Northernmost record of a whale shark Rhincodon typus from the Sea of Okhotsk.

The whale shark Rhincodon typus is the world's largest fish and it occurs in tropical, subtropical and warm temperate waters. Here, the northernmost record of R. typus is reported, when it was found in the Sea of Okhotsk for the first time. This occurrence can be explained by the unusually high sea surface temperature during the summer of 2012.

Selective insufficiency of IFN-gamma secretion in patients with hyper-IgE syndrome.

BACKGROUND: Hyper-immunoglobulin E (IgE) syndrome is a complex immune deficiency characterized by chronic eczematous dermatitis, recurrent staphylococcal infections, pneumatoceles, reduced neutrophil chemotaxis, and variably impaired T cell function. Although decreased interferon-gamma (IFN-gamma) production in patients with hyper-IgE syndrome is pointed out and known as a cause of reduced neutrophil chemotaxis, precise mechanism of their inadequate production of IFN-gamma remains unknown. To elucidate the pathogenesis of the defective production of IFN-gamma in patients with hyper-IgE syndrome, we assessed the in vitro production and secretion of IFN-gamma by peripheral blood mononuclear cells (PBMCs) from patients with hyper-IgE syndrome. METHODS: Chemotaxis of neutrophils, mRNA levels of several cytokines, intracellular production and extracellular secretion of IFN-gamma, interleukin-2 (IL-2), and IL-4 by PBMCs from three patients with hyper-IgE syndrome were determined. RESULTS: The transcription of IFN-gamma mRNA and the production of its protein molecules progressed normally. However, selective insufficiency in the secretion of IFN-gamma molecules was found in patients with hyper-IgE syndrome. Confocal laser scanning microscopy clearly demonstrated the accumulation of IFN-gamma in patients with hyper-IgE syndrome. CONCLUSION: We demonstrated that there was a selective insufficiency in the secretion of IFN-gamma in patients with hyper-IgE syndrome. We hope that this fact would offer a new paradigm for understanding this disease.

Design and synthesis of carboxylate inhibitors for matrix metalloproteinases.

A series of carboxylate compounds were prepared from N(alpha)-substituted 2,3-diaminopropionic acid and were tested for efficacy as matrix metalloproteinase (MMP) inhibitors. During modeling of the initial compound 10a, we utilized three-dimensional structure modeling software (InsightII/Discover Ver. 2.98). Some of the prepared carboxylate derivatives, such as carbamate compounds (12c,d, 22) and sulfonamide compounds (14b,c), proved to be effective MMP-1 inhibitors (with IC50 values of a 10(-6) M order), depending on the substituent at the N(alpha)-position of 2,3-diaminopropionic acid. Some of them were also evaluated for inhibition of stromelysin-1 (MMP-3), and the sulfonamide compound 14c exceeded the lead compound 5b in its MMP-3 inhibitory potency. For the carbamate compounds, we investigated the minimum molecular size at which the MMP-1 inhibitory potency was maintained, and found that this was P3-P1' compound 10b.

[Why there were few isolations of tubercle bacilli in young children with pulmonary tuberculosis?].

We retrospectively evaluated the factors influencing the isolation of tubercle bacilli in 51 children under 14 years of age with pulmonary tuberculosis who were admitted to Yokohama City University Hospital from 1975 to 1998. Young children (0-6 years of age) with pulmonary tuberculosis were significantly less positive by smear and culture than elder children (7-14 years of age) with pulmonary tuberculosis. According to the Japanese Society for Tuberculosis classification of finding on chest X-ray film for pulmonary tuberculosis, the culture-positive patients with type II (cavitary lesions) were found in all, the culture-positive patients with type III (non-cavitary lesions) in 39.3%, and the culture-positive patients with type H (hilar and mediastinal lymphadenopathys) in 35.3%. Patients with cavitary lesions (type II) were significantly more positive by smear and culture than patients with non-cavitary lesions (type III + type H). Only 15.8% of the young children with pulmonary tuberculosis had received BCG vaccine and all had non-cavitary lesions (type III and type H). But, 84.6% out of the older children had received BCG vaccine and half had cavitary lesions. Taken together, the result was that there were few isolation of tubercle bacilli in young children with pulmonary tuberculosis because they had non-cavitary tuberculosis without delayed-type hypersensitivity to tubercle bacilli.

[Analysis of tuberculin reaction of tuberculous children below 4 years of age].

To clarify whether the size of tuberculin reaction could be used as an useful index of the severity of tuberculosis, we analyzed the sizes of tuberculin reaction (TR) of 60 children below 4 years of age with active tuberculosis at the time of diagnosis. Of 60 patients, 53 (88.9%) had positive reactions to tuberculin. The mean size of TR of 60 patients was 24.0 +/- 13.9 mm and maximum size was 60 mm. Seven patients who had no reaction to the tuberculin skin test consisted of three primary complex and four serious tuberculosis (two miliary tuberculosis and two tuberculous meningitis). The patients without BCG vaccination showed significantly smaller TR than the patients with BCG vaccination (p < 0.05). The patients less than 1 year of age showed significantly smaller TR than the patients of 4 years of age (p < 0.05). The patients with serious tuberculosis showed significantly smaller TR than the patients with primary complex (p < 0.05). Of patients with primary complex, there were no difference of the size of TR between the patients with pulmonary tuberculosis (III) and hilar lymphadenopathy (H). Together with, it did not necessarily mean that negative TR showed no infection with tuberculosis and the sizes of TR depended on the severity of tuberculosis in infantis and young children.

[Effective combination therapy of plasma exchange and subsequent cyclophosphamide pulses for catastrophic antiphospholipid antibody syndrome: a case report].

A 7-year-old girl with catastrophic antiphospholipid antibody syndrome was described. She firstly admitted to the local hospital with the complaints of persistent fever and abdominal pain, and was diagnosed as systemic lupus erythematosus with the laboratory findings as follows; positive for antinuclear antibody, anti-DNA antibody, and platelet-associated IgG, thrombocytopenia, and hypocomplementemia. 10 days after the initiation of oral prednisolone, she suddenly manifested tonic convulsion and unconsciousness accompanied by high fever. Because of the unresponsiveness to the methylprednisolone pulse therapy for supposed CNS lupus, she was transferred to our hospital. Her unconsciousness persisted, and pulsation on dorsalis pedis was not palpable on admission. Laboratory investigation revealed the falsely positive VDRL, a prolonged aPTT, positive for lupus-anticoagulant and antiphospholipid antibody. The magnetic resonance image demonstrated multiple spotty hyperintensity (T2) in the brain consistent with multiple hemorrhagic infarcts. Arteriogram demonstrated the infarct of dorsalis pedis, and coronary aneurysms. These findings were compatible with the criteria of catastrophic antiphospholipid antibody syndrome, she was diagnosed as catastrophic antiphospholipid antibody syndrome. The plasma exchange and subsequent cyclophosphamide-pulse therapy, which was given once a month for first 6 months, and later, at 3 months intervals, was effectively administered. This combination and oral anti-thrombotic therapy revealed effective for this kind of fatal disorder.

[Computed tomography with normal chest radiography in childhood tuberculosis].

During the recent 2 years we experienced 5 children (2 months-5 years old) with lung tuberculosis, all of whom had positive tuberculin skin-tests, and were in close contact with their family members who had active tuberculosis. However, no abnormal findings on chest X-ray films were pointed out by 2 independent roentogenologists, and no increased levels of inflammatory markers including WBC numbers, CRP, and ESR were detected in all but one child. Moreover, mycobacterial examination of sputa and/or gastric aspirates by microscope, culture technique, and PCR amplification revealed no causative bacilli in 4 children. To clarify whether these children were affected by Mycobacterium tuberculosis, chest CT scan was applied. Surprisingly, all 5 children were revealed to have abnormal changes including primary complexes in the lung field. Taken together, it is important to pursuit the apparent lung tuberculosis in children with a positive family history and positive tuberculin skin-test.

[Improvement of the maintenance therapy after methylprednisolone pulse therapy--effect of prednisolone combined with immunosuppressants].

OBJECTIVES: We investigated the effect of the combination therapy of prednisolone (PSL) and immunosuppressants after methylprednisolone pulse therapy. METHODS: A protocol of PSL (15-20 mg/day) and mizoribine (150-200 mg/day) after methylprednisolone (mPSL) pulses was used for 2 years to treat 7 patients (PSL + MZB group). Cyclophosphamide (CYC) pulse therapy was added to the combined therapy in 4 patients with severe lupus nephritis. The total dose of predinisolone, and side effects were compared with those in 6 patients who were treated with PSL (30 mg/kg) alone after mPSL pulse therapy (PSL group). RESULTS: No relapses occurred in the PSL + MZB group, although all of 6 patients relapsed in the PSL Group. The total doses of PSL in the PSL + MZB group was about 70% of the PSL Group. There were two patients with Herpes-Zoster infection and one patient with liver dysfunction as side effects, with no differences in the frequency of side effects between the was groups. CONCLUSIONS: Combination maintenance therapy with prednisolone and immunosuppressants after methylprednisolone pulse therapy was effective in preventing relapse.

Recombinant IFN-gamma treatment of a patient with hyperimmunoglobulin E syndrome triggered autoimmune thrombocytopenia.

We report a pediatric patient with hyperimmunoglobulin E syndrome (HIES) treated with recombinant IFN-gamma (rIFN-gamma) for 2 1/4 years who developed autoimmune thrombocytopenia and was positive for serum antiplatelet antibody and antinuclear antibody (ANA). She was then treated with i.v. methylprednisolone pulse therapy followed by oral immunosuppressive drugs. With this therapy, her platelet count increased and was maintained within the normal range for more than a year. We retrospectively examined her sera stored at -40 degrees C for ANA and found that the ANA level was increased from 1:40 to 1:640 with the rIFN-y therapy. Therefore, we believe that, in this case, rIFN-y treatment may have played a crucial role in triggering autoimmune thrombocytopenia. Furthermore, this case demonstrates that caution must be observed in administering rIFN-gamma to genetically predisposed patients.

[Clinical analysis of 11 cases of juvenile dermatomyositis and polymyositis].

Juvenile dermatomyositis (JDM) is characterized by microvasculopathy of the striated muscle, which indicates different etiology, clinical manifestation and prognosis from the adult-onset dermatomyositis. We experienced 10 cases of JDM and 1 case of juvenile polymyositis (JPM) in the recent 14 years, and analyzed clinical manifestation, laboratory findings, treatment anrognosis. The cases were 9 girls and 2 boys. The onset of the disease was 2 years of age in 2 patients, and 9 to 13 years of age in 9 patients. During the follow-up courses, no cases were dead or complicated with neoplasm. Skin rash was the most frequent manifestation at the onset, and facial erythema was common. Muscle weakness was observed only in 4 cases at the onset, and in all cases muscle enzymes including creatine kinase and aldolase were elevated. The clinical course was classified into three groups; monocyclic (5 cases), chronic and recurrent (4 cases), and fulminant (2 cases). Prognosis depended not on the degree of the elevated serum muscle enzymes, but on the initial therapy employed at the onset of the disease. Five cases including 2 cases of fulminant type were initially treated with methylprednisolon pulse therapy, and all of these had no recurrence. On the other hand, 6 cases were started the therapy with p.o. prednisolone. Four of them had frequent recurrences in accordance with tapering of prednisolone. These cases were effectively treated with the combination with immunosuppressants. In previous reports, JDM and JPM were reported to be a disorder which had relatively favorable prognosis. But we found that one third of the cases had chronic and recurrent courses. Methylprednisolone pulses as initial therapy may be effective in preventing the chronicity and recurrence of the disease.

[A case of macrophage activation syndrome developed with systemic juvenile rheumatoid arthritis].

We reported a child of macrophage activation syndrome (MAS) associated with the course of systemic juvenile rheumatoid arthritis (sJRA). The clinical and laboratory findings in our case was ascribed to the overproduced inflammatory cytokines especially TNF-alpha by activated macrophages. Moreover, macrophage-colony stimulating factor (M-CSF) was also elevated in the active phase of the disease, and decreased in the convalescent phase, indicating that M-CSF can be the most potent stimulator of macrophages to produce inflammatory cytokines. Cyclosporine A along with plasmaexchange and corticosteroid, instead of VP16 or other immunosuppresive agents, was effecting in the management of this severe, life-threatening MAS.

Mixed connective tissue disease in childhood: a nationwide retrospective study in Japan.

Sixty-six children with mixed connective tissue disease (MCTD) were analyzed by a nationwide prospective study. The diagnostic significance of Raynaud's phenomenon and positive anti-RNP antibody was confirmed, and additional symptoms including swelling of fingers, facial erythema, and polyarthralgia, and laboratory findings such as positive rheumatoid factor, hypergammaglobulinemia, and increased levels of myogenic enzymes, were variably positive. These clinical and laboratory characteristics of MCTD were critically different from those of systemic lupus erythematosus, indicating that MCTD is an independent entity of disease.

[A case of staphylococcal scalded skin syndrome caused by exfoliative toxin-B producing MRSA].

We experienced a 6 month-old infant who suffered from staphylococcal scalded skin syndrome (SSSS), whose mother used steroid ointment for the infant's erythematous skin rash for 2 days. On the 3rd day, the infant was admitted to our hospital with fever, erythema on the trunk and extremities, and flaccid blisters and erosions at periorificial areas and the neck. Nikolsky's sign was positive. S. aureus was cultured from the throat, conjunctival inflammatory lesion and exudates. The biological characteristics of the isolates were coagulase type I, enterotoxin-nonproducing, TSST-1-nonproducing, protease pattern: D type, and plasmid profile: 563 kbp. The investigation of exfoliative toxin (ET) revealed negative for ET-A but positive for ET-B, proved by polymerase chain reaction (PCR). The isolated strain of S. aureus was demonstrated to be methicillin-resistant (MRSA), which was further defined to be positive for mec A gene by PCR method. It will be possible for such toxigenic ET-B producing MRSA to gain the dominant status in NICU or closed areas.

[A case of tuberculous meningitis followed by tuberculoma with pan-hypopituitarism].

We reported a case who suffered from tuberculous meningitis at 10 months of age, and progressed to basal tuberculoma despite intensive drug therapy with isoniazid, rifampin, and streptomycin. Pan-hypopituitaliam due to basal tuberculoma was effectively replaced by the administration of anti-diuretic hormone (DDAVP) and levothyroxine sodium. Basal tuberculoma was finally removed by surgical operation. Histopathological examination of the tuberculoma revealed Mycobacterium tuberculosis and Langhans giant cells. During the 6 years after the operation, her growth rate was found to be retarded, and the administration of human growth hormone was started. Remarkable catch-up growth was demonstrated. We like to emphasize that infantile tuberculosis, mostly a result of intafamilial transmission, may manifest meningitis in the early phase of the disease, and it sometimes progresses to basal tuberculoma unresponsive to anti-mycobacterial drug therapy.

Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors.

Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxy]phenyl]propanoi c acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]- 3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4,DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 microM, doubled plasma recalcification time (PRCT) at 0.5 microM, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 microM).

A novel factor Xa inhibitor: structure-activity relationships and selectivity between factor Xa and thrombin.

A series of 3-amidinoaryl-2-[4-[ [(3S)-3-pyrrolidinyl]oxy]phenyl] propanoic acids have been investigated for development of a novel factor Xa inhibitor, possessing a potent inhibitory activity for factor Xa and a selectivity for factor Xa compared to thrombin. In order to study the structure-activity relationships and the selectivity, models of factors Xa complexes formed with the inhibitors were constructed on the basis of X-ray crystallographic data of a trypsin-inhibitor complex. The models showed that the binding mode of the inhibitors to the S1 pocket of the enzyme accounted for the structure-activity relationships and that the difference between Gln192 of factor Xa and Glu192 of thrombin had a key role in the selectivity.