The main rhinovirus respiratory tract adhesion site (ICAM-1) is upregulated in smokers and patients with chronic airflow limitation (CAL).

BACKGROUND: ICAM-1 is a major receptor for ~60% of human rhinoviruses, and non-typeable Haemophilus influenzae, two major pathogens in COPD. Increased cell-surface expression of ICAM-1 in response to tobacco smoke exposure has been suggested. We have investigated epithelial ICAM-1 expression in both the large and small airways, and lung parenchyma in smoking-related chronic airflow limitation (CAL) patients. METHODS: We evaluated epithelial ICAM-1 expression in resected lung tissue: 8 smokers with normal spirometry (NLFS); 29 CAL patients (10 small-airway disease; 9 COPD-smokers; 10 COPD ex-smokers); Controls (NC): 15 normal airway/lung tissues. Immunostaining with anti-ICAM-1 monoclonal antibody was quantified with computerized image analysis. The percent and type of cells expressing ICAM-1 in large and small airway epithelium and parenchyma were enumerated, plus percentage of epithelial goblet and submucosal glands positive for ICAM- 1. RESULTS: A major increase in ICAM-1 expression in epithelial cells was found in both large (p < 0.006) and small airways (p < 0.004) of CAL subjects compared to NC, with NLFS being intermediate. In the CAL group, both basal and luminal areas stained heavily for ICAM-1, so did goblet cells and sub-mucosal glands, however in either NC or NLFS subjects, only epithelial cell luminal surfaces stained. ICAM-1 expression on alveolar pneumocytes (mainly type II) was slightly increased in CAL and NLFS (p < 0.01). Pack-years of smoking correlated with ICAM-1 expression (r = 0.49; p < 0.03). CONCLUSION: Airway ICAM-1 expression is markedly upregulated in CAL group, which could be crucial in rhinoviral and NTHi infections. The parenchymal ICAM-1 is affected by smoking, with no further enhancement in CAL subjects

β-catenin, Twist and Snail: Transcriptional regulation of EMT in smokers and COPD, and relation to airflow obstruction.

COPD is characterised by poorly reversible airflow obstruction usually due to cigarette smoking. The transcription factor clusters of β-catenin/Snail1/Twist has been implicated in the process of epithelial mesenchymal transition (EMT), an intermediate between smoking and airway fibrosis, and indeed lung cancer. We have investigated expression of these transcription factors and their "cellular localization" in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls. An immune-histochemical study compared cellular protein expression of β-catenin, Snail1 and Twist, in these subject groups in 3 large airways compartment: epithelium (basal region), reticular basement membrane (Rbm) and underlying lamina propria (LP). β-catenin and Snail1 expression was generally high in all subjects throughout the airway wall with marked cytoplasmic to nuclear shift in COPD (P < 0.01). Twist expression was generalised in the epithelium in normal but become more basal and nuclear with smoking (P < 0.05). In addition, β-catenin and Snail1 expression, and to lesser extent of Twist, was related to airflow obstruction and to expression of a canonical EMT biomarker (S100A4). The β-catenin-Snail1-Twist transcription factor cluster is up-regulated and nuclear translocated in smokers and COPD, and their expression is closely related to both EMT activity and airway obstruction

Attenuation of leukocyte sequestration by selective blockade of PECAM-1 or VCAM-1 in murine endotoxemia

Background: Molecular mechanisms regulating leukocyte sequestration into the tissue during endotoxemia and/or sepsis are still poorly understood. This in vivo study investigates the biological role of murine PECAM-1 and VCAM-1 for leukocyte sequestration into the lung, liver and striated skin muscle. Methods: Male BALB/c mice were injected intravenously with murine PECAM-1 IgG chimera or monoclonal antibody (mAb) to VCAM-1 ( 3 mg/kg body weight); controls received equivalent doses of IgG2a ( n = 6 per group). Fifteen minutes thereafter, 2 mg/kg body weight of Salmonella abortus equi endotoxin was injected intravenously. At 24 h after the endotoxin challenge, lungs, livers and striated muscle of skin were analyzed for their myeloperoxidase activity. To monitor intravital leukocyte-endothelial cell interactions, fluorescence videomicroscopy was performed in the skin fold chamber model of the BALB/c mouse at 3, 8 and 24 h after injection of endotoxin. Results: Myeloperoxidase activity at 24 h after the endotoxin challenge in lungs (12,171 +/- 2,357 mU/g tissue), livers ( 2,204 +/- 238 mU/g) and striated muscle of the skin ( 1,161 +/- 110 mU/g) was significantly reduced in both treatment groups as compared to controls, with strongest attenuation in the PECAM-1 IgG treatment group. Arteriolar leukocyte sticking at 3 h after endotoxin (230 +/- 46 cells x mm(-2)) was significantly reduced in both treatment groups. Leukocyte sticking in postcapillary venules at 8 h after endotoxin ( 343 +/- 69 cells/mm(2)) was found reduced only in the VCAM-1-mAb-treated animals ( 215 +/- 53 cells/mm(2)), while it was enhanced in animals treated with PECAM-1 IgG ( 572 +/- 126 cells/mm(2)). Conclusion: These data show that both PECAM-1 and VCAM-1 are involved in endotoxin-induced leukocyte sequestration in the lung, liver and muscle, presumably through interference with arteriolar and/or venular leukocyte sticking. Copyright (C) 2004 S. Karger AG, Basel

Light neutralino dark matter in the MSSM and its implication for LHC searches for staus

It was shown in a previous study that a lightest neutralino with mass below 30 GeV was severely constrained in the minimal supersymmetric standard model (MSSM), unless it annihilates via a light stau and thus yields the observed dark matter abundance. In such a scenario, while the stau is the next-to-lightest supersymmetric particle (NLSP), the charginos and the other neutralinos as well as sleptons of the first two families are also likely to be not too far above the mass bounds laid down by the Large Electron Positron (LEP) collider. As the branching ratios of decays of the charginos and the next-to-lightest neutralino into staus are rather large, one expects significant rates of tau-rich final states in such a case. With this in view, we investigate the same-sign ditau and tri-tau signals of this scenario at the Large Hadron Collider (LHC) for two MSSM benchmark points corresponding to light neutralino dark matter. The associated signal rates for these channels are computed, for the centre-of-mass energy of 14 TeV. We find that both channels lead to appreciable rates if the squarks and the gluino are not too far above a TeV, thus allowing to probe scenarios with light neutralinos in the 14 TeV LHC run with 10-100 fb^{-1}.Comment: 19p, 4 Fig

Sex differences in the immune system become evident in the perinatal period in the four core genotypes mouse

We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells

Dimeric SecA Couples the Preprotein Translocation in an Asymmetric Manner

The Sec translocase mediates the post-translational translocation of a number of preproteins through the inner membrane in bacteria. In the initiatory translocation step, SecB targets the preprotein to the translocase by specific interaction with its receptor SecA. The latter is the ATPase of Sec translocase which mediates the post-translational translocation of preprotein through the protein-conducting channel SecYEG in the bacterial inner membrane. We examined the structures of Escherichia coli Sec intermediates in solution as visualized by negatively stained electron microscopy in order to probe the oligomeric states of SecA during this process. The symmetric interaction pattern between the SecA dimer and SecB becomes asymmetric in the presence of proOmpA, and one of the SecA protomers predominantly binds to SecB/proOmpA. Our results suggest that during preprotein translocation, the two SecA protomers are different in structure and may play different roles

E-health: Determinants, opportunities, challenges and the way forward for countries in the WHO African Region

BACKGROUND: The implementation of the 58(th )World Health Assembly resolution on e-health will pose a major challenge for the Member States of the World Health Organization (WHO) African Region due to lack of information and communications technology (ICT) and mass Internet connectivity, compounded by a paucity of ICT-related knowledge and skills. The key objectives of this article are to: (i) explore the key determinants of personal computers (PCs), telephone mainline and cellular and Internet penetration/connectivity in the African Region; and (ii) to propose actions needed to create an enabling environment for e-health services growth and utilization in the Region. METHODS: The effects of school enrolment, per capita income and governance variables on the number of PCs, telephone mainlines, cellular phone subscribers and Internet users were estimated using a double-log regression model and cross-sectional data on various Member States in the African Region. The analysis was based on 45 of the 46 countries that comprise the Region. The data were obtained from the United Nations Development Programme (UNDP), the World Bank and the International Telecommunications Union (ITU) sources. RESULTS: There were a number of main findings: (i) the adult literacy and total number of Internet users had a statistically significant (at 5% level in a t-distribution test) positive effect on the number of PCs in a country; (ii) the combined school enrolment rate and per capita income had a statistically significant direct effect on the number of telephone mainlines and cellular telephone subscribers; (iii) the regulatory quality had statistically significant negative effect on the number of telephone mainlines; (iv) similarly, the combined school enrolment ratio and the number of telephone mainlines had a statistically significant positive relationship with Internet usage; and (v) there were major inequalities in ICT connectivity between upper-middle, lower-middle and low income countries in the Region. By focusing on the adoption of specific technologies we attempted to interpret correlates in terms of relationships instead of absolute "causals". CONCLUSION: In order to improve access to health care, especially for the majority of Africans living in remote rural areas, there is need to boost the availability and utilization of e-health services. Thus, universal access to e-health ought to be a vision for all countries in the African Region. Each country ought to develop a road map in a strategic e-health plan that will, over time, enable its citizens to realize that vision

Murine hematopoietic stem cell activity is derived from pre-circulation embryos but not yolk sacs.

The embryonic site of definitive hematopoietic stem cell (dHSC) origination has been debated for decades. Although an intra-embryonic origin is well supported, the yolk sac (YS) contribution to adult hematopoiesis remains controversial. The same developmental origin makes it difficult to identify specific markers that discern between an intraembryonic versus YS-origin using a lineage trace approach. Additionally, the highly migratory nature of blood cells and the inability of pre-circulatory embryonic cells (i.e., 5-7 somite pairs (sp)) to robustly engraft in transplantation, even after culture, has precluded scientists from properly answering these questions. Here we report robust, multi-lineage and serially transplantable dHSC activity from cultured 2-7sp murine embryonic explants (Em-Ex). dHSC are undetectable in 2-7sp YS explants. Additionally, the engraftment from Em-Ex is confined to an emerging CD31+CD45+c-Kit+CD41- population. In sum, our work supports a model in which the embryo, not the YS, is the major source of lifelong definitive hematopoiesis

Deep-Inelastic Inclusive ep Scattering at Low x and a Determination of alpha_s

A precise measurement of the inclusive deep-inelastic e^+p scattering cross section is reported in the kinematic range 1.5<= Q^2 <=150 GeV^2 and 3*10^(-5)<= x <=0.2. The data were recorded with the H1 detector at HERA in 1996 and 1997, and correspond to an integrated luminosity of 20 pb^(-1). The double differential cross section, from which the proton structure function F_2(x,Q^2) and the longitudinal structure function F_L(x,Q^2) are extracted, is measured with typically 1% statistical and 3% systematic uncertainties. The measured partial derivative (dF_2(x,Q^2)/dln Q^2)_x is observed to rise continuously towards small x for fixed Q^2. The cross section data are combined with published H1 measurements at high Q^2 for a next-to-leading order DGLAP QCD analysis.The H1 data determine the gluon momentum distribution in the range 3*10^(-4)<= x <=0.1 to within an experimental accuracy of about 3% for Q^2 =20 GeV^2. A fit of the H1 measurements and the mu p data of the BCDMS collaboration allows the strong coupling constant alpha_s and the gluon distribution to be simultaneously determined. A value of alpha _s(M_Z^2)=0.1150+-0.0017 (exp) +0.0009-0.0005 (model) is obtained in NLO, with an additional theoretical uncertainty of about +-0.005, mainly due to the uncertainty of the renormalisation scale.Comment: 68 pages, 24 figures and 18 table