Glucocorticoid receptor gene polymorphisms associated with progression of lung disease in young patients with cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>The variability in the inflammatory burden of the lung in cystic fibrosis (CF) patients together with the variable effect of glucocorticoid treatment led us to hypothesize that <it>glucocorticoid receptor </it>(<it>GR</it>) gene polymorphisms may affect glucocorticoid sensitivity in CF and, consequently, may contribute to variations in the inflammatory response.</p> <p>Methods</p> <p>We evaluated the association between four <it>GR </it>gene polymorphisms, <it>TthIII</it>, <it>ER22/23EK</it>, <it>N363S </it>and <it>BclI</it>, and disease progression in a cohort of 255 young patients with CF. Genotypes were tested for association with changes in lung function tests, infection with <it>Pseudomonas aeruginosa </it>and nutritional status by multivariable analysis.</p> <p>Results</p> <p>A significant non-corrected for multiple tests association was found between <it>BclI </it>genotypes and decline in lung function measured as the forced expiratory volume in one second (FEV₁) and the forced vital capacity (FVC). Deterioration in FEV₁and FVC was more pronounced in patients with the <it>BclI </it>GG genotype compared to the group of patients with <it>BclI </it>CG and CC genotypes (p = 0.02 and p = 0.04 respectively for the entire cohort and p = 0.01 and p = 0.02 respectively for F508del homozygous patients).</p> <p>Conclusion</p> <p>The <it>BclI </it>polymorphism may modulate the inflammatory burden in the CF lung and in this way influence progression of lung function.</p

Clinical presentation and outcome of Tuberculosis in Human Immunodeficiency Virus infected children on anti-retroviral therapy

<p>Abstract</p> <p>Background</p> <p>The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART.</p> <p>Methods</p> <p>We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005.</p> <p>Results</p> <p>Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%).</p> <p>Conclusion</p> <p>We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.</p

STDP Allows Fast Rate-Modulated Coding with Poisson-Like Spike Trains

Spike timing-dependent plasticity (STDP) has been shown to enable single neurons to detect repeatedly presented spatiotemporal spike patterns. This holds even when such patterns are embedded in equally dense random spiking activity, that is, in the absence of external reference times such as a stimulus onset. Here we demonstrate, both analytically and numerically, that STDP can also learn repeating rate-modulated patterns, which have received more experimental evidence, for example, through post-stimulus time histograms (PSTHs). Each input spike train is generated from a rate function using a stochastic sampling mechanism, chosen to be an inhomogeneous Poisson process here. Learning is feasible provided significant covarying rate modulations occur within the typical timescale of STDP (∼10–20 ms) for sufficiently many inputs (∼100 among 1000 in our simulations), a condition that is met by many experimental PSTHs. Repeated pattern presentations induce spike-time correlations that are captured by STDP. Despite imprecise input spike times and even variable spike counts, a single trained neuron robustly detects the pattern just a few milliseconds after its presentation. Therefore, temporal imprecision and Poisson-like firing variability are not an obstacle to fast temporal coding. STDP provides an appealing mechanism to learn such rate patterns, which, beyond sensory processing, may also be involved in many cognitive tasks

Exploring Chromophore-Binding Pocket: High-Resolution Solid-State 1H–13C Interfacial Correlation NMR Spectra with Windowed PMLG Scheme

High-resolution two-dimensional (2D) 1H–13C heteronuclear correlation spectra are recorded for selective observation of interfacial 3–5.5 Å contacts of the uniformly 13C-labeled phycocyanobilin (PCB) chromophore with its unlabeled binding pocket. The experiment is based on a medium- and long-distance heteronuclear correlation (MELODI–HETCOR) method. For improving 1H spectral resolution, a windowed phase-modulated Lee–Goldburg (wPMLG) decoupling scheme is applied during the t1 evolution period. Our approach allows for identification of chromophore–protein interactions, in particular for elucidation of the hydrogen-bonding networks and charge distributions within the chromophore-binding pocket. The resulting pulse sequence is tested on the cyanobacterial (Cph1) phytochrome sensory module (residues 1–514, Cph1Δ2) containing uniformly 13C- and 15N-labeled PCB chromophore (u-[13C,15N]-PCB-Cph1Δ2) at 17.6 T

Solid-state NMR applied to photosynthetic light-harvesting complexes

This short review describes how solid-state NMR has provided a mechanistic and electronic picture of pigment–protein and pigment–pigment interactions in photosynthetic antenna complexes. NMR results on purple bacterial antenna complexes show how the packing of the protein and the pigments inside the light-harvesting oligomers induces mutual conformational stress. The protein scaffold produces deformation and electrostatic polarization of the BChl macrocycles and leads to a partial electronic charge transfer between the BChls and their coordinating histidines, which can tune the light-harvesting function. In chlorosome antennae assemblies, the NMR template structure reveals how the chromophores can direct their self-assembly into higher macrostructures which, in turn, tune the light-harvesting properties of the individual molecules by controlling their disorder, structural deformation, and electronic polarization without the need for a protein scaffold. These results pave the way for addressing the next challenge, which is to resolve the functional conformational dynamics of the lhc antennae of oxygenic species that allows them to switch between light-emitting and light-energy dissipating states

Genetically Programmed Differences in Epidermal Host Defense between Psoriasis and Atopic Dermatitis Patients

In the past decades, chronic inflammatory diseases such as psoriasis, atopic dermatitis, asthma, Crohn’s disease and celiac disease were generally regarded as immune-mediated conditions involving activated T-cells and proinflammatory cytokines produced by these cells. This paradigm has recently been challenged by the finding that mutations and polymorphisms in epithelium-expressed genes involved in physical barrier function or innate immunity, are risk factors of these conditions. We used a functional genomics approach to analyze cultured keratinocytes from patients with psoriasis or atopic dermatitis and healthy controls. First passage primary cells derived from non-lesional skin were stimulated with pro-inflammatory cytokines, and expression of a panel of 55 genes associated with epidermal differentiation and cutaneous inflammation was measured by quantitative PCR. A subset of these genes was analyzed at the protein level. Using cluster analysis and multivariate analysis of variance we identified groups of genes that were differentially expressed, and could, depending on the stimulus, provide a disease-specific gene expression signature. We found particularly large differences in expression levels of innate immunity genes between keratinocytes from psoriasis patients and atopic dermatitis patients. Our findings indicate that cell-autonomous differences exist between cultured keratinocytes of psoriasis and atopic dermatitis patients, which we interpret to be genetically determined. We hypothesize that polymorphisms of innate immunity genes both with signaling and effector functions are coadapted, each with balancing advantages and disadvantages. In the case of psoriasis, high expression levels of antimicrobial proteins genes putatively confer increased protection against microbial infection, but the biological cost could be a beneficial system gone awry, leading to overt inflammatory disease

Process factors explaining the ineffectiveness of a multidisciplinary fall prevention programme: A process evaluation

<p>Abstract</p> <p>Background</p> <p>Falls are a major health threat to older community-living people, and initiatives to prevent falls should be a public health priority. We evaluated a Dutch version of a successful British fall prevention programme. Results of this Dutch study showed no effects on falls or daily functioning. In parallel to the effect evaluation, we carried out a detailed process evaluation to assess the feasibility of our multidisciplinary fall prevention programme. The present study reports on the results of this process evaluation.</p> <p>Methods</p> <p>Our fall prevention programme comprised a medical and occupational-therapy assessment, resulting in recommendations and/or referrals to other services if indicated. We used self-administered questionnaires, structured telephone interviews, structured recording forms, structured face-to-face interviews and a plenary group discussion to collect data from participants allocated to the intervention group (n = 166) and from all practitioners who performed the assessments (n = 8). The following outcomes were assessed: the extent to which the multidisciplinary fall prevention programme was performed according to protocol, the nature of the recommendations and referrals provided to the participants, participants' self-reported compliance and participants' and practitioners' opinions about the programme.</p> <p>Results</p> <p>Both participants and practitioners judged the programme to be feasible. The programme was largely performed according to protocol. The number of referrals and recommendations ensuing from the medical assessment was relatively small. Participants' self-reported compliance as regards contacting their GP to be informed of the recommendations and/or referrals was low to moderate. However, self-reported compliance with such referrals and recommendations was reasonable to good. A large majority of participants reported they had benefited from the programme.</p> <p>Conclusion</p> <p>The results of the present study show that the programme was feasible for both practitioners and participants. Main factors that seem to be responsible for the lack of effectiveness are the relatively low number of referrals and recommendations ensuing from the medical assessments and participants' low compliance as regards contacting their GP about the results of the medical assessment. We do not recommend implementing the programme in its present form in regular care.</p> <p>Trial registration</p> <p>ISRCTN64716113</p