Serum homocysteine is weakly associated with von Willebrand factor and soluble vascular cell adhesion molecule 1, but not with C-reactive protein in type 2 diabetic and nondiabetic subjects: the Hoorn Study.

Background: Hyperhomocysteinaemia may constitute an independent risk factor for cardiovascular disease, but it is still unclear by which pathophysiological mechanisms homocysteine (tHcy) may promote atherothrombosis. The aim of this study was firstly to examine whether tHcy is associated with endothelial dysfunction, increased adherence of leukocytes, and/or chronic low-grade inflammation, as estimated from plasma levels of von Willebrand factor (vWf), soluble vascular cell adhesion molecule 1 (sVCAM-1) and C-reactive protein (CRP), respectively. Secondly we investigated whether the presence of type 2 diabetes modifies these associations. Materials and Methods: Six hundred and ten subjects of a general population of middle-aged and elderly subjects, 170 of whom had type 2 diabetes, participated in this cross-sectional study. Linear regression analyses were used to study whether tHcy was associated with vWf, sVCAM-1 and CRP, and whether the presence of diabetes modified these associations. Results: After adjustment for confounders, tHcy was significantly but weakly associated with vWf (β=0·15, P=0·05) and sVCAM-1 (β=0·082, P=0·04). tHcy was not significantly associated with CRP (β=0·02, P=0·91). The presence of diabetes did not significantly modify these associations. Conclusions: This study provides evidence that tHcy is, at most, weakly associated with endothelial dysfunction as estimated from plasma vWf, and with leukocyte adhesion as estimated from plasma sVCAM-1. tHcy was not significantly associated with chronic low-grade inflammation as estimated from plasma CRP. Our data thus suggest that the link between tHcy and atherothrombosis cannot be explained by associations of tHcy with vWf, sVCAM-1 or CRP

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

A Recombinant Vaccine Effectively Induces C5a-Specific Neutralizing Antibodies and Prevents Arthritis

OBJECTIVES: To develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a. METHODS: We constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: collagen induced arthritis (CIA), chronic relapsing CIA and collagen antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology. RESULTS: Vaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-collagen antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered. CONCLUSIONS: Exploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity

1H-NMR-Based Metabolic Profiling of Maternal and Umbilical Cord Blood Indicates Altered Materno-Foetal Nutrient Exchange in Preterm Infants

Background: Adequate foetal growth is primarily determined by nutrient availability, which is dependent on placental nutrient transport and foetal metabolism. We have used 1H nuclear magnetic resonance (NMR) spectroscopy to probe the metabolic adaptations associated with premature birth. Methodology: The metabolic profile in 1H NMR spectra of plasma taken immediately after birth from umbilical vein, umbilical artery and maternal blood were recorded for mothers delivering very-low-birth-weight (VLBW) or normo-ponderal full-term (FT) neonates. Principal Findings: Clear distinctions between maternal and cord plasma of all samples were observed by principal component analysis (PCA). Levels of amino acids, glucose, and albumin-lysyl in cord plasma exceeded those in maternal plasma, whereas lipoproteins (notably low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) and lipid levels were lower in cord plasma from both VLBW and FT neonates. The metabolic signature of mothers delivering VLBW infants included decreased levels of acetate and increased levels of lipids, pyruvate, glutamine, valine and threonine. Decreased levels of lipoproteins glucose, pyruvate and albumin-lysyl and increased levels of glutamine were characteristic of cord blood (both arterial and venous) from VLBW infants, along with a decrease in levels of several amino acids in arterial cord blood. Conclusion: These results show that, because of its characteristics and simple non-invasive mode of collection, cord plasma is particularly suited for metabolomic analysis even in VLBW infants and provides new insights into the materno-foetal nutrient exchange in preterm infants

Reoperations after first lumbar disc herniation surgery; a special interest on residives during a 5-year follow-up

BACKGROUND: The overall rate of operations after recurrent lumbar disc herniation has been shown to be 3–11%. However, little is known about the rate of residives. Thus the aim of this study was to explore the cumulative rates of re-operations and especially residive disc herniations at the same side and level as the primary disc herniation after first lumbar disc herniation surgery and the factors that influence the risk of re-operations over a five year follow-up study. METHODS: 166 virgin lumbar disc herniation patients (mean age 42 years, 57% males) were studied. Data on patients' initial disc operations and type and timing of re-operations during the follow-up were collected from patient files. Back and leg pain on visual analog scale and employment status were collected by questionnaires. RESULTS: The cumulative rate of re-operations for lumbar disc herniation was 10.2% (95% Cl 6.0 to 15.1). The rate of residives at initial site was 7.4% (95% Cl 3.7 to 11.3) and rate of lumbar disc herniations at other sites was 3.1% (95% Cl 0.6 to 6.2). The occurrence of residive lumbar disc herniations was evenly distributed across the 5 years. Neither age, gender, preoperative symptoms, physical activity nor employment had effect on the probability of re-operation. CONCLUSION: Seven percent of the lumbar disc patients had a residive lumbar disc operation within five years of their first operation. No specific factors influencing the risk for re-operation were found

Linear-time protein 3-D structure searching with insertions and deletions

<p>Abstract</p> <p>Background</p> <p>Two biomolecular 3-D structures are said to be similar if the RMSD (root mean square deviation) between the two molecules' sequences of 3-D coordinates is less than or equal to some given constant bound. Tools for searching for similar structures in biomolecular 3-D structure databases are becoming increasingly important in the structural biology of the post-genomic era.</p> <p>Results</p> <p>We consider an important, fundamental problem of reporting all substructures in a 3-D structure database of chain molecules (such as proteins) which are similar to a given query 3-D structure, with consideration of indels (<it>i.e.</it>, insertions and deletions). This problem has been believed to be very difficult but its exact computational complexity has not been known. In this paper, we first prove that the problem in unbounded dimensions is NP-hard. We then propose a new algorithm that dramatically improves the average-case time complexity of the problem in 3-D in case the number of indels <it>k </it>is bounded by a constant. Our algorithm solves the above problem for a query of size <it>m </it>and a database of size <it>N </it>in average-case <it>O</it>(<it>N</it>) time, whereas the time complexity of the previously best algorithm was <it>O</it>(<it>Nm</it>^<it>k</it>+1).</p> <p>Conclusions</p> <p>Our results show that although the problem of searching for similar structures in a database based on the RMSD measure with indels is NP-hard in the case of unbounded dimensions, it can be solved in 3-D by a simple average-case linear time algorithm when the number of indels is bounded by a constant.</p

The Cultural Evolution of Democracy: Saltational Changes in A Political Regime Landscape

Transitions to democracy are most often considered the outcome of historical modernization processes. Socio-economic changes, such as increases in per capita GNP, education levels, urbanization and communication, have traditionally been found to be correlates or ‘requisites’ of democratic reform. However, transition times and the number of reform steps have not been studied comprehensively. Here we show that historically, transitions to democracy have mainly occurred through rapid leaps rather than slow and incremental transition steps, with a median time from autocracy to democracy of 2.4 years, and overnight in the reverse direction. Our results show that autocracy and democracy have acted as peaks in an evolutionary landscape of possible modes of institutional arrangements. Only scarcely have there been slow incremental transitions. We discuss our results in relation to the application of phylogenetic comparative methods in cultural evolution and point out that the evolving unit in this system is the institutional arrangement, not the individual country which is instead better regarded as the ‘host’ for the political system

Taxonomic distribution and origins of the extended LHC (light-harvesting complex) antenna protein superfamily

<p>Abstract</p> <p>Background</p> <p>The extended light-harvesting complex (LHC) protein superfamily is a centerpiece of eukaryotic photosynthesis, comprising the LHC family and several families involved in photoprotection, like the LHC-like and the photosystem II subunit S (PSBS). The evolution of this complex superfamily has long remained elusive, partially due to previously missing families.</p> <p>Results</p> <p>In this study we present a meticulous search for LHC-like sequences in public genome and expressed sequence tag databases covering twelve representative photosynthetic eukaryotes from the three primary lineages of plants (Plantae): glaucophytes, red algae and green plants (Viridiplantae). By introducing a coherent classification of the different protein families based on both, hidden Markov model analyses and structural predictions, numerous new LHC-like sequences were identified and several new families were described, including the red lineage chlorophyll <it>a/b</it>-binding-like protein (RedCAP) family from red algae and diatoms. The test of alternative topologies of sequences of the highly conserved chlorophyll-binding core structure of LHC and PSBS proteins significantly supports the independent origins of LHC and PSBS families via two unrelated internal gene duplication events. This result was confirmed by the application of cluster likelihood mapping.</p> <p>Conclusions</p> <p>The independent evolution of LHC and PSBS families is supported by strong phylogenetic evidence. In addition, a possible origin of LHC and PSBS families from different homologous members of the stress-enhanced protein subfamily, a diverse and anciently paralogous group of two-helix proteins, seems likely. The new hypothesis for the evolution of the extended LHC protein superfamily proposed here is in agreement with the character evolution analysis that incorporates the distribution of families and subfamilies across taxonomic lineages. Intriguingly, stress-enhanced proteins, which are universally found in the genomes of green plants, red algae, glaucophytes and in diatoms with complex plastids, could represent an important and previously missing link in the evolution of the extended LHC protein superfamily.</p