A double-blind trial of disodium cromoglycate (Intal) in the treatment of bronchial asthma

The result of a double-blind crossover trial with disodium cromoglycate (Intal) in 22 patients, nine with extrinsic asthma and 13 with intrinsic asthma, is reported. While eight extrinsic asthmatics showed considerable symptomatic improvement, only five of the intrinsic group improved while on disodium cromoglycate. Twelve out of 13 patients with symptomatic improvement had associated decrease in airway obstruction as measured by the FEV₁.It is concluded that disodium cromoglycate is useful in the treatment of asthma, particularly of the extrinsic type.     

Increased activity of 5-lipoxygenase in polymorphonuclear leukocytes from asthmatic patients

The formation of 5-lipoxygenase products of arachidonic acid, 5-HETE and 5,12-diHETE, was determined in 100,000 X g supernatant of polymorphonuclear leukocytes from 17 healthy subjects, 17 patients with extrinsic asthma and 15 patients with intrinsic asthma. After the supernatant was incubated with 14C-arachidonic acid in the presence of calcium and indomethacin, the lipoxygenase products of arachidonic acid were separated by thin layer chromatography. The results were expressed as the percentage conversion of 14C-arachidonic acid into the product per 10(7) cells. The formation of 5,12-diHETE, but not of 5-HETE, was significantly increased in the cells from the group of patients with extrinsic asthma (4.38 +/- 0.78%, mean +/- S.E.; p less than 0.01) and intrinsic asthma (6.09 +/- 1.11%; p less than 0.01), when compared to normal subjects (1.74 +/- 0.30%). Both extrinsic and intrinsic asthmatics had significantly enhanced 5-lipoxygenase activity, which was expressed as the sum of percentage conversion of 14C-arachidonic acid into 5-HETE and 5,12-diHETE. The percentage conversion in normal subjects was 4.19 +/- 0.39%, 6.24 +/- 0.84% for 17 patients with extrinsic asthma (p less than 0.05), and 8.59 +/- 1.29% for 15 patients with intrinsic asthma (p less than 0.01). There was no significant difference between these asthmatic groups. These results indicate that 5-lipoxygenase activity is increased in patients with bronchial asthma.     

Scale-dependent interactions between intrinsic and extrinsic processes reduce variability in protist populations

Interactions between intrinsic processes and extrinsic fluctuations can positively impact population persistence in ways often not predicted by classic ecological models. These interactions only arise when the intrinsic and extrinsic processes operate on the proper relative scales in time or space. Both metapopulation theory and resonance/attenuation theory suggest that interactions which lower population variability will occur when the intrinsic and extrinsic process occur on similar time scales. I performed an aquatic protist microcosm experiment to investigate how the relative frequencies of extrinsic density perturbations and intrinsic resource pulses impacted population variability. Population variability was lowest in the treatments of intermediate frequency, in which the extrinsic fluctuations and intrinsic processes were on the same time scale. This result is consistent with general theoretical predictions, and empirically documents the importance of considering scale in interactions between intrinsic and extrinsic processes that positively impact population persistence.     

Severe vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model

Allergic asthma is a complex immunologically mediated disease associated with increased oxidative stress and altered antioxidant defenses. It was hypothesized that alpha-tocopherol (alpha-T) decreases oxidative stress and therefore its absence may influence allergic inflammatory process, a pathobiology known to be accompanied by oxidative stress. Therefore, selected parameters of allergic asthma sensitization and inflammation were evaluated following ovalbumin sensitization and re-challenge of alpha-T transfer protein (TTP) knock-out mice (TTP(-/-)) that have greatly reduced lung alpha-T levels (e.g.<5%) compared to their litter mate controls (TTP(+/+)). Results showed that severe alpha-T deficiency result in a blunted lung expression of IL-5 mRNA and IL-5 protein and plasma IgE levels compared with TTP(+/+) mice following immune sensitization and rechallenge, although lung lavage eosinophil levels were comparable in both genomic strains. It is concluded that the initial stimulation of immune responses by the TTP(-/-) mice were generally blunted compared to the TTP(+/+) mice, thus diminishing some aspects of subsequent allergic inflammatory processes.     

Mouse embryonic retina delivers information controlling cortical neurogenesis

The relative contribution of extrinsic and intrinsic mechanisms to cortical development is an intensely debated issue and an outstanding question in neurobiology. Currently, the emerging view is that interplay between intrinsic genetic mechanisms and extrinsic information shape different stages of cortical development. Yet, whereas the intrinsic program of early neocortical developmental events has been at least in part decoded, the exact nature and impact of extrinsic signaling are still elusive and controversial. We found that in the mouse developing visual system, acute pharmacological inhibition of spontaneous retinal activity (retinal waves-RWs) during embryonic stages increase the rate of corticogenesis (cell cycle withdrawal). Furthermore, early perturbation of retinal spontaneous activity leads to changes of cortical layer structure at a later time point. These data suggest that mouse embryonic retina delivers long-distance information capable of modulating cell genesis in the developing visual cortex and that spontaneous activity is the candidate long-distance acting extrinsic cue mediating this process. In addition, these data may support spontaneous activity to be a general signal coordinating neurogenesis in other developing sensory pathways or areas of the central nervous system.     

Inhaled corticosteroid use is associated with increased circulating T regulatory cells in children with asthma

Background

T regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use.

Methods

Peripheral blood mononuclear cells from healthy control subjects (N?=?93) and asthmatic children of varying disease severity (N?=?66) were characterized by multi-parameter flow cytometry.

Results

Our findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma.

Conclusion

We conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency.     

Health care trends for older people

Research is showing us a radically different view of aging from the one seen by earlier generations. Attitudes, which were based on the myth that physical and mental decline are inevitable with age, are beginning to change as a result of new scientific information. What we are learning is that aging involves both intrinsic and extrinsic factors. The universal phenomena that occur in all of us as we advance in age are intrinsic characteristics of aging, while extrinsic factors are those characteristics that can be prevented or modified, such as lifestyle choices, environmental exposure, and disease.     

Health care trends for older people.

Research is showing us a radically different view of aging from the one seen by earlier generations. Attitudes, which were based on the myth that physical and mental decline are inevitable with age, are beginning to change as a result of new scientific information. What we are learning is that aging involves both intrinsic and extrinsic factors. The universal phenomena that occur in all of us as we advance in age are intrinsic characteristics of aging, while extrinsic factors are those characteristics that can be prevented or modified, such as lifestyle choices, environmental exposure, and disease.     

Intrinsic and extrinsic drivers of succession: effects of habitat age and season on an aquatic insect community

1. Classic studies of succession, largely dominated by plant community studies, focus on intrinsic drivers of change in community composition, such as inter‐specific competition and changes to the abiotic environment. They often do not consider extrinsic drivers of colonisation, such as seasonal phenology, that can affect community change. 2. Both intrinsic and extrinsic drivers of succession for dipteran communities that occupy ephemeral pools, such as those in artificial containers were investigated. By initiating communities at different times in the season and following them over time, the relative importance of intrinsic (i.e. habitat age) versus extrinsic (i.e. seasonal phenology) drivers of succession were compared. 3. Water‐filled artificial containers were placed in a deciduous forest with 20 containers initiated in each of 3 months. Containers were sampled weekly to assess community composition. Repeated‐measures mixed‐effects analysis of community correspondence analysis (CA) scores enabled us to partition intrinsic and extrinsic effects on succession. Covariates of temperature and precipitation were also tested. 4. Community trajectories (as defined by CA) differed significantly with habitat age and season, indicating that both intrinsic and extrinsic effects influence succession patterns. Comparisons of Akaike Information Criteria corrected for sample sizes (AICcs) showed that habitat age was more important than season for species composition. Temperature and precipitation did not explain composition changes beyond those explained by habitat age and season. 5. Quantification of relative strengths of intrinsic and extrinsic effects on succession in dipteran and other ephemeral communities enables us to disentangle processes that must be understood for predicting changes in community composition.     

Airway exposure levels of lipopolysaccharide determine type 1 versus type 2 experimental asthma

Allergic asthma is characterized by airway inflammation initiated by adaptive immune responses to aeroallergens. Recent data suggest that severe asthma may be a different form of asthma rather than an increase in asthma symptoms and that innate immune responses to LPS can modulate adaptive immune responses to allergens. In this study, we evaluated the hypothesis that airway exposure to different doses of LPS induces different form of asthma. Our study showed that neutrophilic inflammation and IFN-gamma expression were higher in induced sputum from severe asthma patients than from mild to moderate asthmatics. Animal experiments indicated that allergen sensitization with low-dose LPS (0.1 microg) induced type 2 asthma phenotypes, i.e., airway hyperresponsiveness, eosinophilic inflammation, and allergen-specific IgE up-regulation. In contrast, allergen sensitization with high-dose LPS (10 microg) induced asthma phenotypes, i.e., airway hyperresponsiveness and noneosinophilic inflammation that were not developed in IFN-gamma-deficient mice, but unaffected in the absence of IL-4. During the allergen sensitization period, TNF-alpha expression was found to be enhanced by both low- and high-dose LPS, whereas IL-12 expression was only enhanced by high-dose LPS. Interestingly, the asthma phenotypes induced by low-dose LPS, but not by high-dose LPS, were completely inhibited in TNF-alpha receptor-deficient mice, whereas the asthma phenotypes induced by high-dose LPS were abolished in the homozygous null mutation of the STAT4 gene. These findings suggest that airway exposure levels of LPS induces different forms of asthma that are type 1 and type 2 asthma phenotypes by high and low LPS levels, respectively.     

Comparison of allergic lung disease in three mouse strains after systemic or mucosal sensitization with ovalbumin antigen

Murine models of allergic lung disease have many similar traits to asthma in humans and can be used to investigate mechanisms of allergic sensitization and susceptibility factors associated with disease severity. The purpose of this study was to determine strain differences in allergic airway inflammation, immunoglobulin production, and changes in respiratory responses between systemic and mucosal sensitization routes in BALB/cJ, FVB/NJ, and C57BL/6J, and to provide correlations between immune and pathophysiological endpoints. After a single intranasal ovalbumin (OVA) challenge, all three strains of mice systemically sensitized with OVA and adjuvant exhibited higher airflow limitation than non-sensitized mice. No changes were seen in mice that were pre-sensitized via the nose with OVA. Systemic sensitization resulted in an elevated response to methacholine (MCH) in BALB/cJ and FVB/NJ mice and elevated total and OVA-specific IgE levels and pulmonary eosinophils in all three strains. The mucosal sensitization and challenge produced weaker responses in the same general pattern with the C57BL/6J strain producing less serum IgE, IL5, IL13, and eosinophils in lung fluid than the other two strains. The converse was found for IL6 where the C57BL/6J mice had more than twice the amount of this cytokine. The results show that the FVB/NJ and BALB/cJ mice are higher Th2-responders than the C57BL/6J mice and that the levels of pulmonary eosinophilia and cytokines did not fully track with MCH responsiveness. These differences illustrate the need to assess multiple endpoints to provide clearer associations between immune responses and type and severity of allergic lung disease.     

Capturing escape in infectious disease dynamics

Identifying the causes of interannual variability in disease dynamics is important for understanding and managing epidemics. Traditionally, these causes have been classified as intrinsic (e.g. immunity fluctuations) or extrinsic (e.g. climate forcing); ecologists determine the relative contributions of these factors by applying statistical models to time series of cases. Here we address the problem of isolating the drivers of pathogen dynamics that are influenced by antigenic evolution. Recent findings indicate that many pathogens escape immunity in a punctuated manner; for them, we argue that time series of cases alone will be insufficient to isolate causal drivers. We detail observations that can reveal the presence of punctuated immune escape, and which can be used in new statistical approaches to identify extrinsic and intrinsic regulators of disease.     

Disentangling extrinsic from intrinsic factors in disease dynamics: a nonlinear time series approach with an application to cholera

Alternative explanations for disease and other population cycles typically include extrinsic environmental drivers, such as climate variability, and intrinsic nonlinear dynamics resulting from feedbacks within the system, such as species interactions and density dependence. Because these different factors can interact in nonlinear systems and can give rise to oscillations whose frequencies differ from those of extrinsic drivers, it is difficult to identify their respective contributions from temporal population patterns. In the case of disease, immunity is an important intrinsic factor. However, for many diseases, such as cholera, for which immunity is temporary, the duration and decay pattern of immunity is not well known. We present a nonlinear time series model with two related objectives: the reconstruction of immunity patterns from data on cases and population sizes and the identification of the respective roles of extrinsic and intrinsic factors in the dynamics. Extrinsic factors here include both seasonality and long-term changes or interannual variability in forcing. Results with simulated data show that this semiparametric method successfully recovers the decay of immunity and identifies the origin of interannual variability. An application to historical cholera data indicates that temporary immunity can be long-lasting and decays in approximately 9 yr. Extrinsic forcing of transmissibility is identified to have a strong seasonal component along with a long-term decrease. Furthermore, noise appears to sustain the multiple frequencies in the long-term dynamics. Similar semiparametric models should apply to population data other than for disease.     

Differing responses of the two forms of photosystem II carbonic anhydrase to chloride, cations, and pH

The effects of Cl(-), Mn(2+), Ca(2+), and pH on extrinsic and intrinsic photosystem II carbonic anhydrase activity were compared. Under the conditions of our in vitro experiments, extrinsic CA activity, located on the OEC33 protein, was optimum at about 30 mM Cl(-), and strongly inhibited above this concentration. This enzyme is activated by Mn(2+) and stimulated somewhat by Ca(2+). The OEC33 showed dehydration activity that is optimum at pH 6 or below. In contrast, intrinsic CA activity found in the PSII complex after removal of extrinsic proteins was stimulated by Cl(-) up to 0.4 M. Ca(2+) appears to be the required cofactor, which implies that the location of the intrinsic CA activity is in the immediate vicinity of the CaMn(4) complex. Up to now, intrinsic CA has shown only hydration activity that is nearly pH independent.     

Intrinsic and extrinsic contributions to the passive moment at the metacarpophalangeal joint

The purpose of this investigation was to determine whether the passive range of motion at the finger joints is restricted more by intrinsic tissues (cross a single joint) or by extrinsic tissues (cross multiple joints). The passive moment at the metacarpophalangeal (MP) joint of the index finger was modeled as the sum of intrinsic and extrinsic components. The intrinsic component was modeled only as a function of MP joint angle. The extrinsic component was modeled as a function of MP joint angle and wrist angle. With the wrist fixed in seven different positions the passive moment at the MP joint of eight subjects was recorded as the finger was rotated through its range at a constant rate. The moment-angle data were fit by the model and the extrinsic and intrinsic components were calculated for a range of MP joint angles and wrist positions. With the MP joint near its extension limit, the median percent extrinsic contribution was 94% with the wrist extended 60° and 14% with the wrist flexed 60°. These percentages were 40 and 88%, respectively, with the MP joint near its flexion limit. Our findings indicate that at most wrist angles the extrinsic tissues offer greater restraint at the limits of MP joint extension and flexion than the intrinsic tissues. The intrinsic tissues predominate when the wrist is flexed or extended enough to slacken the extrinsic tissues. Additional characteristics of intrinsic and extrinsic tissues can be deduced by examining the parameter values calculated by the model.     

Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma

Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation.     

What drives patrolling behaviour by nasute termites? A model and an empirical assessment

Animals have evolved a number of antipredator strategies, which can reflect both intrinsic and extrinsic factors related to predation risk. In many termite species, a chemically armed soldier caste known as “nasute” engages in patrols upon breaching of foraging galleries, suggesting an adaptive response to imminent risk of mortality. However, the drivers of this collective behaviour are poorly understood. Here, I describe and test a qualitative model of patrolling behaviour upon gallery breaching by the arboreal termite Nasutitermes corniger (Termitidae: Nasutitermitinae). Patrolling behaviour is postulated to change throughout colony ontogeny, thus scaling with colony size. Further, this pattern is expected to be modulated by extrinsic cues for predation risk. Accordingly, patroller number increased with tree circumference at breast height, a surrogate for colony size. However, for any tree size, more soldiers engaged in patrols after repeated breaching, suggesting sensitization to structural damage. In parallel, patrolling rate (i.e., patroller number per time unit) was higher in smaller trees due to a disproportionate increase in patrol duration with patroller number. However, this response only occurred after repeated breaching; otherwise, patrolling rate was constant across tree sizes. Overall, patrolling behaviour by N. corniger seems to reflect intrinsic risks related to colony growth, adjusted by the extrinsic risk imposed by structural damage.     

Molecular and cellular mechanisms in the viral exacerbation of asthma

The aetiology of asthma associated with viral infection is complex. The dynamics that contribute to disease pathogenesis are multifactorial and involve overlapping molecular and cellular mechanisms, particularly the immune response to respiratory virus infection or allergen sensitization. This review summarizes the evidence associated with factors that may contribute to the development or exacerbation of asthma including age, host factors, genetic polymorphisms, altered immune responses, and aspects of viral antigen expression. This review also provides an important perspective of key events linked to the development of asthmatic disease and related pulmonary inflammation from human and animal studies, and discusses their relationship as targets for disease intervention strategies.