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Biomedical subjects

D Cataldo

Publications and source records attributed to D Cataldo.

At least 19 recordsLinked to original sources
PubMed2006

Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC).

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS) motifs in their C-terminal domain. The aim of this work was to evaluate the expression pattern of ADAMs and ADAMTS in non small cell lung carcinomas (NSCLC) and to investigate the possible correlation between their expression and cancer progression. Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemical analyses were performed on NSCLC samples and corresponding nondiseased tissue fragments. Among the ADAMs evaluated (ADAM-8, -9, -10, -12, -15, -17, ADAMTS-1, TS-2 and TS-12), a modulation of ADAM-12 and ADAMTS-1 mRNA expression was observed. Amounts of ADAM-12 mRNA transcripts were increased in tumour tissues as compared to the corresponding controls. In sharp contrast, ADAMTS-1 mRNA levels were significantly lower in tumour tissues when compared to corresponding nondiseased lung. These results were corroborated at the protein level by Western blot and immunohistochemistry. A positive correlation was observed between the mRNA levels of ADAM-12 and those of two vascular endothelial growth factor (VEGF)-A isoforms (VEGF-A(165) and VEGF-A(121)). Taken together, these results providing evidence for an overexpression of ADAM-12 and a lower expression of ADAMTS-1 in non-small-cell lung cancer suggest that these proteases play different functions in cancer progression.

ADAM Proteins↗
PubMed2005

Elevated MMP-12 protein levels in induced sputum from patients with COPD.

BACKGROUND: Several matrix metalloproteinases (MMPs) are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). In mice, MMP-12 plays a crucial role in the development of cigarette smoke induced emphysema. A study was undertaken to investigate the role of MMP-12 in the development of COPD in human smokers. METHODS: Induced sputum samples were collected from patients with stable COPD (n = 28), healthy smokers (n = 14), never smokers (n = 20), and former smokers (n = 14). MMP-12 protein levels in induced sputum were determined by ELISA and compared between the four study groups. MMP-12 enzymatic activity in induced sputum was evaluated by casein zymography and by cleaving of a fluorescence quenched substrate. RESULTS: Median (IQR) MMP-12 levels were significantly higher in COPD patients than in healthy smokers, never smokers, and former smokers (17.5 (7.1-42.1) v 6.7 (3.9-10.4) v 4.2 (2.4-11.3) v 6.1 (4.5-7.6) ng/ml, p = 0.0002). MMP-12 enzymatic activity was significantly higher in patients with COPD than in controls (4.11 (1.4-8.0) v 0.14 (0.1-0.2) microg/microl, p = 0.0002). CONCLUSION: MMP-12 is markedly increased in induced sputum from patients with stable COPD compared with controls, suggesting a role for MMP-12 in the development of COPD in smokers.

Aged↗
PubMed2005

Automated method for the determination of a new matrix metalloproteinase inhibitor in ovine plasma and serum by coupling of restricted access material for on-line sample clean-up to liquid chromatography.

A fully automated liquid chromatographic method was developed for the determination of Ro 28-2653, a new synthetic inhibitor of matrix metalloproteinases (MMPs), in ovine serum and plasma. The method was based on the coupling of a pre-column packed with restricted access material, namely LiChrospher RP-8 ADS (alkyl diol silica), for sample clean-up to an analytical column containing octyl silica stationary phase. One hundred microl of biological sample, to which 2-propanol was automatically added, were injected onto the ADS pre-column, which was then washed with a washing liquid consisting of a mixture of 25 mM phosphate buffer (pH 7.0) and acetonitrile (90:10; v/v) for 10 min. By rotation of the switching valve, the analyte was then eluted in the back-flush mode with the LC mobile phase composed of a mixture of acetonitrile and 25 mM phosphate buffer (pH 7.0) (57:43; v/v). The UV detection was performed at 395 nm. The main parameters likely to influence the sample preparation technique were investigated. The method was then validated over a concentration range from 17.5 to 1950 ng/ml, the first concentration level corresponding to the lower limit of quantitation. At this concentration level, the mean bias and the R.S.D. value for intermediate precision were -2.4% and 4.2%, respectively.

Animals↗
PubMed2004

Cyclodextrins as a potential carrier in drug nebulization.

The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the feasibility of using different cyclodextrins (CDs) to elaborate pharmaceutical formulations for the inhalation route and tested the short-term toxicity of such formulations administered by inhalation to C57BL/6 mice. We have shown that HP-beta-CD, gamma-CD, as well as RAMEB aqueous solutions can undergo aerosolization and that the resulting droplet-size ranges are compatible with pulmonary deposition. In vivo, we have demonstrated that short-term exposure to inhaled HP-beta-CD, gamma-CD and RAMEB solutions are non-toxic after assessing bronchoalveolar lavage (BAL), lung and kidney histology, bronchial responsiveness to methacholine and blood urea. The only change noted is a slight increase in lymphocyte count in the BAL after HP-beta-CD and gamma-CD inhalation. We conclude that CDs are useful in significantly enhancing the solubility of apolar drugs with a view to inhalation therapy although an increase in lymphocyte counts in the BAL after CDs inhalations needs further investigations.

Administration, Inhalation↗
PubMed2004

Membrane associated proteases and their inhibitors in tumour angiogenesis.

Cell surface proteolysis is an important mechanism for generating biologically active proteins that mediate a range of cellular functions and contribute to biological processes such as angiogenesis. Although most studies have focused on the plasminogen system and matrix metalloproteinases (MMPs), recently there has been an increase in the identification of membrane associated proteases, including serine proteases, ADAMs, and membrane-type MMPs (MT-MMPs). Normally, protease activity is tightly controlled by tissue inhibitors of MMPs (TIMPs) and plasminogen activator inhibitors (PAIs). The balance between active proteases and inhibitors is thought to determine the occurrence of proteolysis in vivo. High concentrations of proteolytic system components correlate with poor prognosis in many cancers. Paradoxically, high (not low) PAI-1 or TIMP concentrations predict poor survival in patients with various cancers. Recent observations indicate a much more complex role for protease inhibitors in tumour progression and angiogenesis than initially expected. As knowledge in the field of protease biology has improved, the unforeseen complexities of cell associated enzymes and their interaction with physiological inhibitors have emerged, often revealing unexpected mechanisms of action.

Cell Membrane↗
PubMed2003

[Value of induced sputum in the investigation of asthma].

INTRODUCTION: The technique of induced expectoration generates sputum by the inhalation of hypertonic saline. On account of its non-invasive character, its simplicity, its relative harmlessness, its cost effectiveness and its reproducibility this technique, that appeared in the early 1990's, has rapidly established itself as the technique of choice in the investigation of bronchial inflammation in asthma. STATE OF THE ART: We present the results of our studies that have contributed to the validation of the technique at the methodological level and to the exploitation of the cellular contents as much as the fluid phase of the expectorations in characterising bronchial inflammation in asthmatics. Our results confirm an infiltration of the airways of asthmatics with eosinophils that appears to be proportional to the severity of the illness. We evaluate the effect of inhaled steroids and of theophylline on sputum eosinophilia and bronchial reactivity and discuss the role of eosinophils on bronchial hyperreactivity. Finally we discuss the use of induced expectoration in clinical practice in asthma. PERSPECTIVES: The analysis of induced sputum could well become a valuable tool in the clinical evaluation and monitoring of asthma in the same way as symptoms and abnormalities of lung function. CONCLUSIONS: Induced expectoration has certainly contributed to the understanding of the cellular and molecular mechanisms of asthma as well as the role of bronchial inflammation in the clinical manifestations of the disease.

Asthma↗
PubMed2002

Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness.

BACKGROUND: Although airway eosinophilia is seen as a cardinal feature of asthma, data eosinophilia are still lacking on the proportion of the asthma group exhibiting raised airway eosinophilia. This study aimed to assess the distribution of sputum eosinophil count and its relationship with methacholine bronchial hyperresponsiveness in mild to moderate steroid-naive asthmatic people. METHODS: Sputum was induced by inhalation of hypertonic saline (NaCl 4.5%) in 118 mild to moderate steroid-naive asthmatic people consecutively recruited from our outpatient clinic, and in 44 healthy people. The asthma group was selected on the basis of an forced expiratory volume in 1 s (FEV(1)) of > or = 70% predicted, and a provocative methacholine concentration causing a fall of 20% in FEV(1) (PC20 methacholine; PC(20)M) < or = 16 mg/ml. RESULTS: In the asthma group, the median (range) of the percentage and the absolute values of sputum eosinophils were 4.8% (0-75) and 38 10(3)/g (0-14,191), respectively, vs 0% (0-2.3) (P < 0.001) and 0 10(3)/g (0-53) (P < 0.001) in healthy participants. Based on the 95% percentile for normal values calculated from our healthy group, 69% of the asthma group had significantly raised sputum eosinophil count (that is > 2%). In the asthma group, multiple regression analysis followed by a stepwise procedure revealed that sputum eosinophil count was significantly and inversely associated with PC(20)M accounting for 16% of its total variance (P < 0.001) while neutrophil counts positively related to PC(20)M accounting for 4% of total variance (P < 0.05). By contrast, no significant relationship was found between either eosinophil or neutrophil counts and the slope of forced vital capacity (FVC) vs FEV(1) from the methacholine challenge. CONCLUSIONS: We conclude that two-thirds of people in the mild to moderate asthma group had increased sputum eosinophilia, which plays a limited role in determining the degree of methacholine airway hyperresponsiveness.

Adult↗
PubMed2002

Evidence of mast-cell activation in a subset of patients with eosinophilic chronic obstructive pulmonary disease.

Although asthma has been viewed mainly as an eosinophilic disease, and chronic obstructive pulmonary disease (COPD) as a neutrophilic disease, recent studies have shown increased neutrophil counts in severe asthma and sputum eosinophilia in some COPD patients. In an attempt to further characterise these two syndromes according to pathology, the current authors have conducted a study of induced sputum in 15 subjects with COPD, 17 asthmatics, and 17 nonatopic healthy individuals. Sputum was analysed for cytology and levels of eosinophil cationic protein (ECP), albumin, tryptase and soluble intercellular adhesion molecule-1. The COPD subjects differed from the asthmatics as they had higher sputum neutrophil and lower columnar epithelial cell counts, but there were no differences in any soluble marker studied. When compared to control subjects, both the asthmatic and COPD subjects had raised eosinophil counts and ECP levels. In a subset of COPD subjects with sputum eosinophilia (>3% of total cells), significantly increased levels of tryptase were detected. In conclusion, although chronic obstructive pulmonary disease is a more neutrophilic disease than asthma, the two diseases are difficult to distinguish on the basis of sputum levels of the soluble markers traditionally associated with asthma. However, a subset of patients with chronic obstructive pulmonary disease with airway eosinophilia and mast-cell activation might represent a distinct pathological phenotype.

Adult↗
PubMed2001

Environmental toxicity assessment in the Paraná river delta (Argentina): simultaneous evaluation of selected pollutants and mortality rates of Corbicula fluminea (Bivalvia) early juveniles.

Water and sediment samples were collected in the lower Paraná delta at four sites with different levels of exposure to pollution to evaluate the anthropogenic impact through chemical analyses and mortality bioassays. Individual polychlorinated biphenyls, chlorinated pesticides, aliphatic hydrocarbons, polycyclic aromatic hydrocarbons, and heavy metals were measured in waters, porewaters and sediments. The same three phases were also subjected to toxicity assays with straight-hinged juveniles of Corbicula fluminea. Concentrations of several pollutants were above levels recommended for the protection of aquatic life: in waters, Zn, Cu and Cr were 1.6-4.9 times higher, whereas in the sediments Cr was 1.8-3.6, and benzo(a)pyrene was 2.8-5.6 times higher. Pollutant concentrations followed a clear geographic pattern with highest values in the densely populated area of the Reconquista and Luján rivers, lower levels in the San Antonio, and lowest loadings in the remote Paraná de las Palmas. This gradient was adequately matched by the pattern of mortality rates of C. fluminea early juveniles, which were highest in the Reconquista-Luján (40-93%) and lowest (and not significantly different from the control) in the Paraná (3.3-23%). Mortality rates also increased from surface waters (3.3-53%), to porewaters (12-73%), to sediments (23-93%). Although toxicity was probably mainly due to dissolved contaminants, agreement between chemical and biological evidence of pollution was best for the sediment compartment, whereas porewater and surface water showed a higher degree of variability.

Animals↗
PubMed2001

Matrix metalloproteinases and TIMP-1 production by peripheral blood granulocytes from COPD patients and asthmatics.

Both asthmatic and COPD patients were found to have increased amounts of granulocytes and matrix metalloproteinase-9 (MMP-9) in their sputum. The present study was conducted to investigate whether the elevated amounts of MMP-9 and TIMP-1 found in such patients' airways may be linked to an enhanced secretion by granulocytes. Blood granulocytes from asthmatics (n = 10), COPD patients (n = 11), and healthy controls (n = 11) were isolated and cultured under basal conditions or after stimulation by phorbol 12-myristate 13-acetate (PMA) or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). MMP-9 activity was detected by zymography while MMP-8 and TIMP-1 levels were measured by ELISA. In zymography, pro- and activated forms of MMP-9 were present in each group (healthy subjects, asthmatics, and COPD patients). Spontaneous release was not different between the three groups. Stimulation by fMLP and PMA increased to a similar extent the release of MMP-9 by granulocytes in all the three groups. TIMP-1 levels were also increased after stimulation by PMA and fMLP only in healthy subjects and COPD patients. MMP-8 levels were barely detectable. We conclude that circulating granulocytes from COPD patients and asthmatics do not display an abnormal secretion of MMP-9, and that granulocytes from asthmatics have an impaired ability to release TIMP-1 upon stimulation.

Adult↗
PubMed2001

Induced sputum: comparison between isotonic and hypertonic saline solution inhalation in patients with asthma.

BACKGROUND: Sputum induction by hypertonic saline solution inhalation is widely used to study airways secretions in patients with asthma. However, hypertonic saline solution is a potent indirect bronchoconstrictor. STUDY OBJECTIVES: We studied the validity of isotonic saline solution (0.9%) inhalation as a means to induce sputum by comparing it to hypertonic saline solution (4.5%) inhalation. PATIENTS: Sixteen patients with moderate-to-severe asthma reporting a clinical history of mucus hypersecretion. METHODS: Subjects underwent sputum induction twice at 1-week intervals. Saline solution (hypertonic or isotonic) was inhaled for three periods of 5 min. The parameters assessed in sputum samples were cell counts, sodium, eosinophil cationic protein (ECP), and albumin concentrations, osmolality, and pro-matrix metalloproteinase (MMP)-9 activity by zymography. RESULTS: The maximal fall in peak expiratory flow during sputum induction was greater after inhalation of hypertonic saline solution than after inhalation of isotonic saline solution (p < 0.01). Each subject produced analyzable sputum on both visits. There were no statistically significant differences in total and differential sputum cell counts, and the reproducibility coefficients were high for eosinophils and neutrophils when comparing the two methods. Likewise, sputum levels of ECP and albumin as well as sputum pro-MMP-9 activity were not different between the two methods, and were highly reproducible as shown by high intraclass coefficients (Ri) of correlation (0.72, 0.74, and 0.77 for ECP, albumin, and pro-MMP-9, respectively). Sputum sodium concentrations and osmolality were higher after inhalation of hypertonic saline solution (p < 0.05). CONCLUSION: In patients with moderate-to-severe asthma reporting a clinical history of mucus hypersecretion, inducing sputum by isotonic or hypertonic saline solution inhalation leads to comparable results in eosinophil and neutrophil cell counts and fluid phase mediators/proteins.

Administration, Inhalation↗
PubMed2000

Effect of a 4-week treatment with theophylline on sputum eosinophilia and sputum eosinophil chemotactic activity in steroid-naive asthmatics.

BACKGROUND: The precise mechanism of action of theophylline in asthma is not fully understood but recent data have drawn attention to its potential anti-inflammatory effect. OBJECTIVE: The purpose of this study was to assess the effect of theophylline on sputum eosinophilia and sputum eosinophil chemotactic activity in steroid-naive asthmatics. METHOD: We performed a 4-week randomized double-blind, placebo-controlled, parallel group study in 21 mild to moderate steroid-naive asthmatics whose sputum eosinophilia was found twice > 5% during the run in period. Eleven subjects received 600 mg/24 h theophylline for the first 2 weeks and 900 mg/24 h for the last 2 weeks while 10 subjects took a placebo for 4 weeks. Sputum was induced after 2 and 4 weeks of treatment and 1 week after stopping the treatment. The sputum samples were compared for their cell counts, eosinophil cationic protein (ECP) levels and eosinophil chemotactic activity using micro-Boyden chambers. RESULTS: Serum theophylline concentrations reached 7 and 11 microg/mL at V3 and V4, respectively. Intragroup comparisons showed that theophylline, but not placebo, caused a significant reduction in sputum eosinophil counts at V3 (62 +/- 10% from baseline, P < 0.01) and a strong trend at V4 (67 +/- 16% from baseline, P = 0.07) when compared to baseline. The intergroup difference obtained after comparing the area under the curve over the 4 week treatment period only approached the statistical significance (P = 0.08). At baseline the fluid phase of the sputum contained a significant eosinophil chemotactic activity which was inhibited after a 4-week treatment by theophylline (P < 0. 01) but not by placebo. The mean sputum theophylline levels after 4 weeks of treament (1.7 microg/mL) was lower than that required to cause significant inhibition of eosinophil chemotaxis in vitro. CONCLUSION: Theophylline decreases the natural sputum eosinophil chemotactic activity present in asthmatics. However, when using a small sample size, the 35% reduction in sputum eosinophilia achieved by theophylline failed to reach statistical significance when compared to that seen after placebo.

Administration, Oral↗
PubMed2000

MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease.

BACKGROUND: The course of asthma and chronic obstructive pulmonary disease (COPD) is associated with bronchial morphological changes. Metalloproteinases are thought to play a role in these structural changes. METHODS: We studied the gelatinolytic activity present in the induced sputum from 20 patients with asthma, 20 with COPD and 19 healthy controls. The assessment of gelatinolytic activity was performed by quantitative zymography, and gelatinolytic species were identified by Western blot analysis. Tissue inhibitor of metalloproteinase-1 (TIMP-1) was detected by reverse zymography and ELISA. RESULTS: From zymography, we found significantly higher gelatinolytic activity linked to pro-matrix metalloproteinase-9 (pro-MMP-9) in the sputum from asthmatics (p < 0.0001) and COPD patients (p < 0.0001) compared to the control group. Furthermore, the activated form of MMP-9 (85 kD) was found in the sputum from 60% of asthmatics and 85% of COPD patients, but was absent in that of control subjects (p < 0.0001). Importantly, although less frequently detectable than pro-MMP-9, pro- MMP-2 (72 kD) was found more frequently in asthmatics (50%) than in control subjects (5%) (p < 0. 005). We also described two unusual gelatinolytic species of 45 and 120 kD and showed that they derived from MMP-9 according to their ability to bind gelatin and anti-MMP-9 antibody. Levels of TIMP-1 were higher in asthmatics (p < 0.05) and COPD patients (p < 0.05) than in controls. CONCLUSION: Asthmatics and COPD patients display an increased gelatinolytic activity linked to MMP-2 and MMP-9 and higher levels of TIMP-1 in their sputum.

Adult↗
PubMed2000

[Bronchial morphologic modification in asthma].

Asthma is an inflammatory disease of the airways clinically characterised by recurrent bronchial obstructions at least partially reversible. Recent epidemiologic data suggest that asthmatics have an increased rate of decrease of their expiratory volumes during life. This irreversible lung function impairment is associated with fundamental structural changes of the bronchial wall in terms of conjunctive tissue and smooth muscle composition. We describe these changes and explore the different mechanisms proposed to explain these structural modifications. We also review their consequences in terms of bronchial physiology and their potential influence on bronchial hyperresponsiveness.

Asthma↗
PubMed1999

Airway mast-cell activation in asthmatics is associated with selective sputum eosinophilia.

BACKGROUND: Tryptase is a serine endoprotease selectively released from mast cells. Although mast cells are known to be activated after experimental allergic provocation, their role in naturally occurring asthma is still debated. METHODS: We have investigated the levels of tryptase in the whole induced sputum collected from 51 asthmatics (31 atopic and 20 intrinsic) seen in our outpatient clinic and 22 normal nonatopic healthy volunteers. Tryptase was measured by a new immunoassay based on B12 monoclonal antibody recognition of total tryptase (UniCAP System, Pharmacia) with a sensitivity of 1 ng/ml. RESULTS: While being below the threshold of detection in all normal volunteers, tryptase was detectable in the sputum from 9/51 asthmatics (18%) including five atopic and four intrinsic asthma cases. In these patients, among whom three were asymptomatic asthmatics, the values ranged between 1 and 6.1 ng/ml. The asthmatics with detectable sputum tryptase had greater sputum eosinophil counts (P<0.05) but lower neutrophil counts (P<0.05) than those in whom tryptase was undetectable. When compared to control subjects, asthmatics without tryptase had still greater eosinophil counts (P<0.0001) but also raised neutrophil counts (P<0.05). No significant difference could be found between asthmatics with tryptase and those without tryptase with respect to the age, the baseline lung function, the methacholine bronchial responsiveness, and the frequency of treatment with inhaled steroids. CONCLUSIONS: With the UniCAP System, tryptase was detectable in the sputum from 18% of asthmatics irrespective of atopy and current symptoms. Asthmatics with tryptase appeared to have a selective increase in sputum eosinophil counts while those without tryptase displayed a mixed sputum granulocyte infiltration with raised eosinophil and neutrophil counts.

Adolescent↗
PubMed1999

[Clinical case of the month. A case of acute rhabdomyolysis].

A 83 years old patient was admitted with a complex clinical picture including cutaneous rash, muscular pain, rhabdomyolysis and renal failure. The clinical picture suggests a dermatopolymyositis. Despite of high dose corticotherapy, the patient died on day 22. The anatomical examination shows a cholangiocarcinoma disseminated locally as well as in the lungs and bones.

Acute Disease↗
PubMed1999

The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders.

UNLABELLED: H. pylori infection is putatively associated with extra-digestive disorders and may also play a role in the development of autoimmune thyroid diseases (ATD). It was recently found that monoclonal antibodies to an H. pylori strain with cagA-positivity reacted with follicular cells of the thyroid gland, and that an H. pylori organism possessing the cag pathogenicity island carried a gene encoding for an endogenous peroxidase. The aims of this study was (1); To ascertain whether the infection by strains endowed with an increased inflammatory potential (those expressing CagA) could further enhance the risk of developing ATD (2); To verify the possible existence of an immune cross-reactivity between autoantibodies to peroxidase and thyroglobulin and H. pylori antigens (3). To establish whether thyroid colloid antigens could cross-react with an anti-H. pylori serum. The study was partly designed retrospectively. We examined 41 consecutive women with ATD, and, as a control, 33 consecutive age- and socio-economic class-matched women without autoimmune thyroid disorders, living in the same area as patients, occurred at the same institution in the same period (six months). Both patients and controls were examined serologically for H. pylori infection and CagA status by Western blotting. Some serum samples were absorbed with H. pylori to determine whether the antibody levels decreased. Colloid proteins were resolved electrophoretically and matched with a hyperimmune serum raised in rabbits against a CagA-positive H. pylori. Thirty-two patients (78.0%) tested seropositive for H. pylori infection, vs. 16 controls (48.4%) (P = 0.008, OR = 3.78, RR = 1.61). The prevalence of anti-CagA antibodies was 71.8% in infected patients, and 50% in infected controls (P = 0.161, n.s.). The overall prevalence of infection by CagA-positive H. pylori was significantly higher in patients with ATD (23/41, or 56.0%) than that in controls (8/33, or 24.2%) (P = 0.006, OR = 3.99, RR = 2.31). The other tests gave negative or inexplicable results. IN CONCLUSION: CagA-positive H. pylori infection increases the risk of ATD development.

Adolescent↗