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.

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We examined how work-family conflict (WFC) mediated the relationship between social support (supervisor and family) and burnout, and how sex moderated this relationship (N = 343 Spanish workers). The results sustained hypotheses in accordance with a biosocial model of sex differences. There were full mediation effects of work interference with family (WIF) in the association of work support with burnout for men, and of family support with burnout for women. This suggests that sex moderated these mediation processes. The findings are discussed in terms of a shift in the differential assignment of family roles to men and women, despite the fact that women might be the main contributors to domestic work and related tasks.

Mutations in p73 are rare in cancer. Emerging evidence suggests that the relative expression of various p73 isoforms may contribute to tumorigenesis. Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (⌬N) p73 isoforms. TAp73 possesses pro-apoptotic functions, while ⌬Np73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we report that TAp73, but not ⌬Np73, is covalently modified by NEDD8 under physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a cysteine protease that specifically cleaves NEDD8 conjugates, was shown to deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway increased TAp73-mediated transactivation of p53-and p73-responsive promoter-driven reporter activity, and in conjunction, neddylated TAp73 species were found preferentially in the cytoplasm. These results suggest that Mdm2 attenuates TAp73 transactivation function, at least in part, by promoting NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of a covalent posttranslational modification exclusively targeting the TA isoforms of p73.p73 is a member of the p53 family that binds p53 DNAbinding sites, transactivates p53-target genes, and induces apoptosis (1-3). p73 mutations are rarely observed in cancer (4). However, p73 exists as multiple C-terminal (␣, ␤, ␥, ␦, ⑀, and ) and N-terminal (TA and ⌬N) isoforms, and accumulating evidence suggests that the relative expression and stability of the different N-terminal isoforms of p73 may play a role in tumorigenesis. Full-length TAp73 3 isoforms have pro-apoptotic properties, whereas the N-terminally truncated ⌬Np73 isoforms, which lack the transactivation domain due to the use of a promoter within intron 3 and alternative N-terminal mRNA splicing, have anti-apoptotic properties. ⌬Np73 acts as a negative inhibitor of both TAp73 and p53, either via hetero-oligomerization or through competition for DNA-binding sites (5-10). Furthermore, ⌬Np73 expression has been shown to be elevated in a number of human cancers, including breast, ovarian, hepatocellular, prostate, colon, and neuroblastoma tumors (11-15). Increased ⌬Np73 expression has been associated with poor prognosis in patients, and this finding has been attributed to ⌬Np73 inhibition of p53 and TAp73 causing chemoresistance (10,12,16,17). Conversely, a recent study demonstrated that aged p73 heterozygous mice develop spontaneous tumors, and in comparison with p53 heterozygous mice, mice heterozygous for both p53 and p73 have different tumor spectrums and higher tumor burden and incidence of metastasis, presumably due to the loss of function of the pro-apoptotic TAp73 isoforms (18). Studies have also established a role for TAp73 in chemotherapy-induced apoptosis and the status of TAp73 may be an important determinant of chemotherapeutic efficacy in humans (17,19,20). Therefore, therapeutic modulation of the relative levels of TAp73 and ⌬Np73 isoforms has pote...

Hereditary angioedema (HAE) is a disease caused by defects in the C1 inhibitor gene (SERPING1/C1NH). We screened the entire C1NH gene for mutations in a large series of 87 Spanish families (77 with type I, and 10 with type II HAE) by SSCP, sequencing, Southern blotting, and quantitative multiplex PCR of short fluorescent fragments (QMPSF), and we characterized several defects at the mRNA level. We found large rearrangements in 13 families, and point mutations or microdeletions/insertions in 74 families. The 13 large rearrangements included nine exon deletions, of which at least eight were distinct, two were distinct exon duplications, and two were rearrangements whose precise nature could not be determined. We confirmed that exon 4 is particularly prone to rearrangements. Thirty-six mutations were unreported, and included 10 microdeletions/insertions, 10 missense, five nonsense, eight splicing, and three splicing or missense mutations. Moreover, we detected six novel uncharacterized sequence variants (USV). RT-PCR studies showed that in addition to several intronic splice site mutations tested, the exonic mutations c.882C>G and c.884T>G, located near the 3' end of exon 5, also produced exon skipping. This is the first evidence of SERPING1/C1NH mutations in coding regions that differ from the canonical splice sites that affect splicing, which suggests the presence of an exonic splicing enhancer (ESE) in exon 5.