[Multiple calcifying fibrous pseudotumor of the pleura].

A newly recognized distinctive fibrous soft tissue lesion called "calcifying fibrous pseudotumor" (CFPT) was recently described in the soft tissue of the extremities, trunk, scrotum, groin, neck, or axilla. But CFPT orgining from the pleura is rare. A 44-year-old woman was admitted to our hospital for an investigation of a chest radiographic abnormality. The complete resection was performed through mini-thoracotomy utilizing video assisted thoracoscopic surgery. Microscopically, the lesion was mostly composing dense collagenous tissue and scattered calcifications. The postoperative course was uneventful and no recurrence is observed 18 months after operation. We report succsessful surgical treatment for multiple CFPTs.

Muscle metabolism in patients with polymyositis simultaneously evaluated by using 31P-magnetic resonance spectroscopy and near-infrared spectroscopy.

Simultaneous measurements of muscle energy metabolism using (31)P-magnetic resonance spectroscopy ((31)P-MRS) and the kinetics of muscular oxygen metabolism using near-infrared spectroscopy (NIRS) were conducted in polymyositis (PM) patients. The subjects were 12 PM patients (age 45 +/- 12 years) and 12 normal controls (age 41 +/- 12 years). The muscle phosphocreatine (PCr) index and intracellular pH (pHi) were determined with (31)P-MRS and the changes in intramuscular oxygenated (oxy-Hb), deoxygenated (deoxy-Hb), and total haemoglobin (total Hb) were evaluated with NIRS . The pHi and PCr index before steroid therapy in PM patients were significantly lower during exercise than in normal controls, and their recovery was statistically significantly delayed compared with the controls. The pattern of changes in NIRS over time before steroid therapy in PM patients differed from that in normal controls. There were smaller changes in deoxy-Hb and oxy-Hb during exercise, and total Hb decreased during exercise. In contrast, the kinetics of muscular metabolism after steroid therapy showed changes similar to those seen in normal controls. Simultaneous (31)P-MRS and NIRS measurements to determine the kinetics of muscular metabolism are expected to be useful as a noninvasive approach for the evaluation of treatment effects in PM patients.

Evaluation of the position, mobility, and morphology of the disc by MRI before and after four different treatments for temporomandibular joint disorders.

OBJECTIVES: The purpose of this study was to evaluate changes in disc position, mobility, and morphology in patients with temporomandibular joint disorders (TMD) in response to four different treatments, splint therapy, pumping manipulation, arthrocentesis, and arthroscopic surgery, using magnetic resonance imaging (MRI). METHODS: Eighty-five joints (85 patients) with unilateral internal derangement or osteoarthritis that were successfully treated were included in this study. The patients were divided into four groups as follows: splint therapy group, pumping manipulation group, arthrocentesis group, and arthroscopic surgery group. Changes in the disc position, mobility, and morphology before and after treatment were compared among the four groups using MRI. RESULTS: All discs showed anterior disc displacement (ADD) without reduction before treatment. Only 10% of the joints became ADD with reduction after treatment, and the other joints remained ADD without reduction in spite of treatment. Discs treated by arthroscopic surgery were located more anteriorly compared with pre-treatment. In pre-treatment MRI, the rate of stuck disc increased as the stage of the treatment advanced. In post-treatment MRI, all temporomandibular joints (TMJs) had mobile discs. The disc deformity advanced after arthrocentesis and arthroscopic surgery. CONCLUSIONS: Even though clinical signs and symptoms were alleviated by treatment, most discs remained ADD without reduction on MRI in spite of treatment. This suggests that the four treatments do not necessarily improve the position and deformity of the disc, and that arthroscopic surgery advances the deformity and anterior displacement of the disc. Disc mobility is important for improving clinical signs and symptoms.

[Corrective surgery for pectus excavatum in patients with Marfan syndrome].

OBJECTIVE: Among 1,967 patients who underwent corrective surgery for pectus excavatum in our department between January 1980 and December 2001, 33 patients diagnosed as having Marfan syndrome were evaluated. We evaluated the clinical problems and outcome of the 33 patients. RESULTS: The outcome of corrective surgery for pectus excavatum in the 26 patients who underwent a single technique surgery was generally good. Pectus excavatum was complicated by a total of 25 cases of cardiovascular disorder in 14 of 33 (42%) patients. Six patients underwent corrective surgery for pectus excavatum and cardiovascular disorders simultaneously. Three patients also had disorders of lung, which included spontaneous pneumothorax in 2 patients and progressive emphysematous cyst in 1 patient. The 2 patients with spontaneous pneumothorax underwent resection of bullae together with corrective surgery of pectus excavatum, while the patient with progressive emphysematous cyst underwent resection of bullae in a separate surgery after correction of pectus excavatum. Cardiovascular disorders were aggravated in 6 of the 20 patients who could be follow up. A total of 4 (20%) patients died long after surgery. CONCLUSIONS: We corrected pectus excavatum in 33 patients with Marfan syndrome, and obtained favorable outcomes. The postsurgical outcome depends on progression of lesions of the heart and large vessels, and it is essential to monitor such lesions carefully.

Beta-adrenoceptors: three-dimensional structures and binding sites for ligands.

Recent progress in analyzing the structures and functions of G-protein coupled receptors (GPCRs) including beta-adrenoceptors (beta-ARs) has been made by pharmacological, physiological and molecular biological techniques. The three-dimensional (3D) structures, interaction sites with ligands and conformational changes of these receptor subtypes due to ligand binding are now better understood by the simulation of these receptors using computer-aided molecular modeling. Based on these techniques, numbers and conformations of amino acid sequences of each subtype (beta1-, beta2- and beta3-ARs) were defined and also interaction sites or modes of interaction between ligands and beta-ARs could be analyzed three-dimensionally. In addition, simulation of 3D structures of beta-ARs by molecular modeling could clearly determine the limited size, space or pocket for fitting with ligands. These studies will give some clues for the clarification of other GPCRs. Thus, this review summarizes current findings on chemical structures of ligands, amino acid sequences, 3D structures and important amino acids of beta-AR subtypes for interacting with ligands obtained from mutagenesis, chimeric studies and molecular modeling techniques.

Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation.

BACKGROUND: Although immunosuppressive therapy for myocarditis has attracted a great deal of attention, its effectiveness is controversial. Interleukin (IL)-10 has a variety of immunomodulatory properties. Among the nonviral techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. METHODS AND RESULTS: We examined the applicability of murine IL-10 (mIL-10) gene transfer to the treatment of rats with experimental autoimmune myocarditis. Nine-week-old Lewis rats were inoculated with pig myosin (day 0). A plasmid vector expressing mIL-10 cDNA (800 microgram per rat) was transferred into the tibialis anterior muscles by electroporation 3 times (5 days before immunization and at days 4 and 13); control rats received empty plasmid. Electroporation increased the serum mIL-10 levels to >250 pg/mL. The 21-day survival rate in rats treated with mIL-10 cDNA was higher (15 of 15; 100%) than that of the control group (9 of 15; 60%). Furthermore, mIL-10 treatment significantly attenuated myocardial lesions and improved hemodynamic parameters. CONCLUSIONS: These findings showed that gene transfer into muscle by electroporation in vivo is an effective means of delivery of IL-10 for the treatment of autoimmune myocarditis.

Analysis of lupus activity in end-stage renal disease treated by hemodialysis.

OBJECTIVE: The activity of systemic lupus erythematosus (SLE) has been reported to decrease in patients who have developed end-stage renal disease (ESRD). However, extrarenal symptoms attributable to the disease activity are noted, especially during the first year of dialysis. We studied the clinical course and evaluate the disease activity of SLE in patients with ESRD on hemodialysis for more than 6 months. SUBJECT AND METHODS: Fourteen patients with SLE who had been initiated on maintenance dialysis at our center between 1982 and 1999 were examined retrospectively. Their clinical details, organ system manifestations, serologic profiles and immunosuppressive treatment regimens were reviewed. Patients with and without postdialysis flaras of SLE were compared statistically. RESULTS: Five patients exhibited 6 SLE flares under treatment with corticosteroids. Two flares occurred within the first year of the initiation of dialysis, and in 1 patient, aggravation of the disease activity was noted 98 months after the initiation of dialysis. Polyarthritis was noted in 5 cases and fever in 4 cases. The serum complement levels decreased in all 6 cases with relapse of SLE activity. Compared with the other 9 patients who did not exhibit SLE relapse, no significant differences were found in 5 patients who did with respect to the demographic and serologic features at the initiation of dialysis. CONCLUSION: We conclude that the disease activity does not always burn out in patients of SLE who show progression to ESRD. SLE flares can sometimes occur even after one year of the initiation of dialysis. SLE patients on dialysis should be carefully followed up by clinical and serological monitoring, and treated by appropriate immunosuppressive therapy.

Bopindolol: pharmacological basis and clinical implications.

Bopindolol, a non-selective antagonist of beta 1- and beta 2-adrenoceptors (ARs), has been found by pharmacological, molecular biological techniques and molecular modeling to have several unique properties. Bopindolol produces sustained blockade of beta 1- and beta 2-ARs, has intrinsic sympathomimetic as well as membrane stabilizing actions, inhibits renin secretion, and interacts with 5-HT receptors. Also, our recent molecular modeling studies identified possible interaction sites between bopindolol and beta-AR subtypes. The reviewed studies support our findings that bopindolol is non-selective for beta 1- and beta 2-ARs, has low affinity for beta 3-AR subtype and has pharmacological properties that are likely to be beneficial in the treatment of cardiovascular diseases.

Four strains of spontaneously hyperlipidemic (SHL) mice: phenotypic distinctions determined by genetic backgrounds.

Spontaneously hyperlipidemic (SHL) mice are Japanese wild mice (KOR) with disruption of the apolipoprotein E (Apo E) gene. These mice (KOR-Apoe(shl)) are superhypercholesterolemic and develop severe xanthoma, but their atherosclerosis is relatively mild compared with Apo E knockout mice. First, we tested whether this distinction is due to additional mutation of the Apoc1 and/or Apoc2 genes in KOR-Apoe(shl). Southern blot analysis, but found no gross disruption of these genes. Next, we tested whether the phenotypic distinction is due to differences in the genetic background. To this end, we established three lines of congenic SHL mice with a genetic background of C57BL/6, BALB/c or C3H/He, and named them, respectively, C57BL/6.KOR-Apoe(shl) (B6.KOR-Apoe(shl)), BALB/c.KOR-Apoe(shl) (C.KOR-Apoe(shl)) and C3H/He.KOR-Apoe(shl) (C3.KOR-Apoe(shl)). Hypercholesterolemia was most severe in KOR-Apoe(shl) followed the by others as follows; KOR-Apoe(shl)>>C3.KOR-Apoe(shl)>C.KOR-Apoe(shl)>B6.KOR-Apoe(shl). In contrast, atherosclerosis was most severe in B6.KOR Apoe(shl) followed by the others: B6.KOR-Apoe(shl)>C.KOR-Apoe(shl)>>C3.KOR-Apoe(shl)> or =KOR-Apoe(shl). This order, however, did not match that in xanthoma, which was highly prominent in KOR-Apoe(shl) but mild in B6.KOR-Apoe(shl), C.KOR-Apoe(shl) and C3.KORApoe(shl). This order, however, did not match that in xanthoma, which was highly prominant in KOR-Apoe(shl) but mild in B6.KOR-Apoe(shl), C.KOR-Apoe(shl) and C3.KOR-Apoe(shl). These distinctions suggest that the severity of each of the phenotypes is determined by distinct genetic backgrounds which probably are composed of polymorphism of lipid metabolism-related proteins. We found that apolipoprotein A-I is decreased in each SHL strain and polymorphic between B6.KOR-Apoe(shl) and the other strains examined. This polymorphism may be related to the most severe atherosclerosis observed in B6.KOR-Apoe(shl). It is most likely that combination of such polymorphisms is due to the genetic background accountable for phenotype distinctions.

Thallium-201 scintigraphy was useful in diagnosing ectopic ACTH syndrome due to bronchial carcinoid.

Abstract. Initial investigations of a 70-year-old woman with clinical Cushing's syndrome, including overnight dexamethasone suppression test, CRH test, and pituitary MRI, suggested the presence of ectopic ACTH production. Thoracic computed tomography (CT) scan revealed a mass measuring 7 mm in the right lung, but it was thought to be an incidental opacity, leaving the source of ectopic ACTH undetermined for several years. During this period, although the size of the lung opacity did not change remarkably, serum cortisol levels became elevated to 43 microg/dl, and the patient's symptoms worsened. Tl-201 SPECT demonstrated intense accumulation in the right lung. The mass was surgically resected using thoracoscopy to investigate it as the focus of ACTH production. Histological and immunohistochemical examination confirmed that the area of intense Tl-201 uptake was an ACTH-producing bronchial carcinoid. Plasma ACTH and cortisol levels decreased immediately after the surgery. In conclusion, this case demonstrated Tl-201 scintigraphy as a useful tool in identifying the location of an ACTH-producing bronchial carcinoid.

A novel 5-HT(2) antagonist, sarpogrelate hydrochloride, shows inhibitory effects on both contraction and relaxation mediated by 5-HT receptor subtypes in porcine coronary arteries.

In isolated porcine coronary arteries, concentrations of 5-HT (10(-8) to 3x10(-5) mol/l), alpha-methylserotonin (alpha-Me-5-HT, 10(-8) to 3x10(-5) mol/l) and ergonovine (10(-9) to 3x10(-4) mol/l) produced contraction, whereas high concentrations (10(-5) to 10(-4) mol/l) of these drugs produced relaxation. Both sarpogrelate and ketanserin produced rightward shifts of contraction concentration-response curves induced by 5-HT and alpha-Me-5-HT at the concentration from 10(-9) to 3x10(-5) mol/l, and only sarpogrelate inhibited the relaxation at high concentrations of 5-HT and displayed 155% of maximal contraction at 10(-4) mol/l 5-HT. On the other hand, sarpogrelate and ketanserin did not show any inhibitory effects on the relaxation induced by high concentrations of ergonovine. These results suggested that sarpogrelate and ketanserin show different inhibitory effects on the relaxation induced by high concentrations of 5-HT, indicating that these two drugs may have different affinities to 5-HT receptor subtypes that may be involved in relaxation.

Assessment of affinities of propranolol and bopindolol to membranes from COS-7 cell transiently transfected with beta-1- and beta-2-adrenoceptors using a radioligand-binding assay method.

This study was performed to assess the affinities of propranolol, bopindolol, its two metabolites (18-502, 20-785), pindolol, metoprolol, and atenolol to beta(1)- and beta(2)-adrenoceptor (beta(1)- and beta(2)-AR) subtypes using the membranes of COS-7 cells transiently expressing beta(1)- and beta(2)-AR subtypes. Radioligand-binding assays were performed and the results were compared with those (pKi or pA(2) values) obtained from the membrane-enriched fractions from the rat heart, cerebral cortex, bovine heart, tracheal smooth muscle or guinea-pig heart muscle. The pKi values of propranolol, bopindolol, its two metabolites, atenolol, pindolol and metoprolol to beta(1)-AR subtypes obtained from COS-7 cell membranes were 9.02 +/- 0.04, 7.44 +/- 0.12, 9.38 +/- 0.31, 6. 65 +/- 0.16, 5.55 +/- 0.14, 8.17 +/- 0.15 and 5.99 +/- 0.13, respectively. The rank order of pKi values for these agents to beta-(2)-ARs in COS-7 cell membranes was the same as that of beta(1)-ARs. In addition, good correlations were observed between pKi values of homogenates from various tissues and those of transfected COS-7 cell membranes to beta(1)- and beta(2)-ARs. Although good correlations were also observed between pA(2) values obtained from tracheal smooth muscle (beta(2)-ARs) and pKi values obtained from transfected COS-7 cell membranes to beta(2)-ARs, low correlation coefficient values to beta(1)-ARs were observed, however. In conclusion, these results suggested that binding characteristics of (3)H-CGP-12177 to beta-AR subtypes in these membranes from transfected COS-7 cells are similar to those from membrane fractions of various tissues.

[Clonal rearrangement of intratumoral T-cell receptor beta-chain gene in two patients with thymoma accompanied by pure red cell aplasia].

We encountered two cases of thymoma accompanied by pure red cell aplasia and demonstrating clonal rearrangement of the T-cell receptor beta-chain gene (TCR-beta) in lymphocytes. Patient 1 was a 55-year-old man and Patient 2 was a 43-year-old woman. Both had severe anemia and mediastinal tumors. Bone marrow aspiration was performed and pure red cell aplasia diagnosed. Thymoma was the presumptive diagnosis for the mediastinal tumors, and extended thymectomy was performed. The post-operative diagnosis was invasive thymoma (spindle-cell type) in Patient 1 and non-invasive thymoma (mixed lympho-epithelial type) in Patient 2. The cell compositions (%) obtained with T-cell surface marker analysis were as follows: [table: see text] Southern blot analysis disclosed clonal rearrangement of TCR-beta genes in thymoma thymocytes from both patients.

Structures of TMC-95A-D: novel proteasome inhibitors from Apiospora montagnei sacc. TC 1093.

Four novel proteasome inhibitors, TMC-95A-D (1-4) have been isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093, isolated from a soil sample. All of the molecular formulas of 1-4 were established as C(33)H(38)N(6)O(10) by high-resolution FAB-MS. Their planar structures were determined on the basis of extensive analyses of 1D and 2D NMR, and degradation studies. Compounds 1-4 have the same planar structures to each other, and are unique highly modified cyclic peptides containing L-tyrosine, L-aspargine, highly oxidized L-tryptophan, (Z)-1-propenylamine, and 3-methyl-2-oxopentanoic acid units. The absolute configuration at C-11 and C-36 of 1-4 was determined based on chiral TLC and HPLC analyses of their chemical degradation products. The ROESY analysis along with (1)H-(1)H coupling constants clarified the absolute stereochemistry at C-6, -7, -8, and -14 of the cyclic moieties. These studies revealed the relationships of 1-4 to be diastereomers at C-7 and C-36.

TMC-95A, B, C, and D, novel proteasome inhibitors produced by Apiospora montagnei Sacc. TC 1093. Taxonomy, production, isolation, and biological activities.

In our course of screening for novel proteasome inhibitors, TMC-95A and its diastereomers, TMC-95B to D, were isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093. TMC-95A inhibited the chymotrypsin-like (ChT-L), trypsin-like (T-L), and peptidylglutamyl-peptide hydrolyzing (PGPH) activities of 20S proteasome with IC50 values of 5.4nM, 200nM, and 60nM, respectively. TMC-95B inhibited these activities to the same extent as TMC-95A, while the inhibitory activities of TMC-95C and D were 20 to 150 times weaker than that of TMC-95A and B. TMC-95A did not inhibit m-calpain, cathepsin L, and trypsin at 30 microM, suggesting its high selectivity for proteasome. Taxonomy of the producing strain is also described.

The gamete fusion process is defective in eggs of Cd9-deficient mice.

The cell-surface molecule Cd9, a member of the transmembrane-4 superfamily, interacts with the integrin family and other membrane proteins. and is postulated to participate in cell migration and adhesion. Expression of Cd9 enhances membrane fusion between muscle cells and promotes viral infection in some cells. Fertilization also involves membrane fusion, between gametes. In mammals, the sperm binds to microvilli on the egg surface, and sperm-egg membrane fusion first occurs around the equatorial region of the sperm head12. The fused membrane is then disrupted, and the sperm nucleus as well as the cytoplasm is incorporated into the egg. Cd9 is expressed on the plasma membrane of the mouse egg, and an anti-Cd9 monoclonal antibody inhibits sperm-egg surface interactions. We generated Cd9 mice and found that homozygous mutant females were infertile. Sperm-egg binding was normal, but sperm-egg fusion was almost entirely inhibited in eggs from Cd9 females. Intracellular Ca2 oscillations, which signal fertilization, were absent in almost all mutant eggs; in rare cases, a response occurred after a long time period. In normal animals, Cd9 molecules were expressed on the egg microvilli and became densely concentrated at the sperm attachment site. Thus, our results show that Cd9 is important in the gamete fusion process at fertilization.

TMC-66, a new endothelin converting enzyme inhibitor produced by Streptomyces sp. A5008.

A new endothelin converting enzyme (ECE) inhibitor, TMC-66 was isolated from the fermentation broth of Streptomyces sp. A5008. The structure of TMC-66 was elucidated by spectroscopic analyses to be a new member of benzo[a]naphthacenequinone class of antibiotics. TMC-66 had a highly selective inhibitory activity for ECE with an IC50 value of 2.9 microM. Taxonomy of the producing strain is also described.

Tamsulosin: assessment of affinityof (3)H-P razosin binding to two alpha-1- adrenoceptor subtypes in the canine aorta.

This study was performed to assess the affinity of tamsulosin to the alpha(1L)- in addition to alpha(1B)-adrenoceptor (alpha(1)-AR) subtypes coexisting in the canine aorta using the radioligand binding assay. The antagonistic effects of this drug on contraction of the rat aorta were also assessed, and the results were compared with those obtained with prazosin, amosulalol, labetalol, ketanserin, clonidine and propranolol. The pKi value of tamsulosin to the alpha(1L)-subtype was lower than those of prazosin and HV-723, but higher than those of amosulalol, ketanserin and labetalol. The pKi value of tamsulosin for the alpha(1B)-subtype in the canine aorta was similar to that of prazosin. However, this drug showed a higher pKi value than amosulalol, HV-723, labetalol and ketanserin. On the other hand, the order of inhibition potencies for contraction of the rat aorta by phenylephrine was as follows: prazosin > tamsulosin > amosulalol > HV-723 > labetalol > ketanserin > clonidine > propranolol. Thus, although the affinity of tamsulosin to the alpha(1B)-AR subtype in the canine aorta was as high as that in the bovine prostate reported in our previous study, the affinity (pKi 7. 87) of this drug to alpha(1L)-AR in the canine aorta was lower than that (pKi 8.99) in the bovine prostate. These observations suggested that the pharmacological potencies of tamsulosin in the aorta and prostate may be different.