Kinins and kallikrein in nasal secretion after antigen challenge in patients with allergic rhinitis

This study showed that nasal allergy patients have increased nasal airway resistance and tissue kallikrein activity in nasal lavage in accordance with the severity of symptoms. Nasal airway resistance and tissue kallikrein activity were significantly increased in the nasal lavage collected 15 min after antigen challenge, placement of a disk containing house dust antigen. The free kinin level in the nasal lavage collected 15 min after the antigen challenge was also markedly increased. Pretreatment of patients with d-chlor-pheniramine maleate (histamine H1 receptor antagonist) blunted this increase in nasal airway resistance and tissue kallikrein activity 15 min after the antigen challenge, suggesting that histamine may accelerate excretion of tissue kallikrein in nasal secretions. Camostat mesilate inhibited the in vitro tissue kallikrein activity in nasal lavage collected from allergy patients. Administration of camostat mesilate significantly inhibited nasal airway resistance and tissue kallikrein activity in nasal lavage after the antigen challenge, indicating that kinin generated in the nasal cavity increased nasal airway resistance. These results suggest that tissue kallikrein inhibitors may serve as anti-allergic drugs by suppressing the nasal symptoms of nasal allergy patients.     

Substance P and bradykinin are natural inhibitors of CD13/aminopeptidase N

Aminopeptidase N (EC 3.4.11.2) is an important enzyme that is involved in the degradation of regulatory peptides including enkephalins. We report here that purified and native membrane-bound aminopeptidase N will sequentially and completely hydrolyze both Leu-enkephalin and Met-enkephalin from the amino terminus. Both purified pig aminopeptidase N and the enzyme on live HL60 cells displayed similar Km values for enkephalin. The naturally occurring neuropeptides substance P and bradykinin, and the morphine agonist, morphiceptin, were not hydrolyzed by aminopeptidase N and each inhibited the enzymatic activity. Each of these peptides contains a proline at the second residue. The Ki values for substance P (0.44 microM), bradykinin (9.4 microM), and morphiceptin (169 microM) were obtained with the enzyme on live HL60 cells. The values for the purified enzyme from pig were similar. The potent inhibition of aminopeptidase N by substance P and bradykinin suggests that these peptides may be natural inhibitors of the enzyme.     

Mechanisms of IL-6, IL-8, and GM-CSF release in nasal secretions of allergic patients after nasal challenge

Increasing the amount and type of fluid intake in children with simple constipation remains a common intervention recommended by both the medical profession and lay consumers. Efforts to increase overall water intake and/or high osmolarity liquid intake have no research or physiological basis that would result in softer and/or more frequent stools. The purpose of this project was to identify whether an effect on stooling characteristics would be noted with a concerted effort to increase liquid intake.     

Combined nasal challenge with diesel exhaust particles and allergen induces In vivo IgE isotype switching

In this study we undertook to provide evidence for local in vivo isotype switching to IgE following nasal challenges. Detection of deleted switch circular DNA (switch circles) by a novel nested polymerase chain reaction-based approach was employed as definitive molecular evidence of Ig isotype switching. Nasal challenge in humans with diesel exhaust particles (DEP) plus ragweed antigen has been shown to enhance local IgE production, stimulate local cytokine production, and markedly increase mucosal IgE antibody to ragweed. Four days after combined intranasal DEP plus ragweed challenge, we detected and characterized clones of deleted switch circular DNA (Sepsilon /Smu) representing switching from mu to epsilon from nasal lavage cells. No switch circular DNA was detected in nasal lavage cells following challenge with DEP alone nor with ragweed allergen alone. These results indicate that the combination of mucosal stimulation with DEP and ragweed allergen is capable of driving in vivo isotype switching to IgE in humans with ragweed allergy. These results are the first direct demonstration of in vivo IgE isotype switching in humans.     

Substance P is a possible neurotransmitter in the rat spinothalamic tract

In order to shed some light on the neurotransmitters in the spinothalamic tract (STT), we examined, biochemically and immunohistochemically, the contents of various neurotransmitter candidates in the terminal field of the STT after cervical hemi-chordotomy (HC) and dorsal quadrant-chordotomy (dQC) in the rat. Substance P (SP), calcitonin gene-related peptide (CGRP), enkephalin, neuropeptide Y, neurotensin, oxytocin and dynorphin A were analyzed immunohistochemically. The contents of neuropeptides (SP, CGRP and cholecystokinin octapeptide) were measured by radioimmunoassay and those of amino acids (aspartic acid, glutamic acid, gamma-aminobutyric acid (GABA) and glycine) and noradrenaline were determined using high-performance liquid chromatography. Cervical hemi-chordotomy, but not dQC, caused significant decreases of the SP-like immunoreactivity in and SP content of the ventral thalamus on the ipsilateral side, compared with that on the contralateral side and of rats subjected to sham-operation. However, neither HC nor dQC resulted in any changes in the ventral thalamic contents of other putative neurotransmitters examined. These results suggest that, in rats, the STT contains SP and that SP-positive fibers run in the ventral half of the ascending spinal tract at the cervical level.     

Efficacy and onset of action of fluticasone propionate aqueous nasal spray on nasal symptoms, eosinophil count, and mediator release after nasal allergen challenge in patients with seasonal allergic rhinitis

In order to determine if peripheral blood stem cells (PBSC) collected after priming with G-CSF in AML in first complete remission (CR) can be used for autologous transplantation and to evaluate the efficacy of early intensification therapy as in vivo purging, we studied 35 consecutive patients with AML in first CR. After standard induction and consolidation chemotherapy, 24 of them were treated with one (10 patients) or two (14 patients) cycles of high-dose cytarabine plus etoposide prior to PBSC collection. G-CSF was used as the priming agent. Of the 35 patients scheduled for peripheral blood stem cell transplantation (PBSCT), three relapsed before transplantation, and the 32 remaining underwent PBSCT. High-dose therapy consisted of either total body irradiation plus cyclophosphamide or busulphan plus cyclophosphamide. The median number of CD34+ cells infused was 3.24 x 10(6)/kg (range 0.15-14). The median times to reach a PMN count of 0.5 x 10(9)/l and a platelet count of 50 x 10(9)/l were 12 (8-28) and 30 (11-345) days, respectively. There was no transplant-related mortality. Twelve patients relapsed between 2 and 21 months post-PBSCT. With a median follow-up of 28 months, actuarial disease-free survival (DFS) is 52.41 +/- 9% in the intent-to-treat group and 57.4 +/- 9.8% in patients who underwent PBSCT. The probability of DFS is significantly higher for patients who receive early intensification therapy prior to both PBSC collection and PBSCT as compared with patients that do not: 68.8 +/- 10.27% vs 35.5 +/- 12.6%, P = 0.0418. These results indicate the feasibility of PBSCT in AML using G-CSF-mobilized PBSC. The use of intensification treatment as 'purging in vivo' prior both to collection of PBSC and PBSCT significantly reduces the risk of relapse in this group of patients.     

Fluticasone propionate aqueous nasal spray is safe and effective for children with seasonal allergic rhinitis

INTRODUCTION: Fluticasone propionate aqueous nasal spray, a new topical corticosteroid preparation, is effective when given as 200 micrograms once daily in patients (> 12 years of age) with seasonal allergic rhinitis. STUDY OBJECTIVE: To evaluate the efficacy and safety of fluticasone proprionate aqueous nasal spray in children aged 4 to 11 years with seasonal allergic rhinitis. STUDY DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group. PATIENTS: Two hundred fifty children aged 4 to 11 years with moderate-to-severe nasal symptoms, a positive skin test reaction to a late-summer or autumn allergen, a history of seasonal allergic rhinitis, and documentation of an unsatisfactory response to conventional treatment. INTERVENTIONS: Children were randomly assigned to receive fluticasone propionate, either 100 micrograms or 200 micrograms, or placebo, given by intranasal spray once daily in the morning for 14 days. MEASUREMENTS AND RESULTS: Severity of nasal symptoms (obstruction, rhinorrhea, itching, and sneezing) was recorded on visual analog scales by investigators at weekly visits and by patients (or adult guardian) daily in the evening. According to investigator and patient ratings, both fluticasone propionate 100 micrograms/d and 200 micrograms/d lowered total nasal symptom scores when compared with placebo. Both dosages of fluticasone propionate were more effective than placebo on the basis of investigator-rated overall clinical evaluation of efficacy at the end of treatment, with significant improvement (as opposed to moderate or mild improvement, no change or worsening) noted in 21% to 29% of the active-treatment groups vs 9% in the placebo group. There were no significant differences between the two fluticasone propionate dosages in any efficacy measurement. Morning plasma cortisol concentrations and frequency of drug-related adverse events were similar in the fluticasone propionate and placebo groups. CONCLUSION: In children as young as 4 years, 100 micrograms of fluticasone propionate aqueous nasal spray given once daily is as effective as 200 micrograms given once daily, the usual adult dose for the treatment of seasonal allergic rhinitis. Both fluticasone propionate dosages were well tolerated and neither dosage appears to interfere with the hypothalamic-pituitary-adrenal axis in children.     

Tryptase determination in nasal washings in patients with allergic rhinitis]

An 8-year-old Italian boy, born to consanguineous parents, with clinical, histopathologic, and ultrastructural findings of lipoid proteinosis is reported. The main signs of the syndrome-papulonodular, hyperkeratotic and verrucous lesions distributed over the skin of the head and extremities, hoarseness, and dysphagia-were present in the child. The mother had papulonodular lesions on her hands and also complained of slowness in healing.     

The effect of terfenadine on unilateral nasal challenge with allergen

To investigate the role of H1 receptor-mediated effects in allergic rhinitis, we challenged 12 allergic volunteers with allergen 2 hours after administration of either placebo or 60 mg of terfenadine. Filter paper discs were used for the unilateral administration of allergen and the collection of nasal secretions. Secretion weights, levels of histamine in recovered nasal secretions, and nasal airway resistance (NAR) were measured for each nostril separately, and the number of sneezes was counted. After placebo treatment, allergen challenge led to significant increases in ipsilateral and contralateral secretion weights, ipsilateral histamine levels, ipsilateral NAR, and sneezing. Contralateral histamine levels were not elevated. H1 antagonism with terfenadine markedly reduced the number of sneezes and partially decreased ipsilateral and contralateral secretion weights, without affecting the increase in NAR. Terfenadine premedication also lowered the amount of histamine in ipsilateral secretions after allergen challenge. Performing identical nasal challenges with a 10-fold lower dose of antigen produced similar results. Previous studies showed that terfenadine had no effect on methacholine provocation and completely abolished ipsilateral and contralateral secretion weights after histamine challenge. We conclude that sneezing after allergen challenge is caused almost exclusively by a reflex initiated through H1 receptors and that H1 antagonism has no influence on allergen-induced increases in NAR. Unilateral allergen challenge leads to bilateral increases in secretion weights, which are only partially inhibited by terfenadine, suggesting the involvement of mediators other than histamine in the nasonasal reflex. As reported earlier, terfenadine also decreases allergen-induced histamine release after challenge with the highest dose of antigen.     

Effect of pre-treatment with inhaled furosemide on allergen nasal challenge

Degenerate primers corresponding to consensus sequences in the catalytic domains of known fungal adenylate cyclases were used to isolate gene-specific homologs from the Dutch elm disease pathogen Ophiostoma novo-ulmi, the dimorphic human pathogen Candida albicans, and the commercial mushroom Agaricus bisporus. All three fungi gave the expected PCR product of about 390 bp. Computer searches of the databases revealed that the products generated from O. novo-ulmi and C. albicans were highly similar to the adenylate cyclase gene of Magnaporthe grisea, the rice blast fungus (91% and 79%, respectively). The PCR product from the homobasidiomycete A. bisporus, on the other hand, showed 78% similarity to the uac1 gene of the heterobasidiomycete smut fungus, Ustilago maydis. Southern hybridization indicated that all three fungi contain a single adenylate cyclase gene. Our data suggest that PCR will be highly successful for the isolation of adenylate cyclase sequences from other fungi.     

A gloverin-like antibacterial protein is synthesized in Helicoverpa armigera following bacterial challenge

The elucidation of patterns of cranial skeletal maturation and growth in fossil hominids is possible not only through dental studies but also by mapping different aspects of ossification in both extant African apes and humans. However, knowledge of normal skeletal development in large samples of extant great apes is flimsy. To remedy this situation, this paper offers an extensive survey and thorough discussion of the ossification of the posterior border of the sphenoid greater wing. Indeed, this area provides much information about basicranial skeletal maturation. We investigate three variants: the absence of the foramen spinosum and the position of both the foramen spinosum and the foramen ovale in relation to the sphenosquamosal suture. Providing original data about humans and 1,425 extant great ape skulls and using a sample of 64 fossil hominids, this study aimed to test whether different ossification patterns occurred during the course of human evolution. The incidence of three derived morphologies located on the posterior border of the sphenoid greater wing increases during human evolution at different geological periods. The evolutionary polarity of these three derived morphologies is assessed by outgroup comparison and ontogenetic methods. During human evolution, there is a clear trend for the foramen spinosum to be present and wholly located on the posterior area of the sphenoid greater wing. Moreover, in all the great ape species and in Australopithecus afarensis, the sphenosquamosal suture may split the foramen ovale. Inversely, the foramen ovale always lies wholly within the sphenoid greater wing in Australopithecus africanus, robust australopithecines, early Homo, H. erectus (and/or H. ergaster), and Homo sapiens. From ontogenetic studies in humans, we conclude that, during human evolution, the ossification of the posterior area of the sphenoid greater wing progressively surrounded the middle meningeal artery (passing through the foramen spinosum) and the small meningeal artery (passing through the foramen ovale).     

The relationships between nasal hyperreactivity, quality of life, and nasal symptoms in patients with perennial allergic rhinitis

BACKGROUND: A clinical test that could inform the clinician about the severity of a patient's nasal symptoms and health-related quality of life (QOL) would be very useful. OBJECTIVE: We attempted to determine whether, in patients with perennial allergic rhinitis, nasal challenge with histamine could be used to estimate daily symptoms and QOL. METHODS: Forty-eight patients with perennial allergic rhinitis were challenged with histamine to determine nasal hyperreactivity. Nasal response was monitored by the number of sneezes, the amount of secretion, and a symptom score. Daily nasal symptoms were recorded during the 2 preceding weeks. Patients also completed a rhinitis QOL questionnaire. RESULTS: Responsiveness to histamine and total daily nasal symptoms were moderately correlated (r = 0.51, p = 0.001). Comparison of total daily nasal symptoms with the overall QOL score showed a moderate correlation (r = 0.59, p < 0.001). Nasal response to histamine and overall QOL score were also correlated (r = 0.43, p = 0.002). However, overall QOL and daily nasal symptoms could be predicted by wide 95% confidence intervals only for each decade of nasal responsiveness to histamine (expressed as a composite symptom score). CONCLUSION: In patients with perennial allergic rhinitis nasal hyperreactivity as determined by histamine challenge, QOL, and daily nasal symptoms are moderately correlated. Therefore nasal histamine challenge can be used as a tool for estimating the severity of daily nasal symptoms and QOL, although it cannot predict nasal symptoms and QOL very accurately.     

The prevalence of allergic rhinitis and nasal symptoms in Nottingham

An overview of the most important older and newer results regarding the relationship between violent and criminal behavior on the one hand and schizophrenic illness on the other hand is presented. Four different methods are available to study this relationship: (i) study of the prevalence of mental illness in criminal/violent populations; (ii) study of criminality/violence rate in samples of psychiatric patients; (iii) study of criminality/violence in community samples comparing mental patients with non-patient community residents; and (iv) study of criminality/violence in birth cohorts prospectively. All these methods have been used; but samples composed of schizophrenic patients exclusively were only exceptionally studied. The results indicate that there is a modest but significant relationship between schizophrenia and violence and crime which persists even after controlling for demographic and socio-economic variables. The probability of schizophrenic patients to be criminal or violent depends on the acuity of their illness and is increased by their use of psychoactive substances. Generally, however, violent and criminal acts directly attributable to mental illness account only for a very small proportion of such acts in the society.     

Thrombin generation measured ex vivo following microvascular injury is increased in SLE patients with antiphospholipid-protein antibodies

Antiphospholipid-protein antibodies (APA) include lupus-type anticoagulant (LA) and antibodies recognizing complexes of anionic phospholipids (e.g. cardiolipin) and proteins (e.g. prothrombin and beta2-glycoprotein I). The presence of APA is associated with an increased risk of both arterial and venous thrombosis. However, the pathogenic mechanism leading to thrombosis in patients with APA remains unclear. We studied 32 patients with systemic lupus erythematosus (SLE) who were divided into two groups depending on the presence (n = 19) or absence (n = 13) of APA. Healthy volunteers (n = 12) matched by age and sex served as controls. In all subjects LA and IgG class anticardiolipin antibodies (ACA) were determined. Thrombin generation was monitored ex vivo measuring fibrinopeptide A (FPA) and prothrombin fragment F1 + 2 (F1 + 2) in blood emerging from a skin microvasculature injury, collected at 30 second intervals. In subjects with antiphospholipid antibodies mean FPA and F1 + 2 concentrations were significantly higher at most blood sampling times than in controls. In some SLE patients with APA the process of thrombin generation was clearly disturbed and very high concentrations of fibrinopeptide A were detected already in the first samples collected. Two minutes after skin incision SLE patients without APA produced slightly more FPA, but not F1 + 2, as compared to healthy subjects. Mathematical model applied to analyze the thrombin generation kinetics revealed that APA patients generated significantly greater amounts of thrombin than healthy controls (p = 0.02 for either marker). In contrast, in the same patients generation of thrombin in recalcified plasma in vitro was delayed pointing to the role of endothelium in the phenomenon studied. In summary, these data show for the first time that in SLE patients with antiphospholipid-protein antibodies thrombin generation after small blood vessel injury is markedly increased. Enhanced thrombin generation might explain thrombotic tendency observed in these patients.     

Histopathological changes in Yucatan minipig skin following challenge with sulphur mustard. A sequential study of the first 24 hours following challenge

The importance of calcium in neuronal function has been amply demonstrated in recent years. The discovery of a class of proteins within neurons which bind calcium, therefore, has proven to be a catalyst for the generation of theories and hypotheses regarding mechanisms of neurotoxicity in the CNS. In addition, the distribution of certain calcium-binding proteins changes during neural development, suggesting that they may play a role in organization or pattern generation. We have examined the ontogeny of three related calcium-binding proteins, calbindin-D28, parvalbumin and calretinin, with respect to the ventral and dorsal compartments or tiers of the dopaminergic population in the ventral midbrain. Single and dual-label immunocytochemistry was employed to map the distributions of calcium-binding proteins and tyrosine hydroxylase from E18 through adulthood. The results show that each of the three proteins exhibits a unique developmental sequence and compartment preference, with calbindin D28 clearly related to the later-developing dorsal tier, and parvalbumin and calretinin to the ventral tier of the dopaminergic ventral mesencephalon.     

Characterization of Toscana virus-defective interfering particles generated in vivo

Adenylate kinase (AK), which catalyzes the equilibrium reaction among AMP, ADP, and ATP, is considered to participate in the homeostasis of energy metabolism in cells. Among three vertebrate isozymes, AK isozyme 1 (AK1) is present prominently in the cytosol of skeletal muscle and brain. When mouse embryonal carcinoma P19 cells were differentiated by retinoic acid into neural cells, the amount of AK1 protein and enzyme activity increased about fivefold concomitantly with neurofilament (NF). Double-immunofluorescence staining showed that both AK1 and NF were located in neuronal processes as well as the perinuclear regions in neuron-like cells, but not in glia-like cells. The amount of brain-type creatine kinase increased only twofold during P19 differentiation. The AK isozyme 2, which was not detected in adult mouse brain, was found in P19 cells and did not increase during the differentiation. Mitochondrial AK isozyme 3, which uses GTP instead of ATP as a phosphate donor, was increased significantly. Immunohistochemical analysis with the primary cultured cells from rat cerebral cortex showed similar cellular localization of AK1 to those observed with differentiated P19 cells. These results suggest an important role of this enzyme in neuronal functions and in neuronal differentiation.     

Acoustic rhinometry in the study of the acute nasal allergic response

Acoustic rhinometry is a recently developed method for the objective assessment of nasal patency. In this study, acoustic rhinometry was used to measure changes in nasal cavity dimensions in the immediate response to nasal allergen challenge in eight pollen-sensitive subjects. Acoustic rhinometric changes were compared with subjective symptoms, as well as histamine in nasal secretions, cytology of nasal mucosal scrapings, and changes in olfactory function. A significantly greater decrease in nasal airway caliber occurred following allergen challenge as compared to buffer diluent challenge in the same individuals (70% +/- 7% versus 22% +/- 5%). During an allergic response, a strong correlation was found between the minimum cross-sectional area and the volume of the nasal cavity measured by acoustic rhinometry (r = .9). However, no correlation was observed between nasal airway caliber and concomitant subjective congestion reported by the subjects. A modest decrease in olfactory function was seen following allergen challenge (3.1 +/- 1.4 fewer odors identified correctly out of 20; p = .08). However, the alterations of olfactory function did not correlate with changes in nasal patency. The results presented in this study demonstrate that acoustic rhinometry has great potential as a reproducible method for the objective assessment of nasal obstruction occurring in nasal allergen challenge studies.     

Diagnostic value of nasal provocation testing and rhinomanometry in allergic rhinitis

Assessment of the hemodynamic and anatomic results following balloon angioplasty of discrete native coarctation of the aorta, with particular attention to "remodeling," has required repeat cardiac catheterization and angiography, which is invasive and has limited resolution. Eight patients with hypertension and discrete native coarctation with an otherwise normally developed aortic arch underwent angioplasty at 5.0 +/- 6.8 years of age. Angiographic cross-sectional areas of the aorta indexed to body surface area at the isthmus (I), coarctation site (C), and 1 cm distal to the coarctation site (Cd) pre- and postangioplasty were compared with MRI-indexed cross-sectional areas 18 +/- 10 months (MRI-1) and 35 +/- 11 months (MRI-2) postangioplasty. From preangioplasty to MRI-2, the isthmus was smaller (149 +/- 22 versus 127 +/- 27 mm2/m2; p < 0. 05). The coarctation site was larger postangioplasty (25 +/- 9 versus 116 +/- 40 mm2/m2; p < 0.001) with continued growth at latest follow-up (116 +/- 40 versus 164 +/- 36 mm2/m2; p < 0.01). The segment 1 cm distal to the coarctation site continued to decrease in area at latest follow-up (267 +/- 78 versus 163 +/- 38 mm2/m2; p < 0. 001). I versus C versus Cd at MRI-2 were similar, whereas postangioplasty and MRI-1 cross-sectional area measurements were significantly different. Following angioplasty of discrete native coarctation, the aorta becomes more uniform or undergoes "remodeling." Noninvasive MRI is an effective means of evaluating the anatomic result following balloon angioplasty, obviating the need for repeated invasive cardiac catheterizations.