Role of inflammation in nocturnal asthma.

BACKGROUND--Nocturnal airway narrowing is a common problem for patients with asthma but the role of inflammation in its pathogenesis is unclear. Overnight changes in airway inflammatory cell populations were studied in patients with nocturnal asthma and in control normal subjects. METHODS--Bronchoscopies were performed at 0400 hours and 1600 hours in eight healthy subjects and in 10 patients with nocturnal asthma (> 15% overnight fall in peak flow plus at least one awakening/week with asthma). The two bronchoscopies were separated by at least five days, and both the order of bronchoscopies and site of bronchoalveolar lavage (middle lobe or lingula with contralateral lower lobe bronchial biopsy) were randomised. RESULTS--In the normal subjects there was no difference in cell numbers and differential cell counts in bronchoalveolar lavage fluid between 0400 and 1600 hours, but in the nocturnal asthmatic subjects both eosinophil counts (median 0.11 x 10(5) cells/ml at 0400 hours, 0.05 x 10(5) cells/ml at 1600 hours) and lymphocyte numbers (0.06 x 10(5) cells/ml at 0400 hours, 0.03 x 10(5) cells/ml at 1600 hours) increased at 0400 hours, along with an increase in eosinophil cationic protein levels in bronchoalveolar lavage fluid (3.0 micrograms/ml at 0400 hours, 2.0 micrograms/l at 1600 hours). There were no changes in cell populations in the bronchial biopsies or in alveolar macrophage production of hydrogen peroxide, GM-CSF, or TNF alpha in either normal or asthmatic subjects at 0400 and 1600 hours. There was no correlation between changes in overnight airway function and changes in cell populations in the bronchoalveolar lavage fluid. CONCLUSIONS--This study confirms that there are increases in inflammatory cell populations in the airway fluid at night in asthmatic but not in normal subjects. The results have also shown a nocturnal increase in eosinophil cationic protein levels in bronchoalveolar lavage fluid, but these findings do not prove that these inflammatory changes cause nocturnal airway narrowing.     

Colonoscopic diagnosis of an aorto-appendiceal fistula

A case of an aorto-appendicular, aorto-enteric fistula diagnosed by colonoscopy after presentation with colonic haemorrhage is reported. The role of colonoscopy in such patients is discussed and reported experience is reviewed.     

Cognitive impairment of acute onset in the Consortium to Investigate Vascular Impairment of Cognition (CIVIC) study: occurrence, correlates, and outcomes.

OBJECTIVE: Having demonstrated that dementia of acute onset represents a distinct syndrome with distinct outcomes, the authors investigated whether similar attributes describe cognitive impairment of acute onset (CIAO). METHODS: The authors conducted a secondary analysis of the Consortium to Investigate Vascular Impairment of Cognition study. RESULTS: Ninety patients met our criteria for CIAO. Compared with cognitive impairment of gradual onset, CIAO was associated with vascular features (odds ratio [OR]: 12.3, 95% confidence interval [CI]: 3.2-47.9), dementias other than Alzheimer disease (OR: 6.5, 95% CI: 2.1-20.8), and decreased survival (hazard ratio: 2.8, 95% CI: 1.6-4.6). CONCLUSIONS: Patients with CIAO are clinically identifiable and have distinct outcomes.     

A novel G protein-coupled receptor kinase gene cloned from 4p16.3.

Within the Huntington's disease (HD) candidate region of 4p16.3, the D4S127 locus displays strong linkage disequilibrium with the defect and anchors a conserved haplotype found on many HD chromosomes. To isolate genes from this region we have applied the exon amplification technique to overlapping cosmids spanning D4S127. Here, we report the discovery of a new gene encoding a novel member of a family of protein kinases that specifically phosphorylate the activated forms of G protein-coupled receptors. Such kinases are thought to participate in desensitization of specific receptors, thereby blocking further signal transduction. This gene must now be carefully scrutinized to determine whether it might be involved in HD.     

The stromal cell line S17 supports the growth of lipopolysaccharide-stimulated CBA/N spleen cell colonies in vitro.

The expression of an X-linked defect in the CBA/N strain of mice has been found to result in a number of immune abnormalities. These include low responsiveness to antigens and a greatly reduced ability to respond to many of the common B cell mitogens. An in vitro manifestation of this condition is the virtual inability of CBA/N B cells to form colonies in lipopolysaccharide (LPS)-containing semisolid agar cultures. In this report we show evidence that the colony-forming ability of CBA/N spleen cells can be effectively restored by the bone marrow stromal-derived cell line S17. Spleen cells from 4-5-week-old homozygous CBA/N female mice were grown in double-layer agar cultures containing S17 feeder layers. Control cultures contained the fibroblast-like cell line 95.17 or were treated with medium alone. It was found that at an input cell concentration of 10(4) cells per plate, CBA/N colony formation was increased from a frequency of approximately 1 in 5,000 to 1 in 50 total splenic cells. Studies with purified surface immunoglobulin-positive cells indicate the direct involvement of S17 in this process. The CBA/N colonies formed were dependent on the presence of a mitogen (LPS) and secreted detectable amounts of IgM. Major implications of these findings and the application of this assay system to study the CBA/N defect have been discussed.     

Colonoscopy — how difficult,how painful?

Colonoscopy is sometimes painful for the patient and often difficult for the endoscopist, but it is hard to predict how difficult or painful the examination will be. The purpose of this study was to identify factors that influence difficulty and pain during colonoscopy.Some 1,284 consecutive patients undergoing office colonoscopy by three endoscopists were prospectively studied. A standard questionnaire was completed by the nursing staff, who assessed the degree of difficulty and pain associated with each exam on a four-point scale.There were 682 men and 551 women (sex not recorded in 51). There was no pain in 27%, mild pain in 39%, moderate pain in 25%, and severe pain in 9%. There was no difficulty in 25%, mild difficulty in 33%, moderate difficulty in 28%, and severe difficulty in 14%. Colonoscopy was significantly easier (P<0.001, chi square) and less painful (P<0.001, chi square) in patients after sigmoidectomy. It was more painful after hysterectomy (P<0.05, chi square) and more difficult and painful in women than in men (P<0.01, chi square). There were significant differences between endoscopists in the assessment of pain associated with colonoscopy.Most colonoscopies are associated with little or no pain (66%) and are easy or only mildly difficult to perform (58%). Patients who have had sigmoid resection are especially easy and painless to examine while women, especially after hysterectomy, are at higher risk of having a painful experience. Colonoscopy technique can influence the amount of pain experienced by the patient.     

Interactions of dextromethorphan with theN-methyl-d-aspartate receptor-channel complex: single channel recordings

The actions of dextromethorphan (DXM) on the 50 pS conductance state of theN-methyl-d-aspartate (NMDA) receptor-operated channel were studied using outside-out patches obtained from cultured rat hippocampal pyramidal neurons. DXM (5–50 μM) had no effect on the amplitudes of unitary currents but caused concentration-dependent reductions in channel mean open times and the frequency of channel openings. Channel open probability was reduced in a concentration-dependent manner by DXM and was one-half of the control value at a DXM concentration of 6 μM, with the patch potential held at −60 mV. An IC₅₀ value of 4 μM was obtained for the reduction by DXM of NMDA-evoked rises in [Ca²⁺]_i in cultured rat hippocampal pyramidal neurons loaded with Fura-2. The results were consistent with drug block of the open NMDA channel with an onward (blocking) rate constant of 7.7 × 10⁶ M⁻¹ · s⁻¹ (at −60 mV). The estimated unblocking rate constant was about 10 s⁻¹, a value considerably higher compared to the off-rate constant found for dizocilpine block of the NMDA channel.     

Assignment of the lens intrinsic membrane protein MP19 structural gene to human chromosome 19.

We have isolated and characterized a bovine cDNA clone encoding the bovine lens intrinsic membrane protein, MP19. This cDNA was used as a probe to analyze a panel of Southern blots of human-Chinese hamster somatic cell hybrid DNAs to assign the gene coding for MP19 to its human chromosome. Control human and Chinese hamster DNAs displayed a distinct EcoR1 restriction fragment pattern when hybridized with the bovine MP19 cDNA. When somatic cell hybrid DNAs were restricted with Eco R1 and Southern blots hybridized with the bovine MP19 cDNA, the characteristic human restriction pattern was observed only when human chromosome 19 was present in the hybrid panel. This assignment was confirmed using a human chromosome 19-specific genomic library. A clone from this human chromosome 19-specific library was identified and further characterized. This clone contained a 7.9 kilobase fragment that contained identical DNA sequences with that of the authentic bovine MP19 cDNA, and with a separate human genomic clone containing the MP19 gene.     

CURRENT CONCEPTS IN INFANT NUTRITION

Nutritional needs vary during the first year of life according to the infant's individualized pattern of growth and amount of physical activity. After delivery, the infant must make many physiologic adjustments, develop immunologic defenses, and take in adequate nutrients for survival. The type and consistency of foods change as the gastrointestinal system matures and becomes able to metabolize the components and excrete the needed metabolites of increasingly complex foods. The recommended dietary allowance for infancy is based on the amount of nutrients provided to healthy infants in human milk during the first six months of life and on the consumption of formula and increasing amounts of solid food during the second six months. The introduction of solid foods should parallel the developmental changes that occur within the central nervous system throughout the first year; these provide a level of readiness for the infant to manage foods of various textures from full liquid to soft. Even though significant technologic advances have led to changes in the way infants can be fed, human milk is still the optimal choice. Most women can be encouraged to breast-feed regardless of their own nutritional status or dietary intake. Contraindications can be managed on an individual basis. If women do not elect to breast-feed, suitable commercial formulas are available. The important issue in feeding is that of providing a variety of appropriately prepared foods offered in a nonjudgmental atmosphere so that the foundation is laid for the development of good food habits.     

Allergen activates peripheral blood eosinophil nuclear factor-κB to generate granulocyte macrophage-colony stimulating factor, tumour necrosis factor-α and interleukin-8

BACKGROUND: Allergic inflammation is characterized by the influx and activation of eosinophils. Cytokines generated by both resident and infiltrating cells are responsible for the initiation and maintenance of this pathogenesis. This study focuses on allergen-induced activation of eosinophil NF-kappaB and generation of granulocyte macrophage-colony stimulating factor (GM-CSF), TNF-alpha, and IL-8. METHODS: Peripheral blood eosinophils were enriched to >99.9% by Percoll gradient sedimentation and negative magnetic affinity chromatography. NF-kappaB activation by 10 microg/mL house dust mite (HDM) extract was demonstrated immunocytochemically using a monoclonal antibody against the active form of NF-kappaB (NF-kappaBa). The authenticity of NF-kappaB was confirmed by Western blot. Cytokine production was assessed both by immuno-staining of eosinophils and by assay of cytokines in the cell supernatant. RESULTS: Activation of peripheral blood eosinophils from atopic, but not non-atopic, donors induced activation of NF-kappaB, which peaked at 4 h and was accompanied by a decline in IkappaB-alpha. The activation of authentic NF-kappaB was confirmed in gel shift assays. Supershift assays showed p65 to be the major subunit of eosinophil NF-kappaB. Immunofluorescent confocal microscopy demonstrated localization of NF-kappaBa to the nucleus. Following activation, cytokine immunoreactivity was seen in a fraction of the eosinophils and cytokines were released into the supernatant. The NF-kappaB inhibitors, calpain inhibitor 1 (10 microm), pentoxifylline (0.5 mm), pyrrolidine dithiocarbamate (PDTC, 10 microm) or gliotoxin (1 pg/mL) reduced the generation of GM-CSF, TNF-alpha and IL-8 in parallel with their inhibition of NF-kappaB. CONCLUSIONS: HDM allergen activates human eosinophil NF-kappaB leading to the production of the cytokines GM-CSF, TNF-alpha and IL-8. We speculate that a role for eosinophil NF-kappaB-dependent cytokines is to act as an autocrine loop augmenting the survival of eosinophils in vivo.