The effect of three years of TNF alpha blocking therapy on markers of bone turnover and their predictive value for treatment discontinuation in patients with ankylosing spondylitis: a prospective longitudinal observational cohort study

INTRODUCTION: The aim of this study was to investigate the effect of three years of tumor necrosis factor-alpha (TNF-alpha) blocking therapy on bone turnover as well as to analyze the predictive value of early changes in bone turnover markers (BTM) for treatment discontinuation in patients with ankylosing spondylitis (AS). METHODS: This is a prospective cohort study of 111 consecutive AS outpatients who started TNF-alpha blocking therapy. Clinical assessments and BTM were assessed at baseline, three and six months, as well as at one, two, and three years. Z-scores of BTM were calculated to correct for age and gender. Bone mineral density (BMD) was assessed yearly. RESULTS: After three years, 72 patients (65%) were still using their first TNF-alpha blocking agent. In these patients, TNF-alpha blocking therapy resulted in significantly increased bone-specific alkaline phosphatase, a marker of bone formation; decreased serum collagen-telopeptide (sCTX), a marker of bone resorption; and increased lumbar spine and hip BMD compared to baseline. Baseline to three months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263 to 0.591), AS disease activity score (ASDAS; HR: 0.488, 95% CI: 0.317 to 0.752), and physician's global disease activity (HR: 0.739, 95% CI: 0.600 to 0.909) were independent inversely related predictors of time to treatment discontinuation because of inefficacy or intolerance. Early decrease in sCTX Z-score correlated significantly with good long-term response regarding disease activity, physical function and quality of life. CONCLUSIONS: Three years of TNF-alpha blocking therapy results in a bone turnover balance that favors bone formation, especially mineralization, in combination with continuous improvement of lumbar spine BMD. Early change in sCTX can serve as an objective measure in the evaluation of TNF-alpha blocking therapy in AS, in addition to the currently used more subjective measures

Obstructive sleep apnea in combat-related posttraumatic stress disorder:a controlled polysomnography study

Background: Obstructive sleep apnea (OSA) may be highly prevalent in posttraumatic stress disorder (PTSD) and may exacerbate PTSD complaints. Objective: Our objective was to determine whether the prevalence of OSA was high in a sample of Dutch veterans with PTSD as compared to age- and trauma-matched controls, and whether OSA was associated with more severe PTSD complaints. Methods: We determined the apnea hypopnea indices (AHI) with polysomnographic registrations in 20 veterans with PTSD, 24 veterans without PTSD, and 17 healthy controls. PTSD severity and nightmare complaints were assessed with the Clinician-Administered PTSD Scale (CAPS). Results: The prevalence of an AHI>10 was 29% in PTSD, 21% in trauma controls, and 29% in healthy controls (x2= 0.60, df=2, p=n.s.). The mean CAPS score in patients with OSA (n=6) was significantly higher than in patients without OSA (pB0.05), while nightmare severity was similar in PTSD patients with OSA as compared to PTSD patients without OSA (p=n.s.). Furthermore, there was a significant correlation between AHI and CAPS score in PTSD patients (r=0.46,

Human papillomavirus type 18 is associated with less apoptosis in fibroblast tumours than human papillomavirus type 16.

In human cervical neoplasia human papillomavirus (HPV) type 18 has a higher cancer/cervical intraepithelial neoplasia (CIN) prevalence ratio than HPV 16. Fibrosarcomas derived from rat fibroblasts transfected with HPV 16 or 18 genomes showed increased apoptosis compared with controls. However, HPV 18 was associated with significantly less apoptosis than HPV 16, affording one possible explanation for the more rapidly progressive cervical neoplasia associated with HPV 18

A Micro-Raman Spectroscopic Study of Hydrazine-Treated Human Dental Calculus

Hydrazine has been used to remove organic components and to isolate the mineral(s) from human calculus. Micro-Raman measurements were performed on the mineral phase. After the hydrazine-treatment, not only a large reduction in fluorescence but also an increase in Raman signal was observed. The treatment was essential in minimizing thermally-induced chemical changes which could otherwise occur to the original calculus mineral due to the intense laser light. The Raman spectral features of the mineral were nearly all identical among the Raman spectra obtained at many randomly-selected sites by the micro-Raman microbe with a lateral resolution of approximately 1 μm, and were consistent with those of impure hydroxyapatite containing CO32- and HPO42-. The spectra contained typical hydroxyapatite bands including PO43- bands of the v1, v2, v3 and v4 modes and one OH- stretch band. Other minor bands due to the CO32- v1 and v3 modes and bands possibly due to the HPO42- v1, v2 and v4 modes were observable by the technique despite the hydrazine-treatment that could in principle remove the HPO4 and CO3 ions from the mineral. In comparison with pure synthetic hydroxyapatite, the intensity of the OH- stretch band relative to that of the PO43- v1 band was approximately 70% weaker, and the bandwidth of the phosphate v1 band was 200% broader, reflecting various crystal imperfections presumably present in the calculus mineral

Activation of K-RAS by co-mutation of codons 19 and 20 is transforming.

The K-RAS oncogene is widely mutated in human cancers. Activating mutations in K-RAS give rise to constitutive signalling through the MAPK/ERK and PI3K/AKT pathways promoting increased cell division, reduced apoptosis and transformation. The majority of activating mutations in K-RAS are located in codons 12 and 13. In a human colorectal cancer we identified a novel K-RAS co-mutation that altered codons 19 and 20 resulting in transitions at both codons (L19F/T20A) in the same allele. Using focus forming transformation assays in vitro , we showed that co-mutation of L19F/T20A in K-RAS demonstrated intermediate transforming ability that was greater than that of individual L19F and T20A mutants, but less than that of G12D and G12V K-RAS mutants. This demonstrated the synergistic effects of co-mutation of codons 19 and 20 and illustrated that co-mutation of these codons is functionally significant.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The Gerasimov-Drell-Hearn Sum Rule and the Spin Structure of the Nucleon

The Gerasimov-Drell-Hearn sum rule is one of several dispersive sum rules that connect the Compton scattering amplitudes to the inclusive photoproduction cross sections of the target under investigation. Being based on such universal principles as causality, unitarity, and gauge invariance, these sum rules provide a unique testing ground to study the internal degrees of freedom that hold the system together. The present article reviews these sum rules for the spin-dependent cross sections of the nucleon by presenting an overview of recent experiments and theoretical approaches. The generalization from real to virtual photons provides a microscope of variable resolution: At small virtuality of the photon, the data sample information about the long range phenomena, which are described by effective degrees of freedom (Goldstone bosons and collective resonances), whereas the primary degrees of freedom (quarks and gluons) become visible at the larger virtualities. Through a rich body of new data and several theoretical developments, a unified picture of virtual Compton scattering emerges, which ranges from coherent to incoherent processes, and from the generalized spin polarizabilities on the low-energy side to higher twist effects in deep inelastic lepton scattering.Comment: 32 pages, 19 figures, review articl

Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability.

Oncogenes and oncosuppressors can deregulate cell replication in tumours, and recently have been shown to influence the probability of apoptosis. The effects of human c-myc and mutated (T24) Ha-ras oncogenes on susceptibility to apoptosis were investigated by introducing them into immortalised rat fibroblasts. The resulting family of transfectants showed closely similar measures of proliferation, but widely divergent rates of apoptosis, differing by up to fifteen-fold, that correlated inversely with population expansion rates in vitro. T24-ras transfectants with moderate or high p21ras expression showed reduced apoptosis, and this was reversed by pharmacological inhibition of membrane localisation of p21ras by mevinolin. In contrast, c-myc stimulated apoptosis, and this was further enhanced by serum deprivation. Inducibility of effector proteins represents one possible mechanism of genetic control of the susceptibility to apoptosis, and its investigation showed that c-myc was associated with expression by viable cells of latent calcium/magnesium sensitive endonuclease activity characteristic of apoptosis. In contrast, endonuclease activity was not detected in viable cells of a T24-ras transfectant expressing high levels of p21ras. Thus, there appeared to be differential regulation of susceptibility to apoptosis, positively by c-myc and negatively by activated ras, and this was associated with availability of endonuclease activity. Genetic modulation of apoptosis in human neoplasms is likely to influence net growth rate, retention of cells acquiring new mutations and response to certain chemotherapeutic agents