radiosensitivity observed for the two mammalian species encourages us to use their lymphocytes in cell radiobiology studies.

Animals↗
PubMed1997

Peripheral blood lymphocyte decrease and micronucleus yields during radiotherapy.

PURPOSE: To investigate the relationship between lymphocyte decrease and cytogenetic response in individual patients undergoing radiotherapy. MATERIALS AND METHODS: Peripheral blood lymphocytes obtained from 35 patients with pelvic and from 14 with head and neck tumours before and during radiotherapy were PHA-stimulated in vitro and the cultures prepared for the cytokinesis-block micronucleus test. For some patients only, the micronucleus test was carried out after 2 Gy in vitro X-irradiation, and 3-aminobenzamide (2 mM) was used to calculate the 3AB-index. RESULTS: The initially observed individual variation in the decrease of lymphocytes disappeared with increasing number of radiation exposures, reaching a stable level at about 500/microl lymphocytes in the blood. The slope of the relationship between the reciprocal of the lymphocyte decrease ratio and equivalent dose indicates the radiosensitivity of the lymphocyte pool in individual patients. The micronucleus test performed on lymphocytes obtained from patients during radiotherapy (in vivo) provided a lower cytogenetic response than the in vitro micronucleus yield for the same dose, so it was possible to calculate the cytogenetic recovery factor k. A correlation was found between the 3AB-index calculated before radiotherapy, and the recovery factor k. CONCLUSIONS: The 3AB-index, the micronucleus frequency after 2 Gy in vitro X-irradiation, and the cytogenetic recovery factor are proposed as predictive of individual response to radiotherapy.

Aged↗
PubMed1996

Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc.

We show here that c-Myc antagonizes the cyclin-dependent kinase (CDK) inhibitor p27Kip1. p27 expressed from recombinant retroviruses in Rat1 cells associated with and inhibited cyclin E/CDK2 complexes, induced accumulation of the pRb and p130 proteins in their hypophosphorylated forms, and arrested cells in G1. Prior expression of c-Myc prevented inactivation of cyclin E/CDK2 as well as dephosphorylation of pRb and p130, and allowed continuous cell proliferation in the presence of p27. This effect did not require ubiquitin-mediated degradation of p27. Myc altered neither the susceptibility of cyclin E/CDK2 to inhibition by p27, nor the intrinsic CDK-inhibitory activity of p27, but induced sequestration of p27 in a form unable to bind cyclin E/CDK2. Neither Myc itself nor other G1-cyclin/CDK complexes were directly responsible for p27 sequestration. Retroviral expression of G1 cyclins (D1-3, E or A) or of the Cdc25A phosphatase did not overcome p27-induced arrest. Growth rescue by Myc required dimerization with Max, DNA binding and an intact transcriptional activation domain, as previously shown for cellular transformation. We propose that this activity is mediated by the product of an as yet unknown Myc-Max target gene(s) and represents an essential aspect of Myc's mitogenic and oncogenic functions.

Animals↗
PubMed1996

Beneficial effects of Duraflo II heparin-coated circuits on postperfusion lung dysfunction.

BACKGROUND: Heparin coating of the cardiopulmonary bypass circuit reduces the activation of the terminal part of the complement cascade. Conflicting data are reported concerning neutrophil activation and postoperative lung dysfunction. In this study, we compared three different types of oxygenator: a bubble oxygenator, a conventional hollow-fiber oxygenator, and a heparin-coated oxygenator and circuit. METHODS: Sixty patients undergoing myocardial revascularization were randomly assigned to one of three oxygenator groups. All the patients were free from preoperative lung dysfunction. Lung function was studied with repeated measurements of respiratory index, intrapulmonary shunt, alveolar dead space, ventilation/perfusion ratio, and static thoracopulmonary compliance. RESULTS: Immediately after cardiopulmonary bypass, the intrapulmonary shunt and respiratory index values in the bubble oxygenator and hollow-fiber oxygenator groups increased more than those in the heparin-coated oxygenator group. In the intensive care unit, the between-group difference in intrapulmonary shunt disappeared, but the within-group difference in respiratory index (from baseline) remained for the bubble oxygenator group. The other three variables did not significantly differ between groups. Intubation time and stay in the intensive care unit did not differ between groups. CONCLUSIONS: Heparin-coated circuits exert a protective effect on pulmonary function. However, their use did not modify the postoperative clinical course of patients with normal lung function preoperatively.

Aprotinin↗
PubMed1996

Micronuclei in cytokinesis-blocked lymphocytes may predict patient response to radiotherapy.

We have applied the cytokinesis-block micronucleus assay to peripheral blood lymphocytes of patients undergoing radiotherapy in pelvic and pulmonary sites, in order to evaluate the individual cytogenetic response. Our cytogenetic data correlated with the equivalent whole-body dose are homogeneous and compare well with the data presented by other authors. We have used an exponential mathematical formula to calculate the attenuation of the cytogenetic effect with time. The k coefficient (cytogenetic recovery factor) in the formula expresses the degree of attenuation. In lymphocytes from patients after radiotherapy, the trend of the micronucleus frequency observed after 2 Gy of in vitro X-irradiation demonstrates that the cytogenetic effect obtained in vitro is added to that obtained in vivo. The k coefficient is inversely proportional to the micronucleus frequency observed after 2 Gy in vitro. The micronucleus assay and the cytogenetic recovery factor are proposed as suitable diagnostic tools for application in the field of radiotherapy.

Dose-Response Relationship, Radiation↗
PubMed1995

Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial.

OBJECTIVE: To determine whether preemptive ganciclovir therapy administered daily during antilymphocyte antibody therapy can prevent cytomegalovirus disease in renal transplant recipients who are positive for cytomegalovirus antibody. DESIGN: Randomized, controlled, multicenter trial. SETTING: 6 university-affiliated transplantation centers. PATIENTS: 113 renal transplant recipients who were positive for cytomegalovirus antibody. INTERVENTION: Patients were randomly assigned to receive either 1) ganciclovir, 2.5 mg/kg body weight administered intravenously on every day that antilymphocyte antibody therapy was administered or 2) no anticytomegalovirus therapy. MEASUREMENTS: Patients were observed for 6 months after completion of antilymphocyte antibody therapy for development of cytomegalovirus disease and cytomegalovirus viremia. RESULTS: Cytomegalovirus disease occurred in 14% of patients (9 of 64) who received preemptive ganciclovir therapy and in 33% of controls (16 of 49) (P = 0.018). Cytomegalovirus was isolated from buffy-coat specimens from 17% of patients (11 of 64) receiving preemptive ganciclovir and from 35% of controls (17 of 49) (P = 0.03). Controlling for the reason (induction or treatment of rejection) for using antilymphocyte antibodies in a Cox proportional hazards model, we found that preemptive ganciclovir still protected against cytomegalovirus disease (adjusted relative risk, 0.27; 95% CI, 0.12 to 0.64). No adverse events were attributed to preemptive ganciclovir therapy during or within 6 months of its administration. CONCLUSIONS: Preemptive ganciclovir therapy administered daily during courses of treatment with antilymphocyte antibodies reduced the excessive occurrence of cytomegalovirus disease in renal transplant recipients who were positive for cytomegalovirus antibody. This approach, which links the most potent immunosuppression to intensive antimicrobial therapy, allows preventive therapy to be given to those patients at greatest risk for developing infectious complications. These patients are likely to benefit most from the preventive strategy.

Adolescent↗
PubMed1995

Ruptured aneurysms of the thoracoabdominal aorta: a case series.

Fifteen cases of ruptured thoracoabdominal aneurysm (-TAA) were encountered in 1987-July 1994. These patients included 13 males (86.6%), 2 females (13.4%) with a mean age of 66.3 years (range 58-78). Surgery was performed on 13 patients of whom 6 (46.1%) died within 30 days. The two other patients had died of heart failure prior to surgery. In 8 of these patients (53.4%) the condition was not diagnosed until clear symptoms had appeared. The ruptured aneurysms were thoracic in 9 cases (60%), abdominal in 6 (40%). The maximum aneurysm diameter in the most frequently ruptured group was 6.1-8 cm (in 9 patients-60%)./ For 5 cases (33.4%) the maximum diameter of ruptured aneurysms included dorsolumbar pain. In one patient a concomitant aortobronchial fistula had produced rupture. Low blood pressure was found in 9 cases (60%). In 5 cases (38.4%) curative surgery was performed within 24 hours of the onset of symptoms. In this group, the mortality rate was 40% (2 patients). In the remaining 8 cases, on whom surgery could not be performed within 24 hours (range 25 hours-4 months) the mortality rate was 50% (4 cases). All four cases of paraplegia (30.7%) were encountered among patients in the second group, 2 of whom died. Follow-up revealed a 5-year mortality rate of 71.4%.

Aged↗
PubMed1994

Micronuclei and 3AB index in X-irradiated human lymphocytes in G0 and G1 phases.

We applied the cytokines-block micronucleus assay to observe the radiobiological response of human lymphocytes after X-ray treatment in the G0 and G1 phases. In addition, we used 3-aminobenzamide (3AB) to measure the 3AB index in the two phases. The experimental results show that at 2 Gy the MN yield and the 3AB index are dependent on the cell phase and show considerable inter-individual variability. The radiation-induced MN frequency obtained for 33 subjects is 0.470 +/- 0.063 for the G0 phase and 0.689 +/- 0.139 for the G1 phase; the 3AB index values are 0.326 +/- 0.144 and 0.067 +/- 0.058 for G0 and G1 phases, respectively. At the individual level, the 3AB index for the G1 phase correlates inversely with the cytogenetic effects observed in that phase. We discuss the possibility of applying the MN test combined with the 3AB index to lymphocytes at different phases to study the individual response to radiation (individual radiosensitivity).

Adult↗
PubMed1994

Micronuclei and 3AB index in human and canine lymphocytes after in vitro X-irradiation.

The comparative study of different species could be of interest, both applied and pure, to the field of cytogenetic damage induced by genotoxic agents. For as accurate as possible an evaluation of the inter-species response differences to radiation, we have carried out a comparison between the behaviors of human and canine lymphocytes, using the micronucleus assay (MN test) according to the cytokinesis-block method. Up to 4 Gy doses, canine lymphocytes have been found to be about three times more radiosensitive than human lymphocytes, due to blastization inhibition (binucleation failure), and, for 1 and 2 Gy doses, about 1.3 times more radiosensitive, due to MN yields. We discuss whether the differing chromosome number (dog 78 and man 46) could have any effect on the cytogenetic response. 3-Aminobenzamide, which inhibits poly(ADP-ribose)polymerase activity, is able to increase the genotoxic effect of X-rays in human lymphocytes, with a different response at the individual level. The same phenomenon with the same characteristics is also found in canine lymphocytes at the inter-individual level. Our in vitro radiobiological study confirms that the cytogenetic response obtained in blood from selected breeds of mammalian species can be utilized for applications in environmental studies.

Animals↗
PubMed1994

A guideline nomogram to control intraoperative haemodilution in cardiac surgery.

Intraoperative blood collection prior to cardiopulmonary bypass (CPB) is a common procedure in cardiac surgery. Its aims are to obtain fresh whole blood to be infused after CPB, to use autologous blood in the prime or to avoid too high levels of haematocrit (HCT) during CPB. Calculations to determine the amount of blood to be collected are generally based on theoretical assumptions. In this paper we have set up and controlled, on a clinical basis, a nomogram to be used in order to obtain a standard pre-CPB HCT equal to 38%, using a moderately hypervolaemic haemodilution based on blood collection simultaneous with fluid replacement. Thirty adult patients were evaluated in order to settle the nomogram; subsequently, the nomogram validity was checked on 100 adult patients. Statistical analysis revealed the good clinical usefulness of this instrument.

Adult↗
PubMed1994

Risk factors for renal dysfunction after coronary surgery: the role of cardiopulmonary bypass technique.

We studied 316 patients undergoing cardiopulmonary bypass for coronary artery surgery in order to determine perioperative risk factors for postoperative renal dysfunction. A preliminary univariate analysis was performed by chi 2 analysis for categorical data and Mann-Whitney U-test for continuous variables to detect significant correlations between each risk factor and the occurrence of moderate or severe renal dysfunction. Subsequently, a multiple logistic regression was applied to the three risk factors identified as predictive for severe renal dysfunction. Low cardiac output syndrome and need for banked blood transfusions combined with a low haematocrit value during cardiopulmonary bypass increase the probability of severe renal dysfunction in the postoperative course.

Aged↗
PubMed1994

Micronuclei and 3AB-index in patients receiving iodine-131 therapy.

In 28 blood samples from 21 patients undergoing 131I treatment after surgical thyroidectomy for cancer, the micronucleus (MN) frequency observed in peripheral blood lymphocytes (MN-test on binucleated cells) had a weighted mean of 0.044 +/- 0.006 (SEM), which was significantly different (p < 0.001) from that observed in 93 healthy individuals (0.025 +/- 0.001). The MN frequency (F(MN)) of the patients correlated fairly well (R = 0.736) with the modified activity (Amod) calculated by the following equation: [formula: see text] where Ai is the 131I activity on a determined day, e the logarithm base, di the number of days that have passed between the determined day and the day when the blood was drawn, and k is a day coefficient, defined in this context as the "daily attenuation factor". The use of the value of 0.0003 for k allowed the following equation to be obtained: F(MN) = 7.9 x 10(-5) (+/- 1.4 x 10(-5)).Amod + 0.014 (R = 0.736) The MN frequency was used to estimate, by our DOSIME program, the dose (Gy) received at the individual level in the 131I treatment. In these subjects the calculated dose was well correlated with Amod by the relationship: DBio = 0.0009 (+/- 0.0002).Amod + 0.0675 (R = 0.755) 3-aminobenzamide (3AB), an inhibitor of the poly(ADP-ribose)polymerase enzyme involved in DNA repair, induced and increase in X-ray cytogenetic damage (MN yields), evaluated at the individual level using the 3AB-index (I-3AB). The index was obtained from the MN-yield count after x-irradiation with (MN + 3AB) and without (MN - 3AB) 3AB, using the following formula: I = 1-(MN - 3AB/MN + 3AB).(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1992

Inter-individual differences in radiation response shown by an in vitro micronucleus assay: effects of 3-aminobenzamide on X-ray treatment.

Among the methods of biological dosimetry of ionizing radiation, we propose the cytokinesis-block micronucleus assay for the measurement of the individual dose absorbed. The dose-response curve was determined for in vitro-irradiated lymphocytes from 25 individuals. The dose-response relationship, fitted by the linear-quadratic function, was F(MN) = 0.015 (+/- 0.0016) + 0.043 (+/- 0.0075).D + 0.083 (+/- 0.0045).D2. Our results are compared with those of other authors. 3-aminobenzamide (3AB) combined with X-rays were used to evaluate the micronucleus dose-response relationship in blood from 14 individuals. While it is known that 3AB inhibits poly(ADP-ribose) polymerase activity in vitro, we demonstrate that it also increases the X-ray-induced micronucleus yields. The resulting dose-response relationship varies from subject to subject. The possibility of using this approach to identify the individual radiosensitivity level is discussed.

Adult↗
PubMed1990

In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts.

These studies test whether allograft rejection can be blocked by interference with leukocyte adhesion, using a murine IgG2a mAb (R6.5) reactive with monkey ICAM-1 (CD54). In 16 Cynomolgus renal allograft recipients, R6.5 was administered prophylactically as the sole immunosuppressive agent for 12 days (0.01 to 2 mg/kg/day). Survival in 14 recipients with technically successful grafts was significantly prolonged (24.2 +/- 2.4 vs 9.2 +/- 0.6 days for controls; p less than 0.001). Intercellular adhesion molecule-1 (CD54) (ICAM-1) was expressed on vascular endothelium in the kidney and other organs in the monkey in a pattern similar to that in humans. During cellular rejection in controls, ICAM-1 expression increased on endothelial cells, infiltrating mononuclear leukocytes and tubular cells. Biopsies during R6.5 administration showed decreased T cell infiltration (CD2, CD8, CD4) compared with controls and decreased arterial endothelial inflammation. No changes occurred in circulating T cells, aside from variable coating with mIgG. In six of eight other recipients R6.5 administration (0.5 to 2 mg/kg/day for 10 days) reversed preexisting rejection that resulted from taper of Cyclosporine to subtherapeutic levels. Responding grafts showed decreased edema and hemorrhage but no consistent change in the infiltrate. At 1 h after the first dose, mouse IgG deposited primarily on the graft vascular endothelium without any change in the inflammatory infiltrate. Mouse IgG also deposited on the endothelium of normal organs without eliciting an inflammatory response and was cleared from the endothelium within 4 days. Inasmuch as the principal site of binding was the vascular endothelium, we hypothesize that the antibody blocks adhesion to graft ICAM-1 molecules on the vessels. Anti-ICAM-1 also binds to recipient cells and may interfere with Ag presentation and/or T cell interactions. Whatever the mechanism(s), these studies indicate that an anti-ICAM-1 antibody inhibits T cell mediated injury in vivo, and that ICAM-1 is a critical molecule in the pathogenesis of allograft rejection.

Animals↗