Peripheral blood dendritic cell subtypes are significantly elevated in subjects with asthma

Background Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non‐smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles. Objective Determine peripheral blood DC profiles in subjects with and without asthma with differing smoking histories. Methods Forty‐three asthmatics (17 smokers, nine ex‐smokers and 17 never–smokers) and 16 healthy volunteers (nine smokers and seven never–smokers) were recruited. Spirometry, exhaled nitric oxide and venesection was performed. DC elution was by flow cytometry via the expression of DC surface markers [plasmacytoid (pDC) (BDCA‐2, CD303), type 1 conventional (cDC) (BDCA‐1, CD1c), and type 2 cDC (BDCA‐3, CD141)]. Results Subjects with asthma displayed increases in all DC subtypes compared with normal never‐smokers: [type 1 cDCs – asthma [median% (IQR)]: 0.59% (0.41, 0.74), normal never‐smokers: 0.35% (0.26, 0.43), P=0.013]; type 2 cDCs – asthma: 0.04% (0.02, 0.06), normal never‐smokers: 0.02% (0.01, 0.03), P=0.008 and pDCs – asthma: 0.32% (0.27, 0.46), normal never‐smokers: 0.22% (0.17, 0.31), P=0.043, and increased pDC and type 1 cDCs compared with normal smokers. Smoking did not affect DC proportions in asthma. Cigarette smoking reduced pDC proportions in normal subjects [normal never–smokers: 0.22% (0.17, 0.31); normal smokers: 0.09% (0.08, 0.15), P=0.003]. Conclusions and Clinical Relevance This study shows for the first time that subjects with asthma display a large increase in peripheral blood DC proportions. Cigarette smoking in asthma did not affect the peripheral blood DC profile but did suppress pDC proportions in non‐asthmatic subjects. Asthma is associated with a significant increase in circulating DCs, reflecting increased endobronchial levels and the importance of DCs to the development and maintenance of asthma. (Clinical trials.gov identifier: NCT00411320) Cite this as: M. Spears, C. McSharry, I. Donnelly, L. Jolly, M. Brannigan, J. Thomson, J. Lafferty, R. Chaudhuri, M. Shepherd, E. Cameron and N. C. Thomson, Clinical & Experimental Allergy, 2011 (41) 665–672.     

Classical conditioning of tone-signaled bradycardia modifies 2-deoxyglucose uptake patterns in cortex, thalamus, habenula, caudate-putamen and hippocampal formation

The 2-[14C]deoxyglucose (2-DG) autoradiographic method was used to map metabolic activity in all telencephalic and diencephalic structures of the rat brain during and after classical conditioning. A trial was made of a 4-5 KHz frequency modulated tone (CS) paired with midbrain reticular stimulation (US). The unconditioned response was a rapid bradycardia elicited by the US. Alert rats were injected with 2-DG, placed in a sound-proof chamber, and subjected during 90 min to a given treatment: (1) the CS before conditioning, (2) the US alone, (3) the paired CS-US (acquisition), (4) the CS after conditioning (extinction), (5) the US prior to the CS (sensitization), (6) the unpaired CS-US (pseudoconditioning), (7) the CS after pseudoconditioning and (8) no stimulation. The prefrontal cortex showed discrete regions with enhanced 2-DG uptake during conditioning and pseudoconditioning. A columnar organization was well-defined in the posterior parietal cortex of rats subjected to CS-US pairing. The medial thalamus was greatly activated in all groups subjected to reticular stimulation. The dorsomedial nucleus showed its largest activation during conditioning. The lateral habenula and a caudal portion of caudate-putamen showed an overall increase in 2-DG uptake during conditioning. The hippocampal formation showed a specific pattern of metabolic activation during conditioning and after conditioning. A laminar densitometric analysis showed that 2-DG uptake was concentrated in a central band along the sides of the hippocampal fissure which corresponded to the molecular layers. Only this neuropil band of greater metabolic activity showed the learning-related changes. In addition, the hippocampal formation was the only nonauditory structure in the forebrain which clearly responded to the acquired signal value of the tone CS after conditioning. These changes revealed by 2-DG provide a first demonstration of forebrain substrates with localized metabolic alterations related to learning and reticular sensitization.     

Another Look at Functionalism and the Emotions

Two chronic problems have plagued functionalism in the philosophy of mind. The first is the chauvinism/liberalism dilemma, the second the absent qualia problem. The first problem is addressed by blocking excessively liberal counterexamples at a level of functional abstraction that is high enough to avoid chauvinism. This argument introduces the notion of emotional functional organization (EFO). The second problem is addressed by granting Block's skeptical conclusions with respect to mentality as such, while arguing that qualitative experience is a concomitant of human mentality considered as a special case: a system with EFO implemented in an organic substrate.This revised version was published online in October 2005 with corrections to the Cover Date.     

The Role of Serotonin Receptor Subtypes in the Behavioural Effects of Neuroleptic Drugs. A Paw Test Study in Rats

The present study was designed to evaluate the roles of serotonin 5-HT_1A and 5-HT₂ receptors in the effects of neuroleptic drugs in the paw test. This behavioural test has been shown to model both the antipsychotic efficacy as well as the extrapyramidal side-effect liability of neuroleptic drugs. Whereas the 5-HT_1A receptor agonist 8-hydroxy-2-(di- n -propylamino)tetralin (8-OHDPAT) reduced the effects of the classical neuroleptic haloperidol, it increased the effects of the atypical neuroleptic clozapine. The 5-HT₂ receptor antagonist ketanserin as well as the 5-HT_1C/5-HT₂ receptor antagonist ritanserin, on the other hand reduced the effects of haloperidol, whereas the 5-HT_1C/5-HT₂ receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOl) reduced the effects of clozapine. The most important finding, however, was that the behavioural effects of different (putative) neuroleptics (fluphenazine, SCH-39166, remoxipride, prothipendyl, thioridazine and risperidone) were differentially influenced by both 8-OHDPAT and DOl, suggesting that there are important differences between the neuronal mechanisms underlying the behavioural effects of these neuroleptic drugs, even within the subclasses of classical and atypical neuroleptics.     

张琪教授运用经方治疗肾病的经验

仲景制方,结构严谨,疗效卓著,被后世医家誉为“经方”.张琪教授临证数十载,善用经方疗诸疾,尤其以经方治疗慢性肾炎更具特色:宣肺温肾,以桂枝去芍药加麻辛附子汤消水肿;清上温下,以瓜萎瞿麦丸祛寒清热;湿热壅滞,以牡蛎泽泻散退饮除水气;调和营卫,以桂枝加黄芪汤消蛋白.张老用药精专,疗效显著,自有平中见奇之妙.     

Increased pineal melatonin content coupled to restricted water availability in a Pavlovian conditioning paradigm in rats

Summary The objective of this study was to assess whether rat pineal melatonin content could be modified in a classical conditioning paradigm. In rats kept under light (200 lux) from 06.00 to 18.00h daily, the time of lights off was selected as the unconditioned stimulus (US). Restricted water availability (from 10 min before to 10 min after light-dark, LD, transition) was the conditioned stimulus (CS). The conditioned and unconditioned responses were measured as the changes in pineal melatonin levels 4 h after LD transition. In animals under regular lighting conditions, lights out at 18.00 h (the US) caused a 4.4–7.8-fold increase of pineal melatonin concentration 4 h after later, when compared to animals maintained under light for the 4 h-period. After a training period of 7 days of restricted water availability (the CS), significantly augmented pineal melatonin levels were found in rats that were exposed to water but were maintained under light for the 4 h period after expected LD transition. The control animals for this experiment, i.e., rats which had undergone the training period, were kept for 4 h under light after expected LD transition, and did not receive water at LD transition, exhibited very low pineal melatonin levels. The conditioned increase of pineal melatonin content attained lower values than those in rats exposed to normal lighting conditions. It also fulfilled the contingency criterion, that is, it caused at trial a significant elevation of pineal melatonin content only when water availability was applied from 10 min previously to LD transition during training, and not 20 min after LD transition. After a training period of 7 days, restricted water availability applied 4 h before lights off (at 14.00 h), caused an enhanced production of melatonin 4 h later, regardless of the animals being exposed either to a dark or to a light environment. The results indicate that pineal melatonin production can be manipulated in a classical conditioning paradigm, when an appropriate CS stimulus is used.     

Classical conditioning rapidly induces specific changes in frequency receptive fields of single neurons in secondary and ventral ectosylvian auditory cortical fields

To determine if learning-induced changes in the response of auditory cortical neurons to a conditioned stimulus (CS) reflect general changes in cellular excitability or alterations in signal processing that are specific to that stimulus, we determined frequency receptive fields (FRFs) of single neurons in secondary and ventral ectosylvian auditory fields of the cat during classical conditioning. Associative changes in FRFs of most cells were specific to the frequency of the CS, established rapidly and reversed by extinction. Thus, learning causes specific changes in cortical processing of sounds whose significance is acquired.     

Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene

Classical galactosemia is an autosomal recessive disorder caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. Our group developed a disease-specific database containing all of the reported sequence variants in GALT (Available at: http://arup.utah.edu/database/galactosemia/GALT_welcome.php; Last accessed: 13 April 2007). Currently the database contains a total of 229 sequence variants, of which 196 are mutations (including nine novel mutations identified in our laboratory), 31 polymorphisms in both introns and exons, and two variants of unknown or uncertain significance. All sequence variants have been verified for their position within the GALT gene and named following standard nomenclature. Sequence variants are reported with accompanying information on protein effect, classification of mutation vs. polymorphism, mutation type (when applicable) based on how each was first described in the literature, and accompanying link to pertinent publication. Unpublished variants are described with relevant clinical information that supports their classification as causative of the disease vs. polymorphisms. Other features of this database include disease information, relevant links for galactosemia and literature, reference sequences, ability to query by various criteria, and submit of novel variations to the database. This free online scientific resource was developed with the clinical laboratory in mind to serve as a reference and repository for novel findings that are periodically collected, verified, and updated into the database.     

Reduced specificity of Erns antibody ELISAs for samples from piglets with maternally derived antibodies induced by vaccination of sows with classical swine fever marker vaccine CP7_E2alf

Successful implementation of marker vaccines against classical swine fever virus is dependent on a reliable accompanying diagnostic assay that allows differentiation of infected from vaccinated animals (DIVA ) as well as the development of a testing scheme during emergency vaccination. In this context, special attention needs to be paid to breeding farms, because the offspring of marker vaccinated sows possess maternally derived antibodies (MDA s). So far, limited information is available on the influence of MDA s on serological testing in the context of a DIVA strategy. Therefore, two commercially available E^rns antibody ELISA s were compared, using serum samples of piglets with a high‐to‐moderate titre of MDA s against marker vaccine CP 7_E2alf. False‐positive results were detected by both E^rns antibody ELISA s for serum samples of piglets with an age of up to 4 weeks. Interestingly, most samples tested false‐positive in the first E^rns antibody ELISA were identified correctly by the other E^rns antibody ELISA and vice versa. In conclusion, in case of emergency vaccination of sows, the specificity of both ELISA s in newborn piglets younger than 4 weeks may be relatively low. This could be addressed in a testing strategy by either not sampling piglets up to the age of 4 weeks or using both ELISA s in a screening‐confirmation set‐up.