Objective. To analyze various quantitative measures of inflammatory activity and joint damage, including articular, radiographic, laboratory questionnaire, and physical function measures, in regard to changes in status in surviving patients and prediction of mortality in non-survivors over

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Quantitative magnetization transfer (qMT) imaging in skeletal muscle may be confounded by intramuscular adipose components, low signal-to-noise ratios (SNRs), and voluntary and involuntary motion artifacts. Collectively, these issues could create bias and error in parameter fitting. In this study, technical considerations related these factors were systematically investigated and solutions were proposed. First, numerical simulations indicate that the presence of an additional fat component significantly underestimates the pool size ratio (F). Therefore, fat-signal suppression (or water-selective excitation) is recommended for qMT imaging of skeletal muscle. Second, to minimize the effect of motion and muscle contraction artifacts in datasets collected with a conventional 14-point sampling scheme, a rapid two-parameter model was adapted from previous studies in the brain and spinal cord. The consecutive pair of sampling points with highest accuracy and precision for estimating F was determined with numerical simulations. Its performance with respect to SNR and incorrect parameter assumptions was systematically evaluated. QMT data fitting was performed in healthy control subjects and polymyositis patients, using both the two- and five-parameter models. The experimental results were consistent with the predictions from the numerical simulations. These data support the use of the two-parameter modeling approach for qMT imaging of skeletal muscle as a means to reduce total imaging time and/or permit additional signal averaging.

Objective Low-dose methotrexate [MTX] is an effective therapy for rheumatoid arthritis yet its mechanism of action is incompletely understood. Here, we explored induction of apoptosis by MTX. Methods We employed flow cytometry to assess changes in levels of intracellular proteins, reactive oxygen species [ROS], and apoptosis.Quantitative polymerase chain reaction was usedtoassess changes in transcript levels of select target genes in response to MTX. Results MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN. Conclusions Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease.

The problem of collecting and enforcing taxes arises from the fact that they are not self-enforcing; the mere existence of provisions in a statute book is only an authorization for a flow of money into the public treasury. Not until persons with legal authority to compel observance of the statute analyze its provisions, study its authorizations and limitations, and then enforce its terms does it become more than a list of words in a book.The tax administrator is concerned only with the most effective employment of available means for achieving the end of adequate tax collections under the statute he administers. Of no moment to him are the social effects of his tax law. That is the legislator's concern, as it is the concern of the judiciary that both taxpayer and administrator observe the law.' The administrator's means for realizing the desired end are three. They are (I) the application of legal devices available for enforcing compliance, (2) the disposal of personnel and regard for "economic" factors affecting collections, and (3) the conduct of public and taxpayer relations. It is the purpose of this article to examine these means and to attempt an evaluation of them. Since nearly all tax administrators are faced with the problem of what "is" rather than what "should be," the distinction between theoretically perfect conditions and actual, less than perfect conditions is kept in mind throughout. APPLICATION OF LEGAL DEvicEsAll tax laws contain legal devices designed to enforce compliance with their provisions. Any one of them is useful only in limited situations. The good tax law will therefore contain different "tools" for different situations, and the good tax administrator will use all the tools provided in the statutes to handle the various cranky col-*A. B., 1929,