Secular trend in body height and weight of Australian children and adolescents

Secular changes in growth and maturation have been well documented in various world populations, with secular increase especially noticeable in the developed countries. To assess the trend in both adult size and tempo of growth we compared the data on stature and body weight obtained in 1992-1993 from 1,804 Melbourne school students aged 5 to 17 with historical data collected from white Australians during the last 100 years. We illustrate the age-dependent trend in stature and body weight by means of regression surfaces. These were constructed by fitting local regression models to historical data and by simple plots showing the overall, and per decade, secular increase in both these measures at peripubertal and adult ages. Because of limited information on sample sizes and variability provided by the historical data, statistical comparisons have been performed only between the present 1992-1993 survey and two earlier independent surveys conducted in 1985 and 1970. The results have shown secular increase in adult stature over the last century, with the rate of increase varying between 0.4 and 2.1 cm/decade in males and 0.01 and 1.6 cm/decade in females. While secular increase in stature has significantly slowed down during the last two decades, the increase in body weight is still continuing at a high rate, and this increase is more pronounced in females. The period of strong secular increase, especially in the tempo of growth, coincided both with the shift toward earlier menarche and the improvement of socioeconomic conditions of the Australian population. The need for further studies to identify factors determining the continuing increase in body weight is emphasized, and caution in using the existing national growth standards for stature and weight is recommended.     

Rapid reversibility of the allergen-induced pulmonary late-phase reaction by an intravenous beta 2-agonist

This studywas performed to determine the degree to which₂-adrenergic receptor agonistscan reverse the allergen-induced late reduction in lungfunction. On two occasions, seven asthmatic subjects wereadministered terbutaline or its vehicle by intravenous infusion 7 hafter inhaled allergen, at which point the forced expiratory volume in1 s was 57% of baseline. On another occasion, terbutaline was infusedat baseline to determine maximal attainable bronchodilation. Afterallergen challenge, terbutaline rapidly improved lung function. At theend of terbutaline infusion, the forced expiratory volume in 1 sreached 100 ± 1.3% of baseline and 84.2 ± 4.3% of maximalattainable value, but the bronchodilating effect of the -agonist didnot plateau. The values for forced vital capacity were 102 ± 1.3%of baseline and 95.1 ± 3% of maximal attainablevalue. The kinetics of the terbutaline effect, when it wasinfused at baseline, were similar to those in the late phase. Becausethe late-phase reduction in lung function is rapidly reversible by₂-adrenergic agonists, weconclude that it is caused mainly by bronchial smooth muscle spasm.

     

Neuroblastoma Tyrosine Kinase Signaling Networks Involve FYN and LYN in Endosomes and Lipid Rafts

Protein phosphorylation plays a central role in creating a highly dynamic network of interacting proteins that reads and responds to signals from growth factors in the cellular microenvironment. Cells of the neural crest employ multiple signaling mechanisms to control migration and differentiation during development. It is known that defects in these mechanisms cause neuroblastoma, but how multiple signaling pathways interact to govern cell behavior is unknown. In a phosphoproteomic study of neuroblastoma cell lines and cell fractions, including endosomes and detergent-resistant membranes, 1622 phosphorylated proteins were detected, including more than half of the receptor tyrosine kinases in the human genome. Data were analyzed using a combination of graph theory and pattern recognition techniques that resolve data structure into networks that incorporate statistical relationships and protein-protein interaction data. Clusters of proteins in these networks are indicative of functional signaling pathways. The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases, especially FYN and LYN. Changes in intracellular localization of activated FYN and LYN were observed in response to stimulation of the receptor tyrosine kinases, ALK and KIT. The results suggest a mechanism to distinguish signaling responses to activation of different receptors, or combinations of receptors, that govern the behavior of the neural crest, which gives rise to neuroblastoma.     

An Allergic Lung Microenvironment Suppresses Carbon Nanotube-Induced Inflammasome Activation via STAT6-Dependent Inhibition of Caspase-1

Background

Multi-walled carbon nanotubes (MWCNTs) represent a human health risk as mice exposed by inhalation display pulmonary fibrosis. Production of IL-1β via inflammasome activation is a mechanism of MWCNT-induced acute inflammation and has been implicated in chronic fibrogenesis. Mice sensitized to allergens have elevated T-helper 2 (Th2) cytokines, IL-4 and IL-13, and are susceptible to MWCNT-induced airway fibrosis. We postulated that Th2 cytokines would modulate MWCNT-induced inflammasome activation and IL-1β release in vitro and in vivo during allergic inflammation.

Methods

THP-1 macrophages were primed with LPS, exposed to MWCNTs and/or IL-4 or IL-13 for 24 hours, and analyzed for indicators of inflammasome activation. C57BL6 mice were sensitized to house dust mite (HDM) allergen and MWCNTs were delivered to the lungs by oropharyngeal aspiration. Mice were euthanized 1 or 21 days post-MWCNT exposure and evaluated for lung inflammasome components and allergic inflammatory responses.

Results

Priming of THP-1 macrophages with LPS increased pro-IL-1β and subsequent exposure to MWCNTs induced IL-1β secretion. IL-4 or IL-13 decreased MWCNT-induced IL-1β secretion by THP-1 cells and reduced pro-caspase-1 but not pro-IL-1β. Treatment of THP-1 cells with STAT6 inhibitors, either Leflunomide or JAK I inhibitor, blocked suppression of caspase activity by IL-4 and IL-13. In vivo, MWCNTs alone caused neutrophilic infiltration into the lungs of mice 1 day post-exposure and increased IL-1β in bronchoalveolar lavage fluid (BALF) and pro-caspase-1 immuno-staining in macrophages and airway epithelium. HDM sensitization alone caused eosinophilic inflammation with increased IL-13. MWCNT exposure after HDM sensitization increased total cell numbers in BALF, but decreased numbers of neutrophils and IL-1β in BALF as well as reduced pro-caspase-1 in lung tissue. Despite reduced IL-1β mice exposed to MWCNTs after HDM developed more severe airway fibrosis by 21 days and had increased pro-fibrogenic cytokine mRNAs.

Conclusions

These data indicate that Th2 cytokines suppress MWCNT-induced inflammasome activation via STAT6-dependent down-regulation of pro-caspase-1 and suggest that suppression of inflammasome activation and IL-1β by an allergic lung microenvironment is a mechanism through which MWCNTs exacerbate allergen-induced airway fibrosis.     

Citizenship,Belonging, and Moldovan Migrants in Post-Soviet Russia

Drawing on ethnographic research among transnational Moldovan households in Moscow, this essay considers how ideals of belonging, assertions of historically inflected rights, and aspirations for mobility are all part of the everyday practice of citizenship. Mobile subjects encountering increasingly restrictive post-Soviet citizenship regimes often recall incorporation into a greater historical polity than their current passports would suggest. Three key areas are examined: the intersection of citizenship regimes and popular understandings of belonging; the sense of rights driven by cultural logics informed by previous history; and the way in which ideals and practices of citizenship are diverse among migrants from apparently homogeneous migration streams. The post-Soviet context where the Soviet promise of enfranchisement continues to inform how people on the margins view citizenship illustrates just how deeply citizenship regimes come to be incorporated into popular understandings of belonging even long after formal citizenship ceases to exist.     

(Not) Keeping the stem straight: a proteomic analysis of maritime pine seedlings undergoing phototropism and gravitropism

Background  

Plants are subjected to continuous stimuli from the environment and have evolved an ability to respond through various growth and development processes. Phototropism and gravitropism responses enable the plant to reorient with regard to light and gravity.     

Is it possible to manipulate root anchorage in young trees?

The optimal root system architecture for increased tree anchorage has not yet been determined and in particular, the role of the tap root remains elusive. In Maritime pine (Pinus pinaster Ait.), tap roots may play an important role in anchoring young trees, but in adult trees, their growth is often impeded by the presence of a hard pan layer in the soil and the tap root becomes a minor component of tree anchorage. To understand better the role of the tap root in young trees, we grew cuttings (no tap root present) and seedlings where the tap root had (?) or had not (+) been pruned, in the field for 7 years. The force (F) necessary to deflect the stem sideways was then measured and divided by stem cross-sectional area (CSA), giving a parameter analogous to stress during bending. Root systems were extracted and root architecture and wood mechanical properties (density and longitudinal modulus of elasticity, E _L ) determined. In seedlings (?) tap roots, new roots had regenerated where the tap root had been pruned, whereas in cuttings, one or two lateral roots had grown downwards and acted as tap roots. Cuttings had significantly less lateral roots than the other treatments, but those near the soil surface were 14% and 23% thicker than plants (+) and (?) tap roots, respectively. Cuttings were smaller than seedlings, but were not relatively less resistant to stem deflection, probably because the thicker lateral roots compensated for their lower number. Apart from stem volume which was greater in trees (+) tap roots, no significant differences with regard to size or any root system variable were found in plants (?) or (+) tap roots. In all treatments, lateral roots were structurally reinforced through extra growth along the direction of the prevailing wind, which also improved tap root anchorage. Predictors of log F/CSA differed depending on treatment: in trees (?) tap roots, a combination of the predictors stem taper and %volume allocated to deep roots was highly regressed with log F/CSA (R ² = 0.83), unlike plants (+) tap roots where the combined predictors of lateral root number and root depth were best regressed with log F/CSA (R ² = 0.80). In cuttings, no clear relationships between log F/CSA and any parameter could be found. Wood density and E _L did not differ between roots, but did diminish with increasing distance from the stem in lateral roots. E _L was significantly lower in lateral roots from cuttings. Results showed that nursery techniques influence plant development but that the architectural pattern of Maritime pine root systems is stable, developing a sinker root system even when grown from cuttings. Anchorage is affected but the consequences for the long-term are still not known. Numerical modelling may be the only viable method to investigate the function that each root plays in adult tree anchorage.     

Synthetic prostacyclin analogs differentially regulate macrophage function via distinct analog-receptor binding specificities

PGI(2) (prostacyclin) is a lipid mediator with vasodilatory and antithrombotic effects used in the treatment of vasoconstrictive/ischemic diseases including pulmonary artery hypertension. However, emerging research supports a role for PGs, including PGI(2), in the regulation of both innate and acquired immunity. As PGI(2) is unstable, we sought to define the effects of various PGI(2) analogs on resident alveolar macrophage (AM) and peritoneal macrophage (PM) innate immune functions. The effects of iloprost, carbaprostacyclin, and treprostinil on the regulation of phagocytosis, bacterial killing, and inflammatory mediator production were determined in both macrophage populations from rats. Iloprost failed to suppress AM functions to the same degree that it did in PMs, a characteristic shared by carbaprostacyclin. This difference reflected greater expression of the G(alphas) protein-coupled I prostanoid receptor and greater cAMP generation in PMs than AMs. Treprostinil inhibited phagocytosis, bacterial killing, and cytokine generation in AMs to a much greater degree than the other PGI(2) analogs and more closely resembled the effects of PGE(2). Studies with the E prostanoid (EP) 2 receptor antagonist AH-6809 and EP2-null macrophages indicated that this was due in part to the previously unknown ability of treprostinil to stimulate the EP2 receptor. The present investigation for the first time identifies differences in immunoregulatory properties of clinically administered PGI(2) analogs. These studies are the first to explore the capacity of PGI(2) to regulate bacterial killing and phagocytosis in macrophages, and our findings may hold important consequences regarding the risk of infection for patients receiving such agents.     

Reversal of agonist selectivity by mutations of conserved amino acids in the binding site of nicotinic acetylcholine receptors

Homomeric alpha7 and heteromeric alpha4beta2 nicotinic acetylcholine receptors (nAChR) can be distinguished by their pharmacological properties, including agonist specificity. We introduced point mutations of conserved amino acids within the C loop, a region of the receptor critical for agonist binding, and we examined the expression of the mutant receptors in Xenopus oocytes. Mutation of either a conserved C loop tyrosine (188) to phenylalanine or a nearby conserved aspartate (197) to alanine resulted in alpha7 receptors for which the alpha7-selective agonist 3-(4-hydroxy, 2-methoxybenzylidene) anabaseine (4OH-GTS-21) had roughly the same potency as for wild-type receptors, whereas the physiologic agonist acetylcholine (ACh) showed drastically reduced potency for these mutant receptors. Corresponding mutations in alpha4 receptors co-expressed with beta2 resulted in alpha4beta2 receptors for which ACh potency was relatively unchanged, although the efficacy of the alpha7-selective agonist 4OH-GTS-21 was increased greatly relative to that of ACh. We also investigated the significance of a conserved lysine (145 in alpha7), proposed to form a stable salt bridge with Asp-197 in the resting state of the receptor. Mutations of this residue in both alpha7 and alpha4 resulted in receptors that were largely unresponsive to both ACh and 4OH-GTS-21. Our results suggest that initiation of gating depends both on specific interactions between residues in the C loop domain and, depending on receptor subtype, the physiochemical properties of the agonist, so that in the altered environment of the alpha4Y190F-binding site, large hydrophobic benzylidene anabaseines may close the C loop and initiate channel gating more effectively than the polar agonist ACh.