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     

Signaling by the Drosophila epidermal growth factor receptor pathway during development

In 1997 we wrote a review entitled "A thousand and one roles for the Drosophila epidermal growth factor (EGF) receptor (DER/EGFR)." We are not there yet in terms of the number of developmental roles assigned to this receptor in Drosophila. Nevertheless, DER has certainly emerged as one of the key players in development, since it is used repeatedly to direct cell fate choices, cell division, cell survival, and migration. A battery of activating ligands and an inhibitory ligand achieves this versatility. For the ligands that are produced as membrane-bound precursors, trafficking and processing are the key regulatory steps, determining the eventual temporal and spatial pattern of receptor activation. In most cases DER is activated at a short range, in the cells adjacent to the ones producing the active ligand. This activation dictates a binary choice. In some instances DER is also activated over a longer range, and multiple cell fate choices may be induced, according to its level of activation. A battery of negative feedback loops assures the limited range of DER induction. The distinct responses to DER activation in the different tissues depend upon combinatorial interactions with other signaling pathways and tissue-specific factors, at the level of target-gene regulation.     

A synergistic effect of albumin and fibrinogen on immunoglobulin-induced red blood cell aggregation

Therapeutic administration of immunoglobulins (Ig) has the potential to precipitate thrombotic events. This phenomenon may be explained by red blood cell (RBC) aggregation, which can be potentiated by Ig. The contribution of plasma albumin and fibrinogen to Ig-induced RBC aggregation is unclear. We examined RBC aggregation in three settings: 1) patients receiving therapeutic infusions of Ig; 2) patients receiving plasma supplemented in vitro with Ig; and 3) patients receiving RBC suspensions in standard buffer with varying concentrations of albumin, Ig, and fibrinogen. Ig infusion augmented aggregation of RBCs from patients with normal or high plasma levels of albumin but decreased aggregation in those with lower plasma albumin concentrations. In vitro, RBC aggregation was significantly increased only when all three components, fibrinogen, albumin, and Ig, were present at or above normal concentrations in the suspension but was unaffected when any one of the components was absent from the suspension. Our results suggest a three-way interaction among fibrinogen, Ig, and albumin that synergistically induces RBC aggregation in plasma. Understanding these interactions may help predict clinically important phenomena related to RBC aggregation, such as thrombotic complications of Ig infusion.     

Monozoic cysts of Hepatozoon canis

Small monozoic cysts found in the spleen of dogs infected with Hepatozoon canis are described from naturally and experimentally infected dogs. These forms of H. canis resemble cysts formed by other Hepatozoon species that infect frogs, lizards, and grey squirrels as intermediate hosts. The H. canis cyst stage differs in size and morphology from the large cysts of H. americanum, the second Hepatozoon species known to infect dogs.     

Keren,a new ligand of the Drosophila epidermal growth factor receptor,undergoes two modes of cleavage

Spitz (Spi) is the most prominent ligand of the Drosophila EGF receptor (DER). It is produced as an inactive membrane precursor which is retained in the endoplasmic reticulum (ER). To allow cleavage, Star transports Spi to the Golgi, where it undergoes cleavage by Rhomboid (Rho). Since some DER phenotypes are not mimicked by any of its known activating ligands, we identified an additional ligand by database searches, and termed it Keren (Krn). Krn is a functional homolog of Spi since it can rescue the spi mutant phenotype in a Rho- and Star-dependent manner. In contrast to Spi, however, Krn also possesses a Rho/Star-independent ability to undergo low-level cleavage and activate DER, as evident both in cell culture and in flies. The difference in basal activity correlates with the cellular localization of the two ligands. While Spi is retained in the ER, the retention of Krn is only partial. Examining Spi/Krn chimeric and deletion constructs implicates the Spi cytoplasmic domain in inhibiting its basal activity. Low-level activity of Krn calls for tightly regulated expression of the Krn precursor.     

Chaotic nonlinear dynamics of prestimulus EEG and the structure of auditory evoked potentials

The dynamic pattern of a prestimulus EEG was studied by the fractal analysis technique. The character of this pattern was shown to affect the structure of cortical auditory evoked potentials (EP). A monoperiodic pattern in the control frequency band was accompanied by a formation of several new attractors with low dimensionality attributed to simultaneous functioning of several weakly connected dynamic systems with an indefinite trend of a leading process. During development of multiperiodic processes in EEG segments, the fractal analysis revealed a tendency for a formation of a single complex dynamic system with high dimensionality of the attractor. Characteristic changes in parameters of the primary and middle-latency EP components, their correlation, and factor models are related with the character of nonlinear patterns. Analysis of variance revealed the most effective role of pattern changes in the EEG alpha control band. The structure of combination of parameters of the EP primary components into connected complexes depends on the nonlinear prestimulus EEG patterns. The above predictors determine differently directed and differently pronounced changes in parameters of the middle-latency positive waves.     

Voltage-Dependent Anion Channel Proteins in Synaptosomes of the Torpedo Electric Organ: Immunolocalization, Purification, and Characterization

In this study, we purified and characterized the voltage-dependent anion channel (VDAC) from the Torpedo electric organ. Using immunogold labeling, VDAC was colocalized with the voltage-gated Ca²⁺ channel in the synaptic plasma membrane. By immunoblot analysis, five protein bands in synaptosomes isolated from the Torpedo electric organ cross reacted with two monoclonal anti-VDAC antibody. No more than about 7 to 10% mitochondrial contains could be detected in any synaptosomal membrane preparation tested. This was estimated by comparing the specific activity in mitochondria and synaptosomes of succinate–cytochrome-c oxidoreductase and antimycin-insensitive NADH–cytochrome-c oxidoreductase activities; mitochondrial inner and outer membrane marker enzymes, respectively. [¹⁴C]DCCD (dicyclohexylcarbodiimide), which specifically label mitochondrial VDAC, labeled four 30–35 kDa protein bands that were found to interact with the anti-VDAC antibody. The distribution of the Torpedo VDAC protein bands was different among membranes isolated from various tissues. VDAC was purified from synaptosomes and a separation between two of the proteins was obtained. The two purified proteins were characterized by their single channel activity and partial amino acid sequences. Upon reconstitution into a planar lipid bilayer, the purified VDACs showed voltage-dependent channel activity with properties similar to those of purified mitochondrial VDAC. Amino acid sequence of four peptides, derived from VDAC band II, exhibited high homology to sequences present in human VDAC1 (98%), VDAC2 (91.8%), and VDAC3 (90%), while another peptide, derived from VDAC band III, showed lower homology to either VDAC1 (88.4%) or VDAC2 (79%). Two more peptides show high homology to the sequence present in mouse brain VDAC3 (100 and 78%). In addition, we demonstrate the translocation of ATP into synaptosomes, which is inhibited by DCCD and by the anion transport inhibitor DIDS. The possible function of VDAC in the synaptic plasma membrane is discussed.