Repeated measurement of nasal lavage fluid chemokines in school-age children with asthma.

BACKGROUND: Inflammatory processes at the mucosal surface may play a role in maintenance of asthma pathophysiology. Cross-sectional studies in asthmatic patients suggest that chemokines such as interleukin 8 (IL-8) are overproduced by respiratory epithelium. OBJECTIVE: To test the hypothesis that chemokine levels are persistently elevated in the respiratory secretions of asthmatic children at a stable baseline. METHODS: We measured nasal lavage fluid (NLF) levels of chemokines and other mediators at 3- to 4-month intervals in a longitudinal study of asthmatic children, with nonasthmatic siblings as controls. RESULTS: In a linear mixed-model analysis, both family and day of visit had significant effects on nasal mediators. Thus, data for 12 asthmatic-nonasthmatic sibling pairs who had 3 or more same-day visits were analyzed separately. For sibling pairs, median eosinophil cationic protein levels derived from serial measurements in NLF were elevated in asthmatic patients compared with nonasthmatic patients, with a near-significant tendency for elevation of total protein and eotaxin levels as well. However, no significant differences were found for IL-8 or several other chemokines. Ratios of IL-13 or IL-5 to interferon-gamma released by house dust mite antigen-stimulated peripheral blood mononuclear cells, tested on a single occasion, were significantly increased for asthmatic patients. CONCLUSIONS: Substantial temporal and family-related variability exists in nasal inflammation in asthmatic children. Although higher levels of eosinophil cationic protein are usually present in NLF of patients with stable asthma compared with patients without asthma, chemokines other than eotaxin are not consistently increased. Eosinophil activation at the mucosal surface is a more consistent predictor of asthmatic symptoms than nonspecific elevation of epithelium-derived inflammatory chemokine levels.     

Regulation of murine hematopoiesis by arachidonic acid metabolites

Arachidonic acid metabolites have been shown to exert a variety of regulatory effects on cellular activation and proliferation. Recently, a role for these products as regulators of hematopoiesis was suggested and evidence provided that products of the lipoxygenase pathway, specifically leukotrienes, are essential for human myeloid colony formation in vitro. In this report the broader role of these metabolites in hematopoiesis was examined using murine bone marrow stem cell assays for both myeloid and lymphoid cell lines. The effects of lipoxygenase and/or cyclooxygenase pathway inhibitors on stem cell colony formation were evaluated and compared to qualitative and quantitative changes in arachidonic acid metabolism that occurred in similarly treated bone marrow cell cultures. Interruption of the lipoxygenase pathway by esculetin or nordihydroguaiaretic acid resulted in decreased colony formation in both lymphoid and myeloid stem cells. This inhibition of colony growth was partly reversed by the addition of leukotrienes and was particularly evident in B-cell progenitor cultures to which was added LTB4. Inhibition of the cyclooxygenase pathway by indomethacin or ibuprofen had a slight stimulatory effect on myeloid colony formation, while slightly inhibiting the formation of lymphoid colonies. These results support a direct role for lipoxygenase products in myeloid colony formation and lymphoid stem cell proliferation. A more complex role for cyclooxygenase metabolites in the hematopoietic process appears probable.     

Maternal self-medication and provision of nevirapine to newborns by women in Rakai, Uganda

To assess the effectiveness of maternal self-administration of nevirapine for prevention of mother-to-child transmission (MTCT) of HIV, we conducted a program to provide maternal and newborn doses of nevirapine to pregnant women in rural Uganda. Women provided blood for HIV testing and were offered voluntary counseling and testing (VCT) during annual community HIV surveys. HIV-positive women who accepted VCT were offered nevirapine tablets and syrup. Blood samples were collected postpartum from women and their babies. Infants were tested for HIV by polymerase chain reaction (PCR), and a subsample of maternal and infant blood was assayed for nevirapine. Among the 981 women tested for HIV, 900 (91.7%) accepted VCT, of whom 105 (11.7%) were HIV-positive. Ninety-three women accepted nevirapine, of whom 81 (87.1%) were followed postpartum; 75 (92.6%) reported receipt of the drug, and 69 reported taking the tablets (85.2%). There were 81 liveborn babies (3 sets of twins), and 67 (84.8%) received the syrup. In a subsample of 25 mothers reporting receipt of the drug, nevirapine was detected in 22 (88.0%) and 24 (96.0%) babies tested. PCR of 67 infant blood samples identified 5 HIV-positive (MTCT rate = 7.5%, 95% confidence interval [CI]: 0.3%-16.6%). Mothers can administer nevirapine to themselves and their newborns and can achieve low rates of perinatal HIV infection.     

Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene

Plasma amyloid beta protein (Abeta42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Abeta aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Abeta. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Abeta42 and LOAD. PLAU SNP compound genotypes composed of haplotype pairs showed significant association with AD in three independent case-control series. PLAU SNP haplotypes associated significantly with plasma Abeta42 in 10 extended LOAD families. One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L). We analyzed PLAU_1 for association with AD in six case-control series and 24 extended LOAD families. The CT and TT PLAU_1 genotypes showed association (P=0.05) with an overall estimated odds ratio of 1.2 (1.0-1.5). The CT and TT genotypes of PLAU_1 were also associated with significant age-dependent elevation of plasma Abeta42 in 24 extended LOAD families (P=0.0006). In knockout mice lacking the PLAU gene, plasma--but not brain--Abeta42 as well as Abeta40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Abeta42, LOAD and variants in the IDE or VR22 region. These results provide strong evidence that PLAU or a nearby gene is involved in the development of LOAD. PLAU_1 is a plausible pathogenic mutation that could act by increasing Abeta42, but additional biological experiments are required to show this definitively.     

Impact of hemochromatosis screening in patients with indeterminate results: the hemochromatosis and iron overload screening study.

PURPOSE: Assess the quality of life impact of receiving indeterminate test results for hemochromatosis, a disorder involving HFE genetic mutations and/or elevated serum transferrin saturation and ferritin. METHODS: The study sample was from the Hemochromatosis and Iron Overload Screening Study, a large observational study of hemochromatosis among primary care patients in the US and Canada using HFE genotype and serum transferrin saturation and ferritin screening. Study subjects included 2,304 patients found with hemochromatosis risk of uncertain clinical significance. Assessed was SF-36 general health and emotional well-being before screening and six weeks after participants received their test results. Health worries were assessed after screening. RESULTS: Of the study subjects, 1,268 participants (51.5%) completed both assessments. Compared to normal controls, those with HFE mutations or elevated serum transferrin saturation and ferritin levels of uncertain significance were more likely to report diminished general health and mental well-being, and more health worries. These effects were associated with participants' belief of having tested positive for hemochromatosis or iron overload. CONCLUSION: Notification of indeterminate results from screening may be associated with mild negative effects on well-being, and might be a potential participant risk in screening programs for disorders with uncertain genotype-phenotype.     

Crystal-Deficient Alveolar Soft Part Sarcoma

Classically, ultrastructural examination of alveolar soft part sarcoma reveals large, dramatic, rhomboid to needlelike crystals with a characteristic substructure. In this study of four cases of alveolar soft part sarcoma, only two exhibited large crystals, which were rare. All four cases, however, exhibited round, electron-dense granules, and in the two cases without large crystals these granules rarely exhibited elongation with the characteristic substructure of alveolar soft part sarcoma that permits definitive diagnosis. Two of these cases had been previously studied at other institutions, where crystals were not identified ultrastructurally and electron microscopy was considered noncontributory. Large crystals, then, may be rare or absent in alveolar soft part sarcoma. Careful search may be necessary to find granules with the characteristic periodic substructure.     

Anatomic and physiologic development of the photoreceptor of the kitten

Summary The postnatal development of the photoreceptor of the cat was studied using physiological and anatomical methods. The late receptor potential (LRP) was recorded in vitro and the threshold and maximum amplitude determined. The same specimens used in the electrophysiological studies were then prepared for microscopy, and rod cell outer and inner segment length and diameter, photoreceptor density, and inter-receptor distance were determined. A small LRP was first recorded at 9–10 days, but only at very high stimulus intensities. Thereafter, there was a rapid decrease in the threshold and an increase in the amplitude of the LRP. The threshold reached adult values at 17–18 days, while the amplitude of the LRP was adultlike at 23–26 days. Of the anatomical parameters examined, inter-receptor spacing and rod cell diameters seem to be most clearly associated, respectively, with the attainment of adult LRP threshold and amplitude. Outer segment length was adult-like at 35–43 days of age and thus postdated physiological maturity of the photoreceptor. These observations suggest that the surface area of the rod cell outer segment tips is more critical in the development of the adult LRP than is the number of discs in the outer segment. In addition, changes over time in the mean diameter and length of rod cell inner segments follows the pattern of ontogenetic changes in LRP amplitude. These findings imply a close relationship during ontogeny between the metabolic functions of the inner segment and phototransduction at the outer segment disc.This study was supported by the Florida Lions Eye Bank (GST) and by a grant, 2-RO1-EY00376-08, from the National Eye Institute, National Institutes of Health, Bethesda, Maryland (DIH)Andrew Labbie and Joseph Muroff were participants in the Community Laboratory Research Programm sponsored by the Dade County Public School System, Miami, Florida