Kinetics of the reaction of ferrous ions with hydroxyl radicals in the temperature range 25-300 °C.

The kinetics and mechanism of the reaction between OH radicals and ferrous ions in the temperature range 25-300 °C were studied using pulse radiolysis. At temperatures <150 °C the rate of reaction is essentially independent of temperature, while at temperatures >150 °C the activation energy is 45.8 ± 3.0 kJ mol-1. The change in activation energy is attributed to a change in the dominant mechanism from hydrogen atom transfer (HAT) to dissociative ligand interchange. The kinetic isotope effect (KIE) was measured by repeating experiments in heavy water. A value of 2.9 was measured at room temperature where HAT is the dominant mechanism. The KIE decreases to zero at temperatures > 150 °C as ligand interchange becomes dominant and the O-H bond is no longer involved in the reaction.

Testing for pediatric obstructive sleep apnea when health care resources are rationed.

IMPORTANCE: Evaluation of pediatric obstructive sleep apnea in resource-limited health care systems necessitates testing modalities that are accurate and more cost-effective than polysomnography. OBJECTIVE: To trace the clinical pathway of children referred to our sleep laboratory for possible obstructive sleep apnea who were evaluated using nocturnal pulse oximetry and the McGill Oximetry Score. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of children 2 to 17 years old with suspected obstructive sleep apnea due to adenotonsillar hypertrophy, conducted at a Canadian pediatric tertiary care center. INTERVENTIONS: Nocturnal pulse oximetry studies scored using the McGill Oximetry Score. MAIN OUTCOMES AND MEASURES: For children who underwent adenotonsillectomy we determined the length of time from oximetry to surgery, postoperative length of stay, postoperative readmissions, and emergency department visits in the month following surgery and major surgical complications. We analyzed these outcomes by oximetry result. We compared the cost savings of our diagnostic approach with those of other diagnostic models. RESULTS: Among 362 children, the median age was 4.8 years (interquartile range, 3.3-6.7), and 61% were male. Two-hundred-sixty-six (73%) and 96 (27%), respectively, had inconclusive and abnormal oximetry results. Eighty of 96 of children with abnormal oximetry results (83%) and 81 of 266 children with inconclusive oximetry results (30%) underwent adenotonsillectomy. Thirty-three of 266 children (12%) underwent further evaluation with polysomnography; of 14 diagnosed as having OSA, 12 underwent adenotonsillectomy. Children with abnormal oximetry results were operated on soonest after testing and triaged based on oximetry results. No child with an inconclusive oximetry result required hospitalization for more than 1 night postoperatively; 14% of children (11 of 80) with an abnormal oximetry result required hospitalization for 2 or 3 nights (χ2 = 12.0; P = .001). Rates of readmissions and emergency department visits were low, irrespective of oximetry results (whether inconclusive or abnormal). We show that our oximetry-based diagnostic approach results in considerable cost savings compared with a polysomnography-for-all approach. CONCLUSIONS AND RELEVANCE: Oximetry studies evaluated with the McGill Oximetry Score expedite diagnosis and treatment of children with adenotonsillar hypertrophy referred for suspected sleep-disordered breathing. When resources for testing for sleep-disordered breathing are rationed or severely limited, our proposed diagnostic approach can help maximize cost-savings and allows sleep laboratories to focus resources on medically complex children requiring polysomnographic evaluation of suspected sleep disorders.

Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists.

The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.

Pulse rate and pulse rate variability decrease after adenotonsillectomy for obstructive sleep apnea.

BACKGROUND: Data suggest that obstructive sleep apnea syndrome (OSA) results in sympathetic stimulation, brady/tachycardia and cardiac stress. Heart rate variability, but not baseline heart rate, is known to be elevated in pediatric OSA. Our patients with moderate to severe OSA (McGill Oximetry Scores of 3 or 4) have been re-evaluated with pulse oximetry after adenotonsillectomy (T&A). We hypothesized that pulse rate (PR) and pulse rate variability (PRV) would decrease after treatment of OSA with T&A. METHODS: This retrospective before-after study comprised pre- and post-operative oximetries and parental questionnaires of children 1-18 years old with moderate to severe OSA from September 2004 to August 2005, inclusive. We excluded patients with significant comorbidities. RESULTS: In 25 subjects, age at surgery was 4.3 +/- 3.6 years (mean +/- SD). OSA symptoms decreased or resolved, saturation metrics improved, and parental concern about breathing during sleep decreased following T&A. PR decreased in 21 of 25 patients after T&A (mean PR from 99.7 +/- 11.2 to 90.1 +/- 10.7 bpm, P < 0.001; maximum PR from 150.6 +/- 14.5 to 137.4 +/- 15.6 bpm, P < 0.001). PRV, as measured by the standard deviation of the PR, decreased in 23 of 25 patients after T&A (from 10.3 +/- 2.1 to 8.2 +/- 1.6 bpm, [P < 0.001]). Pulse accelerations greater than 6, 7, 8 bpm also decreased post-operatively. CONCLUSIONS: Nocturnal pulse oximetry complements clinical history to document improvement and/or resolution of moderate to severe OSA in children. Resolution of tachycardia and diminished PRV after T&A illustrate the stress that recurrent airway obstruction during sleep places on the cardiovascular system. Further work will be required to determine if PR and PRV as measured by pulse oximetry would be useful in the diagnosis and follow-up of OSA in children.

Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARalpha/gamma dual agonists, and X-ray crystallographic studies.

A new series of alpha-aryl or alpha-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARalpha and PPARgamma was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARgamma-ligand-binding domain was obtained and discussed in this report.

Differences in pulse oximetry technology can affect detection of sleep-disorderd breathing in children.

UNLABELLED: Newer pulse oximeters have been developed to be motion resistant and thus have few false alarms. However, they have not yet been evaluated in a pediatric sleep laboratory setting. While evaluating new oximeters for use in our laboratory, we obtained simultaneous pulse oximetry data from two Masimo oximeters and from two Nellcor oximeters during nocturnal polysomnography in children referred for sleep-disordered breathing (SDB). In series 1, comprising 24 patients, comparisons were made between a Masimo oximeter with 4-second averaging time and the Nellcor N-200 oximeter set for 3 to 5 second averaging. A maximum of 20 events per patient were randomly selected for analysis, an "event" being a desaturation of > or = 4% registered by either oximeter. Interobserver agreement for event classification was 93%. Eighty-eight percent of 220 desaturation events occurring during wakefulness and 38% of 194 events occurring during sleep were classified as motion artifact on the Nellcor oximeter. Neither the Masimo oximeter nor the transcutaneous oxygen probe confirmed that the desaturation was real, in most of these cases. During sleep, there were 119 events detected by either or both oximeters: 113 (95%) by the Nellcor versus 82 (69%) by the Masimo. For these 119 events, the extent of desaturation was slightly less for the Masimo than the Nellcor oximeter, 4.5 +/- 2.4% versus 5.5 +/- 2.5%, respectively. In series 2, 22 patients were studied comparing a Masimo Radical oximeter with 2 second averaging to the Nellcor N-200 oximeter. The extent of desaturation was slightly greater for the Masimo oximeter. The Masimo oximeter detected more non-artifactual desaturation events occurring during sleep than the Nellcor oximeter, 90% versus 76% (chi2 = 9.9, p < 0.01). In series 3, comprising 128 events in 5 patients, a Nellcor N-395 oximeter detected fewer desaturations during non-movement, sleep periods and had more movement related "desaturation" events, compared to a Masimo Radical oximeter. CONCLUSIONS: The Masimo oximeters register many fewer false desaturations due to motion artifact. Using 4-second averaging, a Masimo oximeter detected significantly fewer SaO2 dips than the Nellcor N-200 oximeter but using 2-second averaging, the Masimo oximeter detected more SaO2 dips than the Nellcor N-200 oximeter. The sensitivity and motion artifact rejection characteristics of the Nellcor N-395 oximeter are not adequate for a pediatric sleep laboratory setting. These findings suggest that in a pediatric sleep laboratory, use of a Masimo oximeter with very short averaging time could significantly reduce workload and improve reliability of desaturation detection.