Successful TCR-based immunotherapy for autoimmune myocarditis with DNA vaccines after rapid identification of pathogenic TCR

The identification of TCRs of autoimmune disease-inducing T cells within a short period of time is a key factor for designing TCR-based immunotherapy during the course of the disease. In this study, we show that experimental autoimmune carditis-associated TCRs, Vbeta8.2 and Vbeta10, were determined by complementarity-determining region 3 (CDR3)-spectratyping analysis and subsequent sequencing of the CDR3 region of spectratype-derived TCR clones. Immunotherapy targeting both Vbeta8.2 and Vbeta10 TCRs using mAbs and DNA vaccines significantly reduced the histological severity of experimental autoimmune carditis and completely suppressed the inflammation in some animals. Since depletion or suppression of one of two types of effector cells does not improve the severity of the disease significantly, combined TCR-based immunotherapy should be considered as a primary therapy for T cell-mediated autoimmune diseases. TCR-based immunotherapy after rapid identification of autoimmune disease-associated TCRs by CDR3 spectratyping can be applicable, not only to animal, but also to human autoimmune diseases whose pathomechanism is poorly understood.     

Principles in bone physiology

The view that nonmechanical agents dominate control of osteoblasts and osteoclasts and thus postnatal changes in bone strength and mass (agent --> effector cells --> disease) is obsolete. Nonmechanical agents include hormones, calcium, vitamin D, cytokines, gender, genetics, etc. This paradigm overlooks all tissue level features, biomechanics and relationships found after 1960. This more recent information led to the Utah paradigm of skeletal physiology, proposed by Harold Frost in 1995. The Utah paradigm's view is that mechanical factors dominate control of the biologic mechanisms that control changes in postnatal bone and mass. Nonmechanical agents could help or hinder the influence of the mechanical factors but could not replace them. The simplified scheme is as follows: [reaction: see text] New evidence supports the Utah paradigm which we view as a supplement to many former views, not as a negation of them.     

Anabolic agents and osteoporosis: quo vadis?

There are preclinical studies and limited clinical experiences with bone and muscle anabolic agents (e.g., parathyroid hormone (PTH), sodium fluoride (NaF), prostaglandins (PGs), growth hormones (GH), etc.) that show they have significant advantages over antiremodeling agents in patients with established osteoporosis. The strength of anabolic therapy is as follows: it rapidly reverses bone loss in laboratory animal models and humans, the quality of bone with some agents is believed to be normal, an increase in bone strength in animal models, and a reduction of spinal fracture rate with PTH. The weaknesses of this therapy are high cost, poor understanding of mechanism of action, parenteral mode of administration, rapid bone loss following termination of treatment, abnormal quality of bone, lack of tissue specificity, and undesirable side effects. Both animal and clinical studies have shown one can preserve the bone gain following termination of treatment with antiremodeling agents or exercise based on the lose, restore and maintain (LRM) concept. However, the more important efficacy issues which need to be addressed are tissue specificity and reduction of undesirable side effects. This report will address these issues with the suggestions that the potentiation of the mechanical loading osteogenic response by anabolic agents can overcome the disadvantages which accompany the use of anabolic agents. In addition, the possible role of nitric oxide (NO), an agent required for mechanical loading-induced bone formation, will be discussed.     

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q

Pyoderma gangrenosum, cystic acne, and aseptic arthritis are clinically distinct disorders within the broad class of inflammatory diseases. Although this triad of symptoms is rarely observed in a single patient, a three-generation kindred with autosomal-dominant transmission of these three disorders has been reported as "PAPA syndrome" (MIM 604416). We report mapping of a disease locus for familial pyoderma gangrenosum-acne-arthritis to the long arm of chromosome 15 (maximum two-point LOD score, 5.83; recombination fraction [straight theta] 0 at locus D15S206). Under the assumption of complete penetrance, haplotype analysis of recombination events defined a disease interval of 10 cM, between D15S1023 and D15S979. Successful identification of a single disease locus for this syndrome suggests that these clinically distinct disorders may share a genetic etiology. These data further indicate the role of genes outside the major histocompatibility locus in inflammatory disease.     

Improved Production of a Bioadhesive Precursor Protein by Fed-Batch Cultivation of a Recombinant Escherichia coli with a pLysS Vector

In batch cultivation, growth of a recombinant Escherichia coli with an inducible T7 expression system and maximum expression of a bioadhesive precursor (BP) protein was similar in the strains with and without the plasmid vector, pLysS. In fed-batch cultivation, however, the strain harboring pLysS grew slower and had a lower level of BP protein expression than that obtained with the strain without pLysS. This suggests that the presence of pLysS in the T7 expression system strongly affects the cell growth and expression of BP protein in high cell density cultivation.     

Discovery of halo-nitrobenzamides with potential application against human African trypanosomiasis

A series of halo-nitrobenzamide were synthesized and evaluated for their ability to block proliferation of Trypanosoma brucei brucei. A number of these compounds had significant activity against the parasite, particularly 2-chloro-N-(4-chlorophenyl)-5-nitrobenzamide 17 which exhibited low micromolar inhibitory potency against T. brucei and selectivity towards both malaria and mammalian cells.     

Interocular Retinal Nerve Fiber Layer Thickness Difference in Normal Adults

PurposeTo determine the interocular retinal nerve fiber layer (RNFL) thickness difference of normal subjects.MethodsBoth eyes of 230 normal adults received peripapillary RNFL thickness measurements using OCT. The effect of ocular cyclotorsion on the RNFL thickness profile was mathematically corrected. The fractional and absolute interocular RNFL thickness differences at 256 points of peripapillary area were calculated. We divided the subjects into 3 groups according to the locations of superior and inferior peak thickness, respectively, and compared the interocular RNFL thickness differences between the subgroups.ResultsThe fractional interocular RNFL thickness difference exhibited smaller regional variations than the absolute interocular difference. The means of fractional interocular differences were 0.100 ± 0.077 in the temporal half area and 0.146 ± 0.105 in the nasal half area, and the tolerance limits for the 95th and 99th distributions were about 0.246 and 0.344 in the temporal half area and 0.293 and 0.408 in the nasal half area, respectively. The fractional interocular differences of subgroups classified by the locations of superior and inferior peak RNFL thickness showed difference at smaller areas than the absolute interocular differences (19 and 8 points versus 49 and 23 points, respectively).ConclusionGlaucoma can be strongly suspected, if interocular fractional RNFL thickness difference is over 25% at 5 consecutive points or over 35% at 3 consecutive points in the temporal half area. The fractional interocular comparison is a better diagnostic approach because the fractional interocular RNFL thickness difference is less influenced by the locations of peak RNFL thickness.