Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma

Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene (cys-LT) production, probably by removing PGE2-dependent inhibition. To investigate why aspirin does not cause bronchoconstriction in all individuals, we immunostained enzymes of the leukotriene and prostanoid pathways in bronchial biopsies from AIA patients, aspirin-tolerant asthma (ATA) patients, and normal (N) subjects. Counts of cells expressing the terminal enzyme for cys-LT synthesis, LTC4 synthase, were fivefold higher in AIA biopsies (11.5+/-2.2 cells/mm2, n = 10) than in ATA biopsies (2.2+/-0.7, n = 10; P = 0. 0006) and 18-fold higher than in N biopsies (0.6+/-0.4, n = 9; P = 0. 0002). Immunostaining for 5-lipoxygenase, its activating protein (FLAP), LTA4 hydrolase, cyclooxygenase (COX)-1, and COX-2 did not differ. Enhanced baseline cys-LT levels in bronchoalveolar lavage (BAL) fluid of AIA patients correlated uniquely with bronchial counts of LTC4 synthase+ cells (rho = 0.83, P = 0.01). Lysine-aspirin challenge released additional cys-LTs into BAL fluid in AIA patients (200+/-120 pg/ml, n = 8) but not in ATA patients (0. 7+/-5.1, n = 5; P = 0.007). Bronchial responsiveness to lysine-aspirin correlated exclusively with LTC4 synthase+ cell counts (rho = -0.63, P = 0.049, n = 10). Aspirin may remove PGE2-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cys-LTs leading to bronchoconstriction.     

Frequency of ApoB and ApoE gene mutations as causes of hypobetalipoproteinemia in the framingham offspring population

Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generated by an error-prone DNA polymerase, and the mismatch repair pathway may process the mispairs. To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2-/- mice were immunized with oxazolone, and B cells were analyzed for mutation in their VkappaOx1 light chain genes. The frequency of mutation in the repair-deficient mice was similar to that in Msh2+/+ mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bias for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G.C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C.     

Influence of the estrous cycle on the sensitivity to catecholamines in right atria from rats submitted to foot-shock stress

We investigated the mechanisms of the alterations in sensitivity to catecholamines in right atria from female rats exhibiting regular 4-day estrous cycles after three foot-shock sessions at estrus, metestrus, and diestrus or at diestrus, proestrus, and estrus. Right atria from stressed rats sacrificed at diestrus showed subsensitivity to noradrenaline and adrenaline. After in vitro sympathetic denervation (38 microM 6-hydroxydopamine) plus inhibition of neuronal reuptake (0.1 microM desipramine) subsensitivity to noradrenaline was abolished, but it was again evident when extraneuronal uptake was also inhibited (10 microM phenoxybenzamine and 30 microM corticosterone). The same pretreatment abolished the subsensitivity to adrenaline. After addition of 1 microM butoxamine, a beta 2-adrenoceptor antagonist, the tissues from stressed rats were subsensitive to adrenaline. Right atria from stressed rats sacrificed at estrus did not show any alteration in sensitivity to catecholamines. We conclude that after foot-shock stress, right atria from female rats sacrificed at diestrus showed subsensitivity of the chronotropic response to catecholamines as a result of a conformational alteration of beta 1-adrenoceptors, simultaneously with an increase in beta 2-adrenoceptor-mediated response. The mechanisms seem to be similar to those which underlie stress-induced alterations in catecholamine sensitivity in right atria from male rats. However, during estrus there are some protective factors that prevent the effects of stress on right atria.     

Immunogenetic analysis of the heavy chain variable regions of IgE from patients allergic to peanuts

Although the histologic examination of routine tissues, such as hernia sacs and intervertebral disks, has shown a low incidence of detecting clinically significant unsuspected disease, the cost-effectiveness of histologic examination has not been determined. By using a theoretical model that assumed variable costs and gains in life expectancy secondary to detecting clinically significant disease, a threshold incidence of disease detection at which histologic examination is cost-effective was determined. By using the University of lowa (Iowa City) cost of examination (approximately $25), at least 1 of every 2,000 examinations would have to show clinically significant disease for histologic examination to be cost-effective. This threshold incidence decreases as production costs decrease or life-year values increase. Before definitive policy conclusions can be made, additional studies are needed to better define the trade-off between cost and the value of information and the incidence of detecting clinically significant disease.     

Does the mode of donor death influence the early outcome of lung transplantation? A review of lung transplantation from donors involved in major trauma

BACKGROUND: Pulmonary dysfunction, often delayed in presentation, is among the sequelae of major trauma. Transplantation of lungs from donors involved in major trauma therefore carries a risk of early graft dysfunction. This study was conducted to assess this risk. METHODS: A retrospective comparison of the outcome from 123 donors (57 donors resulting from major trauma, group T, and 66 donors with nontraumatic origin, group NT) in 125 consecutive technically successful lung or heart-lung transplantations. Variables analyzed included the following: clinical and bacteriologic details of donors and indexes of early graft dysfunction in the recipients. RESULTS: Group T donors were more likely to be younger and male (p < 0.05) and more likely to have had lung ventilation for over 48 hours (p < 0.05) than group NT donors. Microbial contamination of routine donor bronchial lavage (72 of 122, 61%) was no higher in group T (34 of 57, 60%), but, in this group, enteric gram-negative bacilli were more common (30% versus 7%; p < 0.05). Male patients were more likely to receive lungs from group T donors (35 male, 23 female), and female patients were more likely to receive lungs from group NT donors (27 male, 40 female). Mode of donor death did not affect the following indexes of early graft function: length of postoperative ventilation, ratio of arterial oxygen tension to fractional concentration of inspired oxygen at 1 or 24 hours after transplantation, or the incidence of diffuse alveolar damage in lung biopsy specimens at 7 days. Thirty-day mortality (28%) was no higher among recipients of group T lungs, but six recipient deaths were donor-related (donor-transmitted pneumonia in five and donor acquired fat embolism in one case). CONCLUSION: The use of donors involved in major trauma does not increase the risk of early complications after lung transplantation providing their specific characteristics are recognized.     

Effects of ear plugging on single-unit azimuth sensitivity in cat primary auditory cortex. I. Evidence for monaural directional cues

1. Single-unit recordings were carried out in primary auditory cortex (AI) of barbiturate-anesthetized cats. Neurons, sensitive to sound direction in the horizontal plane (azimuth), were identified by their responses to noise bursts, presented in the free field, that varied in azimuth and sound pressure level (SPL). SPLs typically varied between 0 and 80 dB and were presented at each azimuth that was tested. Each azimuth-sensitive neuron responded well to some SPLs at certain azimuths and did not respond well to any SPL at other azimuths. This report describes AI neurons that were sensitive to the azimuth of monaurally presented noise bursts. 2. Unilateral ear plugging was used to test each azimuth-sensitive neuron's response to monaural stimulation. Ear plugs, produced by injecting a plastic ear mold compound into the concha and ear canal, attenuated sound reaching the tympanic membrane by 25-70 dB. Binaural interactions were inferred by comparing responses obtained under binaural (no plug) and monaural (ear plug) conditions. 3. Of the total sample of 131 azimuth-sensitive cells whose responses to ear plugging were studied, 27 were sensitive to the azimuth of monaurally presented noise bursts. We refer to these as monaural directional (MD) cells, and this report describes their properties. The remainder of the sample consisted of cells that either required binaural stimulation for azimuth sensitivity (63/131), because they were insensitive to azimuth under unilateral ear plug conditions or responded too unreliably to permit detailed conclusions regarding the effect of ear plugging (41/131). 4. Most (25/27) MD cells received either monaural input (MD-E0) or binaural excitatory/inhibitory input (MD-EI), as inferred from ear plugging. Two MD cells showed other characteristics. The contralateral ear was excitatory for 25/27 MD cells. 5. MD-E0 cells (22%, 6/27) were monaural. They were unaffected by unilateral ear plugging, showing that they received excitatory input from one ear, and that stimulation of the other ear was without apparent effect. On the other hand, some monaural cells in AI were insensitive to the azimuth of noise bursts, showing that sensitivity to monaural directional cues is not a property of all monaural cells in AI. 6. MD-EI cells (70%, 19/27) exhibited an increase in responsiveness on the side of the plugged ear, showing that they received excitatory drive from one ear and inhibitory drive from the other. MD-EI cells remained azimuth sensitive with the inhibitory ear plugged, showing that they were sensitive to monaural directional cues at the excitatory ear.(ABSTRACT TRUNCATED AT 400 WORDS)