The effects of the nasal antihistamines olopatadine and azelastine in nasal allergen provocation.

BACKGROUND: Olopatadine, an antihistamine used in allergic conjunctivitis, is under development as a nasal preparation for the treatment of allergic rhinitis. OBJECTIVES: To evaluate the efficacy of olopatadine in suppressing symptoms and biomarkers of the immediate reaction induced by nasal allergen provocation and to compare olopatadine with azelastine in the same model. METHODS: The study was approved by the Johns Hopkins University institutional review board, and all subjects gave written consent. We studied 20 asymptomatic subjects with seasonal allergic rhinitis. The study had 2 randomized, double-blind, placebo-controlled, crossover phases that evaluated 2 concentrations of olopatadine, 0.1% and 0.2%. In a third exploratory phase, olopatadine, 0.1%, was compared with topical azelastine, 0.1%, in a patient-masked design. Efficacy variables were the allergen-induced sneezes, other clinical symptoms, and the levels of histamine, tryptase, albumin, lysozyme, and cysteinyl-leukotrienes (third study only) in nasal lavage fluids. RESULTS: Both concentrations of olopatadine produced significant inhibition of all nasal symptoms, compared with placebo. Olopatadine, 0.1%, inhibited lysozyme levels, but olopatadine, 0.2%, inhibited histamine, albumin, and lysozyme. The effects of olopatadine, 0.1%, were comparable to those of azelastine, 0.1%. CONCLUSIONS: Olopatadine, at 0.1% and 0.2% concentrations, was effective in suppressing allergen-induced nasal symptoms. At 0.2%, olopatadine provided evidence suggestive of inhibition of mast cell degranulation.     

Thrombin enhancement of interleukin-1 and tumor necrosis factor-alpha induced polymorphonuclear leukocyte migration.

BACKGROUND: Cytokines such as IL-1 alpha and tumor necrosis factor-alpha (TNF-alpha) activate vascular endothelium to express leukocyte adhesion molecules that promote polymorphonuclear leukocyte (PMNL) migration and to synthesize tissue factor, thus making the endothelium a procoagulant surface. alpha-Thrombin, generated during coagulation, also activates endothelial cells. Since all these processes are likely involved in inflammation, the effect of alpha-thrombin on PMNL interaction with cytokine activated endothelium was investigated. EXPERIMENTAL DESIGN: Human umbilical vein endothelium was grown on polycarbonate filters to investigate the effects interleukin-1 alpha (IL-1 alpha), TNF-alpha, and alpha-thrombin on PMNL transendothelial migration quantitated with 51Cr-labeled PMNL, and on endothelial monolayer permeability, quantitated with 125I-labeled albumin (HSA). To evaluate the expression of endothelial-leukocyte adhesion molecules, enzyme-linked immunosorbent assay was performed on human umbilical vein endothelium monolayers. The effect of thrombin on PMNL accumulation and plasma exudation in inflammation was studied in a rabbit dermal model, using 51Cr-labeled blood leukocytes and [125I]HSA respectively. RESULTS: On resting human umbilical vein endothelium, alpha-thrombin induced a transient increase (2.5- to 4-fold) in monolayer permeability lasting 30 minutes. Slight but significant transendothelial migration of 51Cr-labeled PMNL was induced by alpha-thrombin (7.4 +/- 0.6% of cells added, unstimulated = 1.9 +/- 0.4%), although this response was less than that induced by f-norLeu-Leu-Phe (17%), IL-1 alpha (29%) or TNF-alpha (21%). alpha-Thrombin enhanced the initial rate of IL-1, TNF-alpha and f-norLeu-Leu-Phe induced PMNL transendothelial migration in an additive or supradditive manner (e.g., with IL-1 alpha+alpha-thrombin, migration was 58% greater than additive at 15 to 30 minutes, p < 0.001). Catalytically inactivated alpha-thrombin, D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone and diisopropyl-fluorophosphate alpha-thrombin, did not enhance migration or permeability. In dermal inflammation in rabbits, alpha-thrombin (10 units/site) induced an increase in plasma protein exudation, with only a mild infiltration of PMNL. However, alpha-thrombin synergistically enhanced the PMNL infiltration induced by IL-1 alpha, TNF-alpha, but not that induced by zymosan activated plasma (C5a) or IL-8 (neutrophil-activating peptide-1). These measurements were confirmed histologically. Investigations into the mechanisms of the enhancement of PMNL migration indicated that individually vascular permeability changes, prostaglandins, platelet activating factor, and P-selectin expression did not account for the observation effects. CONCLUSIONS: Alpha-thrombin may have a role in synergistically enhancing PMNL infiltration at sites of inflammation, in part via enzymatic action on the cytokine activated endothelium. The mechanisms involved in this effect are likely a complex interaction.     

New instruments, bone liners, and tray for finger joint arthroplasty

Titanium circumferential grommets have been developed for finger joint arthroplasty that fit on the base of the silicone implant stems to protect the flexible hinge from tearing and fracture. To facilitate grommet insertion, new intramedullary bone rasps have been devised with a reverse cutting tooth pattern, an extended shaft for an improved view of the surgical field, and a redesigned cutting head to allow for grommet insertion. Surgical accessibility and ease of recognition have been facilitated by the development of color-coded sizers. All of the instruments necessary for finger joint surgery are available in a molded tray that has also been redesigned with a transparent lid and clearly labeled compartments for accurate determination of instruments and implant sizers.     

Mu opioid receptors are in somatodendritic and axonal compartments of GABAergic neurons in rat hippocampal formation

Activation of mu opioid receptors (MORs) has a net excitatory effect in the hippocampal formation through inhibition of gamma-amino butyric acid (GABA)-containing interneurons. To determine the precise subcellular targets of MOR agonists, immunoreactivity against MOR1 and GABA was examined in single sections of the hippocampal formation prepared for dual-labeling electron microscopy. In both the CA1 region of hippocampus and the dentate gyrus, MOR-like immunoreactivity (-li) was present in neuronal somata, dendrites, axons, and axon terminals, as well as a very few glial processes. Axon terminals with MOR-li formed symmetric synapses with principal cell dendrites and somata. Many MOR-labeled profiles of all types also contained GABA-li, and the vast majority possessed the ultrastructural characteristics of interneurons. Additionally, in the dentate gyrus a very small proportion of granule cell dendrites contained MOR-li. MOR-li, identified using immunogold-silver particles, was often affiliated with the extrasynaptic regions of neuronal plasma membranes, consistent with responsiveness to diffusing endogenous neuropeptide ligands. Semiquantitative analysis of the distribution of MOR-li revealed significantly more "presynaptic" (axons and terminals) than "postsynaptic" (somata and dendrites) labeled profiles in most laminae. We conclude that in addition to previously described somatodendritic MOR-li, a substantial amount of MOR-li in hippocampal formation is presynaptic. Furthermore, MORs are almost exclusively in GABAergic interneurons.     

The reliability of the "absent cistern sign" in assessing LP shunt function

OBJECTIVE: One of the difficulties with lumboperitoneal (LP) shunts has been non-invasively ascertaining shunt function. It has been previously reported that in the presence of a functioning LP shunt the perimesencephalic cisterns become obliterated--the "absent cistern sign". In order to more rigorously test this association we performed a retrospective analysis of LP shunt patients at the Hospital for Sick Children, Toronto. METHODS: The CT scans of all patients undergoing LP shunting over a 17 year period were reviewed. The "absent cistern sign" and ventricular size were compared against the results of either an isotope shunt study or surgical findings performed within 2 days of the CT. RESULTS: There were 38 CT scans (27 patients) performed within 2 days of an isotope shunt study and 15 CT scans (14 patients) performed within 2 days of a surgical intervention. These results give the absent cistern sign a sensitivity of 75% and a specificity of 57% when compared to the shunt isotope findings and a sensitivity of 100% and a specificity of 50% when compared to the surgical findings. Over 30% of the CT scans showed ventriculomegaly in the presence of a functioning shunt and, conversely, nearly 45% of the CT scans had normal or small lateral ventricles in the presence of a malfunctioning shunt. CONCLUSIONS: The "absent cistern sign" appears to reliably rule out a completely blocked shunt, but is less reliable in detecting a normal or partially obstructed shunt. Ventricular size correlates poorly with LP shunt function.     

Planning and budgeting in the crippled children''s sector through goal programming.

This article describes how the goal programming methodology was applied to a state level Crippled Children's Program. The various organizational goals are incorporated into the programming model to indicate the trade-offs associated with the resource allocation process. Alternative allocations are presented in terms of a "what if" approach to programming.