Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry

<p>Abstract</p> <p>Background</p> <p>Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry.</p> <p>Methods</p> <p>Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15^thpercentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin^®or Prolastin^®], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.</p> <p>Results</p> <p>Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.</p> <p>Conclusions</p> <p>The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.</p> <p>Trial registration</p> <p>The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.</p

Solid Friction from stick-slip to pinning and aging

We review the present state of understanding of solid friction at low velocities and for systems with negligibly small wear effects. We first analyze in detail the behavior of friction at interfaces between wacroscopic hard rough solids, whose main dynamical features are well described by the Rice-Ruina rate and state dependent constitutive law. We show that it results from two combined effects : (i) the threshold rheology of nanometer-thick junctions jammed under confinement into a soft glassy structure (ii) geometric aging, i.e. slow growth of the real arrea of contact via asperity creep interrupted by sliding. Closer analysis leads to identifying a second aging-rejuvenation process, at work within the junctions themselves. We compare the effects of structural aging at such multicontact, very highly confined, interfaces with those met under different confinement levels, namely boundary lubricated contacts and extended adhesive interfaces involving soft materials (hydrogels, elastomers). This leads us to propose a classification of frictional junctions in terms of the relative importance of jamming and adsoprtion-induced metastability.Comment: 28 page

Cross-Cultural Validation of the Inventory of School Motivation (ISM) in the Asian Setting: Hong Kong and the Philippines

Students’ achievement goals in school have received increasing research attention because they have been shown to be important in predicting important outcomes. As such, there has been a growing interest in measuring and comparing them across different cultural groups. However, these comparisons cannot be made until validity evidence has been attained to support the use of an instrument in the new cultural setting. In this study, we investigated the cross-cultural applicability of the Inventory of School Motivation (ISM, McInerney et al. American Educational Research Journal 34:207-236, 1997) in the Hong Kong Chinese and Philippine contexts using both within-network and between-network approaches to construct validation. The ISM measures four types of achievement goals: mastery, performance, social, and extrinsic goals. 1,406 high school students from Hong Kong (n = 697) and the Philippines (n = 709) participated. Results of the within-network test showed that the ISM had good internal consistency reliability and the confirmatory factor analysis provided support for the hypothesized four-factor model. Multigroup confirmatory factor analyses supported invariance of factor loadings across the two samples. The between-network test also indicated that these achievement goals correlated systematically with different aspects of students’ self-concepts. These findings support the applicability of the ISM among Hong Kong Chinese and Filipino students

Management of primary chronic headache in the general population: the Akershus study of chronic headache

Primary chronic headaches cause more disability and necessitate high utilisation of health care. Our knowledge is based on selected populations, while information from the general population is largely lacking. An age and gender-stratified cross-sectional epidemiological survey included 30,000 persons aged 30–44 years. Respondents with self-reported chronic headache were interviewed by physicians. The International Classification of Headache Disorders was used. Of all primary chronic headache sufferers, 80% had consulted their general practitioner (GP), of these 19% had also consulted a neurologist and 4% had been hospitalised. Co-occurrence of migraine increased the probability of contact with a physician. A high Severity of Dependence Scale score increased the probability for contact with a physician. Complementary and alternative medicine (CAM) was used by 62%, most often physiotherapy, acupuncture and chiropractic. Contact with a physician increased the probability of use of CAM. Acute headache medications were taken by 87%, while only 3% used prophylactic medication. GPs manage the majority of those with primary chronic headache, 1/5 never consults a physician for their headache, while approximately 1/5 is referred to a neurologist or hospitalised. Acute headache medication was frequently overused, while prophylactic medication was rarely used. Thus, avoidance of acute headache medication overuse and increased use of prophylactic medication may improve the management of primary chronic headaches in the future

Boundary Conditions for Elastohydrodynamics of Circular Point Contacts

The paper presents the solution of an elastohydrodynamic point contact condition using inlet and outlet lubricant entrainment with partial counter-flow. The inlet and outlet boundaries are determined using potential flow analysis for the pure rolling of contiguous surfaces. This shows that Swift–Stieber boundary conditions best conform to the observed partial counter-flow at the inlet conjunction, satisfying the compatibility condition. For the outlet region, the same is true when Prandtl–Hopkins boundary conditions are employed. Using these boundary conditions, the predictions conform closely to the measured pressure distribution using a deposited pressure-sensitive micro-transducer in a ball-to-flat race contact. Furthermore, the predicted conjunctional shape closely conforms to the often observed characteristic keyhole conjunction through optical interferometry. The combined numerical–experimental analysis with realistic boundary conditions described here has not hitherto been reported in the literature

Inhibition of Competence Development, Horizontal Gene Transfer and Virulence in Streptococcus pneumoniae by a Modified Competence Stimulating Peptide

Competence stimulating peptide (CSP) is a 17-amino acid peptide pheromone secreted by Streptococcus pneumoniae. Upon binding of CSP to its membrane-associated receptor kinase ComD, a cascade of signaling events is initiated, leading to activation of the competence regulon by the response regulator ComE. Genes encoding proteins that are involved in DNA uptake and transformation, as well as virulence, are upregulated. Previous studies have shown that disruption of key components in the competence regulon inhibits DNA transformation and attenuates virulence. Thus, synthetic analogues that competitively inhibit CSPs may serve as attractive drugs to control pneumococcal infection and to reduce horizontal gene transfer during infection. We performed amino acid substitutions on conserved amino acid residues of CSP1 in an effort to disable DNA transformation and to attenuate the virulence of S. pneumoniae. One of the mutated peptides, CSP1-E1A, inhibited development of competence in DNA transformation by outcompeting CSP1 in time and concentration-dependent manners. CSP1-E1A reduced the expression of pneumococcal virulence factors choline binding protein D (CbpD) and autolysin A (LytA) in vitro, and significantly reduced mouse mortality after lung infection. Furthermore, CSP1-E1A attenuated the acquisition of an antibiotic resistance gene and a capsule gene in vivo. Finally, we demonstrated that the strategy of using a peptide inhibitor is applicable to other CSP subtype, including CSP2. CSP1-E1A and CSP2-E1A were able to cross inhibit the induction of competence and DNA transformation in pneumococcal strains with incompatible ComD subtypes. These results demonstrate the applicability of generating competitive analogues of CSPs as drugs to control horizontal transfer of antibiotic resistance and virulence genes, and to attenuate virulence during infection by S. pneumoniae

The Functional Interplay between Protein Kinase CK2 and CCA1 Transcriptional Activity Is Essential for Clock Temperature Compensation in Arabidopsis

Circadian rhythms are daily biological oscillations driven by an endogenous mechanism known as circadian clock. The protein kinase CK2 is one of the few clock components that is evolutionary conserved among different taxonomic groups. CK2 regulates the stability and nuclear localization of essential clock proteins in mammals, fungi, and insects. Two CK2 regulatory subunits, CKB3 and CKB4, have been also linked with the Arabidopsis thaliana circadian system. However, the biological relevance and the precise mechanisms of CK2 function within the plant clockwork are not known. By using ChIP and Double–ChIP experiments together with in vivo luminescence assays at different temperatures, we were able to identify a temperature-dependent function for CK2 modulating circadian period length. Our study uncovers a previously unpredicted mechanism for CK2 antagonizing the key clock regulator CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1). CK2 activity does not alter protein accumulation or subcellular localization but interferes with CCA1 binding affinity to the promoters of the oscillator genes. High temperatures enhance the CCA1 binding activity, which is precisely counterbalanced by the CK2 opposing function. Altering this balance by over-expression, mutation, or pharmacological inhibition affects the temperature compensation profile, providing a mechanism by which plants regulate circadian period at changing temperatures. Therefore, our study establishes a new model demonstrating that two opposing and temperature-dependent activities (CCA1-CK2) are essential for clock temperature compensation in Arabidopsis