Small ruminant lentivirus Tat protein induces apoptosis in caprine cells in vitro by the intrinsic pathway

The small ruminant lentiviruses, caprine arthritis-encephalitis virus (CAEV) and maedi visna virus (MVV) naturally cause inflammatory disease in goats and sheep, provoking chronic lesions in several different organs. We have previously demonstrated that in vitro infection of caprine cells by CAEV induces apoptosis through the intrinsic pathway (Rea-Boutrois, A., Pontini, G., Greenland, T., Mehlen, P., Chebloune, Y., Verdier, G. and Legras-Lachuer, C. 2008). In the present study, we used Tat deleted viruses and SLRV Tat-expression vectors to show that the SRLV Tat proteins are responsible for this apoptosis. We have also studied the activation of caspases-3, -8 and -9 by fluorescent assays in caprine cells expressing SRLV Tat proteins, and the effects of transfected dominant negative variants of these caspases, to show that Tat-associated apoptosis depends on activation of caspases-3 and -9, but not -8. A simultaneous disruption of mitochondrial membrane potential indicates an involvement of the mitochondrial pathway.     

Lack of trans-activation function for Maedi Visna virus and Caprine arthritis encephalitis virus Tat proteins

All lentiviruses contain an open reading frame located shortly upstream or inside of the env gene and encoding a small protein which has been designated Tat. This designation was mainly with respect to the positional analogy with the first exon of the trans-activator protein of the well studied human immunodeficiency virus type 1 (HIV-1). In this work we comparatively studied the trans- activation activity induced by Tat proteins of the small ruminant Maedi Visna virus (MVV) of sheep and Caprine arthritis encephalitis virus (CAEV) of goats on MVV and CAEV LTRs with that induced by the human lentivirus HIV-1 on its own LTR. The HIV-1 LTR alone weakly expresses the reporter GFP gene except when the HIV-1 Tat protein is coexpressed, the GFP expression is increased 60-fold. In similar conditions only minimal trans-activation increasing two- to three-fold the MVV and CAEV LTR activity was found with MVV Tat protein, and no trans-activation activity was detected in any used cell type or with any virus strain when CAEV Tat was tested. These results indicate that the small ruminant lentiviruses (SRLV) differ from the primate lentiviruses in their control of expression from the viral LTRs and put into question the biological role of the encoded protein named "Tat."     

重组人生长激素治疗生长激素缺乏症对肺功能的影响

目的研究重组人生长激素(rhGH)治疗生长激素缺乏症(GHD)对肺功能的影响。方法10例GHD伴促性腺激素缺乏的男性患儿,年龄15.6±3.2岁,身高年龄(HA)8.82±1.81岁,给予rhGH(健高宁)治疗,剂量为0.11U·kg     

Effect of albuterol on maximal exercise capacity in cystic fibrosis

BACKGROUND: Inhaled, short-acting beta-adrenergic agonists (SAbetaAs) are widely prescribed in cystic fibrosis (CF) subjects, despite a lack of convincing data for efficacy and the potential for these agents to result in airway instability. We tested the hypothesis that inhaled albuterol would improve maximal exercise performance in CF subjects with airflow obstruction, as a result of acute bronchodilation. METHODS: Randomized, double-blind, placebo-controlled crossover study of the effect of inhaled albuterol on maximal exercise performance in 20 stable adult CF patients (mean +/- SD age, 23.3 +/- 6.1 years; FEV(1), 57.65 +/- 17.13% of predicted). RESULTS: Ventilatory limitation to exercise was demonstrated in 16 subjects (80%). Significant bronchodilation occurred with exercise alone (end-exercise FEV(1), 2.24 +/- 0.8 L; vs preexercise FEV(1), 2.09 +/- 0.77 L; p < 0.0001), but albuterol resulted in significantly greater exercise-induced bronchodilation than placebo (change in FEV(1), 0.3 +/- 0.15 L vs 0.15 +/- 0.11 L; 95% confidence interval [CI], + 0.07 to + 0.23; p < 0.001). However, there was no difference in maximal workload achieved (albuterol, 158 +/- 46 W; vs placebo, 158 +/- 45 W; 95% CI, - 4.41 to + 4.71; p = 0.95), nor any other measure of exercise performance including maximal oxygen uptake. CONCLUSIONS: Despite causing significant acute bronchodilation, inhaled albuterol did not improve maximal exercise performance in ventilatory-limited CF adults, adding to the body of literature that fails to show any clinical benefit of SAbetaAs in CF subjects. The current results provide further evidence to question the widespread use of these agents, although the potential for adrenergic beta-agonists to instead improve submaximal exercise performance merits further investigation.     

Increased load on the respiratory muscles in obstructive sleep apnea

We wished to quantify, in patients with obstructive sleep apnoea (OSA), the activity of the respiratory muscles in relation to upper airway occlusion and patency in sleep. We hypothesized that particular levels of neuromuscular activation are directly associated with upper airway patency. 21 patients with previously diagnosed OSA and 21 healthy control subjects underwent respiratory muscle testing and polysomnography. Neural respiratory drive, as measured by the electromyogram of the diaphragm (EMG_di) was elevated in the obese OSA patients, awake and supine (13.1(5.6)%max), compared to normal subjects (mean (SD) 8.1(2.3)%max, p < 0.01). During unobstructed breathing in sleep (stage N2) normal subjects had an EMG_di of 7.7(3.9) compared to 22.8(19.2)%max in the OSA group (p < 0.001). Prior to airway occlusion, EMG_{submandibular} and EMG_di dropped markedly, and then, following occlusion, increased progressively to their highest levels at airflow onset. Patients with OSA require specific and increased levels of neural respiratory drive to sustain ventilation in sleep.     

Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma

Twenty-seven subjects with asthma and normal baseline lung function were challenged with aerosols of methacholine (M) and by isocapnic hyperventilation with cold air (HV). Stimulus-effect relationships were determined for each provocational technique on separate days and were expressed as the dose required to produce a 20% fall in forced expired volume in 1 sec (FEV₁) obtained by linear interpolation from log stimulus vs. response curves (PD₂₀). Each stimulus was applied with a sufficient intensity to produce a 20% or greater fall in FEV₁ in each subject. The PD₂₀ for M correlated significantly with the PD₂₀ for HV (p < 0.001) when the latter was expressed in liters per minute. The correlation between cumulative M PD₂₀ and HV PD₂₀ expressed as a percent of maximal voluntary ventilation was significant but less strong. We conclude that the airway response to HV reflects nonspecific bronchial hyperresponsiveness and that the dose of HV is best determined as the absolute level of ventilation.     

Clinical relevance of the venom-specific immunoglobulin G antibody level during immunotherapy

Parameters associated with successful venom immunotherapy in insect allergy were sought by comparison of treatment failures with successes. Half-dose treatment was completely protective in 32 patients (successes) but was only partially effective in eight (failures). The outcome of treatment was not related to the severity of pretreatment sting reactions, to the degree of skin-test sensitivity, to an atopic personal history, or to age or gender. The mean yellow jacket venom-specific IgG antibody level (by the Staph-A solid-phase radioimmunoassay) was significantly less in the failures (3.9 ± 0.6 μg/ml) than in the successes (7.3 ± 1.1 μg/ml) (p < 0.01). When the failures were successfully treated, their mean IgG level (6.1 ± 1.3 μg/ml) was significantly greater than that associated with treatment failure (p < 0.025). Patients with an IgG antibody level above 5.0 μg/ml were significantly more likely to be fully protected (p < 0.02). Those whose IgG levels were less than 5 μg/ml had a risk of reaction similar to that in untreated patients. We conclude that early in the maintenance phase of low-dose venom immunotherapy, the risk of a reaction to a challenge sting is significantly greater for those patients with low levels of venom-specific IgG antibodies.