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Background: Chronic spontaneous urticaria (CsU) is a frequent dermatological disease that might last for months or years with high impact on quality of life. Known causes are autoreactive phenomena, infections or intolerances, rarely IgE-mediated allergies. One-third of CsU patients benefit from a low-pseudoallergen diet. Additionally, it is often discussed, that reducing histamine ingestion alone might improve clinical symptoms and quality of life in CsU patients despite the uncertain role of the histamine-degrading enzyme diamine oxidase (DAO)., Objective: Aim of this study was to investigate the impact of low-histamine diet on symptoms and quality of life in patients with CsU., Methods: Patients suffering from CsU accompanied by gastrointestinal symptoms were included in the study. They underwent low-histamine diet for at least 3 weeks. During the whole study, urticaria activity score (UAS) was recorded daily in a patient's diary. Quality of life was assessed during screening, baseline and post diet visits by completing questionnaires (DLQI and Cu-Q(2)oL). DAO activity was measured before and after elimination diet., Results: A total of 75% of the patients had a benefit from the low-histamine diet. Thirty-four of 56 patients (61%) reached the primary endpoint of the study, an improvement of UAS 4 of ≥3. Overall, a significant reduction from 9.05 to 4.23 points (P = 0.004) was achieved; the average reduction in a strongly affected subgroup was 8.59 points (P < 0.001). DAO activity remained stable., Conclusion: Low-histamine diet is a therapeutically useful, simple and cost-free tool to decrease symptoms and increase quality of life in CsU patients with gastrointestinal involvement. Further research is needed to understand the role of diamine oxidase., (© 2016 European Academy of Dermatology and Venereology.)

Background: Matrix metalloproteinase (MMP)-9, an enzyme that contributes to inflammatory responses and subsequent tissue remodelling, has recently been suggested to be a good biomarker for monitoring disease activity in patients with chronic urticaria (CU). Here, we assessed whether total MMP-9 and/or active MMP-9 plasma levels are increased and correlated to disease activity in patients with CU., Methods: Total MMP-9 and active MMP-9 plasma levels were determined by ELISA in 70 CU patients and control subjects (patients with psoriasis and healthy controls). CU activity was measured using weekly and daily composite symptom scores (urticaria activity score) calculated from the number of wheals and the intensity of pruritus., Results: Significantly increased levels of total and active MMP-9 were detected in patients with CU as compared to healthy controls. Interestingly, patients with psoriasis also had clearly elevated plasma levels of total and active MMP-9, indicating that MMP-9 plasma levels do not specifically reflect CU activity. Most notably, total and active MMP-9 levels were not correlated with disease activity in CU or psoriasis patients., Conclusion: Plasma MMP-9 is not a good CU biomarker and should not be used for assessing the efficacy of treatment in CU patients or their spontaneous changes in disease activity.

Background: Cysteinyl leukotriene production seems to be dysregulated in patients with hypersensitivity to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). However, the underlying pathogenic mechanisms of these reactions are poorly understood. Previous studies have suggested a role for the A-444C polymorphism on the leukotriene C4 synthase gene (LTC4S) in aspirin-induced urticaria (AIU), but the results are controversial., Objective: To evaluate in a case-control study whether the A-444C polymorphism in the promoter region of LTC4S is associated with AIU and atopic phenotypes in a Venezuelan population., Methods: One hundred ten patients with AIU and 165 nonallergic controls were included. AIU was diagnosed by clinical history and confirmed by double-blind placebo-controlled oral provocation tests with NSAIDs. Genotyping of A-444C was performed by real-time polymerase chain reaction using Taqman probes. Atopy was defined as a positive skin test result to any of the 25 aeroallergens tested. Total and mite-specific immunoglobulin (Ig) E levels in serum were quantified using an enzyme-linked immunosorbent assay, Results: A-444C was associated with AIU. The C allele was more frequent in patients with the cutaneous pattern of AIU and in patients with low skin reactivity to histamine. There was no association between A-444C and asthma, atopy, or total IgE levels., Conclusion: The C allele of the A-444C polymorphism is a risk factor for AIU in our population and could be a genetic marker for this phenotype. Furthermore, this single-nucleotide polymorphism is mainly associated with the cutaneous clinical pattern and with low skin response to histamine.

The pathogenic mechanism of acetyl salicylic acid (ASA)-induced urticaria (AIU) is not fully understood. We compared the levels of neutrophil activation and related cytokines in patients with ASA-intolerant acute urticaria (AIAU) and ASA-intolerant chronic urticaria (AICU). A total of 51 patients with AIAU, 88 patients with AICU, and 102 normal controls (NC) were enrolled in this study. The serum levels of myeloperoxidase (MPO), interleukin-8 (IL-8), and IL-18 were compared among the three groups. The serum levels of MPO were highest in the AIAU group, followed by the AICU and NC groups, and the serum levels of IL-18 were significantly higher in the AIAU and AICU groups than in NC group. Within the AIU groups, significant correlations were noted between the levels of MPO and IL-8, and IL-8 and IL-18. In conclusion, neutrophil activation, which was associated with the levels of IL-8 and IL-18 in the AIAU group, may be involved in the pathogenic mechanism of AIU. A role for IL-18 in the pathogenesis of AIU is also suggested.

Background: It has been suggested that oxidative stress is a crucial event in some forms of urticaria., Aim: To evaluate the blood oxidant/antioxidant profile of patients suffering from urticaria induced by nonsteroidal anti-inflammatory drugs (NSAIDs)., Methods: We measured the activity of the antioxidant enzymes copper-zinc superoxide dismutase (Cu/ZnSOD), glutathione peroxidase (GSH-Px), and catalase (CAT), and the levels of malondialdehyde (a marker of lipid peroxidation) in the plasma and erythrocytes of 12 females with NSAID-induced urticaria and in 19 healthy controls., Results: The enzyme activity in plasma (CuZn/SOD) and in erythrocytes (CuZn/SOD, GSH-Px, and CAT) did not differ significantly between urticaria patients and controls. Moreover, the levels of malondialdehyde in plasma and erythrocytes did not differ significantly between the 2 groups., Conclusions: It seems that processes associated with urticaria induced by NSAIDs may not modify antioxidant enzyme activity and may not enhance lipid peroxidation in peripheral blood.

Adverse drug reactions with an immunological basis (ADRIB) may involve activation of other concomitant, non-specific mechanisms, amplifying the specific response and contributing to the severity and duration. One concomitant mechanism could be the generation of reactive oxygen species (ROS) and/or their detoxification by anti-oxidants, including anti-oxidant enzymes. We analysed the activity of the anti-oxidant enzymes Cu/Zn-superoxide dismutase (SOD), catalase (CAT) and cellular glutathione peroxidase (GPX), as well as certain markers of oxidative damage (thiobarbituric acid reactive substances (TBARS) and carbonyl content) in peripheral blood mononuclear cells from patients with non-immediate ADRIB using spectrophotometric methods and the anti-oxidant enzymes expression by quantitative real-time reverse transcription-polymerase chain reaction. SOD activity and expression were increased in all types of non-immediate reactions (urticaria, maculopapular exanthema and toxic epidermal necrolysis). Regarding oxidative damage, TBARS were increased in urticaria and maculopapular exanthema, and carbonyl groups in all types of reactions. Our observations indicate that oxidative damage occurs in non-immediate reactions. Carbonyl stress and the inadequacy of the anti-oxidant defences are probable causes.

Aspirin was introduced into medicine over a century ago and has become the most popular drug in the world. Although the first hypersensitivity reaction was described soon after aspirin had been marketed, only recently a phenomenon of cysteinyl leukotriene overproduction brought new insights on a balance between pro- and anti-inflammatory mediators derived from arachidonic acid. We describe the most common clinical presentations of aspirin hypersensitivity, i.e. aspirin-induced asthma, rhinosinusitis and aspirin-induced urticaria. We also present their biochemical background. Despite relatively high incidence of these reactions, aspirin hypersensitivity remains underdiagnosed worldwide. Acute reactions of aspirin hypersensitivity are elicited via cyclooxygenase inhibition by non-steroid anti-inflammatory drugs. Coxibs, selective inhibitors of cyclooxygenase-2 isoenzyme, do not precipitate symptoms in susceptible patients. Though hypersensitivity correlates with cyclooxygenase-1 inhibition, diminished tissue expression was described only for cyclooxygenase-2. Aspirin-induced asthma and aspirin-induced urticaria, in a substantial part of the patients, are driven by a release of mediators from activated mast cells. These cells in physiological conditions are under inhibitory control of prostaglandin E2. The origin of aspirin hypersensitivity remains unknown, but accumulating data from genetic studies strongly suggest that environmental factor, possibly a common viral infection, can trigger the disease in susceptible subjects.

Certain skin disorders, such as contact dermatitis and chronic urticaria, are characterized by inflammation involving mast cells and worsen by stress. The underlying mechanism of this effect, however, is not known. The skin appears to have the equivalent of a hypothalamic-pituitary-adrenal (HPA) axis, including local expression of corticotropin-releasing hormone (CRH) and its receptors (CRH-R). We have reported that acute stress and intradermal administration of CRH stimulate skin mast cells and increase vascular permeability through CRH-R1 activation. In this study, we investigated the expression of CRH-R1, the main CRH-R subtype in human skin, and the mast cell related gene histidine decarboxylase (HDC), which regulates the production of histamine, in normal and pathological skin biopsies. Quantitative real time PCR revealed that chronic urticaria expresses high levels of CRH-R1 and HDC as compared to normal foreskin, breast skin and cultured human keratinocytes. The lichen simplex samples had high expression of CRH-R1, but low HDC. These results implicate CRH-R in chronic urticaria, which is often exacerbated by stress.

Background: Proteasomes, nonlysosomal proteolytic structures, are implicated in cell growth and differentiation. An abnormal expression has been described in haematopoietic malignancies and in some solid tumours., Objectives: To study the plasma proteasome levels in patients with malignant melanoma (MM) using an enzyme-linked immunosorbent assay (ELISA) technique, and to compare them with the values obtained in a normal population and in patients with severe psoriasis or chronic idiopathic urticaria (CIU)., Methods: Plasma proteasome level was measured using a sandwich ELISA test in normal donors (n = 14), and in patients with stage I/II (n = 13), stage III (n = 6) and stage IV (n = 10) MM, severe psoriasis (n = 13) and CIU (n = 6). Tissue proteasome expression was also detected by immunohistology using a monoclonal antibody in paraffin-embedded samples of normal tissue, psoriasis skin and MM., Results: In normal donors, mean +/- SEM plasma proteasome concentration was 2138 +/- 221 ng mL(-1). Patients with stages III and IV MM exhibited a significantly higher value (3373 +/- 470 ng mL(-1) and 8931 +/- 1232 ng mL(-1), respectively). Values in patients with stage I/II MM and CIU were not significantly different from those in normal volunteers. Patients with severe psoriasis also exhibited increased values (3398 +/- 374 ng mL(-1)) but to a lesser extent than in patients with stage IV MM. There was a significant correlation of proteasome levels with serum lactate dehydrogenase in the MM group. Tissue expression as demonstrated by immunohistochemistry paralleled these findings. The strongest expression was seen on MM slides and to a lesser extent in psoriasis samples, the weakest expression being observed in normal skin., Conclusions: Proteasomes are strongly expressed in cutaneous MM; high levels of circulating proteasomes are detected in patients with metastatic MM with a high melanoma burden, and at a lesser extent in psoriatic patients, which suggests proteasomes represent a marker more of nonspecific inflammation than of early cancer.

Background: Matrix metalloproteinase (MMP)-9 is produced by many inflammatory cells such as macrophages, neutrophils, mast cells, eosinophils and T lymphocytes. Activated T cells are capable, through cell-cell contact, of inducing MMP-9 expression in human mast cells., Objective: To investigate the activation status of peripheral CD4+ T cells and the level of MMP-9 in the plasma of patients with chronic urticaria (CU), and whether MMP-9 levels are in association with CU severity., Methods: Study subjects included 29 patients with CU and 30 healthy control subjects. At the time of assessment, patients were divided into subgroups according to urticarial severity. Plasma levels of total MMP-9 (free pro-MMP-9 and free MMP-9) were determined by ELISA. CD4+ lymphocytes were positively selected with magnetic microbeads. After 48 h of activation, CD4+ T cells were assayed for both nuclear factor-kappa B (NF-kappa B) expression and proliferation., Results: Plasma levels of MMP-9 were found to be significantly higher in 29 CU patients compared with 18 healthy controls (186 +/- 174 vs. 31 +/- 21 ng/mL, P<0.0001). We also found a significant correlation between MMP-9 levels and urticarial severity (r = 0.92, P<0.001). In addition, CD4+ T cells from CU patients expressed higher levels of NF-kappa B than CD4+ T cells from healthy controls (82 +/- 30 vs. 69 +/- 20 optical density, P = 0.007). Finally, as compared with seven healthy individuals, DNA synthesis in CD4+ T cells from seven CU patients was found to be significantly elevated (1000 +/- 240 vs. 751 +/- 166 counts per minute, P = 0.01)., Conclusion: Increased levels of MMP-9 are found in CU patients, and particularly among those with severe disease. We also demonstrated that CD4+ T cells from such patients are highly activated.

We studied the involvement of oxidative stress in chronic idiopathic urticaria (CIU), assessing the activities of superoxide dismutase (SOD) and glutathione and the levels of malondialdeyde (MDA), a marker of lipid peroxidation, in samples taken from lesional skin (n = 16) and nonlesional skin (n = 11) of CIU patients. The activity of SOD and glutathione and the levels of MDA were markedly increased in lesional skin as compared with skin of healthy subjects, whereas no differences were detected between nonlesional skin of CIU patients and control samples. Immuno-dot blot assay revealed an up-regulation of Mn-SOD expression in lesional skin. These findings show that oxidative stress is crucially involved in CIU. The evidence of lipid peroxidation and compensatory increase of Mn-SOD and glutathione activities in lesional skin, in the absence of any alteration in uninvolved skin, suggests that oxidative stress is secondary to the development of inflammation.

Background: Chymase released by mast cells can participate in the immediate allergic wheal. However, chymase may be susceptible to inactivation by protease inhibitors during degranulation., Objective: To study the inactivation of chymase and the release of histamine in the immediate allergic wheal reaction., Methods: Ten sensitive atopic subjects were prick-tested with the cow dander allergen, and skin biopsies were taken from the control skin and from the challenge site at 30 and 120 min. Tryptase (Tact) and chymase (Cact) activities in mast cells were measured enzyme-histochemically. Sequential double-staining was used to demonstrate the activity and immunoreactivity (Cprot) of chymase in the same mast cell as well as alpha1-proteinase inhibitor (alpha1-PI) and alpha1-antichymotrypsin (alpha1-AC) in Tact+ cells. Skin microdialysis was used to monitor histamine release after the allergen challenge for up to 120 min, Results: The numbers of Tact+ and Cact+ cells were already maximally decreased at 30 min by 37 +/- 17% and 61 +/- 31%, respectively (mean +/- SD, P < 0.0001). At the same time the Cact+/Cprot+ ratio decreased from 82 +/- 15% to 43 +/- 16% (P < 0.0001). The cumulative histamine release at 30 min correlated negatively with the Cact+/Tact+ (P = 0.047) and Cact+/Cprot+ (P = 0.024) ratios, but positively with the decrease in the number of Cact+ cells (P = 0.024). These data indicate that the higher the histamine release the lower the chymase activity. Also the number of Tact+ cells in the control skin correlated positively with the cumulative histamine release at 120 min (P = 0.043). In the control skin, 95 +/- 6% and 76 +/- 8% of the Tact+ cells displayed alpha1-AC and alpha1-PI, respectively., Conclusion: In addition to extensive degranulation of mast cells, chymase is also rapidly inactivated after the allergen challenge, possibly by pre-existing chymase inhibitors in the mast cells. This inactivation is associated with the release of histamine.

Background: Acquired cutis laxa is a rare disease characterized by sagging skin, premature wrinkling and reduced skin elasticity., Observation: We report a 21-year-old woman, who presented with acquired cutis laxa on the face and the ear lobes. Urticarial papules had preceded for 6 years. There was no systemic involvement. Skin specimens were obtained from lax skin and urticarial papules, and from healthy controls. Histology showed only few perivascular lymphocytes in lax ear skin and a dense inflammatory infiltrate in urticarial skin. In both biopsies elastic fibres were decreased as demonstrated by computerized morphometric analyses. Elastase activities of fibroblasts in culture were evaluated. There was a 2- to 3-fold increase in elastase activity in urticarial skin fibroblasts, contrasting with a normal elastase activity in lax ear skin., Conclusion: Our findings suggest that the inflammatory cells could play a significant role in the destruction of elastic fibres.

We present a 48-year-old patient who complained for 1 year about urticarial reactions which appeared always when he ingested alcoholic beverages. Skin prick tests with ethanol were negative but positive with 10% acetic acid in the patient. Normal controls tested negative with acetic acid. Skin prick tests to common immediate-type allergens were negative. The patient underwent a double-blind, placebo-controlled challenge test. A few minutes after challenge with ethanol but not with placebo, the patient developed erythema and wheals on the chest and the upper arms. The tryptase serum level rose from undetectable (0.1 U/ml) before challenge to 3.8 U/ml after skin lesions had appeared. This case demonstrates that increased tryptase serum levels can help in the diagnosis of ethanol-induced urticaria.

We evaluated the usefulness of individual tryptase levels and variations after adverse drug reactions in 64 patients. Our aim was to find a tool for the diagnosis of drug allergy. Thirty-seven subjects were confirmed to have drug allergy, 12 had nonsteroidal anti-inflammatory drug (NSAID) reactions, five had negative controlled drug challenges (NAAR), and 10 had symptoms after placebo intake (PLA). Serum tryptase levels greatly increased after anaphylactic shocks (2242%) and anaphylaxis (710.5%). Patients with allergic urticaria and those with idiosyncratic responses to acetylsalicylic acid (ASA) exhibited a small increase in serum tryptase (49.5% and 38.2%, respectively). In the other two groups (NAAR and PLA), no variation in this serum protease was observed. The time of appearance of the serum tryptase peak differed considerably among patients with similar clinical reactions (from 30 min to 6 h) and was independent of the latent period, severity of symptoms, or the amount of tryptase released. We conclude that serum tryptase determinations are helpful in the diagnosis of anaphylactic shock and anaphylaxis, but serial measurements may be needed to confirm mast-cell participation in milder reactions.

The measurement of Tryptase by the Fluoro-Immuno-Enzymatic (FEIA) method is nowadays possible on the Pharmacia CAP system (automatic UniCAP). This measurement is more comprehensive as it measures the release of serum tryptase from both the tissue mastocytes (MCTC) as well as the mucosal mastocytes (MCM). Technically the measurements are comparable with those made by the method of radio-immunology (RIA), are absolutely reproducible and surprisingly at 100%. It has also been possible to evaluate the two techniques of FEIA and RIA on negative and positive pools. This new FEIA technique for serum tryptase is applicable: to anaphylactic and/or anaphylactoid accidents at the time of induction of anesthesia, in general conditions such as haemorrhagic recto colitis (RCH), Crohn's disease, and mastocytosis. Finally these measurements can be used during nasal and bronchial provocation tests, as the measurements may be made on nasal and bronchial lavage liquids. The sensitivity and the very good reproducibility of this new technique of FEIA for tryptase is of very great interest and avoids use of radio-active isotopes.

Urticarial dermographism and delayed pressure urticaria are two forms of physical urticaria which are well defined clinically and histologically. Previous studies have shown eosinophil granule protein deposition in urticarial reactions, including chronic urticaria, solar urticaria and delayed pressure urticaria. To evaluate and compare the involvement of granulated inflammatory cells in urticarial dermographism and delayed pressure urticaria, we studied sequential biopsies of induced lesions of urticarial dermographism and delayed pressure urticaria by indirect immunofluorescence, to detect eosinophil granule major basic protein (MBP) and neutrophil granule elastase. Biopsies from dermographic lesions at time 0, 5 min, 15 min, 2 h and 24 h, showed few infiltrating eosinophils, with minimal extracellular MBP deposition, and a few infiltrating neutrophils, with minimal neutrophil elastase deposition, throughout the evolution of the lesions. Sequential biopsies of delayed pressure urticaria at time 0, 20 min, 6, 12 and 24 h, showed eosinophil infiltration with extensive MBP deposition beginning at 20 min, and neutrophil infiltration with variable elastase deposition beginning at 20 min. Control tissue specimens from normal volunteers showed neutrophil infiltration and slight degranulation, but no eosinophil infiltration or degranulation. Comparison of urticarial dermographism with delayed pressure urticaria showed marked differences in the patterns of infiltration. Delayed pressure urticaria, with eosinophil and neutrophil degranulation, was strikingly similar to the IgE-mediated late phase reaction. In contrast, eosinophil and neutrophil involvement in urticarial dermographism was minimal. Considering the extent of eosinophil granule protein deposition and the biological activities of the eosinophil granule proteins, the findings in delayed pressure urticaria point to an important pathophysiological role of eosinophils in the disease.

Tryptase (T), chymase (C), carboxypeptidase A, cathepsin G-like constituent of preformed mediators contained in mastocyte granules, are a group of neutral proteases with proteolytic activity. These enzymes gives differentiation of two groups of mastocytes, MCTC and MCT as a function of the richness of enzymes. Although the functions of these molecules are becoming better and better understood, their exact roles as well as that of their inhibitors, still remain to be explored in urticaria.

Food intolerance is not IgE-mediated but caused by histamine. A diminished histamine degradation based on a deficiency of diaminoxidase is suspected to be the reason. The therapeutic efficacy of a histamine-free diet was evaluated in 100 patients with food intolerance and allergic diseases, who were required to avoid fish, cheese, hardcured sausage, pickled cabbage, wine and beer for 4 weeks. Considerable improvement was observed in 57 patients, 15 of whom had total remission. The most striking treatment results were obtained in food or wine intolerance (80% P < 0.05; treatment of choice), bronchial asthma (80%), headache (64%) and urticaria (58%). After ingestion of food rich in histamine clearcut recurrence of atopic eczema was seen in 50% of the patients affected. Histamine plays a major part in food and wine intolerance. Histamine in food causes worsening of symptoms in atopics and patients suffering from headache. The results obtained indicate a deficiency of diaminoxidase in patients with intolerance to food or wine. Histamine levels in alcoholic beverages should be displayed on the labels.

The authors draw attention to the problem of elevated values of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) serum activities in adolescents which they encountered recently in two patients hospitalized in their clinic. In common practice it is important when evaluating results of ALT, AST and CK in serum to take into account the effect of physical load, encountered frequently in this age group of adolescents.

We have studied the plasma kallikrein amidolytic activity in healthy control subjects (inactive), patients with chronic urticaria (active) and patients with acute urticaria (active) from their admission to the emergency room (active) to the time after which their clinical symptomatology had disappeared (inactive). We found statistically significant differences (p < 0.01) in the active groups of urticaria patients. This leads us to believe that kallikrein participates in the development of symptomatology in these patients.

The levels of tryptase in the suction-blister fluid from patients with chronic urticaria, urticaria pigmentosa, cholinergic urticaria, urticarial dermographism, prurigo of unknown origin, eczema, psoriasis, atopic dermatitis, and from healthy controls were studied. The blister fluid from controls contained up to 15 micrograms/l of tryptase, whereas that from patients with active urticaria contained greater than 50 micrograms/l. This study demonstrates that patients with urticaria have mast cells that readily release tryptase in both the lesional and non-lesional areas of skin.

27 patients with relapsing and giant urticaria accompanied by multiple general respiratory viral infection and herpetism were studied during acute and remittent steps as compared with 13 healthy volunteers. 10 patients were treated with reaferon. Elevated rates of circulating interferon and interferon-dependent enzymes as well as a decreased ability of leukocytes and lymphocytes to produce alpha- and gamma-interferons were detected in these patients. Anomalous reactions of the interferon system were found in the patients with urticaria and general viral respiratory infection simultaneously with impairments of the immunity response: discorrelation between rates of interferon-dependent enzymes and circulating interferon. The course of interferon therapy within 5 days using recombinant alpha 2-interferon did not obviate these deteriorations, although activity of 2-5A synthetase tended to decrease down to the level observed in healthy persons.

An abnormal metabolism of histamine has been suspected in urticaria and the role of diamine oxidase (DAO: histaminase) is therefore of interest. We have studied DAO activity in plasma and jejunal biopsy material and have measured the post-heparin DAO release in 11 control subjects and nine with recurrent urticaria, three of whom had had concurrent episodes of abdominal pain. Two of the nine urticaria subjects had only a minimal rise in plasma DAO activity after heparin, three had a response which was at the lower end of the normal range, and four were normal. In four out of five cases in which jejunal biopsy activity was obtained, there was concordance between mucosal DAO activity and the post-heparin plasma DAO response. Those with abdominal symptoms had abnormally low mucosal DAO activity and the subject who was most severely affected had proven episodes of small bowel oedema.

In 150 patients with different dermatoses and 15 controls the activity of collagen peptidase in serum was determined. No relation to specific skin diseases was found. Negative findings were also observed in the group of collagenoses: only 4 of 14 patients with progressive systemic sclerosis showed an increase of this enzyme activity. These negative results seem noteworthy because it thus is demonstrated that alterations of collagen structure are not necessaryly associated with alterations of collagen peptidase activity.

25 patients with chronic urticaria suspected to be of 'alimentary origin', were studied for a quantitative or qualitative deficiency of pancreatic enzyme secretion. All showed a normal fecal chymotrypsin excretion and 23/25 a normal bentiromide (PABA) and pancreolauryl test. In 2 females the urinary PABA and pancreolauryl tests were borderline pathological. This does not support the hypothesis that a pancreatic deficiency (of the kind which could be identified with the methods used) is associated with chronic urticaria in patients in whom improvement of urticaria occurs under a hydric or low antigenic diet.

Eosinophil diamine oxidase, histaminase, activity was assayed in acute inflammatory states and correlated to disease activity. Correlation to serum and urine histamine, metabolites of histamine and granulocyte histamine metabolizing enzymes was also studied. Using a radiochromatagraphic assay, diamine oxidase, histaminase, activity was determined in human peripheral blood eosinophils from patients with acute inflammatory states including active asthma, cold-induced urticaria and parasitic infestation; eosinophils from non-active asthmatic patients and normals were used as controls. Eosinophils were purified over a metrizamide discontinuous (16-30%) gradient. Total eosinophils were purified over a metrizamide discontinuous (16-30%) gradient. Total eosinophil histaminase activity was increased two- to three-fold in patients with active disease and returned to lower levels in eosinophils from patients without active disease or with treated disease. Thus, the induction of eosinophil histaminase might be a control mechanism for the inflammation induced by histamine during these acute inflammatory states.

The hypothesis that deficiencies of plasma protease inhibitors might play a role in the pathogenesis of chronic urticaria was evaluated. Plasma levels were measured in patients with urticaria and a matched control group for alpha1-antitrypsin, alpha2-macroglobulin, total trypsin-inhibiting capacity, kallikrein-inhibiting capacity, and the complement factors C1 esterase inhibitor, C3, and C4. A total of 92 patients with chronic urticaria or more than three months' duration was studied. Patients with acquired cold urticaria had significantly decreased levels of alpha1-antitrypsin and total antitrypsin activity. In patients with acquired angioneurotic edema, alpha1-antitrypsin levels and antichymotrypsin activities were lowered, with less significant decreases in anti-trypsin and antikallikrein activities. Levels of C1 esterase inhibitor , C3, and C4 were normal in all groups. There was no correlation between the increased sensitivity to intracutaneously administered kallikrein injection and deficiencies of of protease inhibitors.

Lysosome enzymes were measured in patients with allergic dermatosis before and after high altitude climate therapy. The activity of five acid lysosomal hydrolases in the serum of patients with allergic dermatoses before and after 30 days were investigated. In all cases a reduction of the activity of alpha-glucosidase was observed. A similar reduction of the activity of beta-glucuronidase and beta-galactosidase was observed.

A 33-year-old female patient with acquired cold urticaria, together with her 8-year-old healthy daughter, was subjected to a brief period of cold exposure. The effect of this treatment upon a number of key factors of the plasma coagulation, kallikrein and complement systems was investigated. Cold air provocation caused increased fibrinolysis, together with a measurable consumption of the protease inhibitors alpha1-antitrypsin (alpha1AT), alpha2-macroglobulin (alpha2M) and C1Inactivator (C1INA). Kaolin activation of the patient's plasma elaborated exceptionally high levels of esterolytic activity, both before and after cold exposure, indicating pre-enzyme lability. Both subjects had abnormally high serum ratios alpha2M/alpha AT. Impressive leucocytosis was observed in the symptomless child.

Results of a study in 62 patients with urticaria and 30 controls, all under 12 years of age, are reported. The study involved history taking and assays of immunoglobulins A, G, M, D, E, of complement fractions C3c and C4 and estimation of C1 estease inactivator activity in the plasma. Acute urticaria is more frequent than chronic urticaria in children, expecially in subjects with atopic diathesis; papular urticaria (or strophulus infantum) is particularly frequent in children under 6 years of age and in the male. Assays of plasma immunoglobulins demonstrated selective deficiency of IgA in two and significant reduction of this immunoglobulin in a further three cases. The mean levels of IgE proved normal in chronic urticaria, raised in acute urticaria, and very high in papular urticaria. Complement assays demonstrated, in one case, a reduction of C3c below 60 mg/100 ml, persisting after the disappearance of urticaria.