Assessment of airway inflammation: an overview.
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Asthma↗
Biomedical subjects
S Durham
Publications and source records attributed to S Durham.
[Chiari malformations and hydrosyringomyelia].
INTRODUCTION: The association of hindbrain herniation, better known as Chiari malformation, and cystic cavitation of the spinal cord or hydrosyringomyelia has been well described in the literature although there is little consensus regarding its etiology, pathophysiology or optimal treatment. DEVELOPMENT: Despite a well-accepted and utilized classification system of both Chiari malformation and hydrosyringomyelia, there remains considerable disagreement regarding the proper management of these patients. CONCLUSIONS: This article reviews several popular theories on the etiology and pathophysiology of this disorder, briefly discusses the clinical features and radiologic findings associated with Chiari malformation and hydrosyringomyelia, and reviews basic surgical techniques for decompression of the cranial-cervical junction and treatment of the hydrosyringomyelia.
Arnold-Chiari Malformation↗
The use of exfoliative cell samples to map clonal genetic alterations in the oral epithelium of high-risk patients.
Although it is widely accepted that clonal genetic alterations are an essential component of tumor progression, little is known of the distribution of such changes in high-risk lesions or how such clones are altered over time. We explored the feasibility of using exfoliative cells collected by scraping the mucosal surface to detect allelic loss in oral lesions of 22 patients (14 squamous cell carcinomas, 2 carcinomas in situ, and 6 dysplasias). The data show that the patterns of allelic loss observed in these samples closely represent those observed in biopsies of the same region. Furthermore, early indications are that this approach can be used to detect recurrent outgrowth of clones of altered cells in patients after therapy.
Adult↗
Upregulation of alpha GM-CSF-receptor in nonatopic asthma but not in atopic asthma.
BACKGROUND: Intrinsic asthma is characterized by an increased number of activated eosinophils and macrophages and an increased expression of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchial mucosa. OBJECTIVE: This study was carried out to investigate the expression of alpha GM-CSF receptor (alpha GM-CSFr) messenger RNA and protein in the bronchial mucosa of patients with intrinsic or atopic asthma and of control subjects and to correlate the expression of alpha GM-CSFr to the number of EG2+ cells (eosinophils) and CD68+ cells (macrophages) and pulmonary function. METHODS: Nineteen patients with stable asthma (9 with atopic and 10 with intrinsic asthma) and 22 normal control subjects (12 atopic and 10 nonatopic subjects) were recruited, and FEV1 (percent predicted) and PC20 were measured before bronchoscopy. Endobronchial biopsy specimens were obtained and examined for membrane-bound alpha GM-CSFr by using in situ hybridization and immunocytochemistry. RESULTS: alpha GM-CSFr mRNA- and protein-positive cells were identified in biopsy specimens from all four groups studied. There was no significant difference in the number of cells expressing alpha GM-CSFr mRNA and protein in patients with atopic asthma compared with atopic and nonatopic control subjects. However, the numbers of alpha GM-CSFr mRNA- and protein-positive cells were significantly higher in nonatopic patients with asthma compared with atopic patients with asthma and atopic and nonatopic control subjects (p < 0.001). In the patients with intrinsic asthma, the number of alpha GM-CSFr mRNA-positive cells per millimeter of basement membrane correlated with numbers of CD68+ cells (r2 = 0.87, p < 0.001) but not with EG2+ cells, and colocalization studies demonstrated that 80% of the cells expressing alpha GMCSFr mRNA were CD68+. The expression of GM-CSF was also significantly increased in patients with intrinsic asthma compared with those with atopic asthma and control subjects (p < 0.05). In addition, in intrinsic asthma, there was a correlation between alpha GM-CSFr mRNA and FEV1 (r2 = 0.61, p < 0.05). CONCLUSION: These results demonstrate that elevated numbers of cells expressing alpha GM-CSFr can be detected in nonatopic asthma but not in atopic asthma and suggest that this increased expression is predominantly macrophage-associated and may play an important pathophysiologic role in intrinsic asthma.
Adult↗
IL-5 secretion by allergen-stimulated CD4+ T cells in primary culture: relationship to expression of allergic disease.
BACKGROUND: IL-5-producing allergen-specific T cells are thought to play a prominent role in the pathogenesis of allergic inflammation. We hypothesized that T cell allergen-driven IL-5 synthesis is elevated in patients with atopic disease as compared with that in atopic patients free of disease and nonatopic control subjects. OBJECTIVES: The purpose of this study was to compare IL-5 and interferon-gamma (IFN-gamma) secretion and proliferation by peripheral blood T cells from sensitized atopic patients with asthma, rhinitis, and no symptoms and from nonatopic control subjects in response to the allergen Dermatophagoides pteronyssinus (Der p) and the control recall antigen Mycobacterium tuberculosis purified protein derivative (PPD). METHODS: To measure allergen-induced IL-5 production and proliferation, we developed a short-term culture technique that required a single antigenic stimulation of freshly isolated peripheral blood mononuclear cells (PBMC). With this technique, we measured Der p- and PPD-induced IL-5 production and proliferation in PBMC from atopic patients with asthma who were allergic to Der p, atopic patients with rhinitis, atopic patients with no symptoms, and a group of nonatopic normal control subjects. In four experiments, CD4+ or CD8+ T cells were depleted from PBMC to confirm that IL-5 synthesis was T cell dependent. RESULTS: T cell IL-5 production, but not IFN-gamma production, in response to Der p was elevated in atopic patients with asthma and atopic patients with rhinitis compared with findings in atopic patients with no symptoms or nonatopic control subjects. IL-5 production was abrogated by depletion of CD4+, but not CD8+, T cells. In subjects with asthma, allergen-driven IL-5 production correlated with bronchial hyperreactivity. Allergen-induced proliferation was also higher in patients with asthma than in atopic subjects with no symptoms or nonatopic controls. T cell IL-5 and IFN-gamma production and proliferation in response to PPD were similar regardless of atopic status or disease. CONCLUSIONS: Elevated IL-5 production is a characteristic of allergen-specific peripheral blood CD4+ T cells from sensitized patients with atopic disease but not atopy per se.
Allergens↗
IL-5 production by allergen-stimulated T cells following grass pollen immunotherapy for seasonal allergic rhinitis.
Grass pollen immunotherapy for the treatment of seasonal allergic rhinitis ('summer hayfever') results in improvement in symptoms, a reduction in the early and late phase responses to allergen provocation and decreased tissue eosinophilia. Immunotherapy may act by altering the pattern of cytokine production by allergen-specific T cells from a 'Th2-type' (IL-4 and IL-5) profile to a 'Th1-type' (interferon-gamma (IFN-gamma)) profile. We set out to determine whether clinical improvement following specific allergen immunotherapy is accompanied by reduced production of the pro-eosinophilic and archetypal 'Th2-type' cytokine, IL-5. Peripheral blood mononuclear cells (PBMC) were isolated from (i) 13 patients who had received 6 or 7 years' continuous conventional immunotherapy with timothy grass pollen (Phleum pratense); (ii) 14 patients who had received 3 or 4 years of conventional immunotherapy followed by 3 years of placebo treatment; (iii) 12 matched seasonal rhinitic patients who had never received immunotherapy; and (iv) 17 non-atopic normal controls. PBMC were stimulated with 20 microg/ml and 200 microg/ml P. pratense extract, or 10 microg/ml of Mycobacterium tuberculosis purified protein derivative (PPD), at 2 x 10(6) cells/ml and 5 x 10(6) cells/ml. IL-5 concentrations in culture supernatants collected after 6 days' culture were measured by ELISA. IL-5 production in response to stimulation with P. pratense extract was highly reproducible and was elevated in both of the immunotherapy treated groups and the untreated rhinitics relative to non-atopic controls (P<0.005 for each group relative to non-atopic controls, under each of the four conditions tested). However, no significant reduction was observed in IL-5 production when immunotherapy treated patients were compared with untreated rhinitic controls. Moreover, abrogation of the cutaneous late-phase responses to allergen following treatment was not associated with reduced IL-5 production by allergen-stimulated peripheral blood T cells. Reduced IL-5 production by peripheral blood T cells may not be necessary for immunotherapy to be effective. Local immunodulation of T cell responses may play a role in this form of treatment.
Adult↗
IL-13 production by allergen-stimulated T cells is increased in allergic disease and associated with IL-5 but not IFN-gamma expression.
Interleukin-13 (IL-13) shares many, but not all, of the properties of the prototypic T-helper type 2 (Th2) cytokine IL-4, but its role in allergen-driven T-cell responses remains poorly defined. We hypothesized that allergen stimulation of peripheral blood T cells from patients with atopic disease compared with non-atopic controls results in elevated IL-13 synthesis in the context of a 'Th2-type' pattern. Freshly isolated peripheral blood mononuclear cells (PBMC) obtained from sensitized atopic patients with allergic disease, and non-atopic control subjects, were cultured with the allergens Phleum pratense (Timothy grass pollen) or Dermatophagoides pteronyssinus (house dust mite) and the non-allergenic recall antigen Mycobacterium tuberculosis purified protein derivative (PPD). Supernatant concentrations of IL-13, along with IL-5 and interferon-gamma (IFN-gamma) (Th2- and Th1-type cytokines, respectively) were determined by enzyme-linked immunosorbent assay (ELISA). Allergen-induced IL-13 and IL-5 production by T cells from patients with allergic disease was markedly elevated (P = 0.0075 and P = 0.0004, respectively) compared with non-atopic controls, whereas IFN-gamma production was not significantly different. In contrast to allergen, the prototypic Th1-type antigen M. tuberculosis PPD induced an excess of IFN-gamma over IL-13 and IL-5 production, and absolute concentrations of cytokines were not affected by the presence or absence of atopic disease. Addition of exogenous recombinant IFN-gamma or IL-12, cytokines known to inhibit Th2-type responses, significantly inhibited allergen-driven production of both IL-13 and IL-5, but not T-cell proliferation, whereas exogenous IL-4 did not significantly affect production of IL-13 or IL-5. We conclude that allergen-specific T cells from atopic subjects secrete elevated quantities of IL-13 compared with non-atopic controls, in the context of a Th2-type pattern of cytokine production.
Allergens↗
Dermatobia hominis in the accident and emergency department: "I've got you under my skin".
An unusual form of larval infestation from South America is presented which, in view of increasing tourism to South america's tropical areas, may present to any accident and emergency department. Infestation with Dermatobia hominis is reviewed in terms of clinical recognition and life cycle. Techniques of removal are described.
Adult↗
Diagnostic indicators in the early recognition of severe cocaine intoxication.
Acute cocaine intoxication is an ever increasing problem in the United Kingdom. Aggressive resuscitation linked to early diagnosis is essential in preventing death. Three cases of severe cocaine toxicity are presented to highlight certain diagnostic indicators in recognising the condition in patients presenting in a collapsed state to the accident and emergency department. Acidosis was a striking feature. The acute management of such patients is supportive and should involve methods to minimize continuing absorption.
Acidosis↗
Increased interleukin-10 messenger RNA expression in atopic allergy and asthma.
Interleukin-10 (IL-10) inhibits T-lymphocyte proliferation and production of cytokines. We have examined expression of IL-10 messenger RNA (mRNA) in atopic asthma and in allergen and tuberculin skin responses by in situ hybridization. The proportion of bronchoalveolar lavage (BAL) cells positive for IL-10 mRNA was increased in a group of 10 symptomatic asthmatics when compared with control subjects (17.5% versus 5.2% BAL cells positive; P < 0.001). In a separate group of six mild atopic asthmatics, there was an increased proportion of BAL cells positive for IL-10 mRNA 24 h after allergen inhalation challenge compared with diluent challenge BAL from the same subjects (24% versus 10%; P < 0.005). By simultaneous in situ hybridization and immunocytochemistry, IL-10 mRNA was localized to both CD3+ T cells and CD68+ alveolar macrophages in BAL, with a significantly more prominent T-cell signal in the symptomatic asthmatics compared with control subjects and after allergen challenge compared with diluent challenge of the mild asthmatic subjects. It has been suggested that IL-10 production is a late event after T-cell activation. To examine kinetics and specificity of IL-10 mRNA expression, skin biopsies were obtained from atopic, tuberculin-sensitive subjects at 1, 6, and 48 h after cutaneous injection of allergen or tuberculin. With both stimuli, there was an increase in IL-10 mRNA-positive cells at 6 h when compared with control sites injected with appropriate diluent which were biopsied 24 h after injection (P < 0.01 for allergen and P < 0.02 for tuberculin). These findings are compatible with the hypothesis that IL-10 mRNA is expressed in both macrophages and T lymphocytes in the airway in asthma and that IL-10 mRNA expression is induced from T lymphocytes in response to allergen. This response may also occur in other types of cell-mediated inflammation.
Adolescent↗
Secretion of the eosinophil-active cytokines interleukin-5, granulocyte/macrophage colony-stimulating factor and interleukin-3 by bronchoalveolar lavage CD4+ and CD8+ T cell lines in atopic asthmatics, and atopic and non-atopic controls.
Specific eosinophil accumulation and activation within the asthmatic bronchial mucosa are thought to occur at least partly through the actions of cytokines, including interleukin (IL)-5, IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF). Although mRNA encoding some of these cytokines has been demonstrated in bronchoalveolar lavage (BAL) fluid cells and bronchial biopsies from asthmatics, it has yet to be established whether these cells produce the translated products and whether expression is associated with CD4+ T helper or CD8+ cytotoxic T cells. We addressed this problem by raising polyclonal CD4+ and CD8+ T cell lines from the BAL fluid of six atopic asthmatics, five atopic non-asthmatics and seven non-atopic non-asthmatic controls. BAL fluid cells obtained at fiberoptic bronchoscopy were depleted of adherent cells, and then T lymphocytes expanded by stimulation with monoclonal anti-CD3 antibody and recombinant human IL-2. When lymphocytes had expanded to sufficient numbers, CD4+ and CD8+ cells were separated by positive selection with magnetic beads coated with anti-CD4 or anti-CD8 monoclonal antibodies and further expanded. Cytokine secretion by standardized cell numbers was measured by enzyme-linked immunosorbent assays. BAL CD4+ T cell lines from the asthmatics secreted significantly elevated quantities of both IL-5 and GM-CSF as compared with lines from the atopic and non-atopic controls (p = 0.023-0.003). In contrast, IL-3 secretion did not significantly differ between the groups. In some subjects, CD8+ T cell lines also secreted significant quantities of these cytokines and there was a trend for IL-5 secretion by these cells to be higher in asthmatics than non-atopic controls (p = 0.035). These data are consistent with the hypothesis that activated T lymphocytes from asthmatics, particularly of the CD4+ subset, are predisposed to release elevated quantities of cytokines relevant to the accumulation and activation of eosinophils.
Adult↗
Regional cerebral blood flow and CO2 reactivity in fulminant hepatic failure.
Alterations in cerebral hemodynamics are postulated to contribute to brain herniation, a major cause of death in patients with severe hepatic encephalopathy due to fulminant hepatic failure (FHF). In an effort to identify these changes in cerebral hemodynamics, regional and global cerebral blood flow (CBF) and CO2 reactivity were measured using stable xenon-enhanced computed tomography (Xe/CT) in 24 patients within 72 h of onset of severe hepatic encephalopathy. Regional variations in CBF, most notably, a relative decrease in CBF in the anterior circulation and an increase in CBF in the posterior circulation were found. CBF was significantly lower in FHF patients compared with controls, however, these values are well out of the established ischemic range. FHF patients also showed significant impairment in CBF response to hypoventilation, while the CBF response to hyperventilation remained intact. This study suggests that FHF patients demonstrate early changes in both CBF patterns and CO2 reactivity. The relatively "normal" CBF values obtained in FHF patients in severe hepatic encephalopathy coupled with the lack of vasodilatation to hypoventilation suggest a state of uncoupled CBF and metabolism or "luxury perfusion" that could theoretically contribute to vasogenic edema, brain swelling, and cerebral herniation.
Adult↗
Pre-hospital ABCs: getting the right message across!
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Emergency Medical Services↗
Near asphyxiation with a child's dummy.
A case is reported of near asphyxiation in a child caused by impaction of a dummy in the upper airway. Previous similar cases are described and recommendations made for changes in the design of children's dummies to improve their safety profile.
Accidents, Home↗
Peripheral blood CD4 but not CD8 t-lymphocytes in patients with exacerbation of asthma transcribe and translate messenger RNA encoding cytokines which prolong eosinophil survival in the context of a Th2-type pattern: effect of glucocorticoid therapy.
T-lymphocyte (T-LC)-derived cytokines have been implicated in asthma pathogenesis. Activation of peripheral blood CD4 but not CD8 T-LC and a Th2-type pattern of elevated cytokine mRNA expression in BAL fluid T-LC have been observed in asthmatics, but the principal source (CD4 or CD8 T-LC) of these cytokines is unknown. Our objective was to measure expression of Th1- and Th2-type cytokine mRNA and spontaneous secretion of IL-3, IL-5, and GM-CSF by peripheral blood CD4 and CD8 T-LC from asthmatics before and after oral glucocorticoid therapy and non-asthmatic controls. We used in situ hybridization to detect mRNA expression in isolated CD4 and CD8 T-LC, and an in vitro eosinophil survival assay to detect secretion of IL-3, IL-5, and GM-CSF in T-LC culture supernatants. Comparing the asthmatics with the controls, elevated percentages of CD4 T-LC expressed mRNA encoding IL-5, IL-4, and GM-CSF (P < 0.02) but not IL-3, IL-2, or IFN-gamma. In CD8 T-LC, mRNA expression was generally low with no significant differences between the groups. In the asthmatics, the percentages of CD4 T-LC expressing IL-5 mRNA correlated with disease severity and the numbers of peripheral blood eosinophils (P < 0.01). Culture supernatants of asthmatic CD4 but not CD8 T-LC exhibited significantly higher (P = 0.0003) eosinophil survival-prolonging activity compared with controls, in which low activity was detected. Inhibition with anti-cytokine antibodies suggested that GM-CSF, and to a lesser extent IL-5 and IL-3, could account for this activity. After oral glucocorticoid therapy of the asthmatics, lung function improved and the percentages of CD4 T-LC expressing mRNA encoding IL-3, IL-5, and GM-CSF but not IL-2, IL-4, or IFN-gamma were reduced (P < 0.04). Secretion of eosinophil survival-prolonging activity by the CD4 T-LC was also reduced (P = 0.004). We conclude that peripheral blood CD4 but not CD8 T-LC from asthmatics express cytokine mRNA in a Th2-type pattern and show elevated secretion of cytokines prolonging eosinophil survival. Glucocorticoid therapy of asthmatics is associated with a reduction in the percentages of CD4 T-LC expressing IL-3, IL-5, and GM-CSF mRNA and secretion of the corresponding proteins.
Adolescent↗
Expression of the chemokine N51/KC in the thymus and epidermis of transgenic mice results in marked infiltration of a single class of inflammatory cells.
Transgenic mice expressing the chemokine N51/KC in thymus, skin, and tongue showed a marked infiltration of a single class of inflammatory cells (neutrophils) in the sites of transgene expression. In the thymus, neutrophils were most numerous in the cortex and juxta-medullary regions, often forming aggregates or clusters. A similar, but less intense, neutrophilic infiltrate occurred in close proximity to the epidermal basal layer of the tongue and skin. No morphologic evidence of injury was observed in the thymus, skin, or tongue of these transgenic mice, indicating that N51/KC expression induces recruitment but not inflammatory activation of neutrophils. The lack of activation in the thymus resulted in a large senescent neutrophilic population that was phagocytosed by thymic macrophages and epithelial-reticular cells. These results indicate that N51/KC is a neutrophil chemoattractant in vivo and establish these transgenic mice as effective models to study the phenomena of recruitment and clearance of neutrophils, events that are critical for the initiation and resolution of the inflammatory response.
Aging↗
Acute cerebral blood flow response to dopamine-induced hypertension after subarachnoid hemorrhage.
The effects of dopamine-induced hypertension on local cerebral blood flow (CBF) were investigated in 13 patients suspected of suffering clinical vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The CBF was measured in multiple vascular territories using xenon-enhanced computerized tomography (CT) with and without dopamine-induced hypertension. A territorial local CBF of 25 ml/100 gm/min or less was used to define ischemia and was identified in nine of the 13 patients. Raising mean arterial blood pressure from 90 +/- 11 mm Hg to 111 +/- 13 mm Hg (p < 0.05) via dopamine administration increased territorial local CBF above the ischemic range in more than 90% of the uninfarcted territories identified on CT while decreasing local CBF in one-third of the nonischemic territories. Overall, the change in local CBF after dopamine-induced hypertension was correlated with resting local CBF at normotension and was unrelated to the change in blood pressure. Of the 13 patients initially suspected of suffering clinical vasospasm, only 54% had identifiable reversible ischemia. The authors conclude that dopamine-induced hypertension is associated with an increase in flow in patients with ischemia after SAH. However, flow changes associated with dopamine-induced hypertension may not be entirely dependent on changes in systemic blood pressure. The direct cerebrovascular effects of dopamine may have important, yet unpredictable, effects on CBF under clinical pathological conditions. Because there is a potential risk of dopamine-induced ischemia, treatment may be best guided by local CBF measurements.
Adult↗
Erythrocyte-depleted allogeneic human umbilical cord blood transplantation.
Cord blood is a recently recognized source of hematopoietic stem cells. It can be employed successfully to reconstitute hematopoiesis following allogeneic transplantation. One current drawback of cord blood as a treatment has been a risk of transfusion reactions attributable to ABO blood group mismatch. Removal of red cells from the cord blood has led to reduction of the stem cells by 30-50%. In this paper we report red cell depletion by a method that employs 3% gelatin to effectively sediment the erythrocytes and selectively deplete red cells but permits 94% recovery of nucleated cells and enrichment of colony-forming cells by granulocyte-macrophage colony-forming units, erythrocyte burst-forming units, and granulocyte-macrophage-megakaryocyte colony-forming units in the cord blood preparation. This technique has been employed in our study to remove red cells from the cord blood of a male infant delivered by cesarean section, which has permitted treatment of a female sibling suffering from leukemia. The recipient was 8 years old and weighted 36.7/kg. Complete HLA identity between the two siblings was established. A cord blood cell transplant of cryopreserved and later thawed cells (4 x 10(7) nucleated cells per kilogram) was administered to the patient after intensive myeloablative chemotherapy. The patient exhibited a prompt hematologic recovery (absolute neutrophil count > 500 by day 31, 100% male cells in bone marrow and peripheral blood by day 25) and has experienced a 13-month disease-free survival to date.(ABSTRACT TRUNCATED AT 250 WORDS)
Antineoplastic Combined Chemotherapy Protocols↗