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Congenital Frey's syndrome and bilateral trifid mandibular condyle are two different entities. The occurrence of both together is rare and has not been reported in the literature. This article describes the case of a 17-year-old male patient who complained of bilateral warmness, flushing and sweating in the preauricular area after eating spicy and sour foods since childhood. He had no complaint related to the functions of the temporomandibular joint and had no history of facial trauma. The patient was treated with injections of botulinum toxin A and the signs and symptoms of Frey's syndrome improved significantly.

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Evolvability of biopolymers is based on molecular coding. The molecular coding is represented by biopolymer function vs monomeric sequence relationship, that is, a proper fitness landscape on the sequence space. On the other hand, molecular coding is mostly realized by monomeric sequence vs biopolymer structure relationship. We suggest the evolution of evolvability based on flexible or multiplex coding originating from flexible or polymorphic conformation of evolving biopolymers. We report a finding supporting that the amino acid landscape of the standard genetic code for an amino acid property which is more important to the protein function gives higher value of an evolvability measure. We developed a promising molecular construct which realized genotype-phenotype linking in order to study the in vitroprotein evolution to clarify above mentioned protein evolvability.

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In vitro molecular evolution is regarded as a hill-climbing on a fitness landscape in sequence space, where the 'fitness' is a quantitative measure of a certain physicochemical property of a biopolymer. We analyzed a 'cross-section' of the enzymatic activity landscape of dihydrofolate reductase (DHFR) by using a method of analysis of a fitness landscape. We limited the sequence space of interest to the five-dimensional sequence space, where the coordinate corresponds to the 1st, 16th, 20th, 42nd and 92nd site in the DHFR sequence. Thirty six mutants mapped into the limited sequence space were taken in the analysis. As a result, the cross-section is of the rough Mt Fuji type based on the mutational additivity. The ratio of the mean slope to the roughness is 2.8 and the Z-score of the original ratio against a distribution of random references is 7.0, which indicates a large statistical significance. The existence of such a cross-section was discussed in terms of the occurrence probability of sets of five sites distantly separated from each other on the DHFR 3D structure. Our results support the effectiveness of the evolution strategy which exploits the accumulation of advantageous single point mutations in such a cross-section.

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The purpose of this study was to compare the potential of interleukin-4 (IL-4), IL-10, and IL-13 to interrupt two major inflammatory pathways in rheumatoid arthritis (RA), i.e., overexpression of proinflammatory cytokines and cytokine-mediated fibroblast growth. IL-4, IL-10, and IL-13 were all able to significantly inhibit the production of IL-1beta, tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8 by freshly isolated RA synovial tissue cells, IL-10 was most effective in terms of IL-1beta and TNF-alpha reduction. The IL-1 receptor antagonist was enhanced by IL-4 and IL-13, but only slightly enhanced by IL-10. Spontaneous interferon-gamma secretion was diminished by IL-4 and IL-10 but not by IL-13. Addition of anti-IL-10 neutralizing antibody to RA synovial tissue cells resulted in a substantial increase in IL-1beta and TNF-alpha levels, whereas neither anti-IL-4 nor anti-IL-13 antibody had a significant effect. IL-1beta-stimulated proliferation of RA synovial fibroblast cell lines was inhibited by IL-4 and IL-13, but not by IL-10; IL-4 was over tenfold more effective than IL-13. These results suggest that IL-4, IL-10, and IL-13 all have the therapeutic potential to regulate the disease activity mediated by proinflammatory cytokines in RA, but each cytokine may have different potencies.

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We examined properties of adaptive walks by the fittest on "rough Mt. Fuji-type" fitness landscapes, which are modeled by superposing small uncorrelated random component on an additive fitness landscape. A single adaptive walk is carried out by repetition of the evolution cycle composed of (1) mutagenesis process that produces random d-fold point mutants of population size N and (2) selection process that picks out the fittest mutant among them. To comprehend trajectories of the walkers, the fitness landscape is mapped into a (x, y, z)-space, where x, y and z represent, respectively, normalized Hamming distance from the peak on the additive fitness landscape, scaled additive fitness and scaled nonadditive fitness. Thus a single adaptive walk is expressed as the dynamics of a particle in this space. We drew the "hill-climbing" vector field, where each vector represents the most probable step for a walker in a single step. Almost all of the walkers are expected to move along streams of vectors existing on a particular surface that overlies the (x, y)-plane, toward the neighborhood of a characteristic point at which a mutation-selection-random drift balance is reached. We could theoretically predict this reachable point in the case of random sampling search strategy.

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We examined the effectiveness of an "adaptive leap" strategy using the "mutation scrambling" method as an efficient optimization technique (Uchiyama, 2000;J. Biochem.128, 441-447) for cases where mutational (rough) additivity holds in fitness. The mutation scrambling method is composed of the following three processes: (1) preliminary selection of several advantageous single-point mutations introduced in a wild-type sequence; (2) preparation of various multiple-point mutants incorporating the advantageous mutant residue or wild-type residue at each of the selected sites, by scrambling the mutant residues and wild-type residues (this process is called mutation scrambling); and (3) selection of the fittest through screening of the mutant pool. The fitness distribution in the mutant pool is controlled by the mixing ratio of the mutant residues to the wild-type residues. We focused on the mutant fitness distribution and obtained the optimal mixing ratio which efficiently generates superior multiple-point mutants with high fitnesses. As a result, we found that the optimal ratio lies between 7/3 and 9/1 in realistic cases. Particularly, this strategy works well in cases where the number of component mutations is large and the size of the population to be screened is small. Analysis of the mutant fitness distributions with various mixing ratios is also useful to explore local fitness landscapes.

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Apraxia of eyelid opening (ALO) is a non-paralytic motor abnormality characterised by difficulty in initiating the act of eyelid opening without blepharospasm. We found that wearing goggles improved the difficulty of opening eyes in two patients with ALO with parkinsonism. Wearing goggles is a simple method for improving daily life in patients with ALO.

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The effects of human urotensin II on coronary flow were studied in the perfused rat heart. Urotensin II transiently decreased coronary flow, then induced sustained vasodilatation. In the presence of a cyclooxygenase inhibitor, diclofenac, coronary vasodilatation was significantly inhibited. A nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NNA), attenuated the urotensin-induced vasodilatation. These data suggest that urotensin II modulates coronary flow through factors such as cyclooxygenase products and nitric oxide to elicit coronary vasodilatation.

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A method of analysis of a local fitness landscape for a current biopolymer is presented. Based on the assumption of additivity of mutational effects in the biopolymer, we assigned a site-fitness to each residue at each site. The assigned values of site-fitnesses were obtained by the least-squares method to minimize discrepancies between experimental fitnesses and theoretical ones. As test cases, we analyzed a section of a local landscape for the thermostability of prolyl endopeptidase and that for the enzymatic activity of thermolysin. These sections were proved to be of the rough Mt. Fuji-type with straight theta values of larger than 1.0, where straight theta is defined as the ratio of the "mean slope" to the "degree of roughness" on the fitness surface. Furthermore, we theoretically explained discrepancies between the fitnesses of multiple mutants and those predicted based on strict additivity of the component mutations by using a model of the rough Mt. Fuji-type landscape. According to this model, the discrepancies depend on the local landscape property (such as the straight theta value) and the location of the wild type on the landscape and the mean change in fitness by the component mutations. Our results suggest that this model may provide a good approximation of real sections of local landscapes for current biopolymers phenomenologically.

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Assigning the values of a certain physicochemical property for individual amino acids to the corresponding codons, we can make an amino acid property "landscape" on a four valued three dimensional sequence space from a genetic code table. Eleven property landscapes made from the standard genetic code (SGC) were analyzed. The evaluation of correlation for each landscape is done by theta value, which represents the ratio of the mean slope (as an additive term) to the degree of roughness (as a nonadditive term). The theta-values for hydropathy indices, polarity, specific heat, and beta-sheet propensity were considerably large with respect to SGC. This implies that the additivity of the contribution from each letter holds for these properties. To clarify the meaning of the so-called mutational robustness of SGC, we next examined correlations between the amino acid property and the actual "site fitnesses" of a protein. The site fitnesses were derived from a set of binding preference scores of amino acid residues at every site in MHC class I molecule binding peptides (Udaka et al. in press). We found that the SGC's theta value for an amino acid property is correlated with the significance of the property in the protein function. Adaptive walk simulation on fitness (= affinity) landscapes in a base sequence space for these model peptides confirmed better evolvability due to the introduction of SGC.

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We report a 55-year-old man with a chief complaint of wasting and weakness of the left quadriceps muscle. At age 54, he noticed difficulty in running and weakness in the left thigh, which gradually progressed. On the first admission to our hospital, based on the nerve conduction studies (NCS), the muscle biopsy findings showing neurologenic changes, and no abnormality of spinal MRI, we diagnosed as unilateral quadriceps amyotrophy, which resulted from an atypical form of spinal progressive muscular atrophy. One year later, he showed the bilateral hand weakness, conduction blocks on the right median and ulnar nerves by NCS, and the presence of serum anti-GM 1 antibody. From these findings, Lewis-Sumner syndrome was diagnosed. The therapy of high-dose intravenous immunoglobulin moderately improved his symptoms. The clinical symptoms of quadriceps amyotrophy is produced by various disorders including spinal progressive muscular atrophy, spinal extradural arachnoid cyst, rimmed vacuole myopathy, Becker dystrophy, limb-girdle dystrophy, and focal myositis. However, there have been no reports of a case of Lewis-Sumner syndrome. It is important to consider Lewis-Sumner syndrome in the differential diagnosis of quadriceps amyotrophy.

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We report here magnetic resonance imaging (MRI) findings of two patients with benign monomelic amyotrophy of lower limb. Both subjects showed unilateral amyotrophy of the lower limb with a benign clinical course, and the affected muscles demonstrated neurogenic changes. On T1- and T2-weighted MRI, marked atrophy and increased signal intensity were found mainly in gastrocnemius and soleus muscles. Moreover, MRI examination also revealed that thigh muscles including semitendinosus, semimembranosus, and vastus intermedius and lateralis muscles were involved in one of the patients. We concluded that muscle MRI is very useful for detecting affected muscles, especially deep skeletal muscles in patients with benign monomelic amyotrophy of lower limb.

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OBJECTIVE: To examine the ability of fibroblast-like synoviocytes in rheumatoid arthritis (RA) to produce interleukin-7 (IL-7) and IL-15, and the ability of these cytokines to induce the proliferation of synovium-infiltrating T cells. METHODS: Messenger RNA (mRNA) and protein levels of IL-7 and IL-15 in synovial tissue cells and fibroblast cell lines were determined by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. T cell-enriched populations from RA synovial tissues were isolated by deleting adherent cells after a 14-hour incubation in plastic dishes or by expanding T cells during a 14-day incubation of tissue cells with IL-2 alone, and their proliferative responses to IL-7, IL-15, and IL-2 were measured by 3H-thymidine incorporation. RESULTS: Freshly isolated cells from RA synovial tissues more strongly expressed mRNA for both IL-7 and IL-15 compared with the cells from osteoarthritis tissues, and could spontaneously release greater amounts of these cytokine proteins in culture. Fibroblast cell lines prepared from RA patients were able to produce large amounts of IL-15 and small amounts of IL-7 at both the transcriptional and protein levels, and their cytokine production was significantly elevated when stimulated with IL-1 and tumor necrosis factor alpha. Purified synovial tissue macrophages spontaneously released IL-15 but not IL-7, and synovial T cells did not produce either cytokine. IL-7 and IL-15, similar to IL-2, stimulated the proliferation of synovial tissue T cells from RA patients; IL-7 was less potent than IL-15 or IL-2. CONCLUSION: These results indicated that fibroblast-like synoviocytes are an important source of the cytokines with IL-2-like activity, IL-15 and IL-7, in RA joints, and that IL-15 may be mainly responsible for local T cell activation and expansion in the presence of deficient IL-2 production by T cells.

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Mitogen blastogenic responses of lymphocytes from dogs infested with adult Rhipicephalus sanguineus and the effects of salivary gland extracts (SGE) of the tick on the blastogenic responses of lymphocytes from normal dogs were studied. Infestation by R. sanguineus significantly suppressed concanavalin A, phyto-hemagglutinin and pokeweed mitogen responses of lymphocytes from dogs. The inhibition of lymphocyte responses of dogs in the first infestation was greater than that in the second infestation. SGE from R. sanguineus also suppressed all mitogen blastogenic responses of lymphocytes from healthy dogs in vitro. These suppressive effects of SGE on the blastogenic responses of PBL to mitogens were significantly inhibited by trypsin digestion. It is suggested that some proteins in SGE contribute to the suppressive effects of SGE on the blastogenic responses of peripheral blood lymphocytes from dogs.

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Based on the theory of fitness distributions on a Mt. Fuji-type fitness landscape in a multivalued sequence space (Aita & Husimi, 1996 J. theor. Biol. 182, 469-485), we investigated the properties of adaptive walks on the ideal landscape in the case of a cloning-screening-type evolution experiment. We modeled that an adaptive walk is performed by repetition of the evolution cycle composed of the mutagenesis process generating random d-fold point mutants of population size N and the selection process looking for the fittest mutant among them. While an adaptive walk is described in a sequence space, we simplified the description as follows. We mapped the landscape in an x-y plane, where x and y represent a normalized Hamming distance from the global peak and a scaled fitness, respectively. An adaptive walk is described as a trajectory in the plane. The most certain step for a walker to move in a single evolution cycle is represented by a vector in the plane. Then, a walker moves along the streams in the vector field determined by d and N. The walker performs fast hill-climbing until a "trap-line", which traverses the plane. Subsequently, the walker is likely to get trapped in an "apparent local optimum". To continue the walk, apparent local optima must be eliminated by resetting d and N larger. Therefore, for the fastest walk, the optimal schedule of the d-values (initially large d, then small d) is effective, although the economical walk with high cost-performance is different. If a real landscape is just of the Mt. Fuji-type, the walk with the highest cost-performance will be performed by scanning site-directed optimization through all sites. However, in the case of the rough Mt. Fuji-type, which seems to be more realistic, the walking method we have examined will be effective for a walker to sidestep true local optima.Copyright 1998 Academic Press

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The efficacy and safety of minocycline was investigated in Japanese patients with rheumatoid arthritis (RA) who had already received more than three disease modifying anti-rheumatic drugs (DMARDs). Minocycline was administered at 100 mg twice a day to fifteen patients with active RA. The drug efficacy was evaluated by the clinical variables including the number of painful and/or swollen joints, the duration of morning stiffness, grip strength, the erythrocyte sedimentation rate, serum concentrations of C-reactive protein, and the titer of rheumatoid factor. Three patients experienced adverse effects such as dizziness and abdominal pain or discomfort, but only one patient with abdominal pain and dizziness was discontinued. Fourteen RA patients, who had taken minocycline for at least 6 months, were subjected to the clinical evaluation. Among them, 8 patients (54%) showed a significant improvement of clinical valuables for disease activity, beginning even at 4 weeks of the therapy. The continued effects were observed in 8 patients with over 1 year-minocycline therapy. Intriguingly, an active patient with a history of multiple DMARDs-resistancy showed a marked favorable response to this drug. The present study indicates that minocycline may be an effective DMARD with highly safe performance for patients with active and refractory RA. This is the first demonstration of the benefit of minocycline in the Japanese patients.

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Very efficient ligation of oligodeoxyribonucleotides was attained through a simple molecular construct, which is composed of one stem and two branches (Y-shape), with use of T4 RNA ligase. Single-stranded DNAs (naturally, RNAs also) of more than 100 nucleotides (even 800 nts) were considerably ligated, approximately as theoretically expected. Owing to the molecular construct adopted, such a tiny amount of ligation products could be amplified to a sufficient amount by PCR and then recovered as single-stranded DNAs. This advantage of being amplifiable is shown to be useful for both combinatorial chemistry and evolutionary molecular engineering, which deal with a pool of diversity molecules.

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The patient had adult GM1 gangliosidosis (type 3) with severe impairment of mastication caused by dystonia of anterior digastric muscles (jaw-opener) on clenching. This is the first report on jaw dystonia severe enough to cause the masticatory impairment in adult GM1 gangliosidosis. The discordance of closing and opening muscles during mastication might be caused by a basal ganglia lesion in this disease.

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A patient with chorea-acanthocytosis presenting with axonal neuropathy showed an elevation in IgM polyclonal antibodies to the GM1 ganglioside, which were estimated by enzyme-linked immunosorbent assay and complement-mediated liposome immune lysis assay (LILA). This is the first demonstration of such antibodies in chorea-acanthocytosis. Anti-GM1 antibodies might have directly caused the axonal neuropathy by binding to GM1 or cross-reactive antigens in the nerves.

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