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Biomedical subjects

G Doria

Publications and source records attributed to G Doria.

At least 19 recordsLinked to original sources
PubMed2004

[Prevention and treatment of congenital toxoplasmosis: organization protocol].

AIM: Prevention and treatment of congenital toxoplasmosis are still a matter of debate among obstetricians, pediatricians and epidemiologists. There is no consensus about antenatal screening and diagnostic tests, nor there is about treatment for presumed infection in pregnancy. As an example of this type of organisation for health care delivery, a regional model has been promoted as a multidisciplinary approach for prenatal diagnosis of congenital toxoplasmosis. The model had been designed on the national guidelines of the National Health Institute (Istituto Superiore di Sanità, ISS). METHODS: Suspected maternal infections are referred and seen as outpatients at our centre on a specific day of the week; maternal investigation (specific IgG, IgM, IgA and IgG avidity titres) are performed at the Institute of Virology of the University of Bari, and patients are started on spiramycin. All cases of true or presumed seroconversion are counselled for amniotic fluid sampling and the sample is sent to ISS. In cases of late seroconversion and positive amniotic fluid results, patients are prescribed pyrimethamine+sulphonamide+folinic acid and alternate spiramycin until the end of pregnancy. A fetal-neonatal follow-up is performed in all cases. RESULTS: During the period 1999-2001, 180 cases of presumed toxoplasmosis infection have been referred (average 60 cases per year). We have been able to reclute, since the adoption of the national network protocol, 1/3 of presumed regional cases with a positive increasing trend. CONCLUSION: The service for prenatal diagnosis of toxoplasma gondii infection has definitely benefitted from the adoption of this protocol, which combines adherence to a national network and pays respect to regional requirements.

Clinical Protocols↗
PubMed2003

[Second trimester termination of pregnancy with gemeprost: a review of 306 cases].

AIM: Prostaglandin analogues provide an effective method for induction of abortion in the second trimester of pregnancy. The clinical outcome and the risk of complications were evaluated in a group of women having a medical termination of pregnancy with gemeprost. METHODS: Three-hundred and six women undergoing second trimester termination of pregnancy, between January 1998 and July 2002 in our center, were studied. All women were given 1 mg vaginal gemeprost every 3 h up to a maximum of 3 doses in the first 24 hours. If the abortion did not occur within the first 24 hours after initiation of treatment, they were given a 2(nd) course of gemeprost. Outcome measures included failure of the 1st course of gemeprost, length of hospital stay after expulsion of conceptus, heavy blood loss with or without necessity of uterine packing or blood transfusion, and failure of induction. RESULTS: There was a significant difference, with better results in women with previous deliveries (vaginal or abdominal), as to the failure to abort after the 1(st) course of PG (P<0.01). Length of hospital stay, complications and failure of induction were independent from parity. Twelve (3.9%) women failed to abort with gemeprost and required other methods for abortion. CONCLUSIONS: The study confirms the efficacy of gemeprost for mid-trimester termination of pregnancy, although it is a risky and costly procedure, requiring hospitalisation and is associated with higher complication rate than the first trimester surgical abortion.

Abortifacient Agents, Nonsteroidal↗
PubMed2001

Role of DNA-dependent protein kinase in recognition of radiation-induced DNA damage in human peripheral blood mononuclear cells.

The DNA-dependent protein kinase (DNA-PK) complex plays a crucial role in radiation-induced DNA damage recognition. The complex includes the ku heterodimer, which comprises ku 70 and ku 80 subunits, that binds DNA termini of breaks without sequence specificity, and the catalytic subunit DNA-PKCS: The activation of the DNA-PK complex was studied in X-irradiated peripheral blood mononuclear cells (PBMC) from subjects of different ages. Radiation-induced changes in the DNA-binding activity of the ku heterodimer, and in the concentrations of ku 70, ku 80, DNA-PKcs and phosphorylated ku 80 were determined in nuclear and cytoplasmic extracts. DNA-binding activity was increased by irradiation only in the nuclear extract of PBMC from young, but not from elderly subjects, whereas it was found unchanged in cytoplasmic extracts regardless of age. The radiation-induced activation of the DNA-PK complex may result from the increased concentrations of ku 80 and DNA-PKcs in the cytoplasm of PBMC from young, but not from elderly subjects, leading to a higher concentration of phosphorylated ku 80 which readily migrates to the nucleus where, after dimerization with ku 70, binds to DNA breaks. These findings suggest major steps involved in DNA-PK activation, and the intracellular and molecular changes that may account for the age-dependent impairment of DNA repair capacity in irradiated mammalian cells.

Adult↗
PubMed2001

Activity of a nitroxylated analog of daunorubicin, ruboxyl, in B-lymphoproliferative disorders.

A nitroxylated analog of daunorubicin, ruboxyl (RBX), showed low toxicity but significant lympholytic effect in preclinical evaluations. A series of studies in vitro and in animals demonstrate that RBX is a putative agent in the treatment of many neoplasms. We report the results of a study in mice in which RBX showed selective B-lymphocyte immunosuppression. On the basis of this experience, RBX was administered to 3 patients with multiple myeloma and two patients with Waldenström's disease. The results of this pilot clinical study show that this compound has good activity and low myelotoxicity and cardiotoxicity, but seems to be characterized by a threatening immunosuppressive effect.

Aged↗
PubMed2000

Modulation of X-ray-induced damage recognition and repair in ageing human peripheral blood mononuclear cells by an interleukin-6-type cytokine.

We have investigated the effects of an interleukin (IL)-6-type cytokine on the DNA-binding activity of ku and on unscheduled DNA repair in X-ray-treated peripheral blood mononuclear cells (PBMC) from human subjects of different ages. The cytokine used, called K-7/D-6, is an IL-6 variant with increased in vivo and in vitro biological activity compared to the wild type molecule. Ku is the DNA-binding component of the DNA-dependent protein kinase (DNA-PK). It binds the ends of various types of DNA discontinuity and is involved in the repair of DNA breaks caused by V(D)J recombination, isotype switching, physiological oxidation reactions, ionizing radiation and some chemotherapeutic drugs. The ku-dependent repair process, called non-homologous end joining, is the main DNA double strand break repair mechanism in irradiated mammalian cells. Results show that K-7/D-6 significantly increases DNA-binding activity of ku in irradiated PBMC from young but not from elderly subjects. However, K-7/D-6 is able to induce unscheduled DNA repair in irradiated PBMC from both young and elderly subjects. These effects of K-7/D-6 are relevant to the mechanisms of the cellular response to DNA damage.

Adult↗
PubMed2000

Inhibition of IgG1 and IgE production by stimulation of the B cell CTLA-4 receptor.

Although a large amount of information is available on the activity of CTLA-4 in T cells, the role of this receptor in B cells has not been previously characterized. Our results show that CD40 or LPS stimulation in the presence of IL-4 induces CTLA-4 expression in purified B cells; the maximum level is reached in both membrane and intracellular compartments after 48-72 h. Engagement of the B cell CTLA-4 by immobilized mAb inhibits IgG1 and IgE production and reduces the frequency of IgG1- and IgE-expressing B cells. Cepsilon and Cgamma(1) germline mRNA expression as well as NF-kappaB and STAT6 activation, events required for isotype switching, are also inhibited by CTLA-4 engagement. Together these findings show the critical role of CTLA-4 in the control of IL-4-driven isotype switching and suggest new approaches for modulating immediate-type hypersensitivity responses.

Abatacept↗
PubMed2000

Genetics of chemical carcinogenesis: analysis of bidirectional selective breeding inducing maximal resistance or maximal susceptibility to 2-stage skin tumorigenesis in the mouse.

We report on bidirectional selective breeding, initiated from a genetically defined foundation population and carried out to selection limit, for producing lines of mice endowed with maximal resistance (Car-R) or maximal susceptibility (Car-S) to 2-stage skin tumorigenesis. The initial population resulted from a balanced intercrossing of 8 inbred strains of mice. The tumors, induced by a single application of DMBA (initiation) and twice weekly applications of TPA (promotion), were benign papillomas; their number at the end of the promotion period was the phenotype chosen for assortative mating. Afterward, the majority of them regressed while others progressed to malignant carcinomas. The Car-R line was selected through a strong challenge, while the Car-S line selection was based on responses to decreasing concentrations of DMBA and TPA. The selection limit was reached after 14 or 15 generations showing progressive interline divergence, which strongly suggests the interaction of several quantitative trait loci (QTL). The phenotypic difference was extremely large: the tumor response was 73 times higher in Car-S than in Car-R mice, though the applied concentrations of DMBA and TPA were 100 and 40 times lower, respectively. The mean heritability realized during the selective breeding was 0.20 in Car-R and 0.49 in Car-S. Our results are compatible with a minimal QTL estimate of 8 in the Car-R line and of 9 or 10 in the Car-S line. The Car-S line is also much more susceptible to carcinoma induction. An association of coat color with tumorigenesis was observed in interline F2 segregants. The Car-R and Car-S lines, obtained through a long-lasting breeding program, are a unique model for identifying the QTL involved in chemical tumorigenesis and will be provided to interested investigators.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Genetic factors in immunity and aging.

Maximum life span is controlled by genes that regulate molecular mechanisms accounting for the synchrony of structural and functional changes in different cells and tissues of each member of a given species. The role of immune response genes was investigated in aging mice genetically selected for high (H) or low (L) antibody response (Biozzi mice). Results from genetic selection of over 1000 mice showed that genes expressed in the immune system affect life span and diseases. In most cases, the life span is longer in H than in L mice whereas the lymphoma incidence is remarkably higher in L than in H mice. Since DNA repair capacity is a property positively correlated with the maximum life span in several mammalian species, DNA repair was studied by use of hydroxyurea, a cell-synchronizing agent, and found to take place in irradiated human PBMC from young and, to a lesser extent, from adult subjects. Conversely, no repair was detected in irradiated PBMC from elderly subjects. DNA damage recognition and repair pathways involve several nuclear proteins, as double strand breaks are firstly recognized by proteins displaying helicase activity, such as ku 70/80, and then repair is carried out under the control of other proteins. Radiation-induced expression of activated ku(70/80) proteins, in terms of DNA-binding, was found in PBMC from young-adults but not from elderly subjects. Maintenance of DNA integrity is fundamental for normal immune functions, as suggested by the lack of V(D)J recombination in lymphocytes of knock-out mice deficient in ku 70 or ku 80 protein. However, whether the link between genetic factors and life span is mediated by the performance of the immune system remains to be demonstrated.

Adult↗
PubMed2000

Linkage disequilibrium and haplotype mapping of a skin cancer susceptibility locus in outbred mice.

Car-R (carcinogenesis-resistant) and Car-S (carcinogenesis-susceptible) outbred mice, obtained by phenotypic selection from an initial intercross of eight inbred strains, show a >100-fold difference in their susceptibility to two-stage skin tumorigenesis. We found that the lines carry a high degree of genetic polymorphism. with an average heterozygosity of 0.39. This polymorphism allowed the use of linkage disequilibrium (LD) and haplotype analysis for the mapping of a skin cancer modifier locus on Chr 7, in a short region of 6 cM, around the Tyr gene. Car-S mice inherited the susceptibility allele at this locus from the A/J, BALB/c, SJL/J, and SWR/J strains. Our results demonstrate the feasibility and usefulness of mapping disease genes by LD in phenotypically selected, genetically heterogeneous animals.

Animals↗
PubMed2000

Hematopoietic reconstitution after lethal irradiation and bone marrow transplantation: effects of different hematopoietic cytokines on the recovery of thymus, spleen and blood cells.

Lethally irradiated mice were grafted with syngeneic bone marrow cells or left ungrafted. Mice of each group were injected with different hematopoietic cytokines for 5 consecutive days starting immediately after irradiation or left uninjected. The recovery of lymphoid tissues induced by hematopoietic cytokines 7 days after irradiation and bone marrow cell transplantation was comparable to that observed at days 21-28 in irradiated, bone marrow-grafted, but cytokine-uninjected mice. IL-11 or IL-6, in combination with IL-3, was able to hasten thymus, spleen and blood cell numbers and functions. SCF also displayed a detectable effect when used with IL-3. Conversely, the IL-6 superagonist K-7/D-6 was able, when injected alone, to induce significant recovery of thymus, spleen and blood cells. Thus, K-7/D-6 appears to be a most efficient cytokine for fast reconstitution of lymphoid tissues after irradiation and bone marrow transplantation.

Animals↗
PubMed1999

Skin tumorigenesis by initiators and promoters of different chemical structures in lines of mice selectively bred for resistance (Car-r) or susceptibility (Car-s) to two-stage skin carcinogenesis.

Carcinogenesis-resistant (Car-R) and carcinogenesis-susceptible (Car-S) mice were obtained applying a bi-directional selective breeding approach to a two-stage skin carcinogenesis protocol, using 9,10-dimethyl-1,2-benzanthracene (DMBA) as initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoter. Sixteen generations of selection produced a remarkable interline difference in responsiveness to two-stage skin carcinogenesis between Car-R and Car-S: identical DMBA (25 microgram) and TPA (5 microgram) doses induced papillomas in 100% of Car-S compared with 3.3% of Car-R mice and maximal responses of 14.3 or 0.03 papillomas/mouse, respectively, despite the shorter promotion applied to Car-S (49 vs. 208 days). To define the factors determining this great difference, Car-R and Car-S mice were challenged by initiators/promoters chemically unrelated to those used for selection. Both lines were subjected to either initiation by N-methyl-N-nitrosourea (MNU) followed by TPA promotion, or promotion by benzoyl peroxide, or 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) following DMBA initiation. Initiation with MNU induced a 10-fold tumour incidence in Car-S compared with Car-R mice, and a 32-fold difference in tumour induction rate. The 2 lines also differed markedly in susceptibility to benzoyl peroxide promotion: Car-S mice initiated with 25 microgram DMBA and promoted with 7.5 mg benzoyl peroxide showed a 12-fold tumour incidence and a 103-fold tumour induction rate compared with the corresponding Car-R group. Both lines, however, were refractory to chrysarobin promotion. The progression of papillomas to carcinomas was examined in all Car-S groups. The incidence of mice that developed carcinomas was 57% in MNU-initiated mice. Benzoyl peroxide was also able to promote carcinoma development in Car-S mice, though with a lower incidence (30.4%) than TPA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Activation of gp130 signaling in vivo by the IL-6 super-agonist K-7/D-6 accelerates repopulation of lymphoid organs after irradiation.

Stimulation of the gp130 signaling pathway by IL-6 is known to contribute significantly to hematopoietic expansion in vitro, mostly in combination with other cytokines. In the present study we have investigated whether a similar effect can be observed also in vivo using short-term assays in which irradiated mice were analyzed for repopulation of lymphoid organs. Mice were injected with a combination of soluble IL-6Ralpha either with wild-type (wt) human IL-6 or with an IL-6 variant, called K-7/D-6, that shows a 70-fold higher IL-6Ralpha affinity. We observed that while wt IL-6 was able to induce a partial effect only in combination with IL-3, K-7/D-6 bypassed the need for IL-3 and yielded complete recovery. In lethally irradiated mice reconstituted with syngeneic bone marrow cells K-7/D-6 strongly accelerated the repopulation of thymus and spleen and hastened blood neutrophil recovery. These results underscore the potential of the gp130 signaling pathway in hematopoietic reconstitution after myeloablative regimens and open the possibility to fully exploit it with a super-active IL-6 variant.

Animals↗
PubMed1999

Cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibits CD28-induced IkappaBalpha degradation and RelA activation.

Purified CD4+ cells from the spleens of C57BL/6 mice were stimulated with anti-CD3, anti-CD28 and anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibodies. The results show that CTLA-4 stimulation inhibits IL-2 production induced by CD3-CD28 co-stimulation. Since CD3-CD28 co-stimulation induces IkappaBalpha degradation and consequently activates RelA, an NFkappaB family member relevant for the induction of IL-2 mRNA transcription, we tested whether the inhibitory effect of CTLA-4 stimulation interferes with this mechanism. CD3-CD28 co-stimulation was found to induce a drastic decrease in cytoplasmic IkappaBalpha and increase in nuclear RelA. CTLA-4 stimulation abrogates this effect of co-stimulation by increasing the level of cytoplasmic IkappaBalpha and decreasing the nuclear RelA level and DNA-binding activity. In conclusion, our results indicate that the inhibitory effect of CTLA-4 engagement on cytokine production correlates with prevention of IkappaBalpha degradation and inhibition of RelA nuclear translocation.

Abatacept↗
PubMed1999

Effect of age on DNA binding of the ku protein in irradiated human peripheral blood mononuclear cells (PBMC).

DNA binding of the ku protein was investigated in peripheral blood mononuclear cells (PBMC) from 24 subjects of different ages (20-89 years old) displaying age-related changes in DNA repair, mitotic responsiveness, and cytokine production. Ku is an heterodimeric protein composed of two subunits of 70 and 80 kDa, which is involved in the earliest steps of DNA damage recognition. DNA binding of ku 70/80 was found unchanged in normal PBMC from aging subjects but progressively declined in x-ray-irradiated PBMC from young to adult, and elderly subjects. This finding was concomitant with the age-related fall of DNA repair in the whole population.

Adult↗
PubMed1999

Haemopoietic reconstitution after sublethal irradiation: comparison of the effects of different haemopoietic cytokines on murine lymphocytes and bone marrow cells.

Sublethally irradiated mice were injected with recombinant cytokines to stimulate haemopoietic reconstitution. Interleukin (IL)-11 and IL-6 were able to significantly accelerate the recovery of thymus, spleen and bone marrow cells when used in combination with IL-3, but not alone. Stem cell factor (SCF) also displayed detectable effects when used with IL-3. Conversely, the IL-6 superagonist K-7/D-6 was able, even when used alone, to induce recovery of thymus, spleen and bone marrow cells up to the level of unirradiated controls. Together, these results indicate that it is possible to attain complete recovery of lymphoid organs and tissues as early as 7 d after irradiation by use of haemopoietic cytokines.

Animals↗
PubMed1999

Characteristics of gastric-vein lymphocytes with regard to the immune response to Helicobacter pylori.

BACKGROUND: Between peripheral blood and tissue-infiltrating lymphocytes there is an intermediate compartment, the blood of the organ-draining vessels, which could show unusual features. The aim of the present study was to analyse the characteristics of the lymphocytes from the stomach-draining vessels and the cytokine secretion by these lymphocytes. The CagA-mediated lymphocyte activation in Helicobacter pylori-infected subjects and the humoral response to this antigen were evaluated and correlated with clinical data. METHODS: We studied lymphocyte proliferation either with mitogens or with the CagA antigen and cytokine production and IgG anti-CagA by means of an enzyme-linked immunosorbent assay in peripheral blood and gastric-vein blood obtained during surgical intervention. RESULTS: We showed higher proliferative response and cytokine production in lymphocytes from the gastric vein. The mitogenic response to the CagA antigen was highly specific but poorly sensitive for the H. pylori infection in both the compartments. The overall cytokine profile in our patients affected by non-ulcer disease was of the Th0 type. CONCLUSIONS: Gastric-vein-derived lymphocytes seem to show unusual features, as they behave like peripheral blood lymphocytes but show higher responses to all the tested stimuli. It is possible that the interaction of the lymphocytes with the mucosal environment could activate the synthetic mechanisms, making the cells more 'responsive' to the stimulation. The CagA antigen is able to induce a specific T-lymphocyte response and is therefore a valid candidate antigen for the development of a vaccine.

Adult↗
PubMed1999

Neuropeptide Y plasma levels and immunological changes during academic stress.

Academic stress is a good model of psychological stress in humans for studying psychoneuroimmune correlations. We looked for correlations between psychological scores, immune tests and plasma levels of cortisol and neuropeptide Y (NPY). A group of medical students were evaluated at the beginning of the academic year (Baseline) and the day before an examination (Stress). They underwent evaluation by The Profile of Mood States (POMS), The Malaise Inventory, The Self Efficacy Scale and A Global Assessment of Recent Stress (GARS). The lymphocyte subsets, the lymphocyte proliferative response and the cytokine production were also evaluated. We detected modifications of some psychological test scores between the Baseline and Stress evaluation, a significant reduction of lymphocyte proliferation, IL-2 production and percentage of the lymphocyte CD19, and an increase in plasma cortisol levels during stress. The lymphocyte proliferation negatively correlated with the POMS score as well as the percentage of CD16+ cells with NPY plasma levels. NPY levels were not different from Baseline. The emotional and mood states seem to influence immunity. Copyrightz1999S.KargerAG,Basel

Adaptation, Psychological↗