Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

Objective: The aim of the study was to evaluate the expression of tumor necrosis factor (TNF)-a protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNFa, soluble TNF-receptor-2 (sTNFR-2) and indirect parameters of insulin resistance in overweight/obese and lean healthy persons. Design: A cross-sectional case-control study was used. Patients: Twenty-eight overweight/obese probands with normal glucose tolerance (BMI . 27 kg/m 2 ) and 15 lean people (BMI , 25 kg/m 2 ), all of them undergoing planned surgical operation, participated in the study. Methods: Two to four grams of subcutaneous and visceral adipose tissue were removed and studied using semi-quantitative immunohistochemical staining of the TNF-a protein. Serum TNF-a, sTNFR-2 (ELISA) and fasting C-peptide (RIA) were measured. Results: TNF-a protein was expressed in adipocytes of both depots. The expression was evaluated visually and found to be greater in the obese patients. Significantly higher serum TNF-a (5.58^0.87 pg/ml vs 4.21^0.55, mean^S.D., P , 0.01, Mann -Whitney) and sTNFR-2 levels (7.84^3.56 ng/ml vs 4.59^1.35, P ¼ 0.005) were found in the obese subgroup in correlation with the fasting C-peptide level (r ¼ 0.49, P ¼ 0.003; and r ¼ 0.74, P ¼ 0.001) and the C-peptide/ blood glucose ratio (r ¼ 0.47, Spearman, P ¼ 0.005; and r ¼ 0.70, P ¼ 0.001). The cell volume of both adipocyte depots was found to have a significant positive correlation with serum TNF-a and sTNFR-2 levels in the total group of patients (subcutaneous: r ¼ 0.52, P ¼ 0.0003; r ¼ 0.69, P , 0.0001; visceral: r ¼ 0.65, P , 0.0001; r ¼ 0.63, P , 0.0001) and in both subgroups. Conclusions: Adipocyte cell volume of both the subcutaneous and visceral fat depots may be determinants of TNF-a, sTNFR-2 production and obesity-linked insulin resistance.

Among the genes and proteins of the human immune system, complement component C4 is extraordinary in its frequent germline variation in the size and number of genes. Definitive genotypic and phenotypic analyses were performed on a central European population to determine the C4 polygenic and gene size variations and their relationships with serum C4A and C4B protein concentrations and hemolytic activities. In a study population of 128 healthy subjects, the number of C4 genes present in a diploid genome varied between two to five, and 77.4% of the C4 genes belonged to the long form that contains the endogenous retrovirus HERV-K(C4). Intriguingly, higher C4 serum protein levels and higher C4 hemolytic activities were often detected in subjects with short C4 genes than those with long genes only, suggesting a negative epistatic effect of HERV-K(C4) on the expression of C4 proteins. Also, the body mass index appeared to affect the C4 serum levels, particularly in the individuals with medium or high C4 gene dosages, a phenomenon that was dissimilar in several aspects from the established correlation between body mass index and serum C3. As expected, there were strong, positive correlations between total C4 gene dosage and serum C4 protein concentrations, and between serum C4 protein concentrations and C4 hemolytic activities. There were also good correlations between the number of long genes with serum levels of C4A, and the number of short genes with serum levels of C4B. Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system.

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OBJECTIVE -To compare the clinical parameters, C-peptide levels, pattern of islet cellspecific autoantibodies, and prevalence of predisposing genotypes in subjects with latent autoimmune diabetes in adults (LADA) and those with adult-onset type 1 diabetes with rapid progression.RESEARCH DESIGN AND METHODS -We evaluated the clinical parameters, Cpeptide levels, and islet cell-specific autoantibodies in 54 LADA, 57 adult-onset type 1 diabetic, and 190 type 2 diabetic patients. Islet cell autoantibodies were also compared between subgroups of newly diagnosed patients with LADA and those with newly diagnosed adult-onset and childhood-onset type 1 diabetes. The genetic study was performed in subjects with LADA and those with adult-onset type 1 diabetes in comparison with a control population.RESULTS -There were no differences in the clinical parameters between LADA and adultonset type 1 diabetes. Patients with LADA had lower BMI (P Ͻ 0.0001), waist-to-hip ratio (0.0029), total cholesterol (P ϭ 0.001), and triglycerides (P ϭ 0.001); higher HDL cholesterol levels (P Ͻ 0.0001); and lower prevalence of hypertension (P ϭ 0.0028) compared with patients with type 2 diabetes. C-peptide levels were similar at onset (P ϭ 0.403) but decreased less rapidly in LADA than in adult-onset type 1 diabetes (P ϭ 0.0253). Single-autoantibody positivity was more often seen in LADA than in type 1 diabetes (P ϭ 0.0001). The prevalence of predisposing HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 genotypes and the DR4-DQB1*0302 haplotype were increased in both LADA and adult-onset type 1 diabetic subjects compared with the control population. There were no differences in the frequencies of these risk alleles and haplotypes between the two patient groups.CONCLUSIONS -Subjects with LADA had clinical characteristics similar to those with adult-onset type 1 diabetes with rapid progression. C-peptide levels did not differ at onset but decreased less rapidly in LADA. Patients with LADA rather had single islet cell-specific autoantibody positivity. The prevalence of HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 risk alleles and the DR4-DQB1*0302 high-risk haplotype did not differ in the two forms of autoimmune diabetes.