Canakinumab in adults with steroid-refractory pyoderma gangrenosum.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare, neutrophilic, ulcerative skin disease that is difficult to treat, especially when unresponsive to steroids. OBJECTIVES: To determine whether canakinumab is an effective and safe treatment in PG. METHODS: Five adult patients with clinically and histologically confirmed steroid-refractory PG were enrolled in this prospective open-label study. They received canakinumab 150 mg subcutaneously at week 0 with an optional 150 mg at week 2 in case of an inadequate response [Physician's Global Assessment (PGA) ≥ 2], and an optional 150-300 mg at week 8 depending on PGA. The primary clinical end point was clinical improvement (PGA at least -1 from baseline) and/or complete remission (PGA 0 or 1) at week 16. Real-time quantitative polymerase chain reaction was performed on skin samples to quantify cytokine mRNA levels. RESULTS: Interleukin (IL)-1ß and its known target genes IL6, CXCL8 and IL36A were significantly increased in lesional skin of PG. Under canakinumab therapy, four of five patients showed a decrease in target-lesion size, PGA and Dermatology Life Quality Index (DLQI), and three of five achieved complete remission. The mean diameter of target lesions decreased from 4·32 ± 2·6 cm at visit 1 to 0·78 ± 1·3 cm at visit 7 (P = 0·03). Mean DLQI decreased from 15 ± 5 at visit 1 to 8 ± 4 by visit 7 (P = 0·01). Adverse effects were reported in two patients: fatigue in one and worsening of disease at a nontarget lesion in the other. CONCLUSIONS: Our data indicate that IL-1ß plays a key pathogenic role in PG and canakinumab may represent a therapeutic option for steroid-refractory PG.

Validation of leukotriene B4 measurements in exhaled breath condensate.

OBJECTIVE: To qualitatively validate an enzyme immunoassay to measure leukotriene B4 in exhaled breath condensate. Exhaled breath condensate is a new non-invasive method to monitor airway inflammation. SUBJECTS: Twenty-two subjects with different lung diseases attended the outpatient clinic on one occasion for exhaled breath condensate collection. METHODS: Samples were pooled together and purified by reverse-phase high-performance liquid chromatography. The fractions eluted were assayed for leukotriene B4 by enzyme immunoassay. RESULTS: A single peak of leukotriene B4-like immunoreactivity co-eluting with leukotriene B4 standard (retention time: 24 min) was identified by enzyme immunoassay. Reverse phase-high performance liquid chromatography peak of leukotriene B4 was clearly separated from those of 6-trans-leukotriene B4 (retention time: 14 min) and leukotriene B5 (retention time: 18 min) for which the antiserum used in the enzyme immunoassay had the highest cross-reactivity. Leukotriene B4 recovery was 64%. CONCLUSIONS: This study provides evidence for the presence of leukotriene B4 in the exhaled breath condensate and the specificity of the enzyme immunoassay used.

Immediate allergic reactions to beta-lactams: diagnosis and therapy.

Beta-lactams are the antibiotics which most frequently provoke adverse reactions mediated by specific immunological mechanisms. These reactions, classifiable as immediate or non-immediate, can be produced by the four classes of beta-lactams (penicillins, cephalosporins, carbapenems and monobactams) currently available, which share a common beta-lactam ring structure. Immediate reactions occur within the first hour after drug administration and are characterized by urticaria, angioedema, rhinitis, bronchospasm, and anaphylactic shock. Immediate reading skin tests are the quickest and most reliable method for demonstrating the presence of beta-lactam specific IgE antibodies. It is crucial to use in diagnosis the suspected beta-lactams themselves, particularly cephalosporins, in addition to penicillin determinants. Serum specific IgE assays can be used as complementary tests. Negative test results should be interpreted in light of the time elapsed from the last exposure to the responsible beta-lactam. In fact, both in vivo and in vitro test sensitivity is known to decrease over time. In some diagnostic work-ups, patients with a positive history and negative skin and in vitro tests with classic reagents undergo a controlled administration of the suspected beta-lactam. The management of immediate allergic reactions should take into consideration their severity and type. Adrenaline is the drug of choice in the treatment of anaphylactic shock. In addition to adrenaline, corticosteroids and antihistamines should be administered. Histamine H(1) receptor antagonists are the mainstay of the treatment of immediate allergic reactions such as urticaria, rhinitis and conjunctivitis.

Validation of 8-isoprostane and prostaglandin E(2) measurements in exhaled breath condensate.

OBJECTIVE: To qualitatively validate radioimmunoassays for 8-isoprostane and prostaglandin (PG) E(2) in exhaled breath condensate. SUBJECTS: Twenty-two subjects with different lung diseases attended the outpatient clinic on one occasion for exhaled breath condensate collection. METHODS: Samples were pooled together and purified by reverse phase high performance liquid chromatography (RP-HPLC). The eluted fractions were assayed for 8-isoprostane-like immunoreactivity and PGE(2)-like immunoreactivity by radioimmunoassays. In addition, simultaneous measurements of exhaled breath condensate unextracted samples with two anti-8-isoprostane and anti-PGE(2) sera with different cross-reactivity were performed. RESULTS: A single peak of 8-isoprostane-like immunoreactivity and PGE(2)-like immunoreactivity co-eluting with 8-isoprostane (retention time: 13 min) and PGE(2) (retention time: 21 min) standards, respectively, was identified by radioimmunoassays. Testing with two different antisera showed similar results for both 8-isoprostane-like immunoreactivity (limits of agreement = 4.5 pg/ml and - 4.1 pg/ml, n = 12) and PGE(2)-like immunoreactivity (limits of agreement = 6.1 pg/ ml and - 6.1 pg/ml, n = 12). CONCLUSION: This study provides evidence for the specificity of the radioimmunoassays for 8-isoprostane and PGE(2) in exhaled breath condensate. This is critical for proposing these markers as a non-invasive way for monitoring airway inflammation.

Fexofenadine reduces nasal congestion in perennial allergic rhinitis.

BACKGROUND: Nasal congestion is the predominant symptom in perennial allergic rhinitis (PAR), and it seems to be mainly related to the late-phase inflammatory events. The present pilot study aimed to evaluate the therapeutic effect exerted by fexofenadine in patients with PAR due to mite allergy. METHODS: This study was a parallel, double-blind, randomized, three-arm (1:1:1), placebo-controlled study. Thirty-one subjects with PAR were enrolled and received double-blind medication: fexofenadine 120 or 180 mg, or placebo, once a day for 28 days. RESULTS: The total symptom score was reduced by fexofenadine (both dosages) at V2 (P=0.007), whereas placebo did not modify it. Nasal congestion decreased after 1 week of treatment with fexofenadine 120 (P=0.027) and 180 (P=0.01), but not with placebo (P=NS). At V3, fexofenadine (both dosages) significantly reduced nasal congestion (P=0.011 and P=0.007, respectively), by placebo did not show any significant effect. CONCLUSIONS: This pilot study represents the first evidence of the efficacy of fexofenadine in PAR, and also the control of the nasal congestion. We suggest performing larger trials to confirm these preliminary findings.

Modulation of airway caliber by deep inhalation in children.

To elucidate whether deep inhalation (DI) modulates changes in airway caliber in childhood, we measured the effect of DI on respiratory impedance before and after inhaled methacholine or salbutamol in 4- to 7-yr-old children (n = 15) suffering from recurrent wheezing. In all children, the real part of impedance between 12 and 16 Hz (Re[Z](12-16)) increased after methacholine from 5.6 +/- 1.2 to 8.2 +/- 1.6 cmH(2)O. l(-1). s (P < 0.001) and resonance frequency from 18 +/- 3 to 25 +/- 5 Hz (P < 0.001). These changes were partially reversed by DI: Re[Z](12-16) decreased to 7.2 +/- 1.2 cmH(2)O. l(-1). s (P < 0.01) and resonance frequency to 19 +/- 5 Hz (P < 0.001). In nine children, on a separate occasion, Re[Z](12-16) decreased after salbutamol from 8.3 +/- 1.9 to 5.1 +/- 0.9 cmH(2)O. l(-1). s (P < 0.001) and resonance frequency from 21 +/- 6 to 15 +/- 3 Hz (P < 0.05). The decrease of Re[Z](12-16) was partially reversed by DI (to 6.2 +/- 1.4 cmH(2)O. l(-1). s, P < 0. 01), but resonance frequency did not change significantly (P = 0.75). We conclude that in 4- to 7-yr-old children pharmacologically induced changes in airway caliber are modulated by DI. These findings suggest that airway-to-parenchyma interdependence is operative in this age range.

Azelastine eye drops reduce conjunctival hyperresponsiveness to hyperosmolar glucose challenge in children with asymptomatic mite conjunctivitis.

Mite allergy is characterized by a continuous allergen exposure. Persistent inflammation is therefore always detectable; and during symptomless periods as well. It has been reported that mite allergic patients also present a nonspecific hyperreactivity to different stimuli, including hyperosmolar solution. Since azelastine was previously demonstrated to be able to reduce allergic inflammation, the aim of the study was to investigate the effects of the drug on nonspecific conjunctival hyperreactivity in mite-allergic patients. Twenty children with mite allergy were studied. A hyperosmolar conjunctival challenge was performed before and after azelastine eye drops or placebo treatment for a period of 2 weeks. It was found that patients treated with azelastine eye drops showed a significant reduction in nonspecific conjunctival hyperreactivity compared to the placebo group (p = 0.018). It was concluded that azelastine eye drops are able to reduce the nonspecific hyperreactivity present in subjects with mite allergy.

Platelet and lymphocyte benzodiazepine binding in patients with Alzheimer's disease.

Peripheral blood cells, such as platelets or lymphocytes, have been studied in the investigation of systemic derangements and central nervous system biochemical changes occurring in several neuropsychiatric disorders. In the present work, assaying platelet and lymphocyte peripheral-type benzodiazepine binding in patients with Alzheimer's disease (AD) and healthy controls, we found a significantly reduced number of cell receptors in patients' platelets and lymphocytes. These results are discussed with reference to central nervous system biochemical abnormalities in AD. Moreover, the lymphocyte binding data may represent an impairment of the immune response in AD, since lymphocyte surface peripheral-type benzodiazepine receptors seem to be related to immune function.

T-cell interferon gamma binding in patients with dementia of the Alzheimer type.

OBJECTIVE: To study T-cell-dependent immune function in patients with dementia of the Alzheimer type (DAT). DESIGN: Assay interferon gamma binding on T lymphocytes in patients with DAT, as compared with healthy controls. SETTING: The study was performed on ambulatory patients in a tertiary care center, where patients were diagnosed as having DAT according to the National Institute of Neurological Disorders and Stroke criteria. PATIENTS: Thirty-five nondepressed patients with DAT (15 women and 20 men; mean [+/-SD] age, 68.6 +/- 15.8 years) were selected consecutively. They were drug free for at least 3 weeks and did not smoke. Illness severity was evaluated according to the Clinical Dementia Rating Scale. The control group comprised 35 age- and sex-matched, healthy nonsmoking subjects, with no family history of neuropsychiatric disorders. RESULTS: A significant reduction (P < .001) of T-lymphocyte interferon gamma binding was observed in patients with DAT as compared with healthy controls (611 +/- 19 [SE] vs 702 +/- 11 [SE] receptors per cell, respectively), whereas the dissociation constant (ligand-receptor affinity) values were similar in the 2 groups (1.1 +/- 0.06 [SE] and 1.2 +/- 0.06 [SE] nmol/L). CONCLUSION: These data demonstrate a derangement of the immune response in patients with DAT, since cell surface interferon gamma receptors seem to be related with T-lymphocyte immune function.

T lymphocyte benzodiazepine binding is reduced in demented patients.

Blood cells, especially platelets and lymphocytes, are used in neuropsychiatric research as tools for investigating systemic derangements in neuropsychiatric disorders, and as peripheral models for studying central nervous system biochemistry. In the present work, we determined T lymphocyte peripheral-type benzodiazepine binding: a significant reduction of Bmax values was observed in demented patients as compared with healthy controls, whereas Kd values were similar in the two subjects' groups. A significant negative correlation was found between Bmax values and illness severity. These data, which seem to be related to an impairment of immune response and cell energy metabolism in demented patients, may represent a state-dependent marker in monitoring disease course and treatment efficacy.

T-lymphocyte immuno-interferon binding in parkinsonian patients.

Human peripheral blood cells, especially lymphocytes and thrombocytes, are extensively studied in neuropsychiatric research both as tools for investigating systemic derangements in neuropsychiatric disorders, and as peripheral models for getting information on central nervous system biochemistry. Specific interferon (IFN)-gamma receptors have been found on both human lymphocytes and neural cells. The aim of the present study has been to evaluate IFN-gamma binding on peripheral blood T lymphocytes from parkinsonian patients, as compared with that on blood T cells from healthy subjects. We have found that T lymphocytes from parkinsonian patients bear a significantly smaller amount of IFN-gamma receptors than those from controls. Such IFN-gamma binding sites are of the same type in patients and healthy subjects (Kd (mean +/- SEM): 1.4 +/- 0.07 vs. 1.2 +/- 0.06, respectively). These findings, which are not specific for Parkinson's disease, are discussed in terms of its immunopathogenesis, since it has been reported that activated T lymphocytes have decreased amounts of IFN-gamma receptors.

T-lymphocyte peripheral-type benzodiazepine binding in parkinsonian patients.

Human peripheral blood cells, especially lymphocytes and platelets, are being studied increasingly in neuropsychiatric research both as tools for investigating systemic disturbances in neuropsychiatric disorders, and as peripheral models for getting information on central nervous system biochemistry. In this study, we determined T lymphocyte peripheral-type benzodiazepine binding in parkinsonians and controls: significantly reduced B(max) values were found in patients compared with healthy controls, whereas K(d) values were similar. These data argue for an immune response disturbance and a cell energy metabolism impairment in parkinsonian patients, since cell surface peripheral-type benzodiazepine receptors are related with the immune function, and mitochondrial binding sites with energy metabolic pathways.

Monoamine oxidase molecular activity in platelets of parkinsonian and demented patients.

Platelet monoamine oxidase activity levels have been evaluated in several neuropsychiatric disorders, to identify biochemical markers for pathological brain functioning. In the present work, we assayed both total and molecular monoamine oxidase activity in platelets of parkinsonian and demented patients: both showed significantly higher enzyme activity values than healthy controls. Thus, high platelet monoamine oxidase activity levels seem to be related to an increased intrinsic activity of single enzyme molecules. A significant positive correlation was found between platelet monoamine oxidase activity and severity of illness in both disorders: monoamine oxidase activity, therefore, may be considered as a state-dependent marker for neuro-degeneration. Such findings are discussed with reference to central nervous system biochemical abnormalities in parkinsonian and demented subjects; it might be that in both Parkinson's Disease and in dementia of Alzheimer type some central biochemical changes are reflected in certain peripheral tissues (thrombocytes, for instance), or that a systemic derangement accompanies the cerebral involvement.