Association of sleep disordered breathing symptoms with early postoperative analgesic requirement in pediatric ambulatory surgical patients.

INTRODUCTION: Sleep disordered breathing (SDB) symptoms are associated with increased rates of opioid-induced respiratory depression as well as enhanced nociception. Consequently, practitioners often withhold or administer lower intraoperative doses of opioids out of concern for postoperative respiratory depression. Therefore, SDB may be a critical determinant of analgesic requirement in the post-anesthesia care unit (PACU). We investigated whether preoperative SDB classification was independently associated with need for PACU analgesic intervention in a cross-sectional sample of 985 children who underwent elective, painful ambulatory surgical procedures. METHODS: Using prospectively collected data, children aged 4-17yr were grouped into two categories based on whether or not they had symptoms of SDB. Perioperative variables were compared between the exposed and control groups using Chi-squared test for categorical or t-test for continuous variables. Logistic regression analysis was used to assess the association between SDB and the odds of requiring PACU IV opioids. RESULTS: Children with preoperative SDB symptoms (N = 325) compared with the reference group of children who did not have these symptoms had higher rates of PACU analgesic intervention (47.1% vs. 37.4%; p = 0.004) and higher mean arousal pain scores (3.7 ± 3.5 vs.1.9 ± 2.9; p < 0.001). In our primary multivariable logistic regression model adjusted for a number of variables, preoperative SDB symptoms was associated with a two-fold increased odds of receiving PACU intravenous opioid (OR = 2.01, 95%CI, 1.29-3.12; p = 0.002). CONCLUSION: These results suggest that preoperative SDB symptoms in children undergoing ambulatory surgery, exerts a significant influence on PACU pain behavior and analgesic requirement. Mechanisms underlying this enhanced pain experience deserve further elucidation.

Cyclohexanol analogues are positive modulators of GABA(A) receptor currents and act as general anaesthetics in vivo.

GABA(A) receptors meet all the pharmacological criteria required to be considered important general anaesthetic targets. In the following study, the modulatory effects of various commercially available and novel cyclohexanols were investigated on recombinant human γ-aminobutyric acid (GABA(A), α(1)ß(2)γ(2s)) receptors expressed in Xenopus oocytes, and compared to the modulatory effects on GABA currents observed with exposures to the intravenous anaesthetic agent, propofol. Submaximal EC(20) GABA currents were typically enhanced by co-applications of 3-300 µM cyclohexanols. For instance, at 30 µM 2,6-diisopropylcyclohexanol (a novel compound) GABA responses were increased ~3-fold (although similar enhancements were achieved at 3 µM propofol). As regards rank order for modulation by the cyclohexanol analogues at 30 µM, the % enhancements for 2,6-dimethylcyclohexanol~2,6-diethylcyclohexanol~2,6-diisopropylcyclohexanol~2,6-di-sec-butylcyclohexanol ≫2,6-di-tert-butylcyclohexanol~4-tert-butylcyclohexanol>cyclohexanol~cyclopentanol~2-methylcyclohexanol. We further tested the potencies of the cyclohexanol analogues as general anaesthetics using a tadpole in vivo assay. Both 2,6-diisopropylcyclohexanol and 2,6-dimethylcyclohexanol were effective as anaesthetics with EC(50)s of 14.0 µM and 13.1 µM respectively, while other cyclohexanols with bulkier side chains were less potent. In conclusion, our data indicate that cyclohexanols are both positive modulators of GABA(A) receptors currents and anaesthetics. The positioning and size of the alkyl groups at the 2 and 6 positions on the cyclohexanol ring were critical determinants of activity.

Krüppel-like factor 5 controls keratinocyte migration via the integrin-linked kinase.

Migration of epithelial cells is critical for normal homeostasis in gut and skin, but the factors regulating this process are not completely understood. The zinc finger transcription factor Klf5 (IKLF; BTEB2) is highly expressed in proliferating cells of esophagus, skin, and other organs. We hypothesized that Klf5 regulates keratinocyte migration via the integrin-linked kinase (ILK), which, like Klf5, is localized to basal keratinocytes. We stably transduced mouse primary esophageal keratinocytes to overexpress Klf5 or small interfering RNA against Klf5. Klf5 overexpression in keratinocytes increased migration and correlated directly with ILK expression and activation. ILK expression restored migratory capacity in keratinocytes with suppression of Klf5, whereas ILK small interfering RNA blocked the increased migration resulting from Klf5 overexpression. By chromatin immunoprecipitation, electromobility shift assay, and luciferase reporter assays, we confirmed that ILK was a direct target for Klf5. In addition, Klf5 induced the activation of the ILK targets Cdc42 and myosin light chain, which are critical for cell migration and motility but not Rac1, AKT, or GSK3beta. Overall, these results demonstrate that Klf5 is a key regulator of cell migration via ILK and provide new insight into the regulation of epithelial cell migration.

Overexpression of Kruppel-like factor 5 in esophageal epithelia in vivo leads to increased proliferation in basal but not suprabasal cells.

Krüppel-like factor 5 (Klf5; also called IKLF or BTEB2), a zinc-finger transcription factor with proproliferative and transforming properties in vitro, is expressed in proliferating cells of gastrointestinal tract epithelia, including in basal cells of the esophagus. Thus, Klf5 is an excellent candidate to regulate esophageal epithelial proliferation in vivo. Nonetheless, the function of Klf5 in esophageal epithelial homeostasis and tumorigenesis in vivo has not previously been determined. Here, we used the ED-L2 promoter of the Epstein-Barr virus to express Klf5 throughout esophageal epithelia. ED-L2/Klf5 transgenic mice were born at the appropriate Mendelian ratio, survived to at least 1 yr of age, and showed no evidence of esophageal dysplasia or cancer. Staining for bromodeoxyuridine (BrdU) demonstrated increased proliferation in the basal layer of ED-L2/Klf5 mice, but no proliferation was seen in suprabasal cells, despite ectopic expression of Klf5 in these cells. Notably, expression of the KLF family member Klf4, which binds the same DNA sequences as Klf5 and which inhibits proliferation and promotes differentiation, was not altered in ED-L2/Klf5 transgenic mice. In primary esophageal keratinocytes that overexpressed Klf5, expression of Klf4 still inhibited proliferation and promoted differentiation, providing a possible mechanism for the persistence of keratinocyte differentiation in ED-L2/Klf5 mice. To identify additional targets for Klf5 in esophageal epithelia, we performed functional genomic analyses and identified a total of 15 differentially expressed genes. In summary, while Klf5 positively regulates proliferation in basal cells, it is not sufficient to maintain proliferation in the esophageal epithelium.