Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma

Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory‐tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid‐naïve, allergen‐challenged and allergen‐naïve subjects (atopic asthmatics, atopic non‐asthmatics and non‐atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA‐DR⁺ (negative for markers of other cell lineages) were predominantly myeloid and comprised ∼0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4⁺ naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC‐dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05–P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c⁻CD123^high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.     

Closed-loop feedback control of methohexital anesthesia by quantitative EEG analysis in humans

A combined pharmacokinetic and pharmacodynamic model of methohexital was used to establish and evaluate feedback control of methohexital anesthesia in 13 volunteers. The median frequency of the EEG power spectrum served as the pharmacodynamic variable constituting feedback. Median frequency values from 2-3 Hz were chosen as the desired EEG level (set-point). In 11 volunteers, the feedback system succeeded in maintaining a satisfactory depth of anesthesia (i.e., unresponsiveness to verbal commands and tactile stimuli). During feedback control, 75% of all measured median frequency values were in the preset range of 2-3 Hz. This distribution of median frequency was obtained by applying random stimulation (six different acoustic and tactile stimuli) to the volunteers approximately every 1.5 min. The decrease of median frequency from baseline to anesthetic values was primarily induced by increasing the fractional power in the frequency band of 0.5-2 Hz from 12.6 +/- 4.5% (mean +/- SD) to 46.0 +/- 2.5%. The median time to recovery (as defined by opening eyes on command) after cessation of the feedback control period was 20.6 min (10.7-44.5 min) when median EEG frequency was 5.2 Hz (4.7-8.4 Hz). The average requirement of methohexital (mean +/- SD) during the 2 h was 1.02 +/- 0.16 g. It is concluded that pharmacokinetic-pharmacodynamic models of intravenous anesthetics established previously may be used to form a suitable background for model-based feedback control of anesthesia by quantitative EEG analysis. This approach gives a possible solution to the problem of adapting pharmacokinetic and pharmacodynamic data to individuals when using population mean data as starting values for drug therapy.     

Effect of the calcium antagonist nimodipine on hemodynamics, gas exchange and endocrine parameters in opiate anesthesia

During opiate anesthesia (standardized dosage of fentanyl) for operation of cerebral aneurysms after subarachnoid hemorrhage, different hemodynamic, respiratory, metabolic, and endocrine parameters were determined before (1 in Fig. 1-4), after (6), and during consecutive stages of induced hypotension (systolic blood pressure 100 mmHg (2), 90 mmHg (3), 80 mmHg (4, 5) during an interval of 20 min), comparing two groups with different vasodilating drugs. In the first group (nimo/NNP in Figs. 2-4) a constant infusion of nimodipine was applied (1.2 micrograms/kg b.w. X min-1), while sodium nitroprusside (NNP) was added in small amounts as necessary to achieve the respective values of systolic blood pressure. In the second group (NNP in Figs. 2-4) induced hypotension was done with NNP alone (maximal dosage: 8 micrograms/kg X min-1). Each group consisted of 11 patients. Additional nimodipine (in the first group), a calcium antagonist commonly recommended for preventing vasospasm and consequent neurologic deficits after subarachnoid hemorrhage, not only reduced the need for NNP, a vasodilating drug with potential toxicity, by 70%-80% as compared to the second group (Table 1). In addition, the cardiovascular situation was more stable in patients with nimodipine infusion: rapid variations of blood pressure and heart rate as well as tachyphylaxis and rebound, typical for NNP-induced hypotension, were avoided. Nevertheless, comparing the hemodynamic data at fixed stages of hypotension, there were only minor differences between both groups (Fig. 2). Reduction of blood pressure was due to a decrease in vascular resistance and was accompanied by an increase in cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)     

Total anatomic correction of interrupted aortic arch complex. Experience in 4 infants

In two cases of interrupted aortic arch (IAA) of type A, one associated with a ventricular septal defect (VSD) and one with an aortopulmonary window, and two of type B, both associated with a VSD, total anatomic repair was performed at respective ages of 6 months and 24, 8 and 3 days. All four operations were performed through a median sternotomy, using profound hypothermia and circulatory arrest. The repair included resection of the patent ductus arteriosus, direct end-to-side anastomosis of the descending to the ascending aorta and closure of the VSD or, in one case, of the aortopulmonary window. The two oldest infants (with type A IAA) survived. Reexamination two years postoperatively demonstrated good width of the aortic anastomosis with no gradient. In the child who had had an aortopulmonary window there was a proximal tight stenosis of the right pulmonary artery, which was corrected at reoperation. Total anatomic correction of IAA through an anterior approach is technically feasible and the aortic anastomosis seems to grow satisfactorily. The management of very sick neonates with IAA remains a great challenge.     

Differential antagonism of the behavioral depressant and hypothermic effects of 5'-(N-ethylcarboxamide) adenosine by theobromine

The methylxanthine, theobromine (3,7-dimethylxanthine), was tested in mice, to determine whether theobromine could function in vivo as an adenosine receptor antagonist, in keeping with its reported in vitro effects as a blocker of agonist binding to the adenosine A-1 receptor. Theobromine doses, which themselves had no direct effects on spontaneous locomotor activity, completely blocked N6-cyclohexyladenosine-induced suppression of locomotor activity but were without effect on 5'-N-ethylcarboxamide adenosine (NECA)-induced decreases in motor activity. In contrast to the specific antagonism, theobromine blocked the hypothermia induced by both of these adenosine analogs. These results demonstrate that theobromine is an active in vivo adenosine receptor antagonist and that the antagonism of N6-cyclohexyladenosine sensitive systems occurs even though theobromine does not stimulate spontaneous locomotor activity. Thus, the behavioral stimulant effects of methylxanthines may be more related to effects on NECA-sensitive systems, which are not blocked by theobromine. The use of in vivo differences in the effects xanthine may provide a useful tool in the development of compounds to probe the mechanisms of caffeine induced CNS effects.