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.     

Dystrophinopathy in a boy with Chediak-Higashi syndrome

OBJECTIVE: To evaluate the effect of surgery on muscular strength and endurance in patients with primary hyperparathyroidism (HPT). DESIGN: Prospective open study. SETTING: University hospital, Sweden. SUBJECTS: Nine patients undergoing HPT surgery and nine matched patients undergoing thyroid resection who acted as controls. INTERVENTIONS: Concentric and eccentric endurance was evaluated with a test comprising 100 repeatedly executed muscle action at 90 degrees.s-1. Blood samples obtained before and after operation were analysed for calcium, phosphate, thyroid stimulating hormone (TSH), and parathyroid hormone (PTH) concentrations. MAIN OUTCOME MEASURES: Peak torque during maximum voluntary concentric and eccentric muscle actions at 90 degrees.s-1 before, three months and one year after operation. RESULTS: There were no differences in concentric and eccentric peak torque before and after operation either within or between groups. Concentric and eccentric endurance were similar in the HPT group and controls before as well as after operation. The return of calcium and PTH concentrations to their reference ranges after parathyroidectomy did not correlate with changes in concentric and eccentric peak torque. CONCLUSIONS: The subjective improvement in muscle endurance which is often encountered in patients with HPT after operation is not associated with an objective increase in muscle strength or endurance as measured by isokinetic muscle performance.