Risk factors for asthma in inner city children.

Inner city children have the highest prevalence and the highest mortality rates for asthma in the United States. The purpose of this study was to evaluate sensitization and exposure to common indoor allergens among children aged 3 years to 15 years seen for treatment of asthma at Grady Memorial Hospital, Atlanta, Ga. Eighty children in this study were enrolled in the emergency department and 64 in hospital clinics. Dust from 57 homes, assayed for three indoor allergens (dust mite, cat, and cockroach), revealed similar exposure for asthma and control groups. Sixty-nine percent of the children with asthma had IgE antibodies to dust mite, cockroach, or cat; only 27% of the control subjects were similarly sensitized (p < 0.001). Of 35 children with asthma 21 had both sensitization and significant exposure to the relevant allergen; this was true for only 3 of 22 control subjects (odds ratio, 9.5; p < 0.001). Neither sensitization nor exposure to cat allergen was common in this population. The results show that black children in inner city Atlanta are exposed to high levels of mite and cockroach allergens and that a high proportion of the children with asthma are sensitized to these allergens; the combination of sensitization and exposure is a major risk factor for asthma in this population.     

The clastogenic response of the 1q12 heterochromatic region to DNA cross-linking agents is independent of the Fanconi anaemia pathway

Fanconi anaemia (FA) is a rare genetic syndrome of cancer susceptibility characterized by spontaneous and induced chromosome fragility, especially after treatment with cross-linking agents. Recent investigations showed interactions between FA proteins and chromatin remodelling factors. To investigate a potential uneven distribution of the FA pathway through the human genome depending on chromatin conformation, we have analysed chromosome breakage in the largest constitutively heterochromatic region in the human genome, the 1q12 band, in lymphocytes from FA patients, carriers and healthy controls after treatment with the cross-linking agents mitomycin-C (MMC) and diepoxybutane (DEB). As expected, a higher level of MMC-induced cytotoxicity and chromosome breakage was observed in cells from FA patients when compared with normal controls and carriers. However, the increase in 1q12 breakage after increasing concentrations of MMC was of a similar magnitude in FA patients, carriers and controls. Similarly, DEB induced a high level of overall genome chromosome fragility in cells from FA patients when compared with controls with no parallel increase in chromosome breaks specifically involving the heterochromatic band 1q12. We therefore conclude that, unlike the overall genome, the sensitivity of chromosome 1 constitutive heterochromatin to the chromosome breaking activity of cross-linking agents is independent of a functional FA pathway, indicating that the action of the FA pathway is unevenly distributed through the human genome.     

Association between haplotypes, Hind III-VNTR alleles and mutations at the PAH locus in Sicily

In this study we report previously undescribed associations between mutations, haplotypes and a minisatellite polymorphism (Hind III VNTR) of the PAH gene in the Sicilian population. Analysis of the association between mutations and linked polymorphisms between Sicilians and other Mediterranean populations may be a useful tool to study the time-space origin of mutant PAH genes in Southern Europe.     

Molecular mechanisms for the assembly of the T cell receptor-CD3 complex

The T cell receptor (TCR)–CD3 complex represents on of the most intricate membrane receptor structures since it is built from six distinct chains. This complexity led to a number of different proposals for the arrangement of the receptor subunits, its stoichiometry and the mechanisms responsible for receptor triggering. Early work had demonstrated that basic and acidic transmembrane (TM) residues were involved in the assembly but the molecular arrangement could not be deduced due to the complexity of the receptor. Using a novel method for the isolation of intact radiolabeled protein complexes, we demonstrated that the complex assembled in the ER contains only a single TCRβ heterodimer and one copy of each of the CD3δ, CD3γ and ζ–ζ signaling dimers. Surprisingly, assembly of each of the three signaling dimers with TCR was dependent on one of the three basic TCR TM residues as well as both acidic residues located in the TM domains of the interacting signaling dimer. Each assembly step thus results in the formation of a three-helix interface in the membrane that involves one basic and two acidic TM residues, and this arrangement effectively shields these ionizable residues at protein–protein interfaces from the lipid. Since proteins whose TM domains have exposed ionizable residues are not stably integrated into the lipid bilayer, assembly based on shielding of ionizable residues permits full equilibration of the receptor into the lipid bilayer and prevents degradation. Assembly, export of intact receptor complexes and degradation of unassembled components thus rely on the same organizing principle.