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Cerebral proliferative angiopathy (CPA) is a new clinical entity demonstrating a diffuse network of densely enhanced vascular abnormalities with intermingled normal brain parenchyma and is distinguishable from classical arteriovenous malformations by specific clinical and imaging markers. However, the pathophysiological nature of this disease is unclear, and there is no consensus on the treatment. We describe cerebral perfusion abnormalities in a patient with CPA by using N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography (123I-IMP-SPECT) and perfusion-weighted magnetic resonance imaging. The patient, a 13-year-old boy, had reversible focal neurological deficits unrelated to cerebral hemorrhage. 123I-IMP-SPECT at resting state showed preserved uptake within the vascular lesion, yet lower uptake in the area adjacent to the lesion. In addition, acetazolamide-stressed 123I-IMP-SPECT exhibited severely impaired cerebrovascular reactivity over the affected hemisphere, suggesting that his focal neurological deficits were related to the cerebral ischemia. The perfusion abnormalities on 123I-IMP-SPECT in a CPA patient have never been previously reported. The concept of vascular malformation–related hypoperfusion is discussed. [Copyright &y& Elsevier]

IgG4-related disease (IgG4-RD) is a novel disease entity that includes Mikulicz's disease, autoimmune pancreatitis (AIP), and many other conditions. It is characterized by elevated serum IgG4 levels and abundant IgG4-bearing plasmacyte infiltration of involved organs. We postulated that high levels of serum IgG4 would comprise a useful diagnostic tool, but little information is available about IgG4 in conditions other than IgG4-RD, including rheumatic diseases. Several reports have described cutoff values for serum IgG4 when diagnosing IgG4-RD, but these studies mostly used 135 mg/dL in AIP to differentiate from pancreatic cancer instead of rheumatic and other common diseases. There is no evidence for a cutoff serum IgG4 level of 135 mg/dL for rheumatic diseases and common diseases that are often complicated with rheumatic diseases. The aim of this work was to re-evaluate the usual cutoff serum IgG4 value in AIP (135 mg/dL) that is used to diagnose whole IgG4-RD in the setting of a rheumatic clinic by measuring serum IgG4 levels in IgG4-RD and various disorders. We therefore constructed ROC curves of serum IgG4 levels in 418 patients who attended Sapporo Medical University Hospital due to IgG4-RD and various rheumatic and common disorders. The optimal cut-off value of serum IgG4 for a diagnosis of IgG4-RD was 144 mg/dL, and the sensitivity and specificity were 95.10 and 90.76%, respectively. Levels of serum IgG4 were elevated in IgG4-RD, Churg-Strauss syndrome, multicentric Castleman's disease, eosinophilic disorders, and in some patients with rheumatoid arthritis, systemic sclerosis, chronic hepatitis, and liver cirrhosis. The usual cut-off value of 135 mg/dL in AIP is useful for diagnosing whole IgG4-RD, but high levels of serum IgG4 are sometimes observed in not only IgG4-RD but also other rheumatic and common diseases. [ABSTRACT FROM AUTHOR]

Abstract: Steroid degradation by Comamonas testosteroni and Nocardia restrictus have been intensively studied for the purpose of obtaining materials for steroid drug synthesis. C. testosteroni degrades side chains and converts single/double bonds of certain steroid compounds to produce androsta-1,4-diene 3,17-dione or the derivative. Following 9α-hydroxylation leads to aromatization of the A-ring accompanied by cleavage of the B-ring, and aromatized A-ring is hydroxylated at C-4 position, cleaved at Δ4 by meta-cleavage, and divided into 2-hydroxyhexa-2,4-dienoic acid (A-ring) and 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid (B,C,D-ring) by hydrolysis. Reactions and the genes involved in the cleavage and the following degradation of the A-ring are similar to those for bacterial biphenyl degradation, and 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid degradation is suggested to be mainly β-oxidation. Genes involved in A-ring aromatization and degradation form a gene cluster, and the genes involved in β-oxidation of 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid also comprise a large cluster of more than 10 genes. The DNA region between these two main steroid degradation gene clusters contain 3α-hydroxysteroid dehydrogenase gene, Δ5,3-ketosteroid isomerase gene, genes for inversion of an α-oriented-hydroxyl group to a β-oriented-hydroxyl group at C-12 position of cholic acid, and genes possibly involved in the degradation of a side chain at C-17 position of cholic acid, indicating this DNA region of more than 100kb to be a steroid degradation gene hot spot of C. testosteroni. Article from a special issue on steroids and microorganisms. [Copyright &y& Elsevier]

We have developed the bioluminescent Salmonella reverse mutation assay as a tool for detecting mutagenicity applicable for high-throughput screening of new chemicals. In this study, we report the inter-laboratory evaluation of the assay using 10 model chemicals in five independent laboratories located in the USA (Groton, CT; Cambridge, MA and La Jolla, CA), Europe (Sandwich, Kent, UK) and Asia (Nagoya, Japan). The studies were performed in blinded fashion in all sites except for Groton and Cambridge laboratories. The chemicals were tested in at least three independent experiments using strains TA98-lux and TA100-lux in the presence and absence of metabolic activation. The results were statistically evaluated and compared to published results. Seven of the 10 compounds were positive in either TA98-lux and/or TA100-lux in the presence or absence of metabolic activation. The positive compound set included: nitrofurazone, 3-3′-dimethoxybenzidine, benzo[a]pyrene, 1,4-benzoquinone dioxime, 2-amino-5-nitrophenol, 2-bromo-4,6-dinitroaniline and busulfan. The remaining three compounds, namely, anthracene, crystal violet and benzyl chloride were negative in both Salmonella strains. Final results for individual compounds yielded 100% agreement among the laboratories and published data. Detailed comparison of all 40 individual test conditions yielded 93% (37 of 40) agreement among participating laboratories. We conclude that the bioluminescent Salmonella reverse mutation assay is a robust, accurate and economical higher throughput assay applicable for the mutagenicity screening of chemicals. [ABSTRACT FROM PUBLISHER]

BK polyomavirus (BKV) is ubiquitous among humans, usually infecting them asymptomatically during childhood. BKV persists in renal tissue of individuals and their progeny are excreted in urine, particularly in immunocompromised patients. JC virus, another human polyomavirus, has been considered to be transmitted from parents to children during prolonged cohabitation. However, BKV has been supposed to be transmitted not only within but also outside the family. In the present study, to clarify this possibility, we analyzed phylogenetically 35 BKV which were excreted in the urine by Japanese children and adults undergoing stem cell transplantation. Subtypes I, III and IV were detected in 15, two and one children and in 15, one and one adults, respectively. Among 15 subtype I isolates from children, three, four and eight belonged to subgroups Ia, Ib-1 and Ic, respectively. All the three children from whom Ia was detected were less than 9 years old. In contrast in the adults, three subtype I belonged to Ib-1 and the other 12 to Ic. These findings may reflect the recent transmission of BKV Ia strains to Japanese children. [ABSTRACT FROM AUTHOR]

Polyoma BK virus (BKV) is frequently found in the urine of stem cell transplantation (SCT) patients with hemorrhagic cystitis (HC), but also occurs in SCT patients without HC. How BK viruria relates to the development of HC in SCT patients, especially in children, has not yet been fully evaluated. In the present study, we analyzed the relationship of several factors including urinary BKV load to HC development in children and adults undergoing SCT. We employed a quantitative PCR assay and evaluated 37 patients (aged 9 months-62 years) of whom 12 developed HC and 25 did not. Older age was a risk factor for the development of HC; however, other factors such as sex, primary disease, type of SCT, conditioning regimen and aGVHD were not. Peak urinary BKV values in HC patients were not higher than those in non-HC patients. Severity of HC also did not correlate with urinary BKV loads. However, in some patients who secreted higher urinary BKV loads, the peak loads were closely related with the onset of HC. Higher BKV loads may be a risk factor for the development of HC in conjunction with other coexisting factors. J. Med. Virol. 80:2108-2112, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Comamonas testosteroni TA441 degrades steroids such as testosterone via aromatization of the A ring, followed by meta-cleavage of the ring. In the DNA region upstream of the meta-cleavage enzyme gene tesB, two genes required during cholic acid degradation for the inversion of an {alpha}-oriented hydroxyl group on C-12 were identified. A dehydrogenase, SteA, converts 7{alpha},12{alpha}-dihydroxyandrosta-1,4-diene-3,17-dione to 7{alpha}-hydroxyandrosta-1,4-diene-3,12,17-trione, and a hydrogenase, SteB, converts the latter to 7{alpha},12β-dihydroxyandrosta-1,4-diene-3,17-dione. Both enzymes are members of the short-chain dehydrogenase/reductase superfamily. The transformation of 7{alpha},12{alpha}-dihydroxyandrosta-1,4-diene-3,17-dione to 7{alpha},12β-dihydroxyandrosta-1,4-diene-3,17-dione is carried out far more effectively when both SteA and SteB are involved together. These two enzymes are encoded by two adjacent genes and are presumed to be expressed together. Inversion of the hydroxyl group at C-12 is indispensable for the subsequent effective B-ring cleavage of the androstane compound. In addition to the compounds already mentioned, 12{alpha}-hydroxyandrosta-1,4,6-triene-3,17-dione and 12β-hydroxyandrosta-1,4,6-triene-3,17-dione were identified as minor intermediate compounds in cholic acid degradation by C. testosteroni TA441. [ABSTRACT FROM AUTHOR]

Purpose: Posterior fossa epidural hematoma (PFEDH) is an uncommon complication of head injury, which is sometimes associated with acute clinical deterioration (ACD) without significant warning symptoms and may results in death. We investigated clinical characteristics of PFEDH with ACD to identify the process of ACD. Methods: A retrospective case-control review of all patients admitted with a diagnosis of PFEDH between September 1989 and February 1999 was performed. Results: Twenty-one patients (14 men and 7 women) were admitted for PFEDH to Sendai City Hospital. Four patients suffered ACD. All patients had struck their occipital region and had occipital fracture. Patients were treated conservatively on admission because computed tomography (CT) showed no significant findings in 2 patients and PFEDH with minimal symptoms in the others. All patients suffered acute deterioration of consciousness after vomiting. Follow-up CT showed large PFEDH with severe mass effect. Emergency surgery was performed and identified the bleeding point as the venous sinus. The presence of nausea/vomiting was significant risk factor of ACD (Fisher exact test: P = .021). Of the 4 patients, 2 achieved excellent recovery without deficit, 1 was moderately disabled, and 1 died. The outcome of patients with ACD was worse compared to those without ACD (Fisher exact test: P = .046). Conclusions: We should note that vomiting itself could be a significant risk factor of ACD for occipital head trauma. The patients with occipital fracture and vomiting must be observed closely and followed up by CT, even if the initial CT is negative. CT performed shortly after the trauma may reveal no evidence of PFEDH but cannot exclude the development of delayed hematoma. [ABSTRACT FROM AUTHOR]

The ratio of the linearity range Lo to the coil diameter D of the ordinary eddy-current (EC) displacement sensor, Lo/D, is approximately 0.48. In conventional technology, the coil diameter needs to be increased to extend the measuring range of the EC displacement sensor. In this paper, we propose the use of magnetoplated wire (MPW) for the coil winding to improve the Lo/D ratio. An MPW is a copper wire whose circumference is plated with a magnetic thin film. We discuss the physical phenomena and impedance characteristics of the MPW coil and compare them with those of a coil that uses a conventional copper wire (COW). The Lo/D values of an EC sensor with an MPW coil and with a COW coil are 1.0 and 0.48, respectively. These results demonstrate the ability of the MPW coil to double Lo/D value over that of the COW coil. [ABSTRACT FROM AUTHOR]

The sesquiterpene lactone, parthenolide (PTL), possesses strong anticancer activity against various cancer cells. We report that PTL strongly induced apoptosis in 4 multiple myeloma (MM) cell lines and primary MM cells (CD38+ high), but barely induced death in normal lymphocytes (CD38−/+low). PTL-mediated apoptosis correlated well with ROS generation and was almost completely inhibited by L-N-acetylcysteine (L-NAC), indicating the crucial role of oxidative stress in the mechanism. Among 4 MM cell lines, there is considerable difference in susceptibility to PTL. KMM-1 and MM1S cells sensitive to PTL possess less catalase activity than the less sensitive KMS-5 and NCI-H929 cells as well as normal lymphocytes. A catalase inhibitor 3-amino-1,2,4-triazole enhanced their PTL-mediated ROS generation and cell death. The siRNA-mediated knockdown of catalase in KMS-5 cells decreased its activity and sensitized them to PTL. Our findings indicate that PTL induced apoptosis in MM cells depends on increased ROS and intracellular catalase activity is a crucial determinant of their sensitivity to PTL. [ABSTRACT FROM AUTHOR]

Comamonas testosteroni TA441 utilizes testosterone via aromatization of the A ring followed by meta-cleavage of the ring. The product of the meta-cleavage reaction, 4,5.9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1 (10),2-dien-4-oic acid, is degraded by a hydrolase, TesD. We directly isolated and identified two products of TesD as 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid and (2Z,4Z)-2-hydroxyhexa-2,4-dienoic acid. The latter was a pure 4Z isomer. 2-Hydroxyhexa-2,4-dienoic acid was converted by a hydratase, TesE, and the product isolated from the reaction solution was identified as 2-hydroxy-4-hex-2-enolactone, indicating the direct product of TesE to be 4-hydroxy-2-oxohexanoic acid. [ABSTRACT FROM AUTHOR]

A 1-year-6-month-old girl presented with a subcutaneous tumor of the forehead, which had developed since birth. The preoperative examinations showed nasofrontal bone defect with meningocele and subcutaneous tumor with cyst. The patient underwent excision of the tumor and reconstruction of the bone defect. Histologically, the skin tumor exhibited disordered arrangement of striated muscle fibers among normal dermal components, and the cyst was lined by cornified epithelium with a few hair adnexa and contained lamellated keratin. These findings were consistent with rhabdomyomatous mesenchymal hamartoma (RMH) and dermoid cyst. This is an interesting case of RMH co-existing with nasofrontal meningocele and dermoid cyst in the same area. We suggest embryologic errors as a possible etiology, which is incomplete dysjunction of the neural ectoderm from the cutaneous ectoderm. Failure of insertion of mesoderm between the ectoderms caused the bone defect and the disordered proliferation and differentiation of mesoderm-derived tissue, leading to formation of hamartoma.Takeyama J, Hayashi T, Sanada T, Shimanuki Y, Saito M, Shirane R. Rhabdomyomatous mesenchymal hamartoma associated with nasofrontal meningocele and dermoid cyst. [ABSTRACT FROM AUTHOR]

Thalidomide and immunomodulatory drugs (IMiDs), which target multiple myeloma (MM) cells and the bone marrow microenvironment, can overcome drug resistance. These agents also have immunomodulatory effects. Specifically, we have reported that thalidomide increased serum interleukin-2 (IL-2) levels and natural killer (NK) cell numbers in the peripheral blood of responding MM patients. In this study, we investigated the mechanisms whereby IMiDs augment NK cell cytotoxicity. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells cultured with IMiDs were examined in the presence or absence of anti-IL-2 antibody, ciclosporin A or depletion of CD56-positive cells. IMiDs-induced signalling pathways, triggering IL-2 transcription in T cells, were also delineated. IMiDs facilitated the nuclear translocation of nuclear factor of activated T cells-2 and activator protein-1 via activation of phosphoinositide-3 kinase signalling, with resultant IL-2 secretion. IMiDs enhanced both NK cell cytotoxicity and ADCC induced by triggering IL-2 production from T cells. These studies defined the mechanisms whereby IMiDs trigger NK cell-mediated tumour-cell lysis, further supporting their therapeutic use in MM. [ABSTRACT FROM AUTHOR]

Although c-Jun NH2-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27Kip1, without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-?B activation in a dose-dependent fashion, associated with phosphorylation of I?B kinase a (IKKa) and degradation of I?Ba. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-?B activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-?B in MM cells.Oncogene (2003) 22, 8797-8801. doi:10.1038/sj.onc.1206919 [ABSTRACT FROM AUTHOR]

Proteasome inhibitor PS-341 is one of the most promising novel agents against multiple myeloma (MM). We have previously shown that PS-341 inhibits IL-6 triggered phosphorylation of extracellular signal-regulated kinases (ERK) 1/2 (also known as p42/44 mitogen-activated protein kinases) in MM cells. In this study, we further examined whether clinically achievable concentrations of PS-341 could inhibit IL-6 triggered signaling cascades in MM. We found that PS-341 inhibited not only ERK, but also signal transducers and activators of transcription (STAT) 3 as well as Akt phosphorylation. Since gp130 (CD130) dimerizes and is phosphorylated after IL-6 binding to gp80 (IL-6 receptor), we hypothesized that gp130 could be involved in PS-341-induced blockade of signaling cascades mediating MM cell growth, survival, and drug resistance in the bone marrow (BM) microenvironment. In this study, we first demonstrate that PS-341 induces downregulation of gp130 in a time- and dose-dependent manner in vitro, prior to MM cell death. Conversely, downregulation of gp130 is completely abrogated by the pan-caspase inhibitor Z-VAD-FMK, suggesting that downregulation of gp130 is mediated via caspase activation. Z-VAD-FMK also abrogates the inhibitory effect of PS-341 on IL-6-triggered signaling cascades. Importantly, we demonstrate that phosphorylation of ERK, STAT3, and Akt in MM.1S cells induced by either exogenous IL-6 or by binding of MM cells to BM stromal cells is abrogated by PS-341. These studies, therefore, define another novel mechanism whereby PS-341 can overcome the growth and survival advantage in MM cells conferred by the BM milieu. Importantly, this effect on cytokine-induced gp130 signaling cascades may account, at least in part, for the remarkable preclinical sensitivity and clinical responses achieved in MM with PS-341 treatment.Oncogene (2003) 22, 8386-8393. doi:10.1038/sj.onc.1207170 [ABSTRACT FROM AUTHOR]

In Comamonas testosteroni TA441, testosterone is degraded via aromatization of the A ring, which is cleaved by the meta-cleavage enzyme TesB, and further degraded by TesD, the hydrolase for the product of TesB. TesEFG, encoded downstream of TesD, are probably hydratase, aldolase, and dehydrogenase for degradation of 2-oxohex-4-enoicacid, one of the products of TesD. Here we present a new and unique steroid degradation gene cluster in TA441, which consists of ORF18, ORF17, tesI, tesH, ORF11, ORF12, and tesDEFG. TesH and TesI are 3-ketosteroid-Δ¹-dehydrogenase and 3-ketosteroid-Δ[sup 4](5α)-dehydrogenase, respectively, which work in the early steps of steroid degradation. ORF17 probably encodes the reductase component of 9α-hydroxylase for 1,4-androstadiene-3,17-dione, which is the product of TesH in testosterone degradation. Gene disruption experiments showed that these genes are necessary for steroid degradation and do not have any isozymes in TA441. By Northern blot analysis, these genes were shown to be induced when TA441 was incubated with steroids (testosterone and cholic acid) but not with aromatic compounds [phenol, biphenyl, and 3-(3-hydroxyphenyl)propionic acid], indicating that these genes function exclusively in steroid degradation. [ABSTRACT FROM AUTHOR]

Summary. Multiple myeloma (MM) is currently incurable, and novel therapies are needed. In this study, we examined a novel recombinant humanized monoclonal antibody against CD40 (rhuCD40 mAb) and demonstrate for the first time that rhuCD40 mAb induces antibody-dependent cell-mediated cytotoxicity (ADCC) against CD40-positive MM cells. Importantly, we show that rhuCD40 mAb induces autologous ADCC against primary patient MM cells, without triggering ADCC against normal B cells. This study, therefore, both demonstrates that rhuCD40 mAb triggers autologous ADCC against patient MM cells and provides the framework for the clinical evaluation of rhuCD40 mAb immunotherapy to improve patient outcome in MM. [ABSTRACT FROM AUTHOR]

In a previous study we isolated the meta-cleavage enzyme gene, tesB, that encodes an enzyme that carries out a meta-cleavage reaction in the breakdown of testosterone by Comamonas testeroni TA441 (M. Horinouchi et al., Microbiology 147:3367-3375, 2001). Here we report the isolation of a gene, tesD, that encodes a hydrolase which acts on the product of the meta-cleavage reaction. We isolated tesD by using a Tn5 mutant of TA441 that showed limited growth on testosterone. TesD exhibited ca. 40% identity in amino acid sequence with BphDs, known hydrolases of biphenyl degradation in Pseudomonas spp. The TesD-disrupted mutant showed limited growth on testosterone, and the culture shows an intense yellow color. High-pressure liquid chromatography analysis of the culture of TesD-disrupted mutant incubated with testosterone detected five major intermediate compounds, one of which, showing yellow color under neutral conditions, was considered to be the product of the meta-cleavage reaction. The methylation product was analyzed and identified as methyl-4,5-9,10-diseco-3methoxy-5,9,17-trioxoandrosta-l(10),2-dien-4-oate , indicating that the substrate of TesD in testosterone degradation is 4,5-9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-l(10),2-dien-4-oic acid. 4,5-9,10-Diseco-3-hydroxy5,9,17-trioxoandrosta-1 (10),2-dien-4-oic acid was transformed by Escherichia coli-expressed TesD. Downstream of tesD, we identified tesE, F, and G, which encode for enzymes that degrade one of the products of 4,5-9,10diseco-3-hydroxy-5,9,17-trioxoandrosta-l(10),2-dien-4-oic acid converted by TesD. [ABSTRACT FROM AUTHOR]

Investigates novel therapies for multiple myeloma (MM). Role of the bone marrow microenvironment in the pathogenesis of MM; Thalidomide and its immunomodulatory derivatives; Proteasome inhibitors; NF-kappabetta inhibitors; Arsenic trioxide; 2-methyloxyestradiol; PTK787 tyrosine kinase inhibitor.

We describe a 47-year-old woman with severe aplastic anemia with genital bleeding who developed acute severe hepatitis after the administration of danazol while she was receiving cyclosporin. She had been diagnosed with severe aplastic anemia 1 year previously and, while hospitalized, had received methyl prednisolone pulse therapy, which was not successful. She was then referred to our hospital. She was treated with antithymocyte globulin, cyclosporin, granulocyte colony-stimulating factor, and methyl prednisolone; a good response was achieved after 3 months of this therapy. Subsequently, oral administration of cyclosporin was continued, but she was readmitted to our hospital when pancytopenia gradually developed and the genital bleeding recurred. Danazol was administered for pancytopenia and endometriosis. Four days after the first administration of danazol, epigastric pain occurred, and the danazol was stopped. Eighteen days after the first danazol administration, very severe hepatic injury occurred abruptly. The patient died of hepatic failure. Postmortem examination revealed centrilobular massive necrosis of the liver. Danazol was implicated as the agent responsible for causing the hepatic failure. Drug interactions between danazol and cyclosporin may cause adverse effects. [ABSTRACT FROM AUTHOR]