Gene expression profile of human airway epithelium induced by hyperoxia in vivo

Hyperoxia leads to oxidative modification and damage of macromolecules in the respiratory tract with loss of biological functions. Given the lack of antioxidant gene induction with acute exposure to 100% oxygen, we hypothesized that clearance pathways for oxidatively modified proteins may be induced and serve in the immediate cellular response to preserve the epithelial layer. To test this, airway epithelial cells were obtained from individuals under ambient oxygen conditions and after breathing 100% oxygen for 12 h. Gene expression profiling identified induction of genes in the chaperone and proteasome-ubiquitin-conjugation pathways that together comprise an integrated cellular response to manage and degrade damaged proteins. Analyses also revealed gene expression changes associated with oxidoreductase function, cell cycle regulation, and ATP synthesis. Increased HSP70, protein ubiquitination, and intracellular ATP were validated in cells exposed to hyperoxia in vitro. Inhibition of proteasomal degradation revealed the importance of accelerated protein catabolism for energy production of cells exposed to hyperoxia. Thus, the human airway early response to hyperoxia relies predominantly upon induction of cytoprotective chaperones and the ubiquitin-proteasome-dependent protein degradation system to maintain airway homeostatic integrity.     

Respiratory outcome of mid-face advancement with distraction: a comparison between Le Fort III and frontofacial monobloc

Upper airway stenosis in patients with faciocraniosynostosis is very common and often severe. Mid-face advancement, either with a Le Fort III or concomitantly to a monobloc frontofacial advancement, may prevent a tracheotomy or result in its ablation. The amelioration of respiratory function appears to be much better if the mid-face advancement is combined with distraction osteogenesis, although large studies with long-term follow-up are rare. In this study we reviewed the respiratory outcome between Le Fort III with distraction and monobloc advancement with distraction in 55 faciocraniosynostotic patients. Early respiratory results of both procedures were very good and stable at long-term follow-up. The choice between a Le Fort III and a monobloc procedure is made based on presenting morphology, previous surgery, and age. Both can be expected to give a long-lasting improvement of upper airway obstruction.     

Frontal lobe atrophy after prolonged frontal bone defect

After a frontofacial monobloc in a 12-year-old Crouzon patient, the frontal bone was lost to infection. The patient did not attend postoperative appointments and was lost to follow-up. Nine years later, he reappeared requesting surgical reconstruction. This was performed satisfactorily with a titanium plate; however, it became apparent later that he had considerable atrophy of the frontal lobes and had developed the unstable behavior of patients who have undergone a frontal lobotomy. The atrophy would appear to be the consequence of the long-term absence of the frontal bones and the resultant repetitive frontal lobe microtrauma. Frontal infection and subsequent loss of the frontal bone is a recognized complication of monobloc advancement for faciocraniosynostosis and is mainly caused by the communication between the oronasal cavities and the cranial base. The frontal bone defect would normally be repaired after a delay of 6 months to a year with no significant sequelae. We present the unusual case of a patient whose frontal defect was not reconstructed for 9 years and who, as a result, developed frontal lobe atrophy and subsequent severe psychologic and behavioral difficulties.     

NF-kappaB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a preneoplastic condition that frequently develops into overt acute myeloid leukemia (AML). The P39 MDS/AML cell line manifested constitutive NF-kappaB activation. In this cell line, NF-kappaB inhibition by small interfering RNAs specific for p65 or chemical inhibitors including bortezomib resulted in the down-regulation of apoptosis-inhibitory NF-kappaB target genes and subsequent cell death accompanied by loss of mitochondrial transmembrane potential as well as by the mitochondrial release of the caspase activator cytochrome c and the caspase-independent death effectors endonuclease G and apoptosis-inducing factor (AIF). Bone marrow cells from high-risk MDS patients also exhibited constitutive NF-kappaB activation similar to bone marrow samples from MDS/AML patients. Purified hematopoietic stem cells (CD34+) and immature myeloid cells (CD33+) from high-risk MDS patients demonstrated the nuclear translocation of the p65 NF-kappaB subunit. The frequency of cells with nuclear p65 correlated with blast counts, apoptosis suppression, and disease progression. NF-kappaB activation was confined to those cells that carried MDS-associated cytogenetic alterations. Since NF-kappaB inhibition induced rapid apoptosis of bone marrow cells from high-risk MDS patients, we postulate that NF-kappaB activation is responsible for the progressive suppression of apoptosis affecting differentiating MDS cells and thus contributes to malignant transformation. NF-kappaB inhibition may constitute a novel therapeutic strategy if apoptosis induction of MDS stem cells is the goal.     

Candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia

BACKGROUND: Recovery of Candida from the respiratory tract of a critically ill patient receiving mechanical ventilation (MV) usually indicates colonization rather than infection of the respiratory tract. However, interactions between Candida and bacteria, particularly Pseudomonas, have been reported. Thus, Candida colonization of the respiratory tract may predispose to bacterial ventilator-associated pneumonia (VAP). METHODS: In a multicenter study of immunocompetent critically ill patients receiving MV for > 2 days, we compared the incidence of pneumonia in patients with and without (exposed/unexposed) respiratory-tract Candida colonization, matched on study center, admission year, and MV duration. RESULTS: Over the 4-year study period, of the 803 patients meeting study inclusion criteria in the six study centers, 214 patients (26.6%) had respiratory tract Candida colonization. Candida albicans was the most common species (68.7%), followed by Candida glabrata (20.1%) and Candida tropicalis (13.1%). Extrapulmonary Candida colonization was more common in exposed patients (39.7% vs 8.3%, p = 0.01). Exposed patients had longer ICU and hospital stays but similar mortality to unexposed patients. The matched exposed/unexposed nested cohort study identified bronchial Candida colonization as an independent risk factor for pneumonia (24.1% vs 17.6%; adjusted odds ratio [OR], 1.58; 95% confidence interval [CI], 0.94 to 2.68; p = 0.0860); the risk increase was greatest for Pseudomonas pneumonia (9% vs 4.8%; adjusted OR, 2.22; 95% CI, 1.00 to 4.92; p = 0.049). CONCLUSIONS: Candida colonization of the respiratory tract is common in patients receiving MV for > 2 days and is associated with prolonged ICU and hospital stays, and with an increased risk of Pseudomonas VAP.     

Value of D-dimer testing for the exclusion of pulmonary embolism in patients with previous venous thromboembolism

BACKGROUND: D-dimer levels remain elevated in many patients after completion of a 6-month anticoagulant drug course for a first episode of venous thromboembolism (VTE), which may limit the clinical usefulness of D-dimer testing for ruling out a possible recurrence. METHODS: We assessed the safety and usefulness of D-dimer testing in patients with suspected pulmonary embolism (PE) who had experienced a previous VTE. We analyzed data from 2 outcome studies that enrolled 1721 consecutive emergency department patients with clinically suspected PE. Information on the existence of a previous episode of VTE was abstracted from the database. All the patients underwent a sequential diagnostic workup, including an enzyme-linked immunosorbent assay D-dimer test and a 3-month follow-up. RESULTS: The proportion of confirmed PE was 24.1% (415/1719); PE was ruled out by a negative D-dimer test result in 32.7% (462/1411) of the patients without previous VTE but in only 15.9% (49/308) of the patients with previous VTE (P<.001). The 3-month thromboembolic risk was 0% (95% confidence interval, 0.0%-7.9%) in patients with previous VTE and a negative D-dimer test result. The 2-fold lower chance of a negative D-dimer test result in patients with previous VTE was independent of older age, active malignancy, fever, and recent surgery. CONCLUSIONS: In patients with suspected PE and previous VTE, a negative D-dimer test result seems to allow safely ruling out a recurrent event. However, the proportion of negative results is lower in such patients, definitely reducing the clinical usefulness of the D-dimer test in that subgroup.     

Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors

BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.