Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated ...phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.
Patients sensitized to common pets (cat, dog) frequently display an immunoglobulin (Ig) E-mediated response to allergens from other animals.
To evaluate whether individuals sensitized to common pets ...might be at higher risk of developing allergic sensitization to other mammalian allergens.
The study population comprised 900 consecutive patients (300 individuals sensitized to different allergens including those of cat and dog group AL, 300 sensitized to allergens other than those derived from cat and dog group B, and 300 nonsensitized individuals group C, controls). All patients underwent a physical examination, an interview (clinical history, pet ownership, possible exposure data), and skin prick test (SPT) with a standard panel of allergens including cat, dog, horse, rabbit, rat, mouse, guinea pig, hamster, and cow.
A significant difference in allergic sensitization to mammalian allergens was observed in groupA compared with group B (respectively, 244 vs. 17). No sensitization was found in group C.
Since sensitization to pet allergens increases the risk of developing allergy to other furry animals, we suggest performing SPTs with several mammalian allergens to identify allergic sensitization and thus prevent future exposure in individuals who are highly sensitized and environmentally exposed to common pets.
The skin prick test (SPT) is the most appropriate diagnostic approach to identify IgE sensitization to aeroallergens, foods, hymenoptera venom and some pharmacological compounds. SPT is considered a ...safe diagnostic approach, but several fatal or near-fatal reactions have been described. Based on the literature, the occurrence of systemic reactions with inhalant allergens has diminished over the last thirty years, whereas fresh food, hymenoptera venom and antibiotic SPT still carry some risk. In general, the risk of systemic reactions is lower with SPT than with intradermal testing. Some patients (history of previous anaphylactic reactions, small children, pregnant women, uncontrolled asthma, high degree of reactivity) should be considered at higher risk of systemic/anaphylactic reactions. Based on the literature, the risk of fatality due to SPT is extremely remote, and severe/anaphylactic reactions are rare. Nevertheless, this risk cannot be completely excluded, especially in highly susceptible subjects. Physicians who perform SPT should be aware of this and apply simple precautional rules.
Horses play a significant role in people's leisure time in Italy and other countries, but few data are available on IgE-mediated sensitization to horse allergens in patients without occupational ...exposure. We assessed, in a multicentric survey, the prevalence of horse sensitization in atopic subjects and its clinical characteristics.
Allergists from the whole Italian territory were required to collect the results of skin prick tests from at least 100 consecutive subjects. Those patients with a positive skin test to horse dander underwent a detailed interview concerning clinical history, pet ownership and possible exposure.
Data from 3,235 outpatients were collected and 2,097 had at least 1 skin positivity. Among them, 113 (5.38%) were sensitized to horse dander (9 monosensitized). Thirty patients reported direct horse contact (4 owners and 26 for riding or occasional contact), 23 patients were sometimes in contact with horse owners and 60 subjects denied any direct or indirect exposure. Among 9 horse monosensitized patients, 6 had intermittent and mild rhinitis and 3 persistent moderate/severe rhinitis plus asthma. Three of them were horse owners or riders and the remaining had no contact with the animal.
Our data evidence that the rate of sensitization to horse dander is not negligible and probably underestimated. In susceptible, not occupationally exposed individuals, horse contact, but also indirect or no apparent exposure, may induce sensitization. We recommend inclusion of horse allergen in the routine panel for the diagnosis of respiratory allergy.
It is widely acknowledged that avoidance of allergens such as those derived from foods, drugs, latex and stinging insects results in a complete disappearance of symptoms. By contrast, although it has ...been clearly shown that allergens are an important risk factor for the development of respiratory symptoms and that several avoidance measures reduce allergen levels, whether this gives clinical improvement in symptoms is debatable.
Many reasons could be invoked to justify this evident discrepancy. Apart from the intrinsic methodological aspects (e.g. single or combined interventions measure, population studied, severity of respiratory symptoms, outcomes, evaluated parameters, etc.), it is important to outline that a successful approach requires that the avoided allergen is the only and real factor responsible for symptoms, the patient's education and the use of a comprehensive protocol to reduce allergen exposure. Other important factors include the involvement of the patient, the relevance of other allergens/non-specific agents, and exposure to sensitizing agents also outside patient's home.
It is likely that the clinical phase of allergic airway disease and the degree of bronchial (and also nasal) remodelling, in each individual, represent relevant factors for the clinical outcome of allergen avoidance procedures. Since the management of respiratory allergy is a complex strategy (including drugs, allergen avoidance, immunological and educational interventions), it is difficult in real life to distinguish the efficacy of a single intervention in comparison to the others. A combined strategy is likely to produce better clinical results.
The nocebo effect is the onset of untoward reactions following the administration of an indifferent substance. The oral challenge with alternative drugs plays a central role in the management of drug ...allergy and the use of inert substances is part of this procedure. We evaluated the occurrence and clinical characteristics of nocebo effect in patients with adverse drug reactions. Six hundred patients, seen in three different centres (Genoa, Naples and Verona) with a history of reactions to drugs, underwent a blind oral challenge with the administration of an indifferent substance and active drugs. The administration of an inert substance provoked untoward reactions in 54 patients (27%) in Verona, 60 (30%) in Naples and 48 (24%) in Genoa. The overall occurrence of nocebo effect was 27%. The majority of reactions were subjective symptoms (itching, malaise, headache etc), perceived as troublesome by all subjects. The occurrence was significantly higher in women than in men. Our data, collected in a large population, confirm that the nocebo effect occurs frequently in clinical practice. In managing adverse drug reactions through oral challenge the nocebo effect is mandatory to recognize false positive responses.
The increasing frequency of pet ownership (especially cats) in many industrialized countries has raised the level of exposure to the allergens produced by these animals. Moreover, it is likely that ...modern energy-saving systems and the wide use of upholstered furniture has resulted in closer contact between cats (and their allergens) and humans. Many different methods have been developed to quantify the main cat allergen (Fel d 1) in settled dust and in ambient air. The threshold levels of cat allergen inducing sensitization or triggering respiratory symptoms in sensitized patients have been calculated in settled dust, but airborne amounts of Fel d 1 probably represent a more reliable index of allergen exposure. Noticeably, the amount of Fel d 1 may be relatively high also in confined environments where cats have never been kept. It has been demonstrated that clothes of cat owners are the main source for dispersal of allergens in cat-free environments. This fact may be of relevance, because recent studies have shown that allergic sensitization to cats is more likely to develop in children exposed to moderate levels of this allergen than in children exposed to high amounts of Fel d 1. The ubiquity of cat allergen may justify the common observation that allergen avoidance is often insufficient to reduce the risk of developing allergic sensitization and/or symptom exacerbation in highly susceptible patients. Further efforts are needed to improve the efficacy of Fel d 1 avoidance strategies to try to reduce the risk of allergic sensitization to this allergen.
Epidemiological studies showed that bronchial asthma is one of the most common diseases which can complicate pregnancy (1–7%). In about 0.05–2% of the cases, asthma occurs as a life-threatening ...event. In the common medical practice a waiting strategy or, even, the complete refusal for drug therapies are frequently observed. This is justified by the fear of the possible adverse effects of drugs on developing fetus. On the contrary, several studies have demonstrated that severe and uncontrolled asthma may produce serious maternal and fetal complications, such as gestational hypertension and eclampsia, fetal hypoxemia and an increased risk of perinatal death. Therefore, all pregnant women suffering from bronchial asthma should be considered as potentially at high risk of complications and adequately treated. Since asthma is a chronic disease with acute exacerbations, a continuous treatment is mandatory to control symptoms, to prevent acute episodes and to reduce the degree of airway inflammation. The global strategy for asthma management in pregnancy includes five main topics: (1) objective evaluation of maternal/fetal clinical conditions; (2) avoidance/control of triggering factors; (3) pharmacological treatment; (4) educational support; (5) psychological support. As far as drug therapy is concerned, the International Guidelines and Recommendations suggest that the general strategy does not differ significantly from management outside pregnancy. We herein review and discuss the available data and the criteria for the management of asthma in pregnant patients.
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