Inhibition of bleomycin lung toxicity by N-acetyl cysteine in the rat

N-acetyl cysteine (NAC) has recently been shown to have antioxidant properties, and since bleomycin produces pulmonary damage via free oxygen radical toxicity, the possible protective effect of NAC on bleomycin lung toxicity was investigated. Rats received saline (n = 7), NAC (n = 6), bleomycin (n = 7) or bleomycin and NAC (n = 6) by direct intratracheal injection. Seven days later the animals were killed and the lungs processed for histology or morphometry. All rats treated with bleomycin only had typical changes of bleomycin lung toxicity whereas the animals treated with bleomycin and NAC had minimal pathology. The control animals had normal lungs. These results were confirmed by morphometry which demonstrated significantly higher volume densities (p less than .01) of alveolar wall and free alveolar cells in the bleomycin group compared to the other 3 groups. It is concluded that NAC inhibits bleomycin lung toxicity when administered by direct intratracheal injection.     

Pain and attention: attentional disruption or distraction?

The effect of pain processing on attention capacity during visual search was examined in 2 experiments. In the first experiment, we investigated whether pain draws on the same limited resources as attentional task performance. It was hypothesized that pain would negatively affect task performance under different load manipulations. Low and high load conditions of a visual search task were presented in a mixed design combined with a painfully cold or neutral cold pressor test. Performance was not affected by pain. In experiment 2, low and high load conditions were separated in different blocks to study whether pain perception was affected when task load could be anticipated. Again, pain did not significantly affect task performance. In contrast, subjective pain intensity scores were significantly lower after performing the high load compared with the low load condition. Simultaneous recordings of event-related potentials indicated an increased negativity during the pain compared with the control condition. Also, in the early (350 to 450 msec) interval of event-related potentials, an increase in negativity was found for the high load compared with the low load condition. Topographic distributions suggested that pain and task load are mediated by qualitatively different resources. PERSPECTIVE: Our findings indicate that highly demanding attentional task performance and pain processing interfere as a result of difficulties in allocating attention. The clinical relevance of this finding is that performing a highly demanding task might distract attention from pain.     

Influence of calibration on densitometric studies of emphysema progression using computed tomography

The fundamental importance of calibration for any measuring device is indisputable, but computed tomography (CT) calibration in longitudinal lung densitometry studies is largely unexplored. Although the validity of CT as a measure of emphysema has been confirmed in cross-sectional studies, there are limited data on long-term reproducibility, and this is critically important for validating its use as an outcome measure in therapeutic trials. A general understanding of the strengths and pitfalls of CT densitometry is critical for physicians reviewing the published literature using this methodology. In our study of 57 patients with alpha-1 antitrypsin deficiency (phenotype PiZ), progression of voxel index determined from three successive annual scans acquired with a fully calibrated scanner was intimately associated with changes in CT air densitometry, sampled from patient images. Images were therefore reanalyzed, using a correction technique validated in phantom studies that adjusted for changes in measured air density, and the reliability of the voxel index as a measure of emphysema progression was improved. Comparison of adjusted voxel index thresholds indicated the optimum threshold was -950 Hounsfield units. Internal air calibration is therefore critical in longitudinal and multicenter lung densitometry studies of emphysema and incorporation of a correction factor is essential for quantitative image analysis.     

Identifying MRI-detected inflammatory features specific for rheumatoid arthritis: two-fold feature reduction maintains predictive accuracy in clinically suspect arthralgia patients

Objective

MRI-detected inflammation is considered of diagnostic value for rheumatoid arthritis (RA), but its evaluation involves a time-consuming scoring of 61 joint-level features. It is not clear, however, which of these features are specific for RA and whether evaluating a subset of specific features is sufficient to differentiate RA patients. This study aimed to identify a subset of RA-specific features in a case–control setting and validate them in a longitudinal cohort of arthralgia patients.

Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study

Patients with childhood-onset growth hormone (GH) deficiency (GHD) show impairments in mood and cognitive functioning which may resolve following GH substitution. Brain functional magnetic resonance imaging (fMRI) during performance of a memory task was used to assess the cerebral activity of such patients. Thirteen childhood-onset GHD patients (mean age 27.3 +/- 6.9 years) were included in a double-blind, placebo-controlled study. The effects of 6 months of GH replacement or placebo therapy were studied using neuropsychological tests and fMRI. One patient was excluded from the study due to noncompliance with the protocol. Six months of GH substitution in these GHD patients resulted in improved memory functioning, both for long-term and working memory. fMRI showed activations during the working memory task in prefrontal, parietal, motor, and occipital cortices, as well as in the right thalamus and anterior cingulate cortex. Decreased activation in the ventrolateral prefrontal cortex was observed after GH treatment as compared with placebo treatment, indicating decreased effort and more efficient recruitment of the neural system involved. It can be concluded that GH treatment for 6 months improved the long-term as well as the working memory in patients with GHD, and this was associated with decreased brain activation in the ventrolateral prefrontal cortex. GH substitution in GHD patients is beneficial for cognitive functioning, the effects of which can be visualized by means of neuroimaging.     

Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes

The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies.     

Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor

Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.     

Failure of systemic N-acetyl cysteine to protect the rat lung against bleomycin toxicity

In order to see whether systemically administered N-acetyl cysteine (NAC) could protect the lung from bleomycin lung injury, 24 rats were given a constant subcutaneous infusion of NAC (mean 195 mg.kg-1.day-1) for 7 days while 23 rats were given a similar volume of saline. Two days after the start of infusion, half of each group received an endotracheal injection of bleomycin and the other half received a similar volume of saline. All animals were killed 7 days after intratracheal injection and their lungs were prepared for wet-weight to dry-weight ratio (W:D) and morphometric assessment of histological changes. In animals given intratracheal saline, NAC infusion had no effect on weight gain, W:D or morphometry compared to those animals given saline infusions. However, all bleomycin-treated animals had obvious evidence of lung damage. Compared to either group of animals treated with intratracheal saline, the bleomycin-treated groups gained less weight (p less than 0.001), had a higher W:D (p less than 0.001) and an increase in the volume densities of alveolar and duct walls (p less than 0.001), intra-alveolar cells (p less than 0.05) and consolidation (p less than 0.001). There were no significant differences between the two bleomycin-treated groups in any parameter measured. It is concluded that administration of NAC by a constant subcutaneous infusion was not protective against bleomycin lung injury.     

The "destructive index" in nonemphysematous and emphysematous lungs. Morphologic observations and correlation with function

We examined the relationship of the newly described "Destructive Index" (DI) to emphysema using nine nonemphysematous and 13 emphysematous lungs obtained at autopsy. The amount of emphysema was assessed by the panel method (emphysema grade, EG) and measurement of the mean linear intercept (Lm). The DI depends on three components--alveolar wall/duct disruption, DId; alveolar fibrosis, DIf; and classic emphysema, DIe. DIf was a minor component in our series. The mean DI was 5.8 +/- 2.5, 10.9 +/- 3.9, and 55.7 +/- 7.0% (+/- 1 SEM) in the nonemphysematous (panel grade EG = 0), mild (0 less than EG less than or equal to 25), and moderate to severe (30 less than or equal to EG less than or equal to 60) emphysematous lungs, respectively. The increase in the DI in mild emphysema did not reach significant levels (p less than 0.2). The mean DId was 5.6 +/- 2.5, 10.0 +/- 4.0, and 12.8 +/- 3.9% in the above categories, and the DId in mild emphysema did not differ significantly from that of the nonemphysematous lungs. Lm showed a similar trend and alveolar disruption did not precede airspace enlargement, rather both changes appeared to advance in parallel. The DI correlated closely with EG (r = 0.83, p less than 0.01), but this was due to the component of DIe. The DIe increased steeply in the lungs with EG greater than or equal to 30.(ABSTRACT TRUNCATED AT 250 WORDS)