Search

In these two short reports, the authors approach the issue of whether hydroxyurea (HU) use in young males has major irreversible effects on sperm production. Joseph et al analyzed and compared sperm parameters in male patients with sickle cell disease (SCD) who were exposed or not exposed to HU before puberty. They report semen abnormalities in all patients but no differences between groups. Independently, Gille et al provide evidence for the lack of in vivo HU-related decreases in the spermatogonial pool in biopsy specimens from young males with SCD but evidence for a negative effect of SCD itself. Together, these reports suggest that the use of HU in young males does not adversely affect fertility.

Ventilator-associated pneumonia caused by Pseudomonas aeruginosa with impaired sensitivity to ceftazidime is frequent in critically ill patients. The aim of the study was to compare lung tissue deposition and antibacterial efficiency between nebulized and intravenous administrations of ceftazidime in ventilated piglets with pneumonia caused by Pseudomonas aeruginosa with impaired sensitivity to ceftazidime.Ceftazidime was administered 24 h following the intra-bronchial inoculation of Pseudomonas aeruginosa (minimum inhibitory concentration = 16 microg ml(-1)), either by nebulization (25 mg kg(-1) every 3 h, n = 6) or by continuous intravenous infusion (90 mg kg(-1) over 24 h after an initial rapid infusion of 30 mg kg(-1), n = 6). Four non-treated inoculated animals served as controls. All piglets were killed 48 h (intravenous and control groups) or 51 h (aerosol group) after inoculation. Lung tissue concentrations and lung bacterial burden were assessed on multiple post-mortem sub-pleural lung specimens [(lower limit of quantitation = 10(2) colony forming unit (cfu g(-1))].Ceftazidime trough lung tissue concentrations following nebulization were greater than steady-state lung tissue concentrations following continuous intravenous infusion [median and interquartile range, 24.8 (12.6-59.6) microg g(-1) vs. 6.1 (4.6-10.8) microg g(-1)] (p0.001). After 24 h of ceftazidime administration, 83% of pulmonary segments had bacterial counts10(2) cfu g(-1) following nebulization and only 30% following intravenous administration (p0.001). In control animals, 10% of lung segments had bacterial counts10(2) cfu g(-1) 48 h following bronchial inoculation.Nebulized ceftazidime provides more efficient bacterial killing in ventilated piglets with pneumonia caused by Pseudomonas aeruginosa with impaired sensitivity to ceftazidime.

Mechanical ventilation-induced air-space enlargement was investigated in a porcine model of multifocal pneumonia. Following the intrabronchial inoculation of Escherichia coli, 9 piglets (22 +/- 2 kg) were ventilated with a tidal volume (VT) of 15 ml/kg for 43 +/- 15 h. Five noninoculated piglets ventilated for 60 h with the same VT served as control animals. Following death, the lungs were fixed and lung morphometry was assessed. In inoculated animals, unventilated infected and normally ventilated noninfected pulmonary lobules coexisted. In normally ventilated lung regions (1) emphysema-like lesions were present, (2) mean alveolar area and mean linear intercept were significantly greater in inoculated than in control animals, and (3) the degree of alveolar distension correlated with the decrease in respiratory compliance. In unventilated lung areas (1) pseudocysts were frequent, (2) alveolar edema was rare, (3) bronchiolectasis was frequent, (4) mean bronchiolar area was greater in inoculated than in control animals, and (5) the degree of bronchiolar distension correlated with the increase in inspiratory plateau pressure. In conclusion, in piglets with severe bronchopneumonia, air-space enlargement rather than pulmonary edema was the major feature of mechanical ventilation-induced lung barotrauma and resembled lesions previously reported in critically ill patients ventilated using high inspiratory pressures.

Short-term trials of glitazones in nonalcoholic steatohepatitis (NASH) yielded controversial histological results. Longer treatment might result in additional improvement. After a 1-year randomized trial, 53 patients underwent a control liver biopsy and were enrolled in an open-label extension trial of rosiglitazone (RSG), 8 mg/day for 2 additional years. In all, 44 completed the extension phase including 40 with a third liver biopsy. Of these, 22 received placebo (PLB) in the randomized phase (PLB-RSG), and 18 RSG (RSG-RSG). During the 2-year extension phase serum insulin decreased by 26%, homeostasis model assessment (HOMA) by 30%, and alanine aminotransferase (ALT) by 24%. However, there was no significant change in the mean NASH activity score (NAS) (3.8 ± 2.11 versus 3.68 ± 1.8), ballooning score, fibrosis stage (1.76 ± 1.18 versus 1.85 ± 1.19), or area of fibrosis by micromorphometry (4.43% ± 0.68 to 5.54% ± 0.68). In the PLB-RSG group steatosis significantly decreased after 2 years of RSG (median decrease of 15%); in the RSG-RSG group, after an initial decline in the first year of 20%, 2 additional years of RSG did not result in further improvement. Likewise, there was no improvement in the NAS score, ballooning, intralobular inflammation, fibrosis stage, or area of fibrosis with 2 additional years of RSG in the RSG-RSG group. Conclusion: Rosiglitazone has a substantial antisteatogenic effect in the first year of treatment without additional benefit with longer therapy despite a maintained effect on insulin sensitivity and transaminase levels. This suggests that improving insulin sensitivity might not be sufficient in NASH and that additional targets of therapy for liver injury should be explored. (HEPATOLOGY 2009.)

Introduction Air-space enlargement may result from mechanical ventilation and/or lung infection. The aim of this study was to assess how mechanical ventilation and lung infection influence the genesis of bronchiolar and alveolar distention. Methods Four groups of piglets were studied: non-ventilated-non-inoculated (controls, n = 5), non-ventilated-inoculated (n = 6), ventilated-non-inoculated (n = 6), and ventilated-inoculated (n = 8) piglets. The respiratory tract of intubated piglets was inoculated with a highly concentrated solution of Escherichia coli. Mechanical ventilation was maintained during 60 hours with a tidal volume of 15 ml/kg and zero positive end-expiratory pressure. After sacrifice by exsanguination, lungs were fixed for histological and lung morphometry analyses. Results Lung infection was present in all inoculated piglets and in five of the six ventilated-non-inoculated piglets. Mean alveolar and mean bronchiolar areas, measured using an analyzer computer system connected through a high-resolution color camera to an optical microscope, were significantly increased in non-ventilated-inoculated animals (+16% and +11%, respectively, compared to controls), in ventilated-non-inoculated animals (+49% and +49%, respectively, compared to controls), and in ventilated-inoculated animals (+95% and +118%, respectively, compared to controls). Mean alveolar and mean bronchiolar areas significantly correlated with the extension of lung infection (R = 0.50, p < 0.01 and R = 0.67, p < 0.001, respectively). Conclusion Lung infection induces bronchiolar and alveolar distention. Mechanical ventilation induces secondary lung infection and is associated with further air-space enlargement. The combination of primary lung infection and mechanical ventilation markedly increases air-space enlargement, the degree of which depends on the severity and extension of lung infection.

Ventilator-associated pneumonia (VAP) has been described in humans and in experimental animals. The most severe lesions are located in dependent lung segments along a sterno-vertebral axis, however the cephalocaudal distribution of lung infection remains unknown. We used an experimental model to evaluate the distribution of lung infection, considering its anteroposterior and cephalocaudal gradient, and its impact on lung aeration. Ten healthy domestic piglets were anesthetized, paralyzed and mechanically ventilated for 59 hours in the prone position. At the end of the experiment they were sacrificed and their lungs were fixed. Six segments were analyzed: a non-dependant (ND) and a dependant (D) segment of the upper (UL), middle (ML) and lower (LL) lobes. The presence of healthy lung or of histological infectious lesions was analyzed with a semi-quantitative method. The regional distribution of lung infection was compared between upper, middle and lower lobes, as well as between dependant and non-dependant regions. The presence of infectious lesions was correlated with measurements of lung aeration. Nine of the ten piglets developed VAP. Infectious lesions were distributed along a sterno-vertebral and a cephalocaudal gradient; the lower and middle lobes were more frequently infected than the upper lobes. There was an inverse correlation (R= - 0.902) between the development of lung lesions and lung aeration. In conclusion, VAP was a frequent complication in healthy mechanically ventilated piglets, showing an anteroposterior as well as a cephalocaudal gradient. As expected, development of lung infection was accompanied by a corresponding loss of aeration.

Background Pulmonary concentrations of aminoglycosides administered intravenously are usually low in the infected lung parenchyma. Nebulization represents an alternative to increase pulmonary concentrations, although the obstruction of bronchioles by purulent plugs may impair lung deposition by decreasing lung aeration. Methods An experimental bronchopneumonia was induced in anesthetized piglets by inoculating lower lobes with a suspension of 10(6) cfu/ml Escherichia coli. After 24 h of mechanical ventilation, 7 animals received two intravenous injections of 15 mg/kg amikacin, and 11 animals received two nebulizations of 40 mg/kg amikacin at 24-h intervals. One hour following the second administration, animals were killed, and multiple lung specimens were sampled for assessing amikacin pulmonary concentrations and quantifying lung aeration on histologic sections. Results Thirty-eight percent of the nebulized amikacin (15 mg/kg) reached the tracheobronchial tree. Amikacin pulmonary concentrations were always higher after nebulization than after intravenous administration, decreased with the extension of parenchymal infection, and were significantly influenced by lung aeration: 197 +/- 165 versus 6 +/- 5 microg/g in lung segments with focal bronchopneumonia (P = 0.03), 40 +/- 62 versus 5 +/- 3 microg/g in lung segments with confluent bronchopneumonia (P = 0.001), 18 +/- 7 versus 7 +/- 4 microg/g in lung segments with lung aeration of 30% or less, and 65 +/- 9 versus 2 +/- 3 microg/g in lung segments with lung aeration of 50% or more. Conclusions In a porcine model of severe bronchopneumonia, the nebulization of amikacin provided 3-30 times higher pulmonary concentrations than the intravenous administration of an equivalent dose. The greater the lung aeration, the higher were the amikacin pulmonary concentrations found in the infected lung segments.

Summary Background FibroTest ® (FT), and liver stiffness measurement (LSM) are the most validated techniques for the non-invasive assessment of fibrosis in patients with chronic hepatitis C (CHC). The combination between FibroTest ® and LSM has never been assessed using methods assuming that biopsy is not a perfect gold standard. Aim The aim was to assess the performance of a new test the Elasto-FibroTest ® (EFT) combining FibroTest ® and LSM. Methods An integrated data base of 1289 patients with biopsy and 604 healthy volunteers was analyzed. EFT took into account the applicability of both tests, included two algorithms taking one for the diagnosis of advanced fibrosis (EFT-F2) and one for the diagnosis of cirrhosis (EFT-F4). Performances of EFTs were assessed by three methods: area under the ROC curve (AUROC), “Obuchowski method” (OBU) and 1 TAGS the “Latent class with random factor”. Results For the diagnosis of advanced fibrosis EFT-F2 performances (specificity = 0.99 and sensitivity = 0.83) were not greater than the performances of FibroTest ® alone (specificity = 0.93 and sensitivity = 0.99). For the diagnosis of cirrhosis, EFT-F4 performances were greater than those of FibroTest ® alone, particularly for the sensitivity (0.88 vs. 0.74); when compared with LSM, EFT-F4 performances (specificity = 0.99 and sensitivity = 0.99) were also greater than those of LSM alone particularly because of its lower specificity (0.92). Conclusion For the diagnosis of cirrhosis the Elasto-FibroTest ® has higher performances than FibroTest ® or FibroScan ® alone. No improvement in performance has been observed for the diagnosis of advanced fibrosis vs. FibroTest ® alone.

There is controversy about the performance of noninvasive tests such as FibroTest in diagnosing intermediate stages of fibrosis. We investigated whether this controversy results from limitations of biopsy analysis for intermediate-stage fibrosis and inappropriate determination of the standard area under the receiver-operator characteristic curve (AUROC).To determine whether biopsy has a lower diagnostic performance for fibrosis stage F2 (few septa) vs F1 (fibrosis without septa), compared with its performance for F1 vs F0 or F4 vs F3, we determined the fibrotic areas of large surgical samples collected from 20 consecutive patients with chronic liver disease or normal liver tissue that surrounded tumors. We analyzed digitized images of 27,869 virtual biopsies of increasing length and also analyzed data from 6500 patients with interpretable FibroTest results who also underwent biopsy analysis.The overall performance of biopsy analysis (by Obuchowski measure) increased with biopsy length from 0.885 for 5-mm to 0.912 for 30-mm samples (P.0001). The performance of biopsy was lower for the diagnosis of F2 vs F1 samples (weighted AUROC [wAUROC] = 0.505) than for F1 vs F0 (wAUROC = 0.773; 53% difference; P.0001) or F4 vs F3 (wAUROC = 0.700; 39% difference; P.0001), even when 30-mm biopsy samples were used. The performance of FibroTest was also lower for the diagnosis of F2 vs F1 samples (wAUROC = 0.512) than for F1 vs F0 samples (wAUROC = 0.626; 22% difference; P.0001) or F4 vs F3 (wAUROC = 0.628; 23% difference; P.0001). However, the FibroTest had smaller percentage differences among wAUROC values than biopsy.Biopsy has a low level of diagnostic performance for fibrosis stages F2 and F1. The recommendation for biopsy analysis, instead of a validated biomarker panel such as FibroTest, for the diagnosis of intermediate stages of fibrosis is therefore misleading.

Air-space enlargement may result from mechanical ventilation and/or lung infection. The aim of this study was to assess how mechanical ventilation and lung infection influence the genesis of bronchiolar and alveolar distention. Four groups of piglets were studied: non-ventilated-non-inoculated (controls, n = 5), non-ventilated-inoculated (n = 6), ventilated-non-inoculated (n = 6), and ventilated-inoculated (n = 8) piglets. The respiratory tract of intubated piglets was inoculated with a highly concentrated solution of Escherichia coli. Mechanical ventilation was maintained during 60 hours with a tidal volume of 15 ml/kg and zero positive end-expiratory pressure. After sacrifice by exsanguination, lungs were fixed for histological and lung morphometry analyses. Lung infection was present in all inoculated piglets and in five of the six ventilated-non-inoculated piglets. Mean alveolar and mean bronchiolar areas, measured using an analyzer computer system connected through a high-resolution color camera to an optical microscope, were significantly increased in non-ventilated-inoculated animals (+16% and +11%, respectively, compared to controls), in ventilated-non-inoculated animals (+49% and +49%, respectively, compared to controls), and in ventilated-inoculated animals (+95% and +118%, respectively, compared to controls). Mean alveolar and mean bronchiolar areas significantly correlated with the extension of lung infection (R = 0.50, p < 0.01 and R = 0.67, p < 0.001, respectively). Lung infection induces bronchiolar and alveolar distention. Mechanical ventilation induces secondary lung infection and is associated with further air-space enlargement. The combination of primary lung infection and mechanical ventilation markedly increases air-space enlargement, the degree of which depends on the severity and extension of lung infection.