The three key elements of the syndrome commonly referred to as acquired angioedema (AAE), which was first described by Caldwell in 1972 [1], are acquired deficiency of C1 inhibitor (C1-INH), hyperactivation of the classical pathway of human complement and recurrent angioedema symptoms. It is considered a very rare condition with just more than 100 patients reported in the literature [2]. In absence of epidemiological data, we can only speculate about its prevalence. In our list of angioedema patients, we found 1 AAE every 10 patients with the hereditary form of C1-INH deficiency (hereditary angioedema, HAE). HAE minimal prevalence in the population is 1.41/100,000 and usual estimated prevalence between 1:10,000 and 1:50,000 [3, 4]. Therefore, a very crude estimated prevalence of AAE could range between 1:100,000 and 1:500,000. We believe that the actual number is much higher than this because the condition is frequently unrecognized.
From the clinical point of view the angioedema symptoms that characterize AAE can not be differentiated from those present in HAE patients who have a deficiency of C1-INH due to mutations in one of the two alleles coding for this protein [5]. This could be anticipated based on the fact that in both forms angioedema is mediated by bradykinin episodically released by inappropriate activation of the contact-kinin system lacking its major physiologic regulator C1-INH [6, 7]. Thus, similar to HAE patients, patients with AAE have no major urticaria flare. Angioedema recurs at unpredictable intervals, lasting from two to five days and presenting with disfiguring, non pitting, non-pruritic edema of the skin (face, limbs, genitals), severe abdominal pain for edema of the gastrointestinal mucosa leading to temporary bowel occlusion (Figure 1) [8], life-threateing edema of the upper respiratory tract and edema of the oral mucosa and of the tongue [2]. The only significant clinical difference between HAE and AAE is the age of onset of symptoms (Table 1): within the second decade of life for more than 90% of patients with HAE, after the fourth decade for those with AAE. Some additional minor differences can be found looking at different rates of recurrences at specific sites. Angioedema of the gastrointestinal mucosa causing abdominal pain is reported by nearly 80% of patients with HAE while less than 50% of our AAE patients and around 30% of those from Bouillet et al [9] reported such symptoms. Nevertheless, presentation of AAE with abdominal symptoms has been reported in our series and in the literature [10]. Cutaneous angioedema in HAE patients is typically localized to the extremities. Even if this location is also present in patients with AAE, in them angioedema recurs more frequently in the face than in the limbs [9] and we also noticed a rather frequent involvement of tongue and uvula; (Figure 2).
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AAE is first suspected in patients aged 40 or above who present with recurrent cutaneous and/or mucosal angioedema without urticaria, without an evident triggering factor, and without family history of angioedema. Measurement of C1-INH and C4 antigen in such patients is the first step. If both are normal, the deficiency of C1-INH is very unlike. If both are low (with C1-INH below 50% of normal on two separate determinations) diagnosis of C1-INH deficiency is made. If just C4 is reduced, C1-INH functional activity needs to be determined and if low (below 50% of normal on two separate determinations) diagnosis of C1-INH deficiency is made. Once this diagnosis has been made, additional testing is necessary to distinguish between inherited and acquired deficiency. This testing includes determination of C1q which is reduced in 70% of patients with AAE and is normal in HAE. If C1q is reduced, diagnosis of AAE can be established. If C1q is normal, autoantibodies to C1-INH can be investigated and their presence at high titre allows diagnosing AAE. If antibodies are negative, the diagnosis of AAE is assumed when complete screening of C1-INH gene gives no evidence of mutations affecting C1-INH protein. Major limits to this procedure are the inadequate availability and standardization of C1-INH functional measurements [34] and the possibility to look for anti-C1-INH autoantibodies only in a few specialized research laboratories. Therefore, careful harmonization of clinical and laboratory findings is mandatory to establish the diagnosis of AAE.
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Autoantibodies against C1-inhibitor (C1-INH-Ab) have a diagnostic value in acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE), even though antibodies can circulate in complexes, which can be undetectable by proven methods. Our aim was to measure C1-INH/C1-INH-Ab complexes (CAC) and investigate their connection to C1-INH-Ab and the changes in their titer over time.
According to the theory of the idiotype-antiidiotype network, the antibodies produced by our immune system can connect not only to the antigen dedicated by the variable region of the antibody, but variable regions can connect to each other as well. Natural antibodies can occur in a cross-reaction with low affinity, while pathological antibodies usually have higher affinity and serum concentration. This is most common for IgM-type antibodies [34]. The formed immune complexes are able to activate the classical pathway of the complement system which leads to the elevated consumption of the proteins of the complement system.
Antibodies can be found not only in free circulating form, but also in complexes which means that measuring only the free form can cause an error in underestimating the actual amount of antibodies [34].
Our study aimed to use a new method for the measurement of CAC and aimed to uncover a possible connection between C1-INH-Ab and CAC and a pattern of CAC during long term follow-up connected to C1-INH-AAE and the related underlying disease.
11/19 patients had free C1-INH-Ab, 14 patients CAC, 3 patients neither C1-INH-Ab nor CAC, and 5 patients C1-INH-Ab as well as CAC. One patient had only C1-INH-Ab and no CAC, and 8 patients only CAC and no C1-INH-Ab.
Enriques admits that the problems connected to the way in which the touch functions are more complex than those connected to the sight (Ivi, pp. 184-185). Essentially, these problems derive from the fact that: a) a thre- shold of sensations exists, beyond which the cutis cannot distinguish between two quite near points and a single point; b) a given and constant length is perceived as different in different points of the cutis. The first problem concerns the sight, too. This means that the visual and tactile space is not continuous. The item b) is a funda- mental problem, which potentially, could prevent us to evaluate any distance. This impasse is overcome if one thinks that an estimation of the length of an object needs the reference to a specific tactile organ. This organ is usually our hand. Our hand allows us to distinguish between a plane and a curve surface, more than that: due to the specific and regular kind of sensation they produce, our hand makes us capable to distinguish the circle among the curve lines and the sphere among the curve surfaces. But the circle and the sphere are characterised by a typical distance: the radius. This means that our special muscular-tactile faculty, which finds an expression in the action of the hands, is the physiological way in which we acquire the sense of the distances. In contrast to this, it is difficult to get a tactile-muscular imagine of a straight line or of a plane surface. Hence, the muscular- tactile space gives origin to the metric properties. Thus, the metric of each geometry depends on this kind of physiological space (Ivi, pp. 185-187). For example, Euclidean geometry depends on the visual space as to the theorems which deal only with graphic properties, while it depends on both spaces for the theorems which also deal with metrical properties.
2) The geometrical space is a concept which is constructed by our mind in three steps: first of all the mind compares the intuitions provided by the senses; after that it associates the sensations to create a perceptive un- iverse which is not a mere bundle of sensations. This gives origin to our perceptive space, in which we are able to connect the visual with the tactile sensations. Finally, the abstraction from the specific contents of the percep- tive space allows us to reach the idea of a geometrical object in which lines without width and surfaces without thickness exist.
3) With regard to abstract geometry it was born thanks to the complex development of history of mathematics. The space of abstract geometry is not, however, a mere formal and non-intuitive entity. It is connected to the second level intuition, which is a purely mental intuition. It allows us to imagine, in an almost concrete manner, the models of abstract geometry. They can be obtained by means of analytical procedures, but the intuitive view is useful for them to appear to us as a series of worlds connected by structural similarities, despite the different objects of which they are composed. The second level intuition and the modelization permit to get a synthetic view on these geometrical universes.
Thence, intuition and history are the pulsing core geometry and, more in general, of science. However, geo- metry, as far as it was one of the first product of the human spirit and since it is directly connected to the basic intuitions has an absolutely prominent role, as we will see.
2) Since the mind is something plastic and connected to the general social and cultural environment the dif- ferent geometries have been developed in different historical periods. History is hence fundamental for geometry and gnoseology. 2ff7e9595c
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