Reduction of motoric agitation and restlessness by AF102B and tacrine in the macaque

OBJECTIVES/HYPOTHESIS: Until recently, laser-assisted uvulopalatoplasty (LAUP) has been used to treat only snoring and mild cases of obstructive sleep apnea (OSA). The purpose of this study was to evaluate the efficacy and safety of LAUP in patients with mild, moderate, and severe OSA. STUDY DESIGN: A prospective study of 38 patients who completed LAUP for the treatment of OSA who were evaluated based on the severity level of their preoperative apnea. MATERIALS AND METHODS: Between July 1993 and December 1995, 96 patients with a diagnosis of OSA based on polysomnography underwent staged outpatient LAUP treatment. Thirty-eight patients completed treatment and obtained postoperative polysomnography. Postoperative complications and polysomnographic findings were reviewed. RESULTS: Fifteen patients had a diagnosis of mild apnea, 12 had moderate apnea, and 11 had severe apnea based on preoperative polysomnography. The surgical response rates, defined as greater than or equal to 50% reduction in the postoperative respiratory disturbance index (RDI) and a postoperative RDI of less than 20, were 46.7% in the mild apneics, 41.7% in the moderate apneics, and 45.5% in the severe apneics. Postoperative complications in this series included minor bleeding, oral candidiasis, and temporary velopharyngeal insufficiency. There were no serious complications. CONCLUSIONS: In the carefully selected and prepared patient with mild, moderate, or severe OSA, LAUP should be considered a surgical option for the treatment of this disorder. LAUP remains a cost-effective and safe alternative to uvulopalatopharyngoplasty.     

An improved isolated, left ventricular ejecting, murine heart model. Functional and metabolic evaluation

An improved, isolated, left ventricular-ejecting, murine heart model is described and evaluated. Special attention was paid to the design and impedance characteristics of the artificial aortic outflow tract and perfusate composition, which contained glucose (10 mM plus insulin) and pyruvate (1.5 mM) as substrates. Temperature of the isolated perfused hearts was maintained at 38.5 degrees C. During antegrade perfusion (preload 10 mm Hg, afterload 50 mm Hg, 2.5 mM Ca2+) proper design of the aortic outflow tract provided baseline values for cardiac output (CO), left ventricular developed pressure (LVDP) and the maximum first derivative of left ventricular pressure (LV dP/dtmax) of 11.1+/-1.7 ml min-1, 83+/-5 mm Hg and 6283+/-552 mm Hg s-1, respectively, resembling findings in the intact mouse. During 100 min normoxic antegrade perfusion CO declined non-significantly by less than 10%. Varying pre- and afterloads resulted in typical Frank-Starling relationships with maximal CO values of 18.6+/-1.8 ml min-1 at pre- and afterload pressures of 25 and 50 mm Hg, respectively. Left ventricular function curves were constructed at free [Ca2+] of 1.5 and 2.5 mM in the perfusion medium. Significantly higher values for CO, LVDP and LV dP/dtmax and LV dP/dtmin were obtained at 2.5 mM Ca2+ at all loading conditions investigated. Phosphocreatine and creatine levels remained stable throughout the perfusion period. Despite a small but significant decline in tissue ATP content, the sum of adenine nucleotides did not change during the normoxic perfusion period. The tissue content of glycogen increased significantly.     

Evidence for the formation of a novel cyclopentenone isoprostane, 15-A2t-isoprostane (8-iso-prostaglandin A2) in vivo

A2/J2-Isoprostanes (IsoPs) are prostaglandin (PG) A2/J2-like compounds that are produced in vivo as dehydration products of D2/E2-IsoPs. One A2-IsoP that should be formed is 15-A2t-IsoP (8-iso-PGA2). Analogous to cyclopentenone PGs, 15-A2t-IsoP readily undergoes nucleophilic addition to various biomolecules suggesting the compound is capable of exerting potent bioactivity. However, proof that it is definitively formed in vivo is lacking. Evidence is now presented that 15-A2t-IsoP, in fact, is generated in vivo by demonstrating that an endogenous A2-IsoP with a retention time on capillary GC identical with that 15-A2t-IsoP co-chromatographs through four high resolving HPLC purification procedures with authentic radiolabeled 15-A2t-IsoP.     

The effect of diurnally interrupted doses of phosphine over four days on egg mortality of susceptible and resistant strains of Sitophilus oryzae (L.)

Phosphine concentrations in stored grain are uneven and can undergo cyclic fluctuations caused by diurnal changes in solar heat exchange and wind. Experiments were conducted to investigate the influence of daily concentration variations on insect mortality. Values of LT₅₀ and LT_99.9 are presented for Sitophilus oryzae eggs in response to a range of diurnally interrupted phosphine treatments over four days. Egg mortality was determined for three insect strains that varied in susceptibility to the fumigant, at concentrations that ranged from 0.75 mg/L to 3 mg/L for 32-8 h respectively, giving the same Ct product for all treatment combinations. Effects on mortality were analyzed in terms of accumulated phosphine exposure over 4 days of treatment, and in terms of the total elapsed time of treatment. Results were compared to those obtained from continuous treatments having equivalent Ct combinations. Treatments that were interrupted daily extend the total elapsed time required for a given level of mortality and that time increased as concentration increased and daily treatment time decreased. Values of LT_99.9 for a susceptible strain were 67.6 h and 103.6 h, and for a resistant strain were 133.6 h and 179.5 h at concentrations of 1 mg/L and 3 mg/L respectively. However, diurnal treatments were more efficacious than continuous treatments when only dosage time was measured. Values of LT_99.9 for the susceptible strain were 21.0 h compared with 33.8 h and 11.0 h compared with 17.7 h, and for the resistant strain were 35.2 h compared with 57.4 h and 22.2 h compared with 44.3 h at 1 mg/L and 3 mg/L respectively. The findings show that the level of mortality during interrupted treatment is mainly due to the additional time that the fumigant is absent and not a combined affect including insect recovery during the intervening periods. In fact, the dosage time is reduced by an apparent increase in phosphine toxicity.     

Midinfrared spectroscopy and chemometrics to predict diuron sorption coefficients in soils

The potential of mid-infrared (MIR) spectroscopy in combination with partial least-squares (PLS) regression was investigated to predict the soil sorption (distribution) coefficient (K(d)) of a nonionic pesticide (diuron). A calibration set of 101 surface soils collected from South Australia was utilized for reference sorption data and MIR spectra. Principal component analysis (PCA) was performed on the spectra to detect spectral outliers. The MIR-PLS model was developed and validated by dividing the initial data set into four validation sets. The model resulted in a coefficient of determination (R2) of 0.69, a standard error (SE) of 5.57, and a residual predictive deviation (RPD) of 1.63. The normalized sorption coefficient for the organic compound (K(oc)) approach, on the other hand, resulted in R2, SE, and RPD values of 0.42, 7.26, and 1.25, respectively. However, the significant statistical difference between the two models was mainly due to two outliers detected via PCA. Apart from spectral outliers, the performance of the two models was essentially similar for the rest of the calibration set. Outlier detection by the MIR-PLS model may gainfully be employed as a tool for improving prediction of K(d). The MIR-based model can provide a direct estimation of K(d) values based on the integrated properties of organic and mineral matter reflected in the infrared spectra.     

Thirty years of development and application of CFD at Boeing Commercial Airplanes, Seattle

Over the last 30 years, Boeing has developed, manufactured, sold, and supported hundreds of billions of dollars worth of commercial airplanes. During this period, it has been absolutely essential that Boeing aerodynamicists have access to tools that accurately predict and confirm vehicle flight characteristics. Thirty years ago, these tools consisted almost entirely of analytic approximation methods, wind tunnel tests, and flight tests. With the development of increasingly powerful computers, numerical simulations of various approximations to the Navier–Stokes equations began supplementing these tools. Collectively, these numerical simulation methods became known as Computational Fluid Dynamics (CFD). This paper describes the chronology and issues related to the acquisition, development, and use of CFD at Boeing Commercial Airplanes in Seattle. In particular, it describes the evolution of CFD from a curiosity to a full partner with established tools in the design of cost-effective and high-performing commercial transports.     

Prospective evaluation of quality of life after conventional abdominal aortic aneurysm surgery

The authors report a case of paraplegia caused by a lumbar intraspinal paracoccidioidomycosis (PCM) granuloma. Clinical neurological diagnosis of a compressive spinal cord lesion was confirmed by spinal magnetic resonance imaging (MRI). Patient was submitted to surgery with total excision of the lesion. Histopathological analysis confirmed the diagnosis of PCM. Patient is on sulfamethoxazole/trimethoprim combined with fluconazole and is experiencing positive neurological recovery.     

Intracellular calcium regulates agrin-induced acetylcholine receptor clustering

Agrin is an extracellular matrix protein that directs neuromuscular junction formation. Early signal transduction events in agrin-mediated postsynaptic differentiation include activation of a receptor tyrosine kinase and phosphorylation of acetylcholine receptors (AChRs), but later steps in this pathway are unknown. Here, we have investigated the role of intracellular calcium in agrin-induced AChR clustering on cultured myotubes. Clamping intracellular calcium levels by loading with the fast chelator BAPTA inhibited agrin-induced AChR aggregation. In addition, preexisting AChR aggregates dispersed under these conditions, indicating that the maintenance of AChR clusters is similarly dependent on intracellular calcium fluxes. The decrease in AChR clusters in BAPTA-loaded cells was dose-dependent and reversible, and no change in the number or mobility of AChRs was observed. Clamping intracellular calcium did not block agrin-induced tyrosine phosphorylation of the AChR beta-subunit, indicating that intracellular calcium fluxes are likely to act downstream from or parallel to AChR phosphorylation. Finally, the targets of the intracellular calcium are likely to be close to the calcium source, since agrin-induced AChR clustering was unaffected in cells loaded with EGTA, a slower-binding calcium chelator. These findings distinguish a novel step in the signal transduction mechanism of agrin and raise the possibility that the pathways mediating agrin- and activity-driven changes in synaptic architecture could intersect at the level of intracellular calcium fluxes.     

Statistical models of outcome in malpractice lawsuits involving death or neurologically impaired infants

Synaptosomes prepared from mouse brain possess a Na+-dependent transport system for gamma-hydroxybutyrate displaying saturation kinetics, the transport constant (Kt) for which was calculated as 31 +/- 9 micromol/l. Several gamma-hydroxybutyrate and gamma-aminobutyric acid (GABA) structural analogues were tested as potential inhibitors of gamma-hydroxybutyrate transport. The most effective inhibitor was harmaline (Ki = 94 +/- 21 micromol/l), a known competitive inhibitor of Na+ binding to certain transport proteins. 2-Hydroxycinnamic acid, 3-(2-furyl)acrylic acid and citrazinic acid also inhibited transport and were competitive with respect to gamma-hydroxybutyrate. The least effective gamma-hydroxybutyrate analogues were 3-hydroxypropane sulfonic acid (Ki = 4.1 +/- 0.8 mmol/l) 3,5-dihydroxybenzoic acid (Ki = 6.1 +/- 2. 8 mmol/l) and 3-hydroxybenzoic acid (Ki = 6.9 +/- 3.3 mmol/l), although 2-hydroxypropane sulfonic acid and kynurenic acid had no measurable effects. Four inhibitors of GABA transport - nipecotic acid, guvacine, ketamine and beta-alanine and GABA itself, were without effect on gamma-hydroxybutyrate transport. These results show that certain drugs that structurally resemble gamma-hydroxybutyrate have the capacity to compete with gamma-hydroxybutyrate at its recognition site on the transporter. By examining the structure of such inhibitors, we can learn more about the properties of the substrate binding site on the carrier protein. Moreover, the absence of inhibition by GABA uptake inhibitors shows that gamma-hydroxybutyrate transport is a separate entity from GABA transport.