Pollen challenge study of a phototherapy device for reducing the symptoms of hay fever.

OBJECTIVE: The objective was to investigate the effect of intranasal phototherapy delivered by a phototherapy device (allergy reliever SN-206) on symptoms of hay fever (seasonal rhinitis) due to grass pollen in adults. This registered class IIA medical device had been on sale for 15 months with no adverse effects reported but there had been no assessment of efficacy. Previous research had indicated that phototherapy could alleviate symptoms of allergic rhinitis but no double-blind, placebo-controlled trails had been done. RESEARCH DESIGN AND METHODS: The trial is a double-blind, placebo-controlled grass pollen challenge conducted out of the pollen season, on 101 adult male and female hay fever sufferers. Subjects were assigned to placebo or active groups by stratified random sampling using responses to a baseline questionnaire. All subjects used active or placebo devices three times a day for 14 days before pollen challenge. Subjects were monitored for 2.5 h after challenge. MAIN OUTCOME MEASURES: Primary outcome measures were observed severity scores for sneezing, running eyes, running nose, and the amount of eosinophil cationic proteins (ECP) in nasal secretions. Secondary outcome measures were symptom scores by subject report (itching eyes, itching nose, itching throat, itching mouth/palate), and nasal peak inspiratory flow (PIFn) and peak expiratory flow (PEFn). RESULTS: Significant reductions in severity of symptom scores were found for sneezing, running nose, running eyes and itchy mouth/palate (p < or = 0.05). No significant differences were found in the results for itchy eyes, itchy nose, itchy throat, ECPs, PIFn and PEFn. No adverse events occurred. CONCLUSIONS: The results show that the device significantly reduced some hay fever symptoms. The study would have been improved if compliance was monitored electronically and if nasal congestion was monitored by report. The mode of action is unclear. The study does not consider long-term implications of the therapy.

Similarity measures for rational set selection and analysis of combinatorial libraries: the Diverse Property-Derived (DPD) approach.

The generation of new chemical leads for biological targets is a very challenging task for researchers in the pharmaceutical industry. The design of representative screening sets and combinatorial libraries is central to achieving this objective. In this paper, we describe a novel molecular descriptor, the Diverse Property-Derived (DPD) code, that contains information about key molecular and physicochemical properties of a molecule. The utility of this descriptor is explored through its application for the selection of a maximally diverse representative screening set, through the selection of secondary screening sets to obtain more information concerning the structure-activity relationships (SAR) of a particular target receptor, and through the profiling of combinatorial libraries. The usefulness of physicochemical/molecular property descriptors, such as the DPD code, is discussed critically.

A gene for primary congenital glaucoma is not linked to the locus on chromosome 1q for autosomal dominant juvenile-onset open angle glaucoma.

BACKGROUND: Primary congenital glaucoma is an uncommon autosomal recessive condition that results from a developmental defect in the trabecular meshwork and anterior chamber angle, manifesting in the neonatal or infantile period with increased intraocular pressure, corneal enlargement and edema, and optic nerve cupping with consequent loss of vision. Nothing is known about its genetic location. PATIENTS AND METHODS: Linkage analysis was performed in 25 primary congenital glaucoma Saudi Arabian families with six polymorphic DNA markers on chromosome 1q in a region that has shown tight linkage to a locus for autosomal dominant juvenile-onset open angle glaucoma (GLC1A). Twenty-four of these families are highly consanguineous. RESULTS: Each family was shown separately to exclude the 8-centimorgan (cM) interval containing the GLC1A locus. Four families independently demonstrated overlapping regions of exclusion (theta < or = -2) that spanned the entire 8-cM interval. Assignment of a primary congenital glaucoma locus in this region could be excluded by a cadre of 21 families because a primary congenital glaucoma disease locus did not segregate in an autosomal recessive manner on haplotypes constructed with markers in this region. For all families, no affected individuals demonstrated homozygosity of alleles in regions tightly linked to the GLC1A locus. CONCLUSION: These results exclude the 8-cM region on chromosome 1q shown to contain the GLC1A locus from containing a disease locus for primary congenital glaucoma in this population of 25 Saudi Arabian families.

The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase.

Lowe's oculocerebrorenal syndrome (OCRL) is a human X-linked developmental disorder of unknown pathogenesis and has a pleiotropic phenotype affecting the lens, brain and kidneys. The OCRL locus has been mapped to Xq25-q26 by linkage and by finding de novo X; autosome translocations at Xq25-q26 in two unrelated females with OCRL. Here we use yeast artificial chromosomes with inserts that span the X chromosomal breakpoint from a female OCRL patient in order to isolate complementary DNAs for a gene that is interrupted by the translocation. We show that the transcript is absent in both female OCRL patients with X; autosome translocations and that it is absent or abnormally sized in 9 of 13 unrelated male OCRL patients with no detectable genomic rearrangement. The open reading frame encodes a new protein with 71% similarity to human inositol polyphosphate-5-phosphatase. Our results suggest that OCRL may be an inborn error of inositol phosphate metabolism.

The effects of N-3 polyunsaturated fatty acids on the generation of platelet-activating factor-acether by human monocytes.

Human leukocytes generate platelet-activating factor (PAF-acether), a lipid mediator of inflammation, from membrane alkyl phospholipids through the release of arachidonic acid or other fatty acids at the 2-position and subsequent acetylation. Because it was previously demonstrated that fish oil fatty acids suppress human leukocyte arachidonic acid release and metabolism, separate experiments were conducted to investigate the effects of dietary fish oil supplementation and in vitro incubation with fish oil fatty acids on calcium ionophore-stimulated PAF-acether generation in human monocytes. In subjects on their regular diets, a 4-hr incubation of monocyte monolayers with an optimally effective concentration of arachidonic acid of 1 micrograms/ml resulted in a 64% increase of calcium ionophore-induced net PAF-acether generation from 7.75 +/- 0.78 ng/10(6) cells for untreated monolayers to 12.70 +/- 1.21 ng/10(6) cells (mean +/- SEM). Treatment of monolayers with eicosapentaenoic acid (EPA) at the optimal concentration of 1 micrograms/ml decreased net PAF-acether generation by 28%. However, treatment of monocyte monolayers with docosahexaenoic acid did not appreciably affect net PAF-acether generation. The changes in PAF-acether release with each fatty acid added in vitro paralleled those in total PAF-acether generation; the percentage PAF-acether release remained unaffected. Three weeks of dietary supplementation with 18 g MaxEPA daily, providing 3.2 g EPA did not affect the PAF-acether generation of calcium ionophore-stimulated human monocyte monolayers. However, 6 weeks of dietary supplementation resulted in a 47% decrease of net total PAF-acether generation and a concomitant 59% decline in net PAF-acether release; the percentage release of PAF-acether was not affected. Thus, whether added to the diet or introduced in vitro, fish oil-derived fatty acids suppress PAF-acether generation by human monocyte monolayers.

Enhancement of plasma levels of biologically active leukotriene B compounds during anaphylaxis in guinea pigs pretreated by indomethacin or by a fish oil-enriched diet.

The changes in arterial plasma concentrations of immunoreactive leukotriene B (LTB) were compared after antigen challenge of two groups of sensitized, mepyramine-treated, and mechanically ventilated guinea pigs, one fed a diet enriched with fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish oil-enriched diet (FFD) for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid to constitute 8 to 9% of total fatty acid content, whereas these alternative fatty acids constituted less than 1% of the total fatty acid content of the lung tissue of animals on a beef tallow-supplemented diet (BFD). The maximum increase after antigen challenge in immunoreactive LTB4 from 0.16 +/- 0.04 ng/ml to 0.84 +/- 0.25 ng/ml in BFD animals and from 0.47 +/- 0.11 to 5.1 +/- 1.4 ng/ml immunoreactive LTB (LTB4 and LTB5) in FFD animals was significant (p less than 0.02) for each. Furthermore, the increase in total immunoreactive LTB in mepyramine-treated FFD animals was significantly greater than the increase in LTB4 in mepyramine-treated BFD guinea pigs at 2 to 8 min after antigen challenge (p less than 0.05). Resolution of arterial plasma immunoreactive LTB from pooled samples by reverse-phase high-performance liquid chromatography demonstrated that the sum of LTB4 and LTB5 in FFD animals exceeded that of LTB4 in BFD animals and that the quantity of LTB4 in the FFD animals was at least as great as that in the BFD animals during anaphylaxis. The products eluting at the retention times of LTB4 and LTB5 exhibited the chemotactic activity of their respective synthetic standards. The combination of indomethacin and mepyramine markedly augmented the antigen-induced increase in arterial plasma immunoreactive LTB4 concentrations in BFD animals, but had no effect on immunoreactive LTB levels in FFD animals. Limited in vivo measurements showing a lesser increase of plasma immunoreactive thromboxane B2 in the FFD relative to the BFD animals during anaphylaxis and ex vivo measurements showing a decreased LTB4-stimulated (cyclooxygenase product-dependent) contractile response of pulmonary parenchymal strips from the FFD relative to the BFD animals provide evidence for blockade in the cyclooxygenase pathway in the FFD animals. The measurements of arterial plasma LTB indicate that indomethacin treatment alone, which inhibits cyclooxygenase activity, and FFD treatment each augment the metabolism of arachidonic acid by the 5-lipoxygenase pathway in animals pretreated with mepyramine.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of a fish-oil-enriched diet on pulmonary mechanics during anaphylaxis.

The pulmonary mechanical responses observed after antigen challenge in 2 groups of sensitized, mepyramine-treated, mechanically ventilated guinea pigs were compared: one group was fed a diet rich in fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish-oil-enriched diet for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid, which constituted 8 to 9% of the total fatty acid content, whereas these alternative fatty acids constituted less than 1% of total fatty acid content of the lung tissue of animals receiving a diet supplemented with beef tallow. With mepyramine pretreatment, animals receiving a fish oil diet exhibited a significantly greater decrease in dynamic compliance from 1.5 through 4.5 min after antigen challenge than did animals receiving a beef fat diet, whereas the decrements in pulmonary conductance were comparable. The combination of indomethacin and mepyramine markedly augmented the antigen-induced decrease in pulmonary mechanics in animals receiving a beef fat diet but not in those receiving a fish oil diet, such that the overall responses of the 2 groups were similar. These findings indicate that the fish oil diet and the indomethacin pretreatment of animals receiving the beef fat diet each facilitates the nonhistamine-mediated bronchoconstrictor response in pulmonary anaphylaxis.

Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function.

The effects of dietary fish-oil fatty acids on the function of the 5-lipoxygenase pathway of peripheral-blood polymorphonuclear leukocytes and monocytes were determined in seven normal subjects who supplemented their usual diet for six weeks with daily doses of triglycerides containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid. The diet increased the eicosapentaenoic acid content in neutrophils and monocytes more than sevenfold, without changing the quantities of arachidonic acid and docosahexaenoic acid. When the neutrophils were activated, the release of [3H]arachidonic acid and its labeled metabolites was reduced by a mean of 37 per cent, and the maximum generation of three products of the 5-lipoxygenase pathway was reduced by more than 48 per cent. The ionophore-induced release of [3H]arachidonic acid and its labeled metabolites from monocytes in monolayers was reduced by a mean of 39 per cent, and the generation of leukotriene B4 by 58 per cent. The adherence of neutrophils to bovine endothelial-cell monolayers pretreated with leukotriene B4 was inhibited completely, and their average chemotactic response to leukotriene B4 was inhibited by 70 per cent, as compared with values determined before the diet was begun and six weeks after its discontinuation. We conclude that diets enriched with fish-oil-derived fatty acids may have antiinflammatory effects by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the leukotriene B4-mediated functions of neutrophils.

Asthma induced by suggestion: is it due to airway cooling?

The effect of suggestion on the airway response to 10 inhalations of normal saline followed by doubling concentrations of isoproterenol was assessed in 12 normal and 30 asthmatic subjects. It was suggested that the first 5 saline solutions contained a bronchoconstrictor and that the second 5 contained a bronchodilator, or vice versa, and that the first 4 isoproterenol solutions were inert, whereas the last was a bronchodilator. Nine asthmatic, but no normal subjects, bronchoconstricted after saline inhalation, with a mean fall in specific airway conductance (SGaw) of 40%. This was dose-dependent and was abolished when inhalations were carried out at 37 degrees C 100% relative humidity. Suggestion did not affect the airway response to saline or isoproterenol in either group, but it did influence the subjective impression of airway caliber recorded on a visual analogue scale. In this study, the bronchoconstriction after saline inhalation, previously attributed to the effect of suggestion, was caused by airway cooling.

Immunologically induced generation of tetraene and pentaene leukotrienes in the peritoneal cavities of menhaden-fed rats.

The generation of sulfidopeptide leukotrienes and leukotriene B (LTB) in response to an IgG-mediated immune complex reaction in the peritoneal cavities of rats fed either a menhaden oil-supplemented diet or a beef tallow-supplemented diet for 9 to 10 wk was determined with the combined techniques of radioimmunoassay (RIA) and reverse-phase high performance liquid chromatography. Rats on the fish fat diet (FFD) incorporated eicosapentaenoic acid (EPA) into pulmonary and splenic tissues with an EPA:arachidonic acid ratio of approximately 2:1, whereas rats on the beef fat diet (BFD) showed no detectable EPA. The estimated total quantities of immunoreactive sulfidopeptide leukotrienes generated by each group of rats were similar, ranging from 70 to 99 ng/ rat in the FFD groups and 65 to 109 ng/rat in the BFD groups; for rats on the FFD this total included the pentaene products LTC5, LTD5, and LTE5 in quantities ranging from 24 to 39 ng/rat. The total quantities of immunoreactive LTB generated in the two groups of rats were similar, being 6 to 29 ng LTB4/rat for the BFD groups and the sum of LTB4 and LTB5 of 8 to 36 ng/rat for the FFD groups. There was a two- to seven-fold preferential generation of immunoreactive LTB5 over LTB4 in the FFD rats. LTC5 was equipotent with LTC4 in contracting guinea pig pulmonary parenchymal strips and ileal tissues. In contrast, LTB5 was 1/30 to 1/60 as potent and did not reach the same maximum as LTB4 in eliciting neutrophil chemotaxis. The finding that FFD favors the immunologic generation of LTB5, which has attenuated biologic activity when compared to LTB4, suggests that EPA-enriched tissues may produce less pro-inflammatory activity than tissues that are EPA-poor.

Optic disk and visual field correlations in primary open-angle and low-tension glaucoma.

If the amount of visual field loss is less than expected from the amount of optic disk cupping in low-tension glaucoma compared with primary open-angle glaucoma, it might imply a difference between the two conditions in the type of optic nerve lesion produced. To test this hypothesis, three observers independently examined, in a masked fashion, optic disk stereoscopic photographs of 127 eyes with primary open-angle glaucoma and 71 eyes with low-tension glaucoma. For each stereoscopic photograph the observer predicted whether the visual field loss would be mild, moderate, or severe. The visual field were then classified, according to the number of sectors defective on the Goldmann perimeter chart, as having mild (1 to 15 sectors), moderate (16 to 30 sectors), or severe (more than 30 sectors) visual field loss. For no observer did the frequency of underpredictions or overpredictions in the two conditions differ significantly. The results of this study, thus, did not support the theory that the optic disk damage in primary open-angle glaucoma differs from that in low-tension glaucoma.

Asthma and suggestion: psychological or physical?

The effect of suggestion on the airway response to ten inhalations of normal saline followed by doubling concentrations of isoprenaline was assessed in 12 normal and 30 asthmatic subjects. It was suggested that the first 5 saline solutions contained a bronchoconstrictor and the second 5 a bronchodilator, or vice-versa, and that the first four isoprenaline solutions were inert whilst the last was a bronchodilator. Nine asthmatic but no normal subjects bronchoconstricted after saline inhalation with a mean 40% fall in specific airway conductance (sGaw). This was dose-dependent and abolished when inhalations were carried out at 37 degrees C 100% relative humidity. Suggestion did not affect the airway response to saline or isoprenaline in either group. We conclude that bronchoconstriction following saline inhalation, previously attributed to the effect of suggestion, is caused by airway cooling.

Selective effects of myo-inositol administration on sciatic and tibial motor nerve conduction parameters in the streptozocin-diabetic rat.

Time-dependent effects of experimental diabetes and dietary myo-inositol supplementation on motor nerve conduction velocity (MNCV) were assessed in two populations of motor nerve fibers in the rat hind limb. These two populations of large myelinated motor fibers, which innervate the musculature of the calf and the foot, were differentially affected by growth, experimental diabetes, and dietary myo-inositol. Dietary myo-inositol supplementation ameliorated the diabetes-induced MNCV impairment in both nerve fiber populations but with different time courses. These observations suggest metabolic or physiologic heterogeneity among populations of large myelinated motor fibers which may partially explain published discrepancies regarding the efficacy of dietary myo-inositol supplementation in improving slowed MNCV in the streptozocin-diabetic rat.

Biological assay of Cassia podocarpa: a plant related to senna.

Leaves of the plant, Cassia podocarpa, were collected from Opah village near Accra, and dried. A suspension of the powdered leaf was given by gavage to groups of ten mice. A record was kept of the number of wet faeces passed in 24 hours. There was a linear relationship between the log dose of leaf and the number of wet faeces. The effect was maximal between 6 and 24 hours of administration and was larger than has been noted with senna.

Hypercupremia associated with a monoclonal immunoglobulin.

Although copper is an essential constituent of many physiologic systems, most human diseases effect minimal changes in copper homeostasis. Therefore, the association of marked hypercupremia with copper deposition in the ocular media and with a circulating immunoglobulin G in an apparently healthy woman prompted our interest. Balance and radioisotopic studies suggest a normal gastrointestinal and renal threshold for copper but a specific and tight binding between the serum copper and the anomalous protein, the probable result of a preclinical myeloma. Because the response of the hypercupremia to chelation therapy was limited, the multiple myeloma was treated with cytoxic drugs.