Persistence with Statins and Onset of Rheumatoid Arthritis: A Population-Based Cohort Study

Background

The beneficial effects of statins in rheumatoid arthritis (RA) have been suggested previously, but it is unclear whether statins may prevent its development. The aim of this retrospective cohort study was to explore whether persistent use of statins is associated with onset of RA.

Methods and Findings

The computerized medical databases of a large health organization in Israel were used to identify diagnosed RA cases among adults who began statin therapy between 1998 and 2007. Persistence with statins was assessed by calculating the mean proportion of follow-up days covered (PDC) with statins for every study participant. To assess the possible effects of healthy user bias, we also examined the risk of osteoarthritis (OA), a common degenerative joint disease that is unlikely to be affected by use of statins.A total of 211,627 and 193,770 individuals were eligible for the RA and OA cohort analyses, respectively. During the study follow-up period, there were 2,578 incident RA cases (3.07 per 1,000 person-years) and 17,878 incident OA cases (24.34 per 1,000 person-years). The crude incidence density rate of RA among nonpersistent patients (PDC level of <20%) was 51% higher (3.89 per 1,000 person-years) compared to highly persistent patients who were covered with statins for at least 80% of the follow-up period. After adjustment for potential confounders, highly persistent patients had a hazard ratio of 0.58 (95% confidence interval 0.52–0.65) for RA compared with nonpersistent patients. Larger differences were observed in younger patients and in patients initiating treatment with high efficacy statins. In the OA cohort analysis, high persistence with statins was associated only with a modest decrement in risk ratio (hazard ratio = 0.85; 0.81–0.88) compared to nonadherent patients.

Conclusions

The present study demonstrates an association between persistence with statin therapy and reduced risk of developing RA. The relationship between continuation of statin use and OA onset was weak and limited to patients with short-term follow-up. Please see later in the article for the Editors'' Summary     

Monitoring of tumor response to chemotherapy in vivo by a novel small-molecule detector of apoptosis

Utilization of molecular imaging of apoptosis for clinical monitoring of tumor response to anti-cancer treatments in vivo is highly desirable. To address this need, we now present ML-9 (butyl-2-methyl-malonic acid; MW = 173), a rationally designed small-molecule detector of apoptosis, based on a novel alkyl-malonate motif. In proof-of-concept studies, induction of apoptosis in tumor cells by various triggers both in vitro and in vivo was associated with marked uptake of ³H-ML-9 administered in vivo, in correlation with the apoptotic hallmarks of DNA fragmentation, caspase-3 activation and membrane phospholipid scrambling, and with correlative tumor regression. ML-9 uptake following chemotherapy was tumor-specific, with rapid clearance of the tracer from the blood and other non-target organs. Excess of non-labeled “cold” compound competitively blocked ML-9 tumor uptake, thus demonstrating the specificity of ML-9 binding. ML-9 may therefore serve as a platform for a novel class of small-molecule imaging agents for apoptosis, useful for assessment of tumor responsiveness to treatment. H. Grimberg, G. Levin and A. Shirvan contributed equally to this article.     

The Third Intracellular Loop of the 5-Hydroxytryptamine2A Receptor Determines Effector Coupling Specificity

Abstract: 5-Hydroxytryptamine (5-HT) receptors contain seven putative transmembrane domains and couple via different guanine nucleotide binding proteins to specific effector enzymes. Studies with other receptors identify the second and third intracellular loops or the C-terminus of the receptor as important for selective effector coupling. However, it is not known which regions of the 5-HT receptor determine effector coupling specificity. To address this question, we constructed a chimeric 5-HT receptor in which the third intracellular (i3) loop is derived from the 5-HT_2A receptor, which is coupled to activation of phospholipase C, and the rest of the sequence is derived from the 5-HT_1B receptor, which is coupled to inhibition of adenylyl cyclase. The chimeric receptor exhibited ligand binding properties similar to those of the 5-HT_1B receptor and distinct from those of the 5-HT_2A receptor. This suggests that the i3 loop is not critical for the unique pharmacology of the 5-HT_1B receptor. In contrast, the chimeric receptor exhibited signaling properties similar to those of the 5-HT_2A receptor and distinct from those of the 5-HT_1B receptor. This indicates that the i3 loop determines the effector coupling specificity of the 5-HT_2A receptor.     

Thermodynamic constraints shape the structure of carbon fixation pathways

Thermodynamics impose a major constraint on the structure of metabolic pathways. Here, we use carbon fixation pathways to demonstrate how thermodynamics shape the structure of pathways and determine the cellular resources they consume. We analyze the energetic profile of prototypical reactions and show that each reaction type displays a characteristic change in Gibbs energy. Specifically, although carbon fixation pathways display a considerable structural variability, they are all energetically constrained by two types of reactions: carboxylation and carboxyl reduction. In fact, all adenosine triphosphate (ATP) molecules consumed by carbon fixation pathways - with a single exception - are used, directly or indirectly, to power one of these unfavorable reactions. When an indirect coupling is employed, the energy released by ATP hydrolysis is used to establish another chemical bond with high energy of hydrolysis, e.g. a thioester. This bond is cleaved by a downstream enzyme to energize an unfavorable reaction. Notably, many pathways exhibit reduced ATP requirement as they couple unfavorable carboxylation or carboxyl reduction reactions to exergonic reactions other than ATP hydrolysis. In the most extreme example, the reductive acetyl coenzyme A (acetyl-CoA) pathway bypasses almost all ATP-consuming reactions. On the other hand, the reductive pentose phosphate pathway appears to be the least ATP-efficient because it is the only carbon fixation pathway that invests ATP in metabolic aims other than carboxylation and carboxyl reduction. Altogether, our analysis indicates that basic thermodynamic considerations accurately predict the resource investment required to support a metabolic pathway and further identifies biochemical mechanisms that can decrease this requirement.     

Oncofetal H19 RNA promotes tumor metastasis

The oncofetal H19 gene transcribes a long non-coding RNA(lncRNA) that is essential for tumor growth. Here we found that numerous established inducers of epithelial to mesenchymal transition(EMT) also induced H19/miR-675 expression. Both TGF-β and hypoxia concomitantly induced H19 and miR-675 with the induction of EMT markers. We identified the PI3K/AKT pathway mediating the inductions of Slug, H19 RNA and miR-675 in response to TGF-β treatment, while Slug induction depended on H19 RNA. In the EMT induced multidrug resistance model, H19 level was also induced. In a mouse breast cancer model, H19 expression was tightly correlated with metastatic potential. In patients, we detected high H19 expression in all common metastatic sites tested, regardless of tumor primary origin. H19 RNA suppressed the expression of E-cadherin protein. H19 up-regulated Slug expression concomitant with the suppression of E-cadherin protein through a mechanism that involved miR-675. Slug also up-regulated H19 expression and activated its promoter. Altogether, these results may support the existence of a positive feedback loop between Slug and H19/miR-675, that regulates E-cadherin expression. H19 RNA enhanced the invasive potential of cancer cells in vitro and enhanced tumor metastasis in vivo. Additionally, H19 knockdown attenuated the scattering and tumorigenic effects of HGF/SF. Our results present novel mechanistic insights into a critical role for H19 RNA in tumor progression and indicate a previously unknown link between H19/miR-675, Slug and E-cadherin in the regulation of cancer cell EMT programs.     

First record of Pristipomoides multidens (Day, 1871) from the Gulf of Aqaba,with a note on the species of Pristipomoides in the Red Sea (Actinopterygii: Lutjanidae)

The snapper Pristipomoides multidens is reported for the first time from the Gulf of Aqaba. A comparison of mitochondrial cytochrome oxidase subunit 1 (COI) with available data revealed a high similarity with a sample from Mauritius and a lower similarity with samples from the China Sea. The status and distribution of the Red Sea species of Pristipomoides are summarised.     

Evidence against superoxide involvement in tyrosine hydroxylation by mushroom tyrosinase

The possible involvement of superoxide anions in the hydroxylation of tyrosine by mushroom tyrosinase was studied. Superoxide dismutase and scavengers of superoxide ions of smaller MW than superoxide dismutase, such as nitroblue tetrazolium and copper salicylate, had no direct effect on the monohydroxyphenolase activity of mushroom tyrosinase. The kinetics of tyrosine hydroxylation, but not of DOPA oxidation, by mushroom tyrosinase was atrected by the addition of a xanthine-xanthine oxidase system. In the presence of the xanthine-xanthine oxidase system, the lag period of tyrosine hydroxylation was shortened compared to the lag period in the absence of the xanthine-xanthine oxidase system. The xanthine- xanthine oxidase system alone (without mushroom tyrosinase) had no effect on tyrosine conversion to dopachrome. Superoxide dismutase, catalase and hydroxyl radical scavengers counteracted to some extent the shortening of the lag period of tyrosine hydroxylation by mushroom tyrosinase caused by the xanthin e-xanthine oxidase system. It is suggested that the shortening of the lag period is due mainly to hydroxyl radicals generated by the xanthine-xanthine oxidase system via interaction of O₂^?. and hydrogen paroxide (a Haber-Weiss type reaction). The data do not support the direct participation of superoxide anions in tyrosine hydroxylation by mushroom tyrosinase.     

Is One Sputum Specimen as Good as Two during Follow-Up Cultures for Monitoring Multi Drug Resistant Tuberculosis Patients in India?

Background

In India, the Revised National Tuberculosis Control Programme (RNTCP) has adopted the strategy of examining two specimens during follow-up culture examinations to monitor the treatment response of multi-drug resistant tuberculosis (MDR-TB) patients.

Objectives

To determine the incremental yield of the second sputum specimen during follow-up culture examinations among patients with MDR-TB and the effect on case management on changing from two to one specimen follow-up strategy.

Methods

A cross sectional record review of MDR-TB patients registered during 2008–09 under RNTCP was undertaken in three MDR-TB treatment sites of India.

Results

Of 1721 pairs of follow-up sputum culture examinations done among 220 MDR-TB patients, 451(26%) were positive with either of the two specimens; 29(1.7%) were culture positive only on the second specimen indicating the incremental yield. To detect one additional culture positive result on the second specimen, 59 specimens needed to be processed. If we had examined only one specimen, we would have missed 29 culture-positive results. By current RNTCP guidelines, however, a single specimen policy would have altered case management in only 3(0.2%) instances, where patients would have missed a one month extension of the intensive phase of MDR-TB treatment. There is no meaningful advantage in using two specimens for the monitoring of MDR-TB patients. A single specimen policy could be safely implemented with negligible clinical effect on MDR-TB patients and favourable resource implications for RNTCP.