A ligand-independent fast function of RARα promotes exit from metabolic quiescence upon T cell activation and controls T cell differentiation.

Vitamin A metabolites play important roles in T cell activation and differentiation. A conventional model of RARα function relies upon retinoic acid (RA)-liganded RARα binding to specific DNA motifs to regulate gene expression in the nucleus. However, this genomic function fails to explain many of the biological responses of the RA-RARα axis on T cells. We generated a mouse line where RARα is over-expressed in T cells to probe RARα function with unprecedented sensitivity. Using this model together with mice specifically lacking RARα in T cells, we found that RARα is required for prompt exit from metabolic quiescence in resting T cells upon T cell activation. The positive effect of RARα on metabolism is mediated through PI3K and subsequent activation of the Akt and mTOR signaling pathway. This largely non-genomic function of RARα is surprisingly ligand-independent and controls the differentiation of effector and regulatory T cell subsets.

Multi-center evaluation of analytical performance of the Beckman Coulter AU5822 chemistry analyzer.

OBJECTIVES: Our three academic institutions, Indiana University, Northwestern Memorial Hospital, and Wake Forest, were among the first in the United States to implement the Beckman Coulter AU5822 series chemistry analyzers. We undertook this post-hoc multi-center study by merging our data to determine performance characteristics and the impact of methodology changes on analyte measurement. DESIGN AND METHODS: We independently completed performance validation studies including precision, linearity/analytical measurement range, method comparison, and reference range verification. Complete data sets were available from at least one institution for 66 analytes with the following groups: 51 from all three institutions, and 15 from 1 or 2 institutions for a total sample size of 12,064. RESULTS: Precision was similar among institutions. Coefficients of variation (CV) were <10% for 97%. Analytes with CVs >10% included direct bilirubin and digoxin. All analytes exhibited linearity over the analytical measurement range. Method comparison data showed slopes between 0.900-1.100 for 87.9% of the analytes. Slopes for amylase, tobramycin and urine amylase were <0.8; the slope for lipase was >1.5, due to known methodology or standardization differences. Consequently, reference ranges of amylase, urine amylase and lipase required only minor or no modification. CONCLUSION: The four AU5822 analyzers independently evaluated at three sites showed consistent precision, linearity, and correlation results. Since installations, the test results had been well received by clinicians from all three institutions.

Laser irradiation of bone: II. Healing response following treatment by CO2 and Nd:YAG lasers.

BACKGROUND: Currently, the most commonly used lasers for dental procedures are the Nd:YAG and CO2. Studies comparing healing of osteotomy defects prepared with rotary burs to those created by laser irradiation have reported conflicting results. The purpose of this study was to evaluate and compare the histologic healing of bone in rat tibial osteotomy defects created either by a dental bur, CO2 laser with and without removal of the char layer, and Nd:YAG laser with char layer removed and with and without use of an air/water surface cooling spray. METHODS: Tibial osteotomy defects were created in 4 groups of 6 rats each using the following: 1) #6 round bur with simultaneous saline irrigation; 2) CO2 laser with char layer intact; 3) CO2 laser with char layer removed; 4) Nd:YAG laser with air/water surface cooling, and char layer intact; 5) Nd:YAG laser with air/water surface cooling, and char layer removed; and 6) Nd:YAG laser without air/water surface cooling, and char layer removed. Both laser types were used at energy densities typically utilized for oral soft tissue surgery. RESULTS: Progressive healing from day 0 through day 21 post-treatment was observed in all treatment groups. However, compared to controls treated by rotary dental bur, those specimens treated by laser, regardless of laser type, energy density, or other parameters, exhibited a delay in healing that appeared to be related to the presence of residual char in the osseous defect. Specimens treated with the Nd:YAG laser using an air/water surface coolant exhibited a decreased thickness and continuity of the char layer and yielded the only specimens with new bone formation at the surface of the laser ablation defect. In addition, the normal pattern of bone remodeling in the rat tibia appeared to have been altered by laser irradiation. CONCLUSIONS: In this animal model, laser-induced osteotomy defects, when compared to those prepared by rotary bur, exhibited a delayed healing response that appeared to be related to the presence of residual char in the osseous defect.

Multi-center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. II. Clinical results.

The clinical safety and effectiveness of a subgingivally delivered biodegradable drug delivery system containing either 10% doxycycline hyclate (DH), 5% sanguinarium chloride (SC) or no agent (VC) was evaluated in a 9-month multi-center trial. The study was a randomized parallel design with 180 patients who demonstrated moderate to severe periodontitis. All patients had at least two quadrants with a minimum of four qualifying pockets > or = 5 mm that bled on probing. Two of the qualifying pockets were required to be > or = 7 mm. At baseline and at 4 months all qualified sites were treated with the test article administered via syringe. Probing depth reduction (PDR), attachment level gain (ALG), bleeding on probing reduction (BOP), and plaque index were determined monthly. Analysis of efficacy data from the 173 efficacy-evaluable patients indicated that all treatments gave significant positive clinical changes from baseline at all subsequent timepoints. DH was superior to SC and VC in PDR at all timepoints (P < or = 0.01 to 0.001) with a maximum reduction of 2.0 mm at 5 months. For ALG, DH was superior to VC at months 2, 3, 4, 5, 6, 8, and 9 (P < or = 0.04 to 0.002) and superior to SC at months 5, 6, 7, 8, and 9 (P < or = 0.01 to 0.001) with a maximum ALG of 1.2 mm at 6 months. For BOP reduction, DH was superior to VC at all time points (P < or = 0.05) and to SC at months 3, 5, 6, 8, and 9 (P < or = 0.03). For DH, the maximum ALG in deep (> or = 7 mm) pockets was 1.7 mm and PDR 2.9 mm compared to 0.8 mm and 1.6 mm, respectively for moderate (5 to 6 mm) pockets. Test articles were applied without anesthesia and no serious adverse events occurred in the trial. The results of this study indicate that 10% doxycycline hyclate delivered in a biodegradable delivery system is an effective means of reducing the clinical signs of adult periodontitis and exhibits a benign safety profile.