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991.
992.
993.
Control of T helper 2 cell function and allergic airway inflammation by PKCzeta 总被引:2,自引:0,他引:2
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Martin P Villares R Rodriguez-Mascarenhas S Zaballos A Leitges M Kovac J Sizing I Rennert P Márquez G Martínez-A C Diaz-Meco MT Moscat J 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(28):9866-9871
Asthma is a disease of chronic airway inflammation in which T helper (Th) 2 cells play a critical role. The molecular mechanisms controlling Th2 differentiation and function are of paramount importance in biology and immunology. PKCzeta has been implicated in the regulation of apoptosis and NF-kappaB, as well as in the control of T-dependent responses, although no defects were detected in na?ve T cells from PKCzeta-/- mice. Here, we report that PKCzeta is critical for IL-4 signaling and Th2 differentiation. Thus, PKCzeta levels are increased during Th2 differentiation, but not Th1 differentiation, of CD4+ T cells, and the loss of PKCzeta impairs the secretion of Th2 cytokines in vitro and in vivo, as well as the nuclear translocation and tyrosine phosphorylation of Stat6 and Jak1 activation, essential downstream targets of IL-4 signaling. Moreover, PKCzeta-/- mice display dramatic inhibition of ovalbumin-induced allergic airway disease, strongly suggesting that PKCzeta can be a therapeutic target in asthma. 相似文献
994.
Pérez-Peñate G Cabrera Navarro P Ponce González M Górriz Gómez E Pulido Duque J García Quintana A Juliá Serdá G 《Respiration; international review of thoracic diseases》2005,72(4):419-422
Inhaled nitric oxide (iNO) has been shown to be a potent and selective vasodilator in pulmonary arterial hypertension (PAH). However, the clinical experience in prolonged treatment is limited. We assess the safety and effectiveness of long-term administration of iNO in severe PAH. Two female patients were admitted to our hospital because of severe dyspnea (World Health Organization functional class IV) and hypoxemia. They were diagnosed with PAH (primary and secondary to congenital heart disease) and treated with iNO for 2 years. The delivery system consisted of an NO tank of 800 ppm, a modified gas-pulsing device, and nasal cannulas. On iNO treatment the patients showed remarkable improvement of symptoms, oxygenation and 6-min walk distance. After 16 months the patients began to experience a progressive rebound of symptoms. A phosphodiesterase type 5 inhibitor (dipyridamole) was added to iNO. This intervention proved useful in improving clinical deterioration and hemodynamics. This is the first study reporting 2-year iNO therapy in 2 patients with primary and secondary pulmonary hypertension. The combination of dipyridamole with iNO augments the pulmonary vasodilatation and may be useful in managing PAH. 相似文献
995.
Foliage shedding in deciduous forests lifts up long-distance seed dispersal by wind 总被引:2,自引:0,他引:2
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Nathan R Katul GG 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(23):8251-8256
Seed terminal velocity and release height are recognized as key biotic determinants of long-distance dispersal (LDD) of seeds by wind. Yet, potential determinants at the ecosystem level, such as seasonal dynamics in foliage density characterizing many deciduous forests, have received much less attention. We integrated detailed field observations and experiments with a mechanistic wind dispersal model to assess how seasonal variation in foliage density, estimated by leaf-area index (LAI), affects LDD in deciduous forests. We found that the model, previously shown to accurately predict seed dispersal by wind, also reliably describes the effects of LAI variation on wind statistics for a wide range of canopy types. Sparser canopies are characterized by more organized vertical eddy motion that promotes LDD by uplifting seeds to higher elevations where winds are stronger. Yet, sparser canopies are also characterized by reduced mean windspeed aloft. We showed that former effect more than compensates for the latter, i.e., conditions of low LAI are favorable for LDD. This may account for the tendency of many temperate tree species to restrict seed release to either early spring or late fall, when LAI is relatively low. Sensitivity analysis reveals that the typical seasonal variation in LAI can be more important to LDD of seeds by wind than the natural variation in seed terminal velocity. Because our model accurately describes the effects of LAI variation for distinctly different sites, species, and life forms, we suggest that its results reflect a general association between LDD and foliage density dynamics. 相似文献
996.
Coping strategies in relation to unfair treatment or conflicts at work are discussed. ‘Covert coping’ has been assessed by means of a short questionnaire. Its relationship with cardiovascular risk and sick leave has been examined in an epidemiological study (WOLF) of working men and women in Stockholm. The findings indicate that in men ‘covert coping’ is associated with elevated cardiovascular risk and prospective long-term sick leave. In women such a coping strategy is related to current sick leave, but not to cardiovascular risk or long-term sick leave. Openness of coping strategies is also discussed in relation to bouts of anger preceding myocardial infarction. Another epidemiological study (SHEEP, ONSET) has shown that severe bouts of anger are reported significantly more often than expected during the hour preceding myocardial infarction. This was not the case in subjects who reported ‘open coping patterns’, however. Openness of coping strategies is partly determined by the working climate—the higher the decision latitude, the less ‘covert’ the coping strategies. The results support the idea that dialogue in the work place may be health promoting. 相似文献
997.
Ryu J Vicencio AG Yeager ME Kashgarian M Haddad GG Eickelberg O 《Thrombosis and haemostasis》2005,94(1):175-183
Lung development is a highly orchestrated process characterized by timed expression and activation of growth factor and protease/antiprotease systems. This interplay is essential in regulating vasculogenesis, alveolarization, and epithelial to mesenchymal transition during lung development. Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with several respiratory diseases characterized by changes in the lung extracellular matrix (ECM). Here, we characterized the expression pattern of matrix metalloproteases (MMP) and their inhibitors, the tissue inhibitors of metalloproteases (TIMP), in human and mouse lung development. Using MMP/TIMP expression arrays, RT-PCR, Western Blotting, and ELISA analyses, we demonstrate that fetal human lung is characterized by a dominant proteolytic profile with high MMP-2 and little TIMP-3 expression. Adult human lung, in contrast, exhibits a more anti-proteolytic profile with decreased MMP-2 and increased TIMP-3 expression. MMP-14, MMP-20, TIMP-1, and TIMP-2 were constitutively expressed, irrespective of the developmental stage. Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed. Exposure of neonatal mice to chronic hypoxia (10% O2), a stimulus that leads to an arrest of lung development, resulted in upregulation of MMP-2 with a concomitant downregulation of TIMP-2. These results provide a comprehensive analysis of MMP and TIMP expression during human and mouse lung development. MMP-2, TIMP-2, and TIMP-3 may be key regulatory enzymes during lung development, possibly through their complex action on ECM components, membrane receptor ectodomain shedding, and growth factor bioactivity. 相似文献
998.
Fernández-Real JM López-Bermejo A Castro A Broch M Peñarroja G Vendrell J Vázquez G Ricart W 《Thrombosis and haemostasis》2005,94(3):615-619
Recent prospective studies indicate endothelial dysfunction and increased risk for cardiovascular events in patients with serological evidence of multiple infections. Soluble CD14 (sCD 14) plays a key role in the neutralization of lipopolysaccharide (LPS), a well-established bacterial product inducing endothelial dysfunction. Insulin resistance was recently identified as a significant factor influencing circulating sCD 14 concentration. Thus, we investigated the association of circulating sCD14 and endothelial dysfunction in subjects with well-established insulin resistance (patients with type 2 diabetes, n = 40) compared to control non-diabetic subjects (n = 100). To further explore the underlying mechanisms, we also analysed C-reactive protein and circulating NO2-/NO3- and cyclic GMP in the diabetic group. Serum sCD 14 concentration (ELISA) was found to be differently associated with endothelium-dependent vasodilatation (EDVD, high-resolution ultrasound) in diabetic and non-diabetic subjects. In nondiabetic subjects, serum sCD14 and C-reactive protein correlated negatively with EDVD (r = -0.21, p = 0.03, and r = -0.21, p = 0.03, respectively). In a partial correlation analysis, these associations remained significant after controlling for age and weight (sCD 14 and EDVD, r = -0.23, p = 0.023; C-reactive protein and EDVD, r = -0.21, p = 0.03; sCD14 and C-reactive protein, r = 0.30, p = 0.002). In contrast, sCD 14 was positively associated with EDVD in type 2 diabetic patients (r = 0.37, p = 0.019,). Interestingly, sCD14 was also associated with NO2-/NO3- in this group (r = 0.62, p = 0.001, n = 22). EDVD also correlated with cyclic GMP (r = 0.47, p = 0.03, n = 22). In summary, circulating sCD 14 is associated with endothelial function. While in non-diabetic subjects sCD14 behaves as an acute phase reactant, its role in type 2 diabetic patients should be further clarified. These findings need to be confirmed in further studies with larger number of patients. 相似文献
999.
Rodríguez Gil DJ Vacotto M Rapacioli M Scicolone G Flores V Fiszer de Plazas S 《Journal of neuroscience research》2005,81(4):469-480
An in situ hybridisation technique was used to analyse the spatial and temporal pattern of expression of the mRNA encoding the four gamma-aminobutyric acid A (GABA(A)) receptor subunits (alpha1, alpha2, beta2, and gamma2) in the developing chick optic tectum. As a rule, layer i, layer h, and transient cell compartment 3 (TCC3) show the highest levels of expression, especially of alpha1, alpha2 and beta2, which undergo striking changes as a function of time. Apart from these common features, the global pattern is highly complex and dynamic. Such complexity derives from the fact that each subunit exhibits a characteristically distinct pattern of expression and the temporal evolution of each differs in the different layers of the tectum. The influence of several developmental cell behaviours such as proliferation, neuronal migration, programmed cell death, and differentiation must be taken into account to understand pattern complexity and dynamics. Our results suggest that differences in the rate of subunit expression, particularly of alpha1, alpha2, and beta2, could have significant consequences on GABA(A) receptor complex subunit composition along development and on the functional properties of the GABA neurotransmitter system. 相似文献
1000.
Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing 总被引:5,自引:0,他引:5
Paulus MP Feinstein JS Castillo G Simmons AN Stein MB 《Archives of general psychiatry》2005,62(3):282-288
BACKGROUND: Functional neuroimaging may elucidate the pathophysiologic features of anxiety disorders and the site of action of anxiolytic drugs. A large body of evidence suggests that the amygdala and associated limbic structures play a critical role in the expression of anxiety and may be treatment targets for anxiolytic drugs. OBJECTIVE: To determine whether lorazepam dose-dependently attenuates blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) activation in the amygdala and associated limbic structures during an emotion face assessment task. PARTICIPANTS AND DESIGN: Fifteen healthy volunteers participated in a double-blind, placebo-controlled, randomized dose-response study. Subjects underwent imaging 3 times (at least a week apart) and were given either a single-dose placebo or 0.25 mg or 1.0 mg of lorazepam 1 hour prior to an MRI session. During fMRI, subjects completed an emotion face assessment task, which has been shown to elicit amygdala activation. MAIN OUTCOME MEASURES: The BOLD-fMRI activation in amygdala, insula, and medial prefrontal cortex during the emotion face assessment task. RESULTS: Lorazepam significantly attenuated the BOLD-fMRI signal in a dose-dependent manner in bilateral amygdala and insula but not in the medial prefrontal cortex. Lorazepam did not affect the BOLD-fMRI signal in the primary visual cortex. CONCLUSIONS: The current finding provides the first neuroimaging evidence of a dose-dependent change induced by an established therapeutic agent in brain regions known to be critical for the mediation of anxiety. This investigation may help to support the use of BOLD-fMRI with pharmacological probes to investigate the neural circuits underlying anxiety and the use of fMRI as a tool in the development of new anxiolytic agents. 相似文献