Antigen-induced mediator release in primates.

We examined the release of bronchoactive mediators into the airways of allergic primates during the acute response to specific antigen inhalation. Twelve adult male cynomolgus monkeys (Macaca fascicularis) with a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract were anesthetized and intubated for each study. Respiratory system resistance (Rrs) and dynamic lung compliance (CLdyn) were measured before and after antigen inhalation, and the release of mediators into the airways was assessed by bronchoalveolar lavage (BAL). BAL samples were concentrated approximately 5-fold before quantitation of LTC4 and PGD2 by RP-HPLC and radioimmunoassay and histamine by a fluorometric assay. Antigen inhalation resulted in a 40-fold increase in BAL levels of i-LTC4 (1.5 +/- 0.7 to 41.6 +/- 12.7 ng, p less than 0.01), a 10-fold increase in i-PGD2 (2.4 +/- 0.9 to 25.9 +/- 5.5 ng, p less than 0.01), and a 20-fold increase in BAL histamine (1.0 +/- 1.5 to 21.4 +/- 2.3 micrograms, p less than 0.01). Dexamethasone (n = 7) inhibited the antigen-induced increase in BAL i-LTC4 (71 +/- 6%, p less than 0.01) and i-PGD2 (52 +/- 8%, p less than 0.05) while weakly inhibiting histamine release (43 +/- 10%). Indomethacin (n = 7) had a variable effect on i-LTC4 levels (6 +/- 51%), strongly inhibited i-PGD2 (88 +/- 9%, p less than 0.01), and had no effect on histamine release (25 +/- 8%). Pretreatment with iodoxamide tromethamine significantly blocked the release of each mediator, but mepyramine, an H1 antagonist, had no effect on mediator release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Task analysis of the preincision surgical period: an independent observer-based study of 1558 cases

Intense production pressure has focused on the preincision period (from patient-on-table to incision) as an important component of overall operating room efficiency. We conducted a prospective study in which trained independent observers measured the performance of anesthesiologists, surgeons, and nursing staff to determine anesthesia release time (ART, patient-on-table until release for surgical preparation) and surgical preparation time (SPT, start surgical preparation to incision) and the factors, including delays, that affect their duration. We enrolled 1558 patients undergoing elective surgery in a tertiary medical center. The mean ART was 21 +/- 16 min. Mean SPT was 22 +/- 13 min, and mean case length was 207 +/- 123 min. Significant variation was seen in both ART (range, 1-115 min) and SPT (range, 1-130 min). Multivariate regression analysis revealed ASA physical status, age, level of resident training, invasive monitoring, case length, and case number in the room were all positive predictors of ART duration (P < 0.05). In contrast, gender, body mass index, number of anesthesia personnel concurrently in the room, and number of rooms covered per anesthesia attending were not predictors for ART (P > 0.05). Delays affected both ART and SPT and were encountered in 24.5% of all procedures (surgery 66.8%, anesthesiology 21.7%, and logistical 11.5%). For operating room scheduling purposes, we conclude that assigning a constant fixed duration for anesthetic induction is inappropriate and will result in creating erroneous administrative expectations.     

Development and validation of The Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis

BACKGROUND: The Cystic Fibrosis Questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents and adults with cystic fibrosis (CF) > or = 14 years, consisting of 44 items on 12 generic and disease-specific scales. Versions of the CFQ are also available for children with CF and their parents. This study evaluated the psychometric properties of the CFQ in a national study at 18 CF centers in the United States. PARTICIPANTS: The CFQ-teen/adult was administered to 212 patients with CF ranging in age from 14 to 53 years. Test-retest reliability was assessed in a subset of patients over a 10- to 14-day interval. RESULTS: Multitrait analysis indicated a majority of items (95%) correlated more highly with their intended scale than a competing scale, supporting the conceptual model. Internal consistency coefficients indicated the CFQ scales had good reliability (Cronbach alpha = 0.67 to 0.94), and test-retest stability was acceptable (rs = 0.45 to 0.90). Validity was demonstrated by examining relationships between the CFQ, age, pulmonary function, and body mass index. As expected, the CFQ was inversely correlated with age, with older adults reporting lower CFQ scores than younger adults, better nutritional status was positively correlated with several weight-related scales, and the measure differentiated between individuals with varying levels of disease severity. Strong associations were also found between the CFQ and similar scales on the Short Form-36 Health Questionnaire, a well-known generic HRQOL measure. CONCLUSIONS: The results demonstrated that the CFQ-teen/adult is a reliable and valid measure of HRQOL for individuals with CF. It may be utilized in clinical trials to assess the effects of new therapies, to document the progression of disease, and to inform clinical practice.     

Complications occurring in the postanesthesia care unit: a survey.

To identify and quantitate complications occurring in the postanesthesia care unit (PACU), a prospective study evaluated 18,473 consecutive patients entering a PACU at a university teaching hospital. Using a standardized collection form, the incidence of intraoperative and PACU complications was determined. The combined PACU and intraoperative complication rate was 26.7%. Data showed a PACU complication rate of 23.7%, with an overall intraoperative complication rate of 5.1%. Nausea and vomiting (9.8%), the need for upper airway support (6.9%), and hypotension requiring treatment (2.7%) were the most frequently encountered PACU complications. Patients in whom PACU complications developed were analyzed by ASA physical status. Of all patients experiencing nausea and vomiting (n = 1571), the highest percentage were ASA physical status II patients (n = 831). Likewise, in the group of 1450 patients who demonstrated a need for upper airway support, 792 were ASA physical status II. In patients experiencing a major cardiovascular complication, for example, variables associated with a greater risk of developing any PACU complications were ASA physical status (status II), duration of anesthesia (2-4 h), anesthetic technique, emergency procedures, and certain types of surgical procedures (orthopedic or abdominal). For patients admitted with a temperature of less than 35 degrees C the duration of the PACU stay was 152 +/- 46 min compared with 116 +/- 65 min for patients with a temperature greater than or equal to 36 degrees C (P less than 0.01). In conclusion, events occurring during the PACU period continue to be a source of patient morbidity.     

The impact of computer-assisted auscultation on physician referrals of asymptomatic patients with heart murmurs

BACKGROUND: As many as 50-70% of asymptomatic children referred for specialist evaluation or echocardiography because of a murmur have no heart disease. HYPOTHESIS: Computer-assisted auscultation (CAA) can improve the sensitivity and specificity of referrals for evaluation of heart murmurs. METHODS: Seven board-certified primary care physicians were evaluated both without and with use of a computer-based decision-support system using 100 prerecorded patient heart sounds (55 innocent murmurs, 30 pathological murmurs, 15 without murmur). The sensitivity and specificity of their murmur referral decisions relative to American College of Cardiology/American Heart Association (ACC/AHA) guidelines, and sensitivity and specificity of murmur detection and characterization (innocent versus pathological) were measured. RESULTS: Sensitivity for detection of murmurs significantly increased with use of CAA from 76.6 to 89.1% (p <0.001), while specificity remained unaffected (80.0 versus 81.0%). Computer-assisted auscultation improved sensitivity of correctly identifying pathological murmur cases from 82.4 to 90.0%, and specificity of correctly identifying benign cases (with innocent or no murmurs) from 74.9 to 88.8%. (p <0.001). Referral sensitivity increased from 86.7 to 92.9%, while specificity increased from 63.5 to 78.6% using CAA (p <0.001). CONCLUSIONS: Computer-assisted auscultation appears to be a promising new technology for informing the referral decisions of primary care physicians.     

Evolution of the thienopyridine class of inhibitors of IkappaB kinase-beta: part I: hit-to-lead strategies

High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IkappaB kinase-beta (IKKbeta), a key regulatory enzyme in the nuclear factor-kappaB (NF-kappaB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.     

Task analysis of the preincision period in a pediatric operating suite: an independent observer-based study of 656 cases

We designed this cross-sectional investigation to assess anesthesia release time (ART = patient-on-table until release for surgical preparation) and surgical preparation time (start of surgical preparation to incision) of children undergoing anesthesia and surgery (n = 656). Data collected by trained independent observers included variables such as age, ASA physical status, anesthetic technique, and placement of invasive monitoring. We found that mean ART was 11.0 +/- 9.7 min and the mean surgical preparation time was 11.1 +/- 10.0 min. Also, ART ranged from 7 +/- 7 min (for mask anesthesia) to 52 +/- 18 min (general anesthesia/endotracheal tube and invasive hemodynamic monitoring). The percentage of ART of the total case length was 15% +/- 7%, with a wide variability depending on the total case length. We also found that there is a significant variability in ART as a function of the surgical service involved (analysis of variance; P = 0.0001), ASA physical status (P = 0.0001), and age. For example, younger children had a significantly longer ART as compared with older children (P = 0.001). Room coverage ratio by the attending anesthesiologist and training level of the anesthesia resident did not impact ART (P = not significant). We conclude that ART in children undergoing surgery is highly variable and is a function of factors such as the surgical service involved, age of the child, and ASA physical status of the child. These factors should be considered when scheduling a surgical case.     

Prestimulus theta activity predicts correct source memory retrieval

Recent evidence indicates that the processing of a stimulus can be influenced by preceding patterns of brain activity. Here we examine whether prestimulus oscillatory brain activity can influence the ability to retrieve episodic memories. Neural activity in the theta-frequency band (4-8 Hz) was enhanced before presentation of test items which elicited accurate recollection of contextual details of the prior study episode ("source retrieval"), relative to trials for which item recognition was successful but source retrieval failed. Poststimulus theta activity was also related to source retrieval, and the magnitude of poststimulus theta was predicted by the magnitude of the prestimulus theta effects. The results suggest that ongoing neural processes occurring before stimulus onset might play a critical role in readying the brain for successful memory retrieval.     

Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial.

CONTEXT: Seasonal allergic rhinitis is a common IgE-mediated disorder that produces troublesome symptoms. A recombinant humanized monoclonal anti-IgE antibody (omalizumab) forms complexes with free IgE, blocking its interaction with mast cells and basophils and lowering free IgE levels in the circulation. OBJECTIVE: To assess the efficacy and safety of omalizumab for prophylaxis of symptoms in patients with seasonal allergic rhinitis. DESIGN: Randomized, double-blind, dose-ranging, placebo-controlled trial conducted from July 25 through November 21, 1997. SETTING: Twenty-five outpatient centers throughout the United States. PATIENTS: Five hundred thirty-six patients aged 12 to 75 years with at least a 2-year history of moderate to severe ragweed-induced seasonal allergic rhinitis and a baseline IgE level between 30 and 700 IU/mL. INTERVENTIONS: Patients were randomly assigned to receive omalizumab, 50 mg (n = 137), 150 mg (n = 134), or 300 mg (n = 129), or placebo (n = 136) subcutaneously just prior to ragweed season and repeated during the pollen season every 3 weeks in patients with baseline IgE levels of 151 to 700 IU/mL (4 total treatments) and every 4 weeks in patients with baseline IgE levels of 30 to 150 IU/mL (3 total treatments). MAIN OUTCOME MEASURES: Self-assessed daily nasal symptom severity scores (range, 0-3), rescue antihistamine use, and rhinitis-specific quality of life during the 12 weeks from the start of treatment. RESULTS: Nasal symptom severity scores were significantly lower in patients who received 300 mg of omalizumab than in those who received placebo (least squares means, 0.75 vs 0.98, respectively; P =.002). A significant association was observed between IgE reduction and nasal symptoms and rescue antihistamine use. Rhinitis-specific quality of life scores were consistently better in patients who received 300 mg of omalizumab than in those who received lower dosages or placebo and did not decline during peak season. The frequency of adverse events was not significantly different among the omalizumab and placebo groups. CONCLUSION: Omalizumab decreased serum free IgE levels and provided clinical benefit in a dose-dependent fashion in patients with seasonal allergic rhinitis.