Aspects of early arthritis. What determines the evolution of early undifferentiated arthritis and rheumatoid arthritis? An update from the Norfolk Arthritis Register

Over 3500 patients with recent onset inflammatory polyarthritis (IP) have been recruited by the Norfolk Arthritis Register (NOAR) since 1990. Longitudinal data from this cohort have been used to examine the prevalence and predictors of remission, functional disability, radiological outcome, cardiovascular mortality and co-morbidity and the development of non-Hodgkin's lymphoma. Rheumatoid factor titre, high baseline C-reactive protein and high baseline HAQ score are all predictors of a poor outcome. There is a strong association between possession of the shared epitope and the development of erosions. Patients who satisfy the American College of Rheumatology criteria for rheumatoid arthritis (RA) have a worse prognosis than those who do not. However, it appears that these patients are a poorly defined subset of all those with IP rather than having an entirely separate disease entity. New statistical techniques offer exciting possibilities for using longitudinal datasets such as NOAR to explore the long-term effects of treatment in IP and RA.     

Phylogeny of the Drosophila saltans species group based on combined analysis of nuclear and mitochondrial DNA sequences

Nucleotide sequences from two nuclear loci, alcohol dehydrogenase and internal transcribed spacer-1 of the nuclear ribosomal DNA repeats, and two mitochondrial genes, cytochrome oxidase I and cytochrome oxidase II, were determined from nine species in the Drosophila saltans species group. The partition homogeneity test and partitioned Bremer support were used to measure incongruence between phylogenetic hypotheses generated from individual partitions. Individual loci were generally congruent with each other and consistent with the previously proposed morphological hypothesis, although they differed in level of resolution. Since extreme conflict between partitions did not exist, the data were combined and analyzed simultaneously. The total evidence method gave a more resolved and highly supported phylogeny, as indicated by bootstrap proportions and decay indices, than did any of the individual analyses. The cordata and elliptica subgroups, considered to have diverged early in the history of the D. saltans group, were sister taxa to the remainder of the saltans group. The sturtevanti subgroup, represented by D. milleri and D. sturtevanti, occupies an intermediate position in this phylogeny. The saltans and parasaltans subgroups are sister clades and occupy the most recently derived portion of the phylogeny. As with previous morphological studies, phylogenetic relationships within the saltans subgroup were not satisfactorily resolved by the molecular data.      

Localisation of the Vacuolar Proton Pump (V-H+-ATPase) and Carbonic Anhydrase II in the Human Eccrine Sweat Gland

The localisation of the vacuolar proton pump (V-H+ -ATPase) and the enzyme carbonic anhydrase II (CAII) was investigated in the human eccrine sweat gland employing standard immunohistochemical techniques after antigen retrieval using microwave heat treatment and high pressure. The high-pressure antigen retrieval unmasked the presence of V-H+ -ATPase in the clear cells of the secretory coil, with a distribution similar to that previously observed for CAII. However, the dark cells were unreactive to both antibodies. In addition, heat and high-pressure antigen retrieval demonstrated the presence of CAII in the apical zone of luminal cells of the reabsorptive duct, a location not previously reported. The localisation of V-H+ -ATPase and CAII in the secretory coil clear cells suggests that the formation of HCO3- and H+ by carbonic anhydrase II and the transport of H+ by V-H+ -ATPase may play an role in sweat fluid secretion. Their presence at the apex of the duct cells indicates involvement in ductal ion reabsorption.     

Microsolvation of Mg2+, Ca2+: strong influence of formal charges in hydrogen bond networks

A stochastic exploration of the quantum conformational spaces in the microsolvation of divalent cations with explicit consideration of up to six solvent molecules [Mg (H ₂ O) _n )]²⁺, (n?=?3, 4, 5, 6) at the B3LYP, MP2, CCSD(T) levels is presented. We find several cases in which the formal charge in Mg²⁺ causes dissociation of water molecules in the first solvation shell, leaving a hydroxide ion available to interact with the central cation, the released proton being transferred to outer solvation shells in a Grotthus type mechanism; this particular finding sheds light on the capacity of Mg²⁺ to promote formation of hydroxide anions, a process necessary to regulate proton transfer in enzymes with exonuclease activity. Two distinct types of hydrogen bonds, scattered over a wide range of distances (1.35–2.15 Å) were identified. We find that in inner solvation shells, where hydrogen bond networks are severely disturbed, most of the interaction energies come from electrostatic and polarization+charge transfer, while in outer solvation shells the situation approximates that of pure water clusters.

Metabolite profiles and the risk of developing diabetes

Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.     

Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes, and coronary heart disease

Inhibition of the endocannabinoid receptor CB1 improves insulin sensitivity, lowers glycemia, and slows atherosclerosis. We analyzed whether common variants in the gene encoding CB1, CNR1, are associated with insulin resistance, risk of type 2 diabetes (T2D) or coronary heart disease (CHD). We studied 2,411 participants of the Framingham Offspring Study (mean age 60 years, 52% women) for quantitative traits and CHD, and the Framingham SHARe database for T2D risk. We genotyped 19 single-nucleotide polymorphisms (SNPs) that tagged 85% (at r(2) = 0.8) of common (>5%) CNR1 SNPs. Fasting blood glucose and insulin at the 7th (1999-2001) exam were collected. We used age-, sex-, BMI-adjusted models to test additive associations of genotype with homeostasis model assessment of insulin resistance (HOMA(IR)) (linear mixed-effect models), T2D, or CHD. To account for multiple tests of SNPs, we generated empirical P values. The C allele at SNP rs806365 (frequency, 57.4%), ~4.1 kb 3' from CNR1, was associated with increased HOMA(IR) (n = 2,261, β = 0.05 per C, empirical P = 0.01), risk of T2D (674 cases, odds ratio = 1.19 per C, nominal P = 0.01) and CHD (237 cases, hazard ratio = 1.23 per C, nominal P = 0.04). The association of rs806365 with HOMA(IR) was replicated in a meta-analysis of two independent cohorts (National Health and Nutrition Examination Survey III genetic cohort (NHANES-III) plus Partners Case-Control Diabetes Study; 2,540 white individuals, β = 0.037, nominal P = 0.007), but not in the large Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Consortium (n = 29,248, nominal P = 0.74). The association of rs806365 was not replicated either with T2D in Diabetes Genetics Replication and Meta-analysis (DIAGRAM) (n = 10,128, nominal P = 0.31), or with CHD in PROCARDIS (n = 13,614, nominal P = 0.37). Although supported by initial results, we found no reproducible statistical association of common variation at CNR1 with insulin resistance, T2D, or CHD.     

Barriers and facilitators to implement shared decision making in multidisciplinary sciatica care: a qualitative study

Background

Venous thromboembolism (VTE) is a common preventable cause of mortality in hospitalized medical patients. Despite rigorous randomized trials generating strong recommendations for anticoagulant use to prevent VTE, nearly 40% of medical patients receive inappropriate thromboprophylaxis. Knowledge-translation strategies are needed to bridge this gap.

Methods

We conducted a 16-week pilot cluster randomized controlled trial (RCT) to determine the proportion of medical patients that were appropriately managed for thromboprophylaxis (according to the American College of Chest Physician guidelines) within 24 hours of admission, through the use of a multicomponent knowledge-translation intervention. Our primary goal was to determine the feasibility of conducting this study on a larger scale. The intervention comprised clinician education, a paper-based VTE risk assessment algorithm, printed physicians’ orders, and audit and feedback sessions. Medical wards at six hospitals (representing clusters) in Ontario, Canada were included; three were randomized to the multicomponent intervention and three to usual care (i.e., no active strategies for thromboprophylaxis in place). Blinding was not used.

Results

A total of 2,611 patients (1,154 in the intervention and 1,457 in the control group) were eligible and included in the analysis. This multicomponent intervention did not lead to a significant difference in appropriate VTE prophylaxis rates between intervention and control hospitals (appropriate management rate odds ratio = 0.80; 95% confidence interval: 0.50, 1.28; p = 0.36; intra-class correlation coefficient: 0.022), and thus was not considered feasible. Major barriers to effective knowledge translation were poor attendance by clinical staff at education and feedback sessions, difficulty locating preprinted orders, and lack of involvement by clinical and administrative leaders. We identified several factors that may increase uptake of a VTE prophylaxis strategy, including local champions, support from clinical and administrative leaders, mandatory use, and a simple, clinically relevant risk assessment tool.

Conclusions

Hospitals allocated to our multicomponent intervention did not have a higher rate of medical inpatients appropriately managed for thromboprophylaxis than did hospitals that were not allocated to this strategy.     

Outdoor exercise reduces the risk of hypovitaminosis D in the obese

Obesity is associated with lower levels of serum 25-hydroxyvitamin D (25(OH)D). Obese individuals might need higher doses of vitamin D supplementation than the general population. In this cross-sectional study, associations between 25(OH)D serum levels, body mass index (BMI), and outdoor exercise were assessed in a population of 291 ambulatory patients attending the Osteoporosis Center at the University of Miami, mean age 62 ± 13.48 years. Obesity was defined as BMI ≥ 30 kg/m² and hypovitaminosis D as 25(OH)D ≤ 30 ng/ml. Overall, prevalence of obesity was 14.1% and of hypovitaminosis D was 42.4%. Among Hispanics, there was a significantly higher prevalence of hypovitaminosis D in obese (63.2%) compared to non-obese individuals (35.8%). Outdoor exercise had a significant effect on the prevalence of hypovitaminosis D in Hispanics, with a lower prevalence in those performing outdoor exercise (24.1%) compared to those who did not (47.9%). After adjusting for age, gender, and ethnicity, those reporting outdoor exercise were 47% less likely to have hypovitaminosis D, while those with obesity had more than twice the risk. Since outdoor exercise may protect overweight individuals from hypovitaminosis D, prevention programs involving higher doses of vitamin D and/or outdoor exercise may result in additional metabolic and functional benefits in this population.     

Density of insect‐pollinated grassland plants decreases with increasing surrounding land‐use intensity

Pollinator declines have raised concerns about the persistence of plant species that depend on insect pollination, in particular by bees, for their reproduction. The impact of pollinator declines remains unknown for species‐rich plant communities found in temperate seminatural grasslands. We investigated effects of land‐use intensity in the surrounding landscape on the distribution of plant traits related to insect pollination in 239 European seminatural grasslands. Increasing arable land use in the surrounding landscape consistently reduced the density of plants depending on bee and insect pollination. Similarly, the relative abundance of bee‐pollination‐dependent plants increased with higher proportions of non‐arable agricultural land (e.g. permanent grassland). This was paralleled by an overall increase in bee abundance and diversity. By isolating the impact of the surrounding landscape from effects of local habitat quality, we show for the first time that grassland plants dependent on insect pollination are particularly susceptible to increasing land‐use intensity in the landscape.