Characterization of leukotriene B4 binding sites on guinea pig lung macrophages

Specific binding sites for [3H]leukotriene B4 (LTB4) were identified on guinea pig lung macrophages, using high specific activity [3H] LTB4 in the presence or absence of unlabeled LTB4. At 0 degrees C, [3H] LTB4 binding reached equilibrium within 30 min, and addition of a large excess of unlabeled LTB4 resulted in a rapid decrease of specific binding. Binding was saturable, reversible and dependent upon the number of lung macrophages. The KD and Bmax were found to be 3.85 +/- 0.6 nM and 35 +/- 3 fmol/10(6) cells, respectively, as determined from Scatchard analysis. In competition studies for the displacement of [3H]LTB4 from binding sites, LTB4 and its analogs had the following order of potency: LTB4 (Ki = 2.9 +/- 0.8 nM) greater than 5-epi LTB4 (Ki = 58.7 +/- 0.3 nM) greater than 5-deoxy-LTB4 (Ki = 91.7 +/- 0.3 nM) greater than 12-epi LTB4 (Ki = 4.7 +/- 1.2 microM) greater than 5,12-deoxy LTB4 (Ki = 7.6 +/- 0.01 microM) greater than or equal to 12-deoxy LTB4 (Ki = 8.9 +/- 0.01 microM). LTC4 and LTD4 did not displace the [3H] LTB4 binding at concentrations up to 10 microM. [3H]LTB4 was not metabolized during the binding process as determined by reverse-phase high performance liquid chromatography. It was suggested that this binding site might be an LTB4 receptor.     

Specific binding sites for leukotriene B4 in guinea pig brain membranes.

The presence of specific leukotriene B4 (LTB4) binding sites was investigated in membranes prepared from mouse, rat, guinea pig and rabbit brain. Specific binding sites have been found in guinea pig brain membranes (GPBM) but not in the other species studied. Specific binding of LTB4 to GPBM was proportional to membrane concentration, saturable and reversible, reaching a steady-state suggesting equilibrium after 30 min of incubation. Analysis of the binding data showed a single binding site with a Kd = 2.27 +/- 0.55 nM and a Bmax = 576 +/- 89.6 fmol/mg protein. The relative potencies of LTB4 analogs to displace the tritiated ligand were LTB4 greater than 20-hydroxy-LTB4 much greater than 20-carboxy-LTB4 greater than 12-(S)hydroxy-5,8,10,14(Z,Z,E,Z)-eicosatetraenoic acid; LTD4 and LTC4 did not displace the ligand in concentrations up to 50 microM. The binding was inhibited by monovalent cations and GTP[gamma S] and increased by divalent cations. Specific binding was associated to the cerebral cortex. The present results suggest that these specific binding sites could represent functional LTB4 receptors in the guinea pig cerebral cortex with unknown biological effects.     

Simulated Transcatheter Aortic Valve Flow: Implications of Elliptical Deployment and Under‐Expansion at the Aortic Annulus

Clinical use of transcatheter aortic valves (TAVs) has been associated with abnormal deployment, including oval deployment and under‐expansion when placed into calcified aortic annuli. In this study, we performed an integrated computational and experimental investigation to quantify the impact of abnormal deployment at the aortic annulus on TAV hemodynamics. A size 23 mm generic TAV computational model, developed and published previously, was subjected to elliptical deployment at the annulus with eccentricity levels up to 0.68 and to under‐expansion of the TAV at the annulus by up to 25%. The hemodynamic performance was quantified for each TAV deployment configuration. TAV opening geometries were fabricated using stereolithography and then subjected to steady forward flow testing in accordance with ISO‐5840. Centerline pressure profiles were compared to validate the computational model. Our findings show that slight ellipticity of the TAV may not lead to degeneration of hydrodynamic performance. However, under large ellipticity, increases in transvalvular pressure gradients were observed. Under‐expanded deployment has a much greater negative effect on the TAV hemodynamics compared with elliptical deployment. The maximum turbulent viscous shear stress (TVSS) values were found to be significantly larger in under‐expanded TAVs. Although the maximum value of TVSS was not large enough to cause hemolysis in all cases, it may cause platelets activation, especially for under‐expanded deployments.     

Development and validation of the Montreal cognitive assessment for people with hearing impairment (MoCA-H)

Background

Hearing impairment is common among older adults and affects cognitive assessments for identification of dementia which rely on good hearing function. We developed and validated a version of the Montreal Cognitive Assessment (MoCA) for people with hearing impairment.

Methods

We adapted existing MoCA 8.1 items for people with hearing impairment by presenting instructions and stimuli in written rather than spoken format. One Attention domain and two Language domain items required substitution by alternative items. Three and four candidate items respectively were constructed and field-tested along with the items adapted to written form. We used a combination of individual item analysis and item substitution to select the set of alternative items to be included in the final form of the MoCA-H in place of the excluded original items. We then evaluated the performance and reliability of the final tool, including making any required adjustments for demographic factors.

Results

One hundred and fifty-nine hearing-impaired participants, including 76 with normal cognition and 83 with dementia, completed the adapted version of the MoCA. A further 97 participants with normal hearing completed the standard MoCA as well as the novel items developed for the MoCA-H to assess score equivalence between the existing and alternative MoCA items and for independence from hearing impairment. Twenty-eight participants were retested between 2–4 weeks after initial testing. After the selection of optimal item set, the final MoCA-H had an area under the curve of 0.973 (95% CI 0.952–0.994). At a cut-point of 24 points or less sensitivity and specificity for dementia was 92.8% and 90.8%, respectively. The intraclass correlation for test–retest reliability was 0.92 (95%CI 0.78–0.97).

Conclusion

The MoCA-H is a sensitive and reliable means of identifying dementia among adults with acquired hearing impairment.     

Do proton-pump inhibitors increase the risk for nosocomial pneumonia in a medical intensive care unit?

Purpose

The aim of this study was to determine whether the use of gastric acid-suppressive agents increases the risk of nosocomial pneumonia (NP) in a medical intensive care unit population.

Materials and Methods

Retrospective cohort study in a medical intensive care unit of a 554-bed, university-affiliated, academic medical center.

Results

A total of 924 medical records were included in the database during the study period of which 787 patients were included in the study. Out of this cohort,104 patients (13.2%) eventually developed a NP. The risk for patients who received proton-pump inhibitors (adjusted hazard ratio [AHR] 0.63; 95% CI 0.39-1.01) was not significantly different than in non exposed patients. Variables most strongly associated with NP were the administration of sedatives or neuromuscular blockers for at least 2 consecutive days (AHR 3.39;95% CI 1.99-5.75), an Acute Physiology and Chronic Health Evaluation II (APACHE II) severity score greater than 15 (AHR, 3.34; 95% CI 1.82-6.50), and presence of a central venous catheter (AHR, 1.76; 95% CI 1.12-2.76).

Conclusions

Prior use of a proton-pump inhibitor did not correlate with a significant increase in the risk of developing NP. This risk was higher with the administration of sedatives or neuromuscular blockers, increased disease severity, and placement of a central venous catheter.     

Release of mediators of anaphylaxis: inhibition of prostaglandin synthesis and the modification of release of slow reacting substance of anaphylaxis and histamine.

1 When isolated perfused lungs from sensitized guinea-pigs were challenged with antigen, histamine, slow reacting substance of anaphylaxis (SRS-A) and prostaglandin-like substances were released into the effluent. 2 Treatment of the lungs before and during challenge with indomethacin (0.5--10 microgram/ml), sodium aspirin (1--10 microgram/ml), sodium meclofenamate (0.1--1 microgram/ml) or ketoprofen (0.5--5 microgram/ml) inhibited the release of prostaglandins while increasing the output of histamine and SRS-A between three- and five-fold. 3 Diethylcarbamazine (0.2--1 mg/ml) reduced the release of SRS-A and histamine but increased the amount of prostaglandin-like substances produced. 4 Eicosatetraynoic acid (10 microgram/ml) inhibited formation of prostaglandins but did not modify release of histamine and SRS-A. 5 The results with non-steroid anti-inflammatory drugs and diethylcarbamazine suggest that prostaglandins, or some other product of the cyclo-oxygenase system, depress the anaphylactic release of SRS-A and histamine.