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Background: The anti-folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis. Objective: To determine the allele frequencies of five common coding single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in African-Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX. Methods: Allele frequencies in the 677, 1298 and 3 additional SNPs in the MTHFR coding region in 223 (193 Caucasians and 30 African-Americans) patients with rheumatoid arthritis who previously participated in one of two prospective clinical trials were characterised, and genotypes were correlated with the efficacy and toxicity of MTX. Another 308 subjects with rheumatoid arthritis who participated in observational studies, one group predominantly Caucasian and the other African-American, as well as 103 normal controls (53 African-Americans and 50 Caucasians) were used to characterise allele frequencies of these SNPs and their associated haplotypes. Results: Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African-Americans. Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group. Frequencies of the rs4846051C, 677T and 1298C alleles were 0.33, 0.11 and 0.13, respectively, among African-Americans with rheumatoid arthritis. Among Caucasians with rheumatoid arthritis, these allele frequencies were 0.08 (p<0.001 compared with African-Americans with rheumatoid arthritis), 0.30 (p = 0.002) and 0.34 (p<0.001), respectively. There was no association between SNP alleles or haplotypes and response to MTX as measured by the mean change in the 28-joint Disease Activity Score from baseline values. In Caucasians, the 1298 A (major) allele was associated with a significant increase in MTX-related adverse events characteristic of a recessive genetic effect (odds ratio 15.86, 95% confidence interval 1.51 to 167.01; p = 0.021), confirming previous reports. There was an association between scores of MTX toxicity and the rs4846051 C allele, and haplotypes containing this allele, in African-Americans, but not in Caucasians. Conclusions: : These results, although preliminary, highlight racial or ethnic differences in frequencies of common MTHFR SNPs. The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX-related adverse events in Caucasians and African-Americans, respectively, but these findings should be replicated in larger studies. The rs4846051 SNP, which is far more common in African-Americans than in Caucasians, can also be proved to be a useful ancestry informative marker in future studies on genetic admixture.

Objective: We tested whether homocysteine is formed from methionine and other thioethers in vitro and in vivo, because methionine can be chemically demethylated to homocysteine. Design: In in vitro studies, chemical conversions of thioethers (methionine, S-adenosylhomocysteine and cystathionine) into homocysteine were measured under various aerobic conditions. In humans, oral methionine (0.17 mmol/kg body weight) loading tests with and without an oral iron dose (ferrous sulfate, 13 mol/kg) were performed. Setting: A university setting in Birmingham, AL, USA. Subjects: A total of five healthy adult subjects volunteered. Results: The in vitro incubation of methionine, S-adenosylhomocysteine or cystathionine with chelated iron resulted in the formation of homocysteine. These conversions were iron- and pH-dependent (pH optima between 5.0 and 6.0) and it was also chelator-dependent. In humans, oral methionine loading tests resulted in a 45% increase in the area-under-the-curve for plasma total homocysteine concentrations, when iron was given together with methionine. Conclusion: Our data suggest that iron-dependent chemical formation of homocysteine can occur in vivo, and contribute to the plasma total homocysteine pool, since this formation can occur ceaselessly. We hypothesize that plasma total homocysteine concentrations reflect, in part, non-protein-bound iron in the body.

What is life? Where do we come from and how did we evolve? What is the universe and how was it formed? What is the nature of the material world? How does it work? How and why do we think? What does it mean to be human? How do we know?There are many different versions of our creation story. This book tells the version according to modern science. It is a unique account, starting at the Big Bang and travelling right up to the emergence of humans as conscious intelligent beings, 13.8 billion years later. Chapter by chapter, it sets out the current state of scientific knowledge: the origins of space and time; energy, mass, and light; galaxies, stars, and our sun; the habitable earth, and complex life itself. Drawing togetherthe physical and biological sciences, Baggott recounts what we currently know of our history, highlighting the questions science has yet to answer.

Today we are blessed with two extraordinarily successful theories of physics. The first is Albert Einstein's general theory of relativity, which describes the large-scale behaviour of matter in a curved spacetime. This theory is the basis for the standard model of big bang cosmology. The discovery of gravitational waves at the LIGO observatory in the US (and then Virgo, in Italy) is only the most recent of this theory's many triumphs. The second is quantum mechanics. This theory describes the properties and behaviour of matter and radiation at their smallest scales. It is the basis for the standard model of particle physics, which builds up all the visible constituents of the universe out of collections of quarks, electrons and force-carrying particles such as photons. The discovery of the Higgs boson at CERN in Geneva is only the most recent of this theory's many triumphs. But, while they are both highly successful, these two structures leave a lot of important questions unanswered. They are also based on two different interpretations of space and time, and are therefore fundamentally incompatible. We have two descriptions but, as far as we know, we've only ever had one universe. What we need is a quantum theory of gravity. Approaches to formulating such a theory have primarily followed two paths. One leads to String Theory, which has for long been fashionable, and about which much has been written. But String Theory has become mired in problems. In this book, Jim Baggott describes : an approach which takes relativity as its starting point, and leads to a structure called Loop Quantum Gravity. Baggott tells the story through the careers and pioneering work of two of the theory's most prominent contributors, Lee Smolin and Carlo Rovelli. Combining clear discussions of both quantum theory and general relativity, this book offers one of the first efforts to explain the new quantum theory of space and time\"-- Provide by publisher.

Utterly beautiful. Profoundly disconcerting. Quantum theory is quite simply the most successful account of the physical universe ever devised. The pursuit of its implications has been the driving motivation of physicists for 100 years. Jim Baggott traces the story, the personalities and the rivalries, through 40 turning-point moments.

Quantum mechanics is an extraordinarily successful scientific theory. It is also completely baffling. From the moment of its inception, its founders struggled to understand its meaning. This struggle was most famously encapsulated in the debate between Niels Bohr and Albert Einstein; 'Quantum Drama' tells the story of their engagement and its legacy.

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P <0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CY P20A1 and CYP39A1 , solute carrier genes SLC22A2 and SLC7A7 , and the mitochondrial aldehyde dehydrogenase gene ALDH2 . The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.