N-methyl-D-aspartate (NMDA) receptor activation, at the level of the spinal cord, has been shown to play an important role in the facilitation of nociception in several animal models. However, the use of NMDA antagonists as analgesics is limited by serious side effects due to nonselective effects among the NMDA receptor subtypes. Recent discoveries revealed that the transfection of small interfering RNAs (siRNAs) into animal cells resulted in the potent, long-lasting, post-transcriptional silencing of specific genes. Thus, we investigated the effect of intrathecal (i.t.) injection of siRNAs targeting NMDA-R2B receptor subunit protein (NR2B) receptors, a subunit of NMDA receptor, for the modulation of pain. The results indicate that the use of siRNA targeting the NR2B subunit not only decreased the expression of NR2B mRNA and its associated protein, as demonstrated by real-time PCR and Western blotting, but also abolished formalin-induced pain behaviors in rat model. The peak effect occurred on day 3 for mRNA and day 7 for its protein, following i.t. injection of 5 mg of siRNA-NR2B. These data prove the feasibility of i.t. siRNAs in the investigation of functional gene expression in the context of whole animal behavior for the management of chronic pain. Gene Therapy (2005) 12, 59-66.

Several 5-iodotubercidin analogues in the pyrazolo[3,4-d]pyrimidine ring system were synthesized as potential inhibitors of adenosine kinase by a direct Lewis acid-catalyzed glycosylation procedure using both the preformed carbohydrate and the heterocyclic base as starting materials. The 5'-hydroxyl, -chloro, -azido, -deoxy, -amino, and -fluoro derivatives were prepared and evaluated in three systems for biological activity relative to adenosine, the true substrate, and 5-iodotubercidin, a known inhibitor. First, each compound was studied kinetically for inhibition of purified human placental adenosine kinase activity. The order of potency was: iodotubercidin > hydroxyl > amino > or = deoxy > fluoro > chloro >> azido. The Ki values for the 5'-hydroxyl and 5'-amino compounds, the two most potent inhibitors, were 80 and 150 nM, respectively. The inhibition appeared to be essentially competitive in nature, although a noncompetitive component of significance for the more potent inhibitors cannot be ruled out. Second, a bioassay was conducted in which the toxicity of 6-methylmercaptopurine riboside toward human CEM lymphoblasts was reversed by varying concentrations of the compounds. The order of effectiveness of the compounds in this system, representing a functional inhibition of adenosine kinase in cultured cells, was about the same as that with the purified enzyme, except that the 5'-chloro and 5'-fluoro compounds were ineffective. Third, the 5'-hydroxyl derivative was evaluated in vivo in a rat pleurisy inflammation model and displayed biological activity at a dose of 30 mg/kg given orally. Finally, the in vitro toxicity of each compound was assessed in CEM lymphoblasts. Results indicated that the two most potent inhibitors in the pyrazolo[3,4-d]pyrimidine ring system, the 5'-hydroxyl (7) and the 5'-amino (20), were 15-fold and 75-fold, respectively, less growth inhibitory than 5-iodotubercidin.

We investigated the magnetic and ferroelectric properties of c-axis oriented orthorhombic phase HoMnO(3) (o-HMO in Pbnm symmetry setting) thin films grown on Nb-doped SrTiO(3)(001) substrates. The o-HMO films exhibit an antiferromagnetic ordering near 42 K, irrespective of the orientation of the applied field. However, an additional magnetic ordering occurring around 35 K was observed when the field was applied along the c-axis of o-HMO, which was absent when the field was applied in the ab-plane. The magnetocapacitance measured along the c-axis showed that although there is evidence of dielectric constant enhancement when the temperature is below 35 K the expected abrupt change in dielectric constant appears at a much lower temperature and reaches maximum around 13.5 K, indicating that the low-temperature c-axis polarization might be related to the ordering of the Ho(3+) moment. The lattice constant analyses using x-ray diffraction and the observation of a slight magnetization hysteresis suggest that the weak second magnetic transition along the c-axis at 35 K might be more relevant to the strain-induced effect on antiferromagnetism.

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BackgroundPatients with RA who are at a higher risk for progressive and destructive arthritis could be identified using anti-cyclic citrullinated peptide (anti-CCP) levels.1 Treatment guidelines recommend the use of non-biologic DMARDs as initial treatment in RA; but, if warranted, biologic (b)DMARDs could be considered in early treatment of RA.2 Real-world data describing treatment patterns based on anti-CCP designations are limited.ObjectivesThis study evaluated treatment patterns of patients with RA who are anti-CCP positive (+) or negative (–).MethodsThis retrospective study was based on electronic medical record (EMR) data with a supplemental chart review from a large integrated delivery system. Patients newly diagnosed with RA (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 714.0x) were identified between 1 January 2009 and 31 December 2014. The first RA diagnosis date was designated as the index date. Patients were required to have 12 months of continuous activity in the EMR (6 months pre- and 6 months post-index). Based on the baseline anti-CCP test results, patients were categorized as anti-CCP+ (≥7.0 U) or anti-CCP– (<7.0 U). First-line therapy (time to treatment initiation, treatment regimen, treatment changes and response to treatment) was evaluated in the post-index period. Response to treatment was determined based on physicians' notes.ResultsOverall, 217 anti-CCP+ and 191 anti-CCP– patients with RA were included in this study. A higher proportion of anti-CCP+ (153, 70.5%) than anti-CCP– patients (44, 23.0%; p<0.0001) initiated treatment, generally within 1 month after diagnosis (anti-CCP+, mean [SD]: 31.1 [42.1] days and anti-CCP–, 28.1 [37.4] days; p=0.6538). MTX was most commonly used as first-line therapy. More anti-CCP+ than anti-CCP– patients received MTX (73.2 vs 56.8%; p=0.0374), while more anti-CCP– than anti-CCP+ patients received hydroxychloroquine (31.8 vs 13.1%; p=0.0037). Only three anti-CCP+ and no anti-CCP– patients were treated with a bDMARD. Response to treatment was similar between the cohorts (p=0.2444); 22.9% of anti-CCP+ and 18.2% of anti-CCP– patients had a complete response to the first-line therapy, and 33.3% of anti-CCP+ and 25.0% of anti-CCP– patients had a partial response to the first-line therapy. Treatment change, however, significantly differed between the two cohorts (p=0.0058); 11.1 and 9.1% of patients discontinued, 9.8 and 9.1% of patients switched, and 3.9 and 9.1% of patients augmented in the anti-CCP+ and anti-CCP– cohorts, respectively. Treatment changes occurred approximately 3 months after treatment initiation (anti-CCP+, 82.0 [49.7] days and anti-CCP–, 83.8 [52.7] days; p=0.9178).ConclusionsAfter diagnosis of RA, patients who are anti-CCP+ were more likely to start therapy, indicating that physicians were more aggressive in treating this cohort. Patients were treated according to guidelines with non-biologic DMARDs, predominantly MTX. Patterns of treatment change differed between the cohorts; however, treatment...