Activation of protease-activated receptor-2 reduces airways inflammation in experimental allergic asthma.

BACKGROUND: Proteinase-activated receptors (PAR)-2 are members of the family of G-protein-coupled receptors activated by proteases. These receptors are widely expressed in several tissues and in virtually all cells involved in rhinitis and asthma. In particular, proteinases activating PAR-2 may affect airway functions and play a role in human diseases. OBJECTIVE: Assessment of the role of PAR-2 in bronchoconstriction, airway responsiveness and immune response after allergic challenge, in rabbits sensitized to Par j 1, the major allergen of Parietaria judaica pollen. METHODS: Evaluation of antigen challenge in rabbits treated with PAR-2-activating peptide (PAR-2AP) (SLIGRL) or the scrambled peptide LSIGRL or vehicle immediately before allergen exposure measuring airway responsiveness. Characterization of bronchoalveolar lavage (BAL) following histamine challenge and phenotype analysis of cells by flow cytometry and analysis of cytokine production by quantitative PCR. RESULTS: PAR-2AP pre-treatment, but not the scrambled peptide, was able to significantly inhibit bronchoconstriction, airway hyper-responsiveness and to modulate the immune response induced by allergic challenge in sensitized rabbits. The phenotype analysis of the cells recovered from BAL showed an increase in RLA-DR-positive cells while RTLA-positive cells were unchanged. IFN-gamma and IL-2 production were inhibited, with a concomitant increase in IL-10 of about 10-fold over the control values. CONCLUSIONS: In this experimental model, PAR-2 modulates bronchoconstriction interfering with antigen challenge-induced immune response in rabbits sensitized and challenged to Par j 1.

Adoptive transfer of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T cells with in vitro antitumor activity boosts LMP2-specific immune response in a patient with EBV-related nasopharyngeal carcinoma.

BACKGROUND: The outcome of patients with nasopharyngeal carcinoma (NPC) presenting as advanced-stage disease or failing conventional radio-chemotherapy is poor. Thus, additional forms of effective, low-toxicity treatment are warranted to improve NPC prognosis. Since NPC is almost universally associated with Epstein-Barr virus (EBV), cellular immunotherapy with EBV-specific cytotoxic T lymphocytes (CTLs) may prove a successful treatment strategy. Patient and methods A patient with relapsed NPC, refractory to conventional treatments, received salvage adoptive immunotherapy with EBV-specific CTLs reactivated ex vivo from a human leukocyte antigen-identical sibling. EBV-specific immunity, as well as T-cell repertoire in the tumor, before and after immunotherapy, was evaluated. RESULTS: CTL transfer was well tolerated, and a temporary stabilization of disease was obtained. Moreover, notwithstanding the short in-vivo duration of allogeneic CTLs, immunotherapy induced a marked increase of endogenous tumor-infiltrating CD8+ T lymphocytes, and a long-term increase of latent membrane protein 2-specific immunity. CONCLUSIONS: Preliminary data obtained in this patient indicate that EBV-specific CTLs are safe, may exert specific killing of NPC tumor cells in vitro, and induce antitumor effect in vivo.

The involvement of sensory neuropeptides in airway hyper-responsiveness in rabbits sensitized and challenged to Parietaria judaica.

BACKGROUND: C-fibres have received considerable attention in the context of airway hyper-responsiveness (AHR), in fact several lines of evidence suggest that tachykinins might be involved in the pathogenesis of AHR. OBJECTIVE: The aim of this study was to investigate the role of capsaicin-sensitive sensory C-fibres and tachykinins in rabbits sensitized to the major allergen of Parietaria judaica pollen (Par j1). METHODS: Airway responsiveness was determined by exposing sensitized rabbits to cumulative concentrations of aerosolized histamine before and after an allergic challenge and after a pre-treatment with either vehicle or capsaicin or tachykinin receptor antagonists. Bronchoalveolar lavage was performed following histamine challenge and total and differential cell counts were performed. RESULTS: In sensitized rabbits, an AHR to inhaled histamine was observed 24 h after a Par j1 challenge. Capsaicin pre-treatment inhibited the AHR achieved 24 h following antigen exposure (P < 0.01). Pre-treatment with the tachykinin NK2 receptor antagonist, SR 48968, significantly reduced the antigen-induced AHR (P < 0.05), while pre-treatment with tachykinin NK1 (SR 140333) and NK3 (SR 142801) receptor antagonists did not significantly modify it. Bronchoalveolar lavage fluid obtained from vehicle and capsaicin-treated rabbits challenged with Par j1 exhibited no significant differences in total and differential cell counts. CONCLUSIONS: Parietaria judaica-induced AHR in immunized rabbits was shown to be inhibited by pre-treatment with capsaicin, an effect that is not related to an action on the associated pulmonary infiltration of eosinophils. The involvement of NK2 receptor stimulation in this phenomenon also suggests that NK2 receptor antagonists may be useful for investigating mechanisms of bronchopulmonary alterations in asthmatic patients.

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.

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.

Gastroesophageal reflux disease and asthma: an intriguing dilemma.

BACKGROUND: Gastroesophageal reflux disease (GORD) is characterized by typical reflux symptoms and multiple atypical extraesophageal symptoms. Gastric asthma is a prominent extraesophageal manifestation of GORD. There is persistent debate about the pathophysiologic mechanisms triggering asthma by GOR. METHODS: We conducted a review of the literature. RESULTS: The pathogenic mechanism could be either a vagally transmitted reflex or an intratracheal aspiration of refluxed material. In both hypotheses, the role of inflammatory mediators has been proposed. CONCLUSIONS: Neurogenic inflammation is a good theoretic basis for a pathogenic interpretation of the disorder. In atopic patients, food allergy has been recently proposed as a possible cause of GOR and associated respiratory symptoms, and it should be considered in the diagnostic work-up of all patients with GORD.

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.

Soluble intercellular adhesion molecule-1 (sICAM-1) concentrations in Graves' disease patients followed up for development of ophthalmopathy.

It is commonly recognized that a few patients with Graves' disease (GD) develop an overt ophthalmopathy, although most of them show subclinical extraocular muscle enlargement by appropriate imaging techniques. At present, it is not possible to identify the subgroup of GD patients with subclinical retroorbital connective involvement. Recently, it has been shown that increase of soluble intercellular adhesion molecule-1 (sICAM-1) serum levels is correlated to clinical activity score in active Graves' ophthalmopathy (GO) patients with or without hyperthyroidism, suggesting that sICAM-1 serum values could reflect the degree of ocular inflammatory activity. The aim of this longitudinal study was to evaluate sICAM-1 serum levels in GD patients without clinical ophthalmopathy and to assess their possible relationship with occurrence of GO. We measured sICAM-1 serum levels in 103 initially hyperthyroid GD patients without clinical ophthalmopathy and in 100 healthy subjects. All patients were treated with methimazole for 2 yr. Sera were collected from all patients before treatment and then monthly for the first 6 months of therapy, every 2 months in the following 6 months, and finally at the end of the follow-up study. Patients developing GO were excluded from the follow-up at the onset of ophthalmopathy. During the follow-up 17 GD patients (16.5%, group 1) developed overt eye involvement (14 as active inflammatory ophthalmopathy and 3 as ophthalmopathy without clinical retroorbital connective inflammation) and 86 (83.5%, group 2) did not. At start of the study, the mean of sICAM-1 serum concentrations did not differ significantly between the 2 groups, but it was significantly higher than in controls in both groups. No significant correlation between serum sICAM-1 concentrations and free thyroid hormone levels was found in the 2 groups of patients. During the follow-up study, a further increase of sICAM-1 serum levels was observed in 12 of the 14 patients (85.7%) of group 1 who developed active inflammatory ophthalmopathy not only at the onset but also before clinical GO appearance. On the contrary, the 3 patients of group 1 that developed ophthalmopathy without clinical retroorbital inflammation did not show any further increase of sICAM-1 levels at every time of follow-up in comparison with the starting values, even if their sICAM-1 levels were always higher than in normal controls. Finally, group 2 patients showed significantly decreased sICAM-1 levels throughout the follow-up period when compared with the starting values, although they were still significantly higher than in controls. These results indicate that a further increase of sICAM-1 serum levels before the onset of clinical ophthalmopathy may be a marker of subclinical retroorbital connective inflammation in GD patients. Therefore, our study suggests that serial determinations of sICAM-1 serum levels could help to identify and trace at the right time those GD patients prone to developing active inflammatory ophthalmopathy.

[Changed etiopathogenic and clinical features of infective endocarditis]. / Mutati aspetti etiopatogenetici e clinici dell'endocardite infettiva.

The authors report their experience on etiological and clinical aspects of infective endocarditis (IE). A series of 182 consecutive patients, including 83 cases of medical IE, 73 cases of IE in intravenous drug abusers (DA), 22 cases of IE on late prosthetic valves and 4 cases of IE on early prosthetic valves were evaluated since 1976. Medical IE occurred frequently in the elderly patients and in most of the cases (80%) involved natural valves with underlying abnormalities, either rheumatic (42%) or degenerative (33%) or malphormative (25%). Pre-existing valvular pathology was not needed for IE in DA, occurring in 13%, mainly due to a previous IE. In most of the cases IE in DA was a staphylococcal IE (80%) and a right-sided IE (77%). Streptococci were frequent agent both in medical and late prosthetic valves IE (55%): however, a wide pattern of microorganisms, including "unusual" pathogens like nutritionally variant Streptococci, Haemophylus parainfluenzae, Haemophylus paraphrophylus, Coxiella burnetii and the so-called "non pathogen microorganisms" (e.g. Neisseria sicca) was identified as etiological agent. As regards the clinical approach and diagnosis, the Authors underline some atypical clinical presentations of IE: the pulmonary presentation, occurring in right-sided IE, mainly in DA; the neurological presentation, suggesting staphylococcal etiology and left-sided IE; the vasculitis presentation, miming connective tissue diseases; the cardiac presentation, observed in aortic localization (1 case). One or more severe complications occurred in 65% of the patients, contributing to adverse outcomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative clinical evaluation of ceftriaxone in treating lower respiratory tract infections.

To evaluate the clinical and microbiological efficacy and safety of ceftriaxone in comparison with cefotaxime in treating acute lower respiratory tract infections two open randomized trials were performed. Sixty-two adult hospital in-patients were entered and 58 completed the study. The patients suffered from either acute (broncho-)pneumonia (19pts) or severe exacerbation of chronic bronchopneumonia (39 pts). Forty-one of the patients had severe underlying or concurrent diseases. Diagnoses were in all cases confirmed by isolation of the causative pathogen(s) from bronchial brushing or washing under fiberoptic bronchoscopy. Twenty-eight patients were administered at random with either a single 2g daily dose of ceftriaxone or 2g twice daily dose of cefotaxime (1st trial). Successively (2nd trial) ceftriaxone was administered at a dose of 1g once daily either i.v. or i.m. The duration of treatment ranged from 7 to 12 days. A satisfactory response was observed in all patients suffering from acute pneumonia or bronchopneumonia; the eradication rate of the causative pathogen was 73% and 62% for ceftriaxone and cefotaxime, respectively. Concerning the exacerbation of chronic bronchopneumonia (39 patients) an overall satisfactory response to both treatments was registered in about 80% of cases. No significant differences between the 1g and 2g single daily dosing regimens of ceftriaxone appeared. Both ceftriaxone and cefotaxime were well tolerated: no or minimal changes in laboratory values were noticed. It is concluded that a 1g or 2g single daily dose of ceftriaxone were at least as effective as a 2g twice daily dose of cefotaxime in treating acute lower respiratory tract infections due to susceptible pathogens.

Treatment of lower respiratory tract infections with ceftriaxone and cefotaxime. A comparative study.

The microbiological and clinico-therapeutic efficacy and safety of ceftriaxone were compared with those of cefotaxime in an open randomized trial. Fifty-four adult hospitalized patients (37 males and 17 females) suffering from either acute bronchopneumonia (19) or acute exacerbations of chronic bronchopneumonia (35) have been investigated. Four patients were withdrawn from the trial. Underlying diseases were present in 41 patients. Ceftriaxone was administered at a once-a-day dose of either 1 or 2 g (in 13 and 14 patients, respectively) and cefotaxime at a 2 g twice daily dosing regimen (27 patients), both antibiotics being given for 7-12 days. In the ceftriaxone group, 15 out of the 27 patients were cured (55%) and 9 had a favourable clinical response for a total satisfactory response rate of 88%. The causative pathogen was eliminated in 18 (66%) patients. The results obtained in the cefotaxime group did not differ significantly, but 2 patients were excluded from the study because of in vitro resistance of the causative pathogen isolated. Both drugs were well tolerated: no relevant laboratory changes were registered. The results indicate that ceftriaxone at a dosage of 2 or 1 g daily is at least as effective as cefotaxime given daily at a dosage of 4 g in the treatment of severe lower respiratory tract infections.

Clinical evaluation of netilmicin in the field of internal medicine.

An open clinical trial was carried out to evaluate therapeutic efficacy and safety of netilmicin. Forty hospitalized adult patients suffering from complicated urinary tract infections (UTI) (19), lower respiratory tract infections (20), septicemia (3) and soft tissue infection (1) due to in vitro susceptible microorganisms were admitted to the study. Twenty-nine of these patients had severe underlying diseases interfering with host defenses. Twenty-nine out of the 40 patients (73%) were cured and 6 (15%) had a favorable clinical response giving an overall satisfactory clinical response of 88%. Eradication of causative microorganisms was obtained in 29 (73%) patients, and three substitutions during or at the end of treatment were observed. Netilmicin was well tolerated: neither clinical abnormalities of otovestibular function nor hepatic or hematological alterations were found, while only two patients developed a mild and transient increase of BUN and creatinine serum levels.

In vitro antibacterial activity of imipenem against Pseudomonas and Staphylococcus species. Comparison with thirteen other antimicrobial agents.

The in vitro antimicrobial activity of imipenem against recent clinical isolates of Pseudomonas spp. (94 strains) and penicillin-resistant Staphylococcus spp. (50 Staph. aureus and 50 coagulase-negative Staphylococcus) was assessed using the Mueller-Hinton agar dilution method. Results were compared with those simultaneously obtained for amikacin, netilmicin, tobramycin, norfloxacin, piperacillin, ceftazidime, ceftriaxone and azthreonam against Pseudomonas spp., and for rifampicin, clindamycin, netilmicin and cefoxitin, besides penicillin and methacillin, against Staphylococcus spp. About 50 and 90% of 84 Pseudomonas aeruginosa isolates were inhibited by concentrations of imipenem equal to or less than 2 and 8 mg/l respectively. The in vitro activity of imipenem was comparable to that of ceftazidime and norfloxacin, but superior to that of the aminoglycosides and all the other antibiotics tested, in terms of potency by weight. Among other Pseudomonas spp. only P. malthophilia (2 strains) proved resistant to imipenem. Rifampicin was the most active antibiotic by weight against Staph. aureus but imipenem was more active than clindamycin and, especially, netilmicin and cefoxitin. Imipenem was highly active also against coagulase-negative staphylococci, with some differences related to the high incidence of methicillin-resistant strains. MICs of imipenem in Mueller-Hinton broth correlated with those obtained in agar, unlike the aminoglycosides. There were no significant inoculum effects on MICs of imipenem and MBCs were within one twofold dilution of MICs in over 75% of assays.

Preclinical comparative evaluation of aminoglycosides.

Five aminoglycoside antibiotics including gentamicin, sisomicin, tobramycin, amikacin and netilmicin were comparatively tested in vitro against 283 clinical isolates of Pseudomonas, Enterobacteriaceae and Gram-positive cocci, using the agar dilution technique according to I.C.S. recommendations. In respect to potency by weight, netilmicin proved the most active aminoglycoside against E. coli, K. pneumoniae, Enterobacter, Serratia spp. and Staphylococcus aureus, followed by sisomicin or tobramycin in relation to various bacterial species. Against Pseudomonas aeruginosa, sisomicin and tobramycin had the lowest MICs (minimum inhibitory concentrations). Amikacin had overall less activity but the widest spectrum. Rate of killing curves showed few differences among the aminoglycosides tested. Against gentamicin-resistant strains (MIC greater than or equal to 16 micrograms/ml) the activity of netilmicin was comparable to or higher than that of amikacin, except for P. aeruginosa, P. cepacia and indole-positive Proteus, which were inhibited by amikacin only. Netilmicin also showed the highest "therapeutical index" calculated as the ratio between MIC and blood levels for each aminoglycoside against each most important bacterial specie.