Pediatric extubation readiness tests should not use pressure support.

PURPOSE: Pressure support is often used for extubation readiness testing, to overcome perceived imposed work of breathing from endotracheal tubes. We sought to determine whether effort of breathing on continuous positive airway pressure (CPAP) of 5 cmH2O is higher than post-extubation effort, and if this is confounded by endotracheal tube size or post-extubation noninvasive respiratory support. METHODS: Prospective trial in intubated children. Using esophageal manometry we compared effort of breathing with pressure rate product under four conditions: pressure support 10/5 cmH2O, CPAP 5 cmH2O (CPAP), and spontaneous breathing 5 and 60 min post-extubation. Subgroup analysis excluded post-extubation upper airway obstruction (UAO) and stratified by endotracheal tube size and post-extubation noninvasive respiratory support. RESULTS: We included 409 children. Pressure rate product on pressure support [100 (IQR 60, 175)] was lower than CPAP [200 (120, 300)], which was lower than 5 min [300 (150, 500)] and 60 min [255 (175, 400)] post-extubation (all p < 0.01). Excluding 107 patients with post-extubation UAO (where pressure rate product after extubation is expected to be higher), pressure support still underestimated post-extubation effort by 126-147 %, and CPAP underestimated post-extubation effort by 17-25 %. For all endotracheal tube subgroups, ≤3.5 mmID (n = 152), 4-4.5 mmID (n = 102), and ≥5.0 mmID (n = 48), pressure rate product on pressure support was lower than CPAP and post-extubation (all p < 0.0001), while CPAP pressure rate product was not different from post-extubation (all p < 0.05). These findings were similar for patients extubated to noninvasive respiratory support, where pressure rate product on pressure support before extubation was significantly lower than pressure rate product post-extubation on noninvasive respiratory support (p < 0.0001, n = 81). CONCLUSIONS: Regardless of endotracheal tube size, pressure support during extubation readiness tests significantly underestimates post-extubation effort of breathing.

ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21.

To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in high-risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy. Among the molecular signatures associated with chemotherapy, transcripts encoding inhibitor of DNA binding 1 (ID1) were significantly upregulated. The patient biochemical relapse status was monitored in a long-term follow-up. Patients with ID1 upregulation were found to be associated with longer relapse-free survival than patients without ID1 increase. This in vivo clinical association was mechanistically investigated. The chemotherapy-induced ID1 upregulation was recapitulated in the prostate cancer cell line LNCaP. Docetaxel dose-dependently induced ID1 transcription, which was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Stable ID1 overexpression in LNCaP increased cell proliferation, promoted G(1) cell cycle progression, and enhanced docetaxel-induced cytotoxicity. These changes were accompanied by a decrease in cellular mitochondria content, an increase in BCL2 phosphorylation at serine 70, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel-induced cytotoxicity by inhibiting cell death. ID1-mediated chemosensitivity enhancement was in part due to ID1 suppression of p21. Overexpression of p21 in LNCaP-ID1-overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These molecular data provide a mechanistic rationale for the observed in vivo clinical association between ID1 upregulation and relapse-free survival. Taken together, it shows that ID1 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis.

CASSCF molecular orbital calculations reveal a purely pseudopericyclic mechanism for a [3,3] sigmatropic rearrangement.

A comparative CASSCF/6-31G*-level computational study of the concerted [3,3] sigmatropic rearrangements of cis-1-iminyl-2-ketenylcyclopropane (15), cis-1-iminyl-2-propadienylcyclopropane (17), and cis-1-iminyl-2-keteniminylcyclopropane (19) to give products 16, 18, and 20, respectively, was conducted. Analysis of the active space MOs of TS(15-->16), TS(17-->18), and TS(19-->20) suggests that the 17 --> 18 and 19 --> 20 rearrangements are classically pericyclic, whereas the 15 --> 16 rearrangement is pseudopericyclic with two orbital disconnections-one involving the nitrogen lone-pair orbital and the other the carbonyl carbon of the ketene moiety. The novel TS(15-->16) was also found to have a highly planar, tight, geometry, whereas TS(17-->18) and TS(19-->20) were both shown to have the boat-shaped geometry expected for classically pericyclic [3,3] sigmatropic rearrangements. Results of calculations on the [3,3] sigmatropic rearrangements involving additional transition structures, TS(21-->22), TS(23-->24), TS(25-->26), TS(27-->28), TS(29-->30), and TS(31-->32), demonstrate the relative uniqueness of the pseudopericyclic one, TS(15-->16).