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Biomedical subjects

G Mazzarella

Publications and source records attributed to G Mazzarella.

At least 19 recordsLinked to original sources
PubMed2006

Phase II trial of temozolomide in children with recurrent high-grade glioma.

PURPOSE: The objective of the study was to evaluate the efficacy and toxicity of Temozolomide (TMZ) administered for 5 consecutive days in three daily dosing in children with recurrent or refractory high-grade glioma. PATIENTS AND METHODS: Twenty-four patients with a median age of 10.5 years were enrolled onto this open-label, multicenter, phase II study. The patients were previously treated with surgical resection (17 of 24), radiotherapy (19 of 24) and chemotherapy (18 of 24). Therapy was administered orally three times a day for 5 consecutive days at the dose of 200 mg/m(2)/dx5 for chemotherapy naive patients. In patients heavily pretreated with chemotherapy the starting dose was of 150 mg/m(2)/dx5. RESULTS: A total of 95 cycles were administered. The median progression free-survival (PFS) was 3 months for the entire group while disease stabilization was obtained in 7 patients (29.1%), all with supratentorial tumors. No CR or PR was observed. TMZ treatment showed a limited toxicity. Thrombocytopenia was the most common hematological adverse effect. Our data suggest a marginal activity of TMZ in children with recurrent high-grade glioma.

Adolescent↗
PubMed2005

Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat.

AIMS/HYPOTHESIS: A deranged mucosal immune response and dietary factors may play an important role in the pathogenesis of type 1 diabetes. The aims of our work were to look for the presence of small intestinal enteropathy in non-obese diabetic (NOD) mice in relation to the presence of wheat proteins in the diet, and to assess their role in the risk of developing diabetes. METHODS: Female NOD mice were fed a standard or gluten-free diet or a gluten-free diet with the addition of wheat proteins (MGFD). Small intestine architecture, intraepithelial CD3(+) infiltration, epithelial expression of H2-IA, mRNA for IFN-gamma and IL-4 were assessed. RESULTS: NOD mice fed a standard diet showed reduced villous height, increased intraepithelial infiltration by CD3(+) cells and enhanced expression of H2-IA and IFN-gamma mRNA when compared with mice on the gluten-free diet. The cumulative diabetes incidence at 43 weeks of age was 65% in the latter and 97% in the former (p<0.01). Mice on MGFD also showed increased epithelial infiltration and a higher incidence of diabetes. CONCLUSIONS/INTERPRETATION: Mice fed a wheat-containing diet showed a higher incidence of diabetes, signs of small intestinal enteropathy and higher mucosal levels of proinflammatory cytokines.

Animal Feed↗
PubMed2005

Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa.

BACKGROUND: Enteropathy in coeliac disease (CD) is sustained by a gliadin specific Th1 response. Interleukin (IL)-10 can downregulate Th1 immune responses. AIM: We investigated the ability of recombinant human (rh) IL-10 to suppress gliadin induced Th1 response. PATIENTS AND METHODS: IL-10 RNA transcripts were analysed by competitive reverse transcription-polymerase chain reaction in duodenal biopsies from untreated and treated CD patients, non-coeliac enteropathies (NCE), and controls. CD biopsies were cultured with a peptic-tryptic digest of gliadin with or without rhIL-10. The proportion of CD80+ and CD25+ cells in the lamina propria, epithelial expression of Fas, intraepithelial infiltration of CD3+ cells, as well as cytokine synthesis (interferon gamma (IFN-gamma) and IL-2) were measured. Short term T cell lines (TCLs) obtained from treated CD biopsies cultured with gliadin with or without rhIL-10 were analysed by ELISPOT for gliadin specific production of IFN-gamma. RESULTS: In untreated CD and NCE, IL-10 RNA transcripts were significantly upregulated. In ex vivo organ cultures, rhIL-10 downregulated gliadin induced cytokine synthesis, inhibited intraepithelial migration of CD3+ cells, and reduced the proportion of lamina propria CD25+ and CD80+ cells whereas it did not interfere with epithelial Fas expression. In short term TCLs, rhIL-10 abrogated the IFN-gamma response to gliadin. CONCLUSIONS: rhIL-10 suppresses gliadin specific T cell activation. It may interfere with the antigen presenting capacity of lamina propria mononuclear cells as it reduces the expression of CD80. Interestingly, rhIL-10 also induces a long term hyporesponsiveness of gliadin specific mucosal T cells. These results offer new perspectives for therapeutic strategies in coeliac patients based on immune modulation by IL-10.

Adolescent↗
PubMed2003

T lymphocyte phenotypic profile in lung segments affected by cavitary and non-cavitary tuberculosis.

Clinical manifestations of pulmonary tuberculosis (TB) may depend on a complex interaction between the host and the pathogen. Clinical outcomes of pulmonary tuberculosis are variable, ranging from asymptomatic lifelong infection to parenchymal lung destruction, resulting in cavitary lesions. To investigate the hypothesis that local cellular immune response may affect presentation and outcome in tuberculosis, we performed bronchoalveolar lavage (BAL) in lung segments affected by cavitary and non-cavitary tuberculosis. We then correlated the type of cellular response at the level of the involved lung segments with clinical evolution in terms of cavity formation. We found alveolar lymphocytosis in patients with both cavitary and non-cavitary pulmonary tuberculosis, with increased CD4+ lymphocytes in patients with non-cavitary pulmonary tuberculosis. A predominant Th1 immune response has been observed in non-cavitary patients, while cavitary involved segments exhibit the presence of Th2 lymphocyte subsets. These data, while confirming the importance of Th1-type CD4+ cells and IFN-gamma in effective cellular immunity in active pulmonary tuberculosis, also suggest that the presence of Th2 lymphocytes may contribute to tissue necrosis phenomena associated with cavitary evolution of pulmonary tuberculosis. Our observations indicate the importance of the type of local immune response at the site of disease in the development of different clinical characteristics and outcome in pulmonary tuberculosis.

Adult↗
PubMed2003

An immunodominant DQ8 restricted gliadin peptide activates small intestinal immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients.

BACKGROUND: Studies on intestinal T cell clones from the mucosa of patients with coeliac disease have led to the identification of immunogenic gliadin epitopes. One is HLA-DQ8 restricted, its recognition by T cells being increased by introduction of negatively charged residues operated by tissue transglutaminase. AIM: To test HLA-DQ8 restricted epitope in both native (QYPSGQGSFQPSQQNPQA) and deamidated (QYPSGEGSFQPSQENPQA) forms in an organ culture system of treated coeliac mucosa from HLA-DQ8 positive and HLA-DQ8 negative patients. PATIENTS AND METHODS: Jejunal biopsies obtained from 10 patients with coeliac disease (six HLA-DQ8 positive and four HLA-DQ8 negative) were cultured in vitro with a peptic-tryptic digest (PT) of gliadin, or with the native (peptide A) or deamidated (peptide B) peptide. Intraepithelial CD3(+) and lamina propria total CD25(+) and CD3(+)CD25(+) cells were counted, lamina propria intercellular adhesion molecule 1 (ICAM-1) expression was evaluated, as well as that of Fas molecules on epithelial cells. RESULTS: In HLA-DQ8 positive, but not in HLA-DQ8 negative, coeliacs the density of intraepithelial CD3(+) cells, lamina propria total CD25(+), and CD3(+)CD25(+) cells, as well as expression of ICAM-1 and Fas molecules were significantly increased in biopsies cultured with PT, peptide A, or peptide B compared with biopsies cultured in medium alone. CONCLUSION: These data show that the DQ8 restricted gliadin peptide is immunogenic only in the intestinal mucosa of HLA-DQ8 positive coeliac patients in both native and deamidated forms.

Adolescent↗
PubMed2002

Onset of action following formoterol Turbuhaler and salbutamol pMDI in reversible chronic airway obstruction.

Short-acting beta(2)-agonists are currently recommended for symptom relief in asthma and the treatment of mild, acute exacerbations in COPD. However, formoterol has as fast an onset of action as salbutamol with the additional benefit of longer-lasting bronchodilation (approximately 12 h). Furthermore, systemic side effects observed with formoterol are of a similar duration but less pronounced than with short-acting beta(2)-agonists. In this double-blind, randomized, cross-over study, 20 adult patients with reversible chronic airway obstruction (intrinsic asthma or COPD) inhaled single doses of formoterol 9 microg or salbutamol 100 microg (group A) or formoterol 18 microg or salbutamol 200 microg (group B). FEV(1) was measured prior to and 5, 10, 15, 20, 25 and 30 min following inhalation of study drug. No significant differences in FEV(1) values were observed between group A (P=0.704) or group B (P=0.270) at baseline, or at 5 (Group A: P=0.340; Group B: P=0.559) and 15 min (Group A: P=0.526; Group B: P=0.818) post dose. No adverse events were reported during the study. Formoterol Turbuhaler has as rapid an onset of action as salbutamol pMDI when given at the recommended doses.

Adult↗
PubMed2001

Keratinocyte growth factor and coeliac disease.

BACKGROUND: Coeliac disease is characterised by increased epithelial renewal associated with a mucosal T cell response to gliadin. Keratinocyte growth factor (KGF) is produced by cytokine activated gut stromal cells and may be a link between mucosal T cell activation in untreated coeliac disease and epithelial hyperplasia. AIMS: To characterise expression of KGF in coeliac disease. METHODS: KGF transcripts in coeliac disease were measured by quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) and localised using in situ hybridisation. KGF production by gluten reactive CD4+ T cell clones was examined. In addition, KGF transcripts were measured following ex vivo challenge of coeliac biopsies with a peptic-tryptic digest of gliadin. RESULTS: KGF transcripts were elevated in coeliac biopsies compared with normal controls but were not different from non-coeliac disease controls. By in situ hybridisation, KGF mRNA containing cells were present in the upper half of the lamina propria, most abundantly just under the epithelium. There was no signal from cells within the epithelium. Gluten reactive T cell clones did not make KGF. In vitro challenge of coeliac biopsies generated a strong interferon gamma response but a specific KGF response could not be detected because of an extremely high number of KGF transcripts in all cultured biopsies. CONCLUSIONS: KGF is overexpressed in coeliac biopsies and in tissues with non-coeliac enteropathy. No evidence was found for KGF production by intraepithelial lymphocytes or lamina propria T cells.

Adolescent↗
PubMed2000

Arachidonic acid metabolism in inflammatory cells of patients with bronchial asthma.

Over the last few years, the demonstration of beneficial effects of leukotriene receptor antagonists in various forms of asthma has renewed clinical and pharmacologic interest in this class of lipid mediators. Several studies demonstrated an increased biosynthesis of cysteinyl leukotrienes (CysLT) in asthmatic patients. However, the reasons for the dysregulated production of CysLTs in asthmatic patients are not completely defined. An improved method of lipid mediator detection and the availability of cells isolated from human airways (by bronchoalveolar lavage [BAL] and bronchial biopsies) have allowed initial studies to address this issue. Eosinophils retrieved from inflamed airways of asthmatics have a larger arachidonic acid (AA) content than their blood counterpart. The high level of AA in these cells is primarily due to a remodeling of endogenous arachidonate pools with the accumulation of this fatty acid in a triglyceride-associated pool. In addition, elevated levels of a secretory form of phospholipase A2, the key enzyme initiating the cascade of CysLTs, are found in the BAL of asthmatics. Finally, eosinophils isolated from the BAL of asthmatics have an increased expression of LTC4 synthase. The level of expression of this enzyme correlates with the increased amount of CysLTs produced in the airways of these patients. Taken together, these data identify at least two possible mechanisms to explain the excessive CysLT production in asthmatics: 1) an increased content of AA in the glycerolipid pools of inflammatory cells 2) an enhanced activity of key biosynthetic enzymes involved in CysLT synthesis.

Arachidonic Acid↗
PubMed2000

Phenotypic features of alveolar monocytes/macrophages and IL-8 gene activation by IL-1 and TNF-alpha in asthmatic patients.

The alveolar macrophage (AM), a major defense cell in the lung, participates in immune and inflammatory reactions through the release of several regulatory and chemotactic cytokines. In particular, macrophages are considered to play a pivotal proinflammatory role in the production and maintenance of airway inflammation and bronchial hyperreactivity. To assess the phenotypic pattern of AM from asthmatic subjects, we performed the following experiments: 1) cytofluorometric analysis of specific phenotypic features (CD11b, CD14, CD16, CD45, HLA-DR, CD71, CD95, and CD44) 2) assessment of the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and the chemotactic regulatory cytokine IL-8 by unstimulated and lipopolysaccharide-stimulated AM. In these patients, we phenotypically characterized the AM, showing their strong proinflammatory activity also in patients with mild asthma. Their activity has been clarified by our biomolecular data that showed a constitutive basal IL-8 production by AM, and also indicated that IL-1 and TNF-alpha were able to upregulate the ability of activated human AM to produce IL-8 at the protein and messenger ribonucleic acid (mRNA) levels.

Asthma↗
PubMed2000

Respiratory infections and asthma.

Clinical and experimental evidence suggests an important role for respiratory infections in the development of asthma attacks. Viral upper respiratory infections have been associated with 80% of asthma exacerbations in children and 50% of all asthma episodes in adults. Human rhinovirus has been implicated as the principal virus associated with asthma episodes. Separate studies indicate that atypical bacteria such as Chlamydia pneumoniae and Mycoplasma pneumoniae may precipitate asthma symptoms. Although not completely clarified, the intricate pathogenetic mechanisms by which viral infections promote asthma attacks have been extensively investigated in recent years. By contrast, it has not yet been established whether atypical bacterial infections are an epiphenomenon or a pathogenic event in asthma.

Asthma↗
PubMed2000

Mechanisms involved in airway obstruction: the role of smooth muscle.

Structural changes in the airway walls that are probably driven by mediators released as a consequence of chronic allergic inflammation are prominent features of asthma. However, it is not clear how each of the many changes that occur in the airway wall contribute to altered airway function in asthma. Collagen deposition in the subepithelial matrix, around and inside the smooth muscle, would be expected to oppose the effect of smooth-muscle contraction. Conversely, geometric factors would result in exaggerated airway narrowing for a given degree of smooth-muscle shortening; decreased airway wall stiffness and increased airway narrowing for a given amount of force generated by the smooth muscle. Degradation of the matrix may alter the coupling between muscle and lung recoil, allowing exaggerated smooth-muscle shortening. Increase in muscle mass associated with preservation of its contractile capacity could be the most important contributor to exaggerated airway narrowing.

Airway Obstruction↗
PubMed2000

Use of altered peptide ligands to modulate immune responses as a possible immunotherapy for allergies.

Allergies are dramatically increasing in prevalence, and the management of these diseases is a heavy burden on the health-care systems of developed countries. In recent years, many efforts have been made to improve the therapy of allergies and to develop new approaches for immunotherapy. Here we briefly review the use of peptides to modulate T-cell responses to allergens. We focus mainly on the possibility of using altered peptide ligands (APLs), i.e., peptides tailored on immunodominant T epitopes and bearing a single amino-acid substitution, as a tool to modulate immune responses to allergens. These peptides may be recognized by the specific T cells triggered by the agonist peptides, but they are unable to elicit T-cell responses; thus, they could be ideal candidates to modulate immune responses to allergens. The availability of these peptides could allow new approaches for immunotherapies.

Animals↗
PubMed2000

New perspectives in asthma treatment.

The recent advances in the knowledge of the basic mechanisms underlying asthmatic inflammation have significantly contributed to the delineation of new therapeutic perspectives for asthma. There are currently three main approaches to the development of novel antiasthma treatments: 1) improvement in existing classes of drugs 2) identification of new compounds able to interfere with the complex network of proinflammatory mediators, cytokines, chemokines, and adhesion molecules involved in the pathogenesis of asthma 3) utilization of new forms of immunotherapy aimed at blocking the unbalanced Th2 response which characterizes the pathophysiology of asthma. Such a remarkable expansion in available therapeutic options will probably allow us, over the next decade, to treat asthma by more selectively targeting the pathogenetic events responsible for this widespread airway disease.

Anti-Asthmatic Agents↗
PubMed2000

Th1/Th2 lymphocyte polarization in asthma.

Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Inflammation in asthma consists of airway infiltration by mast cells, lymphocytes, and eosinophils. There is accumulating evidence that CD4+ lymphocytes with a Th2-cytokine pattern play a pivotal role in the pathogenesis of asthma. These cells orchestrate the recruitment and activation of the primary effector cells of the allergic response (mast cells and eosinophils), through the release of cytokines such as IL-4, IL-5, and IL-13. Allergic inflammation is also implicated in airway epithelium changes, although the mechanisms by which inflammatory cells and, in particular, T cells interact with the epithelium are not completely clarified. This paper explores the role of T cells in the allergic inflammation of asthma.

Asthma↗
PubMed2000

Role of endogenous nitric oxide in asthma.

Endogenous nitric oxide (NO) is an ubiquitous signaling molecule with important regulatory functions such as regulation of blood pressure, neurotransmission, and host and immune defense. In the respiratory tract, NO is formed and released by various sources including endothelial and epithelial cells, nerves, airway smooth muscle, and inflammatory cells. Recent evidence suggests that endogenous NO is the neurotransmitter of the nonadrenergic noncholinergic inhibitory (iNANC) system, the only bronchorelaxant neural pathway of human airways. A number of studies also suggest that in some species epithelium-derived NO accounts for the functional bronchoprotective role of the so-called epithelium-derived relaxing factor. In human airways, endogenous NO counteracts the bronchoconstriction induced by pharmacologic stimuli such as bradykinin, histamine, and methacholine. On the basis of these and other observations, it is suggested that a reduced synthesis and/or activity of endogenous NO may contribute to the pathogenesis of airway hyperresponsiveness that characterizes asthma and other respiratory disorders. This short paper summarizes the activities of endogenous NO in the airways of experimental animals and man, and discusses the evidence supporting the view that NO confers bronchoprotection.

Animals↗
PubMed2000

Tissue transglutaminase is the target in both rodent and primate tissues for celiac disease-specific autoantibodies.

BACKGROUND: Endomysial antibodies have recently been shown to react with tissue transglutaminase. This study was undertaken to investigate whether the tissue distribution of transglutaminase is also compatible with reticulin, jejunal, and fibroblast autoantibody binding patterns. METHODS: Sera from patients with and without celiac disease, monoclonal tissue transglutaminase antibodies, and sera from mice parenterally immunized against commercially available tissue transglutaminase, transglutaminase complexed with gliadin, or gliadin were used in indirect immunofluorescence and double-staining studies using both rodent and primate tissues as substrates. Also, antibody competition, affinity chromatography, and potassium thiocyanate extraction studies were undertaken. RESULTS: Tissue transglutaminase antibody binding patterns were identical with the extracellular binding patterns seen with celiac patient sera. Human umbilical cord-derived fibroblasts exhibited both cytoplasmic and extracellular matrix staining. Double staining with patients' sera and tissue transglutaminase antibodies showed complete overlapping. Tissue transglutaminase effectively absorbed reticulin-endomysial antibodies from celiac sera, and patients' sera blocked the staining of the monoclonal tissue transglutaminase antibodies. Potassium thiocyanate extraction abolished the staining patterns, but they were elicited again after readdition of tissue transglutaminase. CONCLUSIONS: Reticulin, endomysial, and jejunal antibodies detect transglutaminase in both rodent and primate tissues, indicating that these tissue autoantibodies are identical.

Animals↗