Association of HLA-DR11 with the anaphylactoid reaction caused by nonsteroidal anti-inflammatory drugs

BACKGROUND: Several HLA alleles have been associated with asthma induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The existence of HLA markers linked to other NSAID-induced reactions, such as cutaneous and anaphylactoid reactions, has not been established. OBJECTIVE: The purpose of our work was to study the HLA-DRB1 and HLA-DQB1 alleles in patients with cutaneous and anaphylactoid reactions caused by NSAIDs. METHODS: We have analyzed 114 HLA DRB1 and 26 HLA-DQB1 alleles in 21 patients with anaphylactoid reactions caused by NSAIDs, 47 patients who had exclusively cutaneous reactions during single-blind, placebo-controlled oral challenges with NSAIDs, and 167 tolerant control subjects (29 of whom had also had an IgE-mediated anaphylaxis to different agents). HLA-DRB1 and HLA-DQB1 alleles were typed by the polymerase chain reaction sequence-specific primers method with genomic DNA. RESULTS: The frequency of HLA-DR11 alleles was 58.8% in the anaphylactoid reaction group, compared with 15.9% in the NSAID-tolerant healthy control subjects (OR, 7:3; 95% confidence interval, 2.8-19.0; P <.02) and 6.3% in the group of the patients with a tolerance for NSAIDs and with IgE-mediated anaphylaxis (OR, 18.75; 95% confidence interval, 4.3-81.1; P <.004). No differences were observed among HLA-DR11 alleles analyzed. There were no significant HLA-DQB1 associations with NSAID-induced anaphylactoid reactions. Patients with cutaneous reactions had HLA frequencies that did not differ significantly from the tolerant control subjects. CONCLUSION: The HLA-DRB1*11 alleles showed a positive association with NSAID-induced anaphylactoid reactions.     

New quinoxaline 1,4-di-N-oxides for treatment of tuberculosis

Some quinoxaline 1,4-di-N-oxides derivatives with very different substituents in 2, 3, 6 and 7 positions have been synthesized in order to obtain new hypoxia selective agents. Some of these products have been tested as antituberculosis agents and very interesting results have been obtained from the first screening.     

Vasodilatory effect in rat aorta of eriodictyol obtained from Satureja obovata

The vasodilator effect of eriodictyol (5,7,3',4'-tetrahydroxyflavanone), isolated previously from the medicinal plant Satureja obovata Lag., was studied in rat thoracic aorta rings. Eriodictyol relaxed in a concentration-dependent manner the noradrenaline (10(-6) M) and KCl (80 mM) induced contractions. The relaxant effect was more potent in noradrenaline precontracted preparations (IC50 = 6.11 +/- 0.2 x 10(-5) M) than in those precontracted with KCl (IC50 = 2.96 +/- 0.1 x 10(-4) M). Eriodictyol produced weakly concentration-dependent inhibition of the phasic component induced by KCl and noradrenaline while the inhibition of the tonic phase of these contractions was more pronounced. These effects were endothelium independent. In addition, eriodictyol (10(-5) and 5 x 10(-5) M) inhibited CaCl2 cumulative concentration response curves. Eriodictyol weakly inhibited the release of calcium from the sarcoplasmic reticulum and its contribution to the relaxant effect seems to be slight. We have also observed the relaxant effect of eriodictyol on phorbol-12-myristate-13-acetate (PMA) (10(-7) M) induced contractions both in normal calcium (IC50 = 4.69 +/- 0.3 x 10(-5) M) and calcium-free medium (IC50 = 3.74 +/- 0.4 x 10(-5) M). Finally we studied the effects on protein kinase C (PKC) activity. This flavonoid did not show any activity. These results suggest that the vasodilator effect of eriodictyol in rat thoracic aorta could be partially related to the inhibition of calcium influx or other enzymatic protein subsequent to activation of PKC related to the activation of contractile proteins like myosin light chain kinase (MLCK).     

Different mechanisms involved in the vasorelaxant effect of flavonoids isolated from Satureja obovata

The inhibitory effects of naringenin, eriodictyol, and luteolin (10(-5) and 5 x 10(-5) M), previously isolated from Satureja obovata subsp. obovata var. valentina (Lamiaceae), on rat thoracic aorta were investigated. Flavonoids at the two concentrations assayed (10(-5) and 5 x 10(-5) M) showed different smooth muscle relaxant behaviour in the three phases involved in the noradrenaline (10(-6) M)-induced contractions. The three flavonoids showed an inhibitory effect of the phasic component in order of potency: luteolin > eriodictyol > naringenin. Luteolin and eriodictyol inhibited both tonic-I and tonic-II phases associated to the inhibition of PKC and calcium influx, respectively, whereas naringenin only inhibited the tonic-I phase associated to inhibition of PKC.     

Marrow regeneration after mechanical depletion

The origin of marrow regeneration after mechanical depletion was reinvestigated in mouse chimeras. The results were compatible with the local origin of stem cells from remnants of incompletely removed marrow, but not with their origin from a common precursor of both bone and hemopoietic cell lines. In transplanted femurs depleted by a modified technique of in vivo evacuation of marrow, hemopoietic regeneration failed to occur. The presence of hemopoietic stem cells in the Haversian canals was thus excluded. The demonstration of ample hemopoiesis with minimal bone formation in nondepleted controls in which bone marrow initially became necrotic provided new evidence that osteogenesis was not a prerequisite of hemopoietic regeneration.     

Evaluation of neurodevelopmental outcome in highrisk infants in Australia

An understanding of the neurodevelopmental outcome of long-term survivors of neonatal intensive care is essential for the informed management of preterm or high risk infants. This annotation looks at the current status of neonatal follow-up services in Australasia and highlights problems in the collection and interpretation of data. It suggests that we should work towards achieving a consensus on standard definitions and test regimes and on national data collection.     

Adult height in patients with childhood onset atopic dermatitis

Cross sectional studies have reported impaired growth in children with atopic dermatitis. If this growth impairment is irreversible, it would be expected to adversely influence final height attainment. The standing heights and other anthropometric parameters were assessed in 35 adults with onset of atopic dermatitis before 5 years of age and a control group of 35 adults with adult onset contact dermatitis or psoriasis. There was no significant difference in the standing height SD score, mid-parental height SD score, sitting height SD score, subischial leg length SD score, nor body mass index between the atopic dermatitis and control groups. The standing height SD score was not significantly different among: (a) patients with atopic dermatitis affecting less than 50% of their body surface area and those with greater than 50% affected; (b) patients using the four different potency topical corticosteroids; and (c) patients with atopic dermatitis without asthma and those with coexisting asthma. It is concluded that short stature is not a feature of our group of adult patients with onset of atopic dermatitis before 5 years of age, continuing into adulthood, and severe enough to require specialist care. This suggests that if growth impairment occurs in childhood, it is likely to be temporary and reversible.     

Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells

Cell to cell communication via gap junctions is essential in the maintenance of the homeostatic balance of multicellular organisms. Aberrant intercellular gap junctional communication (GJIC) has been implicated in tumor promotion, neuropathy and teratogenesis. Oxidative stress has also been implicated in similar pathologies such as cancer. We report a potential link between oxidative stress and GJIC. Hydrogen peroxide, a known tumor promoter, inhibited GJIC in WB-F344 rat liver epithelial cells with an I50 value of 200 microM. Inhibition of GJIC by H2O2 was reversible as indicated by the complete recovery of GJIC with the removal of H2O2 via a change of fresh media. Free radical scavengers, such as t-butyl alcohol, propylgallate, and Trolox, did not prevent the inhibition of GJIC by H2O2, which indicated that the effects of H2O2 on GJIC was probably not a consequence of aqueous free radical damage. The depletion of intracellular GSH reversed the inhibitory effect of H2O2 on GJIC. The treatment of glutathione- sufficient cells with H2O2 resulted in the hyperphosphorylation of connexin43, which is the basic subunit of the hexameric gap junction protein, as determined by Western blot analysis. TPA, a well-known tumor promoter, also inhibits GJIC via hyperphosphorylation of GJIC, which is a result of protein kinase-C activation. However, H2O2 also induced hyperphosphorylation in GSH-deficient cells that had normal rates of GJIC. Therefore, the mechanism of GJIC inhibition must be different from the TPA-pathway and involves GSH.      

Dietary polyamines promote the growth of azoxymethane-induced aberrant crypt foci in rat colon

We have examined whether dietary polyamines influence the formation and initial growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rat colon. Effects of a combination of dietary polyamines at three dose levels (putrescine: 50, 280, 740 nmol/g; spermidine: 10, 261, 763 nmol/g; spermine: 1, 31, 91 nmol/g) in the polyamine-poor AIN-76A diet were studied in animals in two different experimental situations: animals treated with AOM alone and animals treated with AOM + difluoromethylornithine (DFMO), a specific inhibitor of endogenous polyamine synthesis. In both experimental situations, dietary polyamines enhanced the growth of ACF, expressed as the number of large ACF (foci with three or more aberrant crypts, ACF > or = 3), whereas the formation of ACF, expressed as the number of ACF, was apparently not altered. In animals treated with AOM alone, maximal growth enhancing effect on ACF was nearly obtained with the median level of dietary polyamine. In rats fed a low polyamine diet, basic AIN-76A, DFMO reduced the growth of AOM-induced ACF by 83%. This inhibitory effect of DFMO was counteracted by dietary polyamines in a dose- dependent manner, and it was abolished at the highest level of polyamines. In conclusion, it was demonstrated that dietary polyamines are able to enhance the growth of AOM-induced ACF. Further, dietary polyamines reversed the DFMO-caused inhibition of ACF growth, probably by compensating for the DFMO-reduced endogenous polyamine synthesis.