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Background Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) associated with membranoproliferative features is an extremely rare entity. Information on clinicopathological features and prognosis in this entity is limited. Methods We reviewed 5,443 renal biopsies processed at our department, and identified 4 patients with PGNMID associated with membranoproliferative features. We evaluated clinicopathological features and outcomes in these patients, and characterized paraprotein deposits by immunofluorescence studies. Results Three out of 4 patients had nephrotic syndrome with renal insufficiency at presentation. Cryoglobulin or monoclonal protein in serum and urine was not detected. Renal biopsy showed membranoproliferative features with or without nodular formation. Tubulointerstitial and vascular alterations were mild in three patients. All patients had glomerular IgG-kappa deposits. Heavy chain subclass analysis performed in 3 patients showed IgG3 deposits. Immunofluorescence studies using antibodies specific for gamma-heavy chain C(H)1, C(H)2, and C(H)3 domains and gamma3 hinge did not show any apparent deletion. Confocal microscopy revealed glomerular colocalization of light and heavy chains. On electron microscopy, granular deposits were predominantly mesangial and subendothelial. All patients were treated with steroids and cytotoxic agents, but no effect on proteinuria was observed. The renal outcome was progressive in all patients. Early death was observed in two elder patients. No patient had overt myeloma or lymphoma at presentation or over the course of follow-up (mean 43 months). Conclusions Our study suggests a predominance of IgG3-kappa glomerular deposits of nondeleted whole immunoglobulin molecules in PGNMID associated with membranoproliferative features. The clinical outcome in patients with this entity appears to be poor.

A 69-year-old female with a 3-year history of polycythemia vera (PV) developed nephrotic syndrome. A renal biopsy showed focal and segmental glomerulosclerosis (FSGS). The patient was treated with prednisolone and myelosuppressive agents. Thereafter, parallel improvement of the two conditions was observed. After 4-year treatment, proteinuria disappeared. To our knowledge, there are five reported cases of FSGS associated with PV. Among them, three patients suffered from progressive azotemia. We suggest that steroid therapy with myelosuppressive agents can resolve the renal lesion in patients with PV.

A 70-year-old man with angioimmunoblastic T-cell lymphoma developed acute renal failure. Laboratory data showed decreased levels of serum C3, C4, and CH50, elevated immunoglobulin M (IgM) levels, and the presence of cryoglobulinemia (IgM-lambda). Renal biopsy showed membranoproliferative glomerulonephritis-like lesions with azan-red-stained thrombi in the glomerular capillary lumen. Immunofluorescence showed that IgM-lambda stained strongly in the glomerular capillary lumen, equal to the azan-red-stained thrombi, whereas C3 and C4 staining was negative. Electron microscopy showed electron-dense deposits in the subendothelial space and glomerular thrombi lacking fine fibrillar structure. These findings suggest that cryoglobulin, which consists of monoclonal IgM-lambda, induced glomerular thrombi and acute renal failure in a patient with angioimmunoblastic T-cell lymphoma.

A single stage transonic centrifugal compressor for a small turbofan engine has been developed. Rig testing has demonstrated an 83.2% adiabatic efficiency with a 7.5:1 total-to-static pressure ratio and a corrected tip speed of 596 m/s. An impeller blade redesign is presented of the original blade geometry, which uses both experimental and numerical results. An in-house developed Navier-Stokes flow solver was applied to the impeller redesign process. To meet the development schedule, a steady flow solver was used for the impeller analysis instead of an unsteady stage analysis. As a result, the following important redesign factors for higher efficiency were found: leading-edge shock control, blade-to-blade loading control, and splitter-loading optimization. Also, the flow physics of a secondary flow mechanism was captured by the computational analysis, and its control was applied during the impeller redesign process. The final stage performance was achieved by rig testing, through use of a coupled pipe diffuser and impeller-inducer bleed system.

A 53-year-old man developed chronic renal failure during a protracted course of sarcoidosis. A renal biopsy showed Congo red-positive homogenous deposits in the subendothelial space of glomerular capillary walls and arterial walls. On electron microscopy, amyloid fibrils were observed in the deposits. Immunohistochemistry showed positive staining for amyloid A (AA) protein. Treatment with prednisolone resulted in poor response, followed by progressive deterioration of renal function requiring hemodialysis. To our knowledge, there are 5 cases with histologically proven renal amyloidosis accompanied by sarcoidosis. Prognosis in these patients is extremely poor. AA-type amyloidosis should be considered as a rare renal complication in the setting of long-standing sarcoidosis.

Miconazole is a strong inhibitor of CYP2C9, one of the main enzymes involved in the metabolism of warfarin. Concurrent use of the two drugs leads to potentially serious adverse effects. Although it is often assumed that use of the oral miconazole gel is acceptable with concomitant warfarin, because of the low bioavailability following buccal administration, drug-drug interactions have been reported following such use. We aimed to investigate case reports of such interactions and develop a pharmacokinetic model to model such interactions.The Medline database from 1966 to October 2010 was used for literature search. Case reports of the potentiation of the anticoagulant effects of warfarin, such as the elevation of prothrombin time (INR), by concomitant administration of warfarin and miconazole oral gel were collected. We quantitatively estimated the extent of inhibition of warfarin metabolism by orally administered miconazole gel and compared our findings with case reports.Metabolism of (S)-warfarin is inhibited potently following administration of a standard dose (200-400 mg/day in Japan) of miconazole gel. This may lead to in an increase in the blood concentration of warfarin and lead to serious adverse effects. The literature reports of clinical interactions with concomitant use of those drugs show that other factors may amplify the effects of any increase in blood concentration.We summarize all reported, clinically significant, cases of drug interaction between miconazole oral gel and warfarin. Pharmacokinetic modelling shows that concomitant administration of warfarin and miconazole oral gel can lead to substantial increase in warfarin concentration. However, our PK/PD model fails to capture the dramatic increases seen in INR values, and hence bleeding complications, reported in the literature. Taken together, the evidence suggests that concomitant use of miconazole gel and warfarin should be avoided. Even over-the-counter products containing miconazole should be used with caution by patients receiving warfarin.

Heat conduction mechanisms in nanofluids, fluids seeded with nanoparticles, have been extensively scrutinized in the past decades to explain some experimental observations of their enhanced thermal conductivity beyond the effective medium theory. Although many mechanisms such as Brownian motion, clustering, ballistic transport, and internanoparticle potential are speculated, experimental proof of any of the mechanisms has been difficult. Here, we investigate the mechanisms experimentally by thermal conductivity measurements and structural analysis for the same materials in both liquid and solid states. These studies strongly suggest that clustering holds the key to the thermal conductivity enhancement of nanofluids.

Summary In this study, we suggested two types of novel metallized tip for the apertureless near-field scanning optical microscope probe. The first is a silver nanorod immobilized tip and the other is a double metallized probe. We calculated the electric field enhancement factor and the electric field distribution of a single sphere, aggregated spheres, an ellipse and a nanorod by the finite-differential time-domain method to improve the silver nanosphere immobilized tip developed in our previous studies. The enhanced field of the nanorod is localized at the external surfaces. The simulation results of the nanorod revealed that the position of the maximum peak is shifted to a longer wavelength and that its electric field enhancement factor increases as the aspect ratio increases. Thus, we developed the silver nanorod immobilized tip, and the tip-enhanced Raman spectrum of rhodamine 6G molecule on the substrate could be measured by the tip though it could not be detected by the previous nanosphere immobilized tip. Further, the finite-differential time-domain calculation predicted that the double metallized tips considerably enhance the electric field and that its enhancement factor in the longer wavelength region (500–600 nm) does not decrease when the tip is rounded. The results show that the proposed metallized tips were useful for the apertureless near-field scanning optical microscope system.

We present a case of purpura associated with concomitant ingestion of cilostazol, aspirin and grapefruit juice. A 79-year-old man with atherosclerosis obliterans, taking cilostazol and aspirin, complained of purpura. Interview by a pharmacist revealed that he had been taking grapefruit juice for a month. His purpura disappeared upon cessation of grapefruit juice, although his medication was not altered. The most probable cause of his purpura is an increase in the blood level of cilostazol because of the inhibition of cilostazol metabolism by components of grapefruit juice. Aspirin may possibly have potentiated the risk of purpura. Grapefruit juice should be avoided in patients taking cilostazol, especially in patients being concomitantly treated with other anticoagulants.

Background Increased serum levels of S100A12, a proinflammatory protein secreted by activated neutrophils, have recently been shown in patients with active inflammatory diseases, such as rheumatoid arthritis and Kawasaki disease. In this study, we investigated serum levels of S100A 12 in patients with small-vessel vasculitis, myeloperoxidase anti-neutrophil cytoplasmic antibodies- (MPO-ANCA) associated pauci-immune glomerulonephritis. Methods Serum S100A12 concentrations were measured by a sandwich enzyme-linked immunosorbent assay (ELISA) in 46 patients with MPO-ANCA-associated glomerulonephritis and 29 healthy controls. We analyzed correlations between serum S100A12 levels and a clinical index of vasculitis activity, the Birmingham Vasculitis Activity Score (BVAS), various laboratory parameters, and pathological activity scores in the patients. We also analyzed changes of serum S100A12 levels in 10 patients after treatment. Results ELISA showed about 4-fold higher levels of serum S100A12 in patients with MPO-ANCA-associated glomerulonephritis than healthy controls. Serum S100A12 levels correlated with the BVAS scores, the peripheral white blood cell count, levels of serum C-reactive protein and creatinine, and pathological activity scores in the patients, but did not correlate with serum MPO-ANCA titers. Serum S100A12 levels after treatment decreased in all the 10 patients examined. Conclusion We demonstrated that increased serum S100A12 levels correlate with clinical, laboratory and pathological parameters of disease activity in patients with MPO-ANCA-associated glomerulonephritis. Serum S100A12 level may be one of the useful markers of disease activity in MPO-ANCA-associated glomerulonephritis.

Background Mutations in 3 genes (NPHP1, NPHP3 and NPHP4) have been identified in patients with juvenile or adolescent nephronophthisis (NPHP) without extrarenal involvement, mainly in patients from western countries. In this study, we analyzed mutations in the NPHP genes of 2 Japanese patients with suspected sporadic juvenile or adolescent NPHP without extrarenal involvement. Methods A renal biopsy was performed in the 2 patients. Genomic DNA was prepared from peripheral blood mononuclear cells of the patients and their family members. The above NPHP genes were examined by deletion analysis or direct automated sequencing of polymerase chain reaction-amplified DNA products. Results Histological findings in the patients were compatible with those of NPHP. In 1 patient, we identified a novel deletion mutation including about half of exons of the NPHP1 gene. In another patient, there was no mutation in the NPHP genes examined. Conclusions We found a novel NPHP1 deletion in 1 patient. To our knowledge, this is the second Japanese NPHP case in which genetic diagnosis was made.

Background Fabry disease is an X-linked recessive disorder resulting from a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). Chronic renal failure is an important cause of death in patients with Fabry disease. We report on patients with Fabry disease (a hemizygous male and his mother) due to a nonsense mutation (R220X) in the alpha-Gal A gene. Methods The proband, a 41-year-old man, and his 71-year-old mother presented with renal and cardiac manifestations of Fabry disease. Histological examination and molecular analysis of the alpha-Gal A gene were performed. Results Typical histological findings of Fabry disease were observed in a renal biopsy specimen from the proband and in renal and myocardial necropsy specimens from the mother. Sequencing of a full-length alpha-Gal A cDNA from the proband indicated a C-T transition at codon 220, resulting in substitution of the predictable termination for arginine (R220X). Examination of genomic alpha-Gal A DNA revealed that the proband was a hemizygote and the mother was a heterozygous carrier for the mutation. Conclusion This is the first detailed report of family members with Fabry disease due to a nonsense mutation (R220X) in the alpha-Gal A gene. Our study indicates that this mutation causes the typical disease in both genders.

An attempt is made to develop a knowledge-based expert system for assessing the durability of bridge decks. The present expert system has a feature that includes a fuzzy set manipulation system which can treat fuzzy sets in the process of data handling, rule representation and inference procedure. Using this system, it is possible to deal with various kinds of uncertainties and ambiguities involved inherently in the data, rules and inference processes in a unified and simple manner. Moreover, it is intended to introduce the concept of neural network for the automatic generation of fuzzy production rules. Several illustrative examples are presented to demonstrate the applicability of the system. >

Supporting rapid response to changing customer requirements, reduction in both time and cost of manufacturing process, and integration within a heterogeneous wide area networked enterprise are necessary to increase worldwide competitiveness in manufacturing. We propose a CORBA based architecture to realize that manufacturing environment. We have developed an ORB for PLC to realize that architecture. And we have developed two prototypes of a remote monitoring system for factory automation, which are a manufacturing line monitoring system and a remote PLC monitoring system which uses a Web browser, to examine feasibility and effectiveness of the proposed architecture. According to experiments with these prototypes, we show the feasibility and effectiveness of our proposed CORBA based architecture.

A novel TCAD database system, MOSQue, is introduced. MOSQue is a database system for impurity profile and electric characteristics data. This system has an easy-to-use GUI which enables design engineers to refer to data for ULSI development systematically. MOSQue is also utilized on parameter tuning for process and device simulators for the purpose of precise design specifications as it efficiently administrates the relations on measured and simulated data.

Back-end-of-the line (BEOL) interconnect process integration for sub-half-micron ASIC applications with both low-cost merit and appropriately high performance is presented. Borderless and stacked contact/via structures to reduce chip size and minimization of ILD thickness without performance degradation are achieved. Blind-CMP, selective tungsten CVD, and fluorine-TEOS ILD with low dielectric constant are selected with process simplification in mind.

The seventh largest chromosome in Japanese populations of the frog Rana rugosa morphologically evolved as a sex chromosome. The sex chromosome is XX/XY type in one geographic form and ZZ/ZW type in another. In contrast, the seventh chromosomes are still homomorphic between the sexes in the other two geographic forms: they are more subtelocentric in the Kanto form and subtelocentric in the western Japanese form. To identify a prototype of the sex chromosomes, we extended our investigation in this study to the Korean form, which is supposed to be close to the phylogenetic origin of this species. The karyotype, a sex-linked gene sequence, and mechanisms of sex determination and gonadal differentiation were all examined. In addition, phylogenetic analyses were performed based on mitochondrial gene sequences and the results of crossings between the Korean and Japanese forms. As a consequence, the more subtelocentric seventh chromosome, shared by the Korean and Japanese Kanto forms, was concluded to be the prototype of the sex chromosomes. Starting at the prototype, a whole process of morphological sex chromosome evolution was reconstructed.

Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QTprolongation. Such a hysteresis pattern for QTprolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.

Crossing experiments revealed that a single recessive gene mutation (yellow) gives rise to the yellow phenotype of Rana rugosa in Japan. Ultrastructural observation of dermal chromatophores showed that the pigment organelles; melanosomes, pterinosomes, and reflecting platelets, all had structural deformities. This suggests that the yellow gene acts at the level of a primordial pigment organelle common to the three types of chromatophore.

A 55-year-old man presented with a smoothly elevated solid choroidal mass with choroidal detachment in the temporal region of the left eye. Both fluorescein and indocyanine green angiography suggested a vascularized lesion such as an angioma. However, radiographic examination revealed a solid, circumscribed, dome-shaped mass. During a 3-month observation, the mass gradually enlarged and invaded the iris. The possibility of malignant melanoma could not be ruled out. Due to rapid and continued growth of the tumor, the eye was enucleated. Histopathologic examination revealed proliferation of spindle-shaped cells surrounding reticulin-positive vessels, which is characteristic of hemangiopericytoma. To our knowledge, this is only the fourth reported case of intraocular hemangiopericytoma and the first diagnosed in a male patient.

Matrix metalloproteinases (MMPs) are involved in tissue remodelling, which is one of the important aspects of inflammatory disease. To assess the balance between the matrix degradation and production, we analysed the in situ expression of MMP-1, -3, -8 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, and type I procollagen (PC-I) in inflammatory bowel disease.Immunohistochemistry using frozen sections was performed in 17 patients with ulcerative colitis (UC) and 16 with Crohn's disease (CD). In both UC and CD, MMPs and TIMPs were expressed by inflammatory cells as well as by fibroblastic cells most prominently in actively inflamed areas in ulcer bases, but sparsely in intact inflamed mucosa in both UC and CD. In UC, inflamed mucosa with erosions expressed these substances focally. Fibroblasts also expressed PC-I. We identified that vascular smooth muscle cells of venules in ulcer bases expressed MMP-1 and -9, TIMP-1 and PC-I. These venules also expressed E-selectin, a cell adhesion molecule to facilitate the leucocyte extravasation, and vascular endothelial growth factor (VEGF) receptor 2, consistent with their property of newly formed vessels.Our results suggest that MMPs are involved in the tissue remodelling, angiogenesis and promotion of leucocyte extravasation in the actively inflamed area in the ulcer base in both UC and CD. MMP-1 expression in the mucosa may be related to the initial step of ulceration in UC. Therapeutic manipulation of extracellular matrix turnover would be an effective therapy to alleviate active inflammation and accelerate ulcer healing.

Tumor-infiltrating lymphocytes, particularly CD8(+) T cells, could be a manifestation of antitumor immunity. We clinicopathologically analyzed the biological significance of tumor-infiltrating lymphocytes in 221 patients with renal cell carcinoma without preoperative treatments. More abundant infiltration of tumor tissue not only by CD8(+) but also CD4(+) T cells was associated with shorter survival of the patients, because of the positive correlation between the number of lymphocytes and representative tumor grade factors. This suggests that immune cell reactions are more pronounced as the tumor grade/biological malignancy progresses, probably because of increased antigenicity of tumor cells. We next analyzed the proliferative activity of CD8(+) T cells that infiltrated in tumor cell nests, which could also reflect antitumor immunity. Higher labeling index of Ki-67, a proliferation-associated antigen, among CD8(+) T cells in contact to tumor cells was associated with a longer survival by both uni- and multivariate analyses. Our data in human renal cell carcinoma suggest that infiltration of tumor tissue by T cells itself does not denote the efficacy of antitumor immunity because of its dependence on the biological malignancy of tumor cells, but infiltration of tumor tissue by CD8(+) T cells bearing more pronounced proliferative activity could reflect effective antitumor immunity. This concept would be important for future immunotherapy of human cancer.

We examined the functional properties of choline transport across the blood-brain barrier (BBB) in mice. We compared the kinetic parameters and transport properties with those found in our in vitro uptake experiments using mouse brain capillary endothelial cells (MBEC4).The permeability coefficient-surface area product (PS) values of [3H]choline at the BBB were estimated by means of an in situ brain perfusion technique in mice.[3H]Choline uptake was well described by a two-component model: a saturable component and a nonsaturable linear component. The [3H]choline uptake was independent of pH and Na+, but was significantly decreased by the replacement of Na+ with K+. Various basic drugs, including substrates and inhibitors of the organic cation transporter, significantly inhibited the [3H]choline uptake. These in situ (in vivo) results corresponded well to the in vitro results and suggest that the choline transporter at the BBB is a member of the organic cation transporter (OCT) family.The choline transport mechanism at the BBB is retained in MBEC4.

In patients with inflammatory conditions such as infection, cytokines induce the production of C-reactive protein(CRP) and serum amyloid A protein(SAA) in hepatic cells. It has been reported that upon viral infection, the serum SAA level increases by a greater degree than the serum CRP level. Procalcitonin (PCT), the precursor of calcitonin, is a new type of inflammatory marker that is specifically induced by bacterial infection, sepsis and lethal multiple organ failure, but not by viral infection, autoimmune diseases, tumors or surgical stress. To evaluate the immunoluminometric assay(LUMI test PCT; Brahms Diagnostics, Berlin, Germany) procedure for determining the PCT level and to study the clinical significance of the serum PCT level, we determined the serum levels of PCT, CRP and SAA in patients with various inflammatory diseases and normal subjects. The serum PCT level in the normal subjects was0.3 ng/ml. Among the patients with inflammatory disease who had a high CRP level(CRP20000 micrograms/dl), the PCT level was elevated only in those patients with severe bacterial infection. These results suggest that determining the PCT level may be useful in the differential diagnosis of severe bacterial infection. The patients who had a low CRP level(CRP150 micrograms/dl), had a PCT level within the normal range. The patients with autoimmune disease, viral infection, and fungal infection did not have an elevated PCT level.

The gastrointestinal mucosa is exposed to myriads of infectious and food antigens, and a unique barrier mechanism handles them on the mucosal surface, and specific immune responses to these antigens call on the mucosal immune system in the mucosal tissues to maintain homeostasis of gastrointestinal functions and structure. Abrogation of these mucosal defense mechanisms may lead to alter immunologic homeostasis in the gastrointestinal tract and to induce pathological features of inflammatory bowel disease (IBD) and Helicobacter pylori-infected chronic active gastritis, including chronic active inflammation, mucosal atrophy and tissue injuries. Regardless of the initiating cause of these long-standing chronic active mucosal inflammations, characteristic immuno-inflammatory mechanisms are involved in their pathogenesis, that is, similar and/or different specific prolonged impaired and excessive immuno-inflammatory responses following the abrogation of the mucosal barrier system are present in the diseased mucosa with IBD and H. pylori infection, respectively.

The clinical learning taken by medical students are an important part of their medical education. To develop a new, effective curriculum for the clinical learning in Clinical Pathology, the instructors defined clear general instructional objectives and specific behavioral objectives, and discussed the learning strategies and evaluation methods. The medical students at our medical school took this new curriculum in Clinical Pathology in 1999. As an evaluation method of this new curriculum, we asked all students to fill out a questionnaire that asked their opinions about the length of each component in the Clinical Pathology rotation, the content of the rotation, etc. Over 80% of the respondents answered that the rotation in Clinical Pathology was useful. Ninety-six percent of the students felt that the experience and knowledge they gained in this Clinical Pathology rotation will be useful in the clinical learning in other departments. Based on the high percentage of favorable responses from the students, we concluded that the new curriculum, which was developed after intensive planning, was successful. In summary, the feedback from students who took the new curriculum in Clinical Pathology showed that this new course was well-accepted by the students and that it created an excellent relationship between the instructors and students. Some of the responses in the questionnaires will be used to improve the Clinical Pathology rotation in the future.

1. The presence of inhibitors of drug efflux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [(3)H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [(3)H]-VBL by Caco-2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [(3)H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3. These results show that the major inhibitor of efflux transport of VBL is different from that of CYP3A4. 4. Further separation of the 60% methanol eluate afforded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [(3)H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [(3)H]-VBL by Caco-2 cells. 5. The order of inhibitory potency of these compounds was FC726DHBGbergamottinbergaptenbergaptol . While, the IC(50) values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and20 microM, respectively. Bergaptol specifically inhibited VBL efflux. 6. DHBG was thus identified as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7. Therefore, the inhibition of efflux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.

We present a case report of propiverine-induced Parkinsonism. We previously reported the induction of catalepsy by amiodarone, aprindine and procaine, which possess a diethylaminomethyl moiety and demonstrated selective blockade of dopamine D2 receptors by these drugs in mice. We hypothesized that drugs possessing a diethylaminomethyl structure may generally induce Parkinsonism and/or catalepsy.Thus, we performed a study to examine whether oxybutynin, pentoxyverine and etafenone, as well as propiverine, induce catalepsy in mice.The intensity of drug-induced catalepsy was in the order: haloperidoletafenonepentoxyverinepropiverineoxybutynin. In vivo occupancy of dopamine D1, D2 and mACh receptors in the striatum was also examined. The in vitro binding affinities to the D1, D2 and mACh receptors in the striatum synaptic membrane were within the ranges of 2.4-140 microM, 380-4,200 nM, and 1.2-2,800 nM, respectively.These results support the idea that any drug possessing a diethylaminomethyl moiety may contribute to the induction of catalepsy, possibly by occupying dopamine receptors.

We reported a rare case of gamma-heavy chain disease. A 63-year-old man had been given a diagnosis of diabetes mellitus at the age of 30 and had received hemodialysis since the age of 55. The patient presented with swollen lymph nodes in the neck. Lymph node biopsy findings suggested immunoblastic lymphadenopathy. The patient was admitted to Kitasato University hospital. Serum protein electrophoresis showed an increase of beta-fraction peak, and immunoelectrophoresis revealed an increase of gamma-heavy chain protein. Further studies of the gamma-heavy chain protein showed that it contained three different components and that the molecular weight of the main component was 34,000 Da. The patient died on the 11th day of hospitalization. The diagnosis at autopsy was unclassified malignant lymphoma.

The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [(3)H]vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [(3)H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 microM), an inhibitor of P-gp. No significant effect on the uptake of 3-O-[(3)H]methylglucose or [(14)C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [(3)H]vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8-heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [(3)H]vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 microM was tangeretinHMFnobiletin. None of these methoxyflavones inhibited 6beta-hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [(3)H]vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.

Our previous clinicopathologic study revealed an inverse association of liver metastasis of colorectal cancer and stromal expression of matrix metalloproteinase-9 (MMP-9) or urokinase receptor (uPAR). This suggests that host cells, particularly macrophages, expressing matrix-degrading enzymes/factors could be protective for the host against hematogenous metastasis. However, our previous study was unable to differentiate whether our results were causes or effects of widely spread cancer. To solve this point, we designed the present study on colorectal cancers that developed hematogenous metastasis after operation, ie., metachronous hematogenous metastasis. These cancers, being solely micrometastasized at the time of operation, allowed us to eliminate possible systemic effects by widely spread cancer. Sixty-two primary tumors with metachronous metastasis showed a decreased number of MMP-9+ stromal cells and CD68+ macrophages along the invasive margin with unchanged uPAR+ stromal area as compared with those in 72 control cases, which were free from tumor metastasis or recurrence for more than 5 years. Therefore, we judged the decrease of MMP-9+ host cells or macrophages in the primary site is irrelevant of effects of widely spread metastasis but probably related to causes of metastasis. Our data also characterized the metachronous metastasis group by uPAR expression in fibroblasts. The number of uPAR+ cancer cells, although small in number, were also larger in the metachronous metastasis group. Our data revealed that macrophages, a major source of uPAR and one of the sources of MMP-9, could be inhibitory to hematogenous metastasis, while uPAR+ fibroblasts and cancer cells, in turn, facilitate hematogenous metastasis. This suggests the functional multiplicity of matrix degradation processes in cancer tissue.

To test the hypothesis that acute inflammatory reaction associates with the development of pressure ulcers in bedridden elderly patients, 40 hospitalized elderly patients suffering from bacterial pneumonia, cerebrovascular disease, and femoral bone fracture were enrolled in this study. All of them were divided into two groups with pressure ulcers (group P; 17 patients) and without one (group N; 23 patients). The blood samples were taken from them within 5 days after the patients being bedridden. Although no significant difference exist in pressure ulcer risk factors (age, gender, Braden scale, underlying diseases, blood pressure, and heart rate) between the two groups, white blood cell, plasma C-reactive protein and fibrinogen in group P increased significantly as compared with those in group N. Besides number of platelets and maximum platelet aggregation rate were significantly higher in group P than in group N. Serum albumin and hemoglobin of both groups decreased after being bedridden, especially hemoglobin in group P was significantly lower than that in group N. While the concentration of serum IL-6 did not indicate a significant difference between both the groups, serum IL-1 beta increased significantly in group P. In conclusion, we suggested that acute inflammatory reaction releasing proinflammatory cytokines affected the development of pressure ulcer in bedridden elderly patients.

Mechanisms causing negative findings of serum C-reactive protein (CRP) in inflammatory disorders and malignant neoplasms were investigated. Patients with advanced prostate cancer manifesting negative CRP and alpha 2M deficiency were found. This finding suggests that alpha 2M, a carrier protein of interleukin-6, mediates CRP synthesis by the liver. Mechanism of synthesis of acute phase proteins including CRP, SAA and others was shown to be different in response to inflammation, alpha 2M-dependence in alpha 2M deficiency, the production of CRP and SAA by human hepatoma cells (HepG2) and the processes on the transcriptional activation of acute phase protein genes. In cases of prostate cancer associated with serum alpha 2M deficiency metastasis to the bones was noted. This finding suggests that alpha 2M inhibits metastasis of prostate cancer. It was suggested that the alpha 2M deficiency develops from complex formation of alpha 2M with proteases including PSA and u-PA, and accelerated catabolism of the complex rather than suppressed production of alpha 2M.

In the 21st Century, laboratory scientists must change their concepts and attitude in order to supply services and information of great value. The laboratory tests comprise an increasing volume, and medical workers frequently need consultation on these tests. Effective utilization of laboratory data are important aspects of evidence-based medicine, and will also contribute to the efficiency of hospital practice and management. Clinical Laboratory of Kitasato University Hospital opened the "Clinical Laboratory Information (Consulting) Center" in July 1995 to respond to the increasing demand for consultation. It has been supporting medical care and research. The Center is located on the second floor of the Clinical Laboratory building of Kitasato University Hospital, and is staffed by one medical technologist and a clinical pathologist specialized in laboratory medicine. The Center staff consults by telephone from 9 am to 5 pm on weekdays, and get inquiries after-work hours and during weekends either by e-mail or fax. The Center aims to improve medical care by providing accurate and up-to-date information on clinical laboratory tests and interpretations. The clinical pathologist of the Center attempts to advise physicians regarding appropriate tests for particular patients. This avoids the ordering of unnecessary tests, which benefits the patient, the physician, and the hospital. The clinical pathologist should keep abreast of new findings on a wide array of clinical laboratory tests. The clinical pathologist should respond immediately to requests and complaints, thereby always seeking to improve oneself and the Center. Our Center is the first clinical laboratory in Japan staffed by both a clinical pathologist and a medical technologist, and our Center could be a pilot study for a new service of hospital clinical laboratories.

Lp(a) has recently begun to attract attention as a risk factor of atherosclerotic disease, especially of ischemic heart disease. The Lp(a) concentration in the serum was shown to be important for chronic hemodialysis patients who have high mortality due to cardiovascular disease. Nicotinic acid derivatives, which are recognized for their capacity to lower the serum Lp(a) concentration, are effective against a high Lp(a) concentration in hemodialysis patients. In this study, niceritrol which is a nicotinic acid derivative was tested on hemodialysis patients and healthy controls by investigating the serum nicotinic acid level. Serum nicotinic acid concentration was also measured by the severity of renal dysfunction of patients untreated by niceritrol. The blood nicotinic acid concentration in healthy controls (n = 4) was changed after 2 hrs by the administration of niceritrol from 9.8 +/- 1.4 ng/ml to 192.7 +/- 23.1 ng/ml then slowly decreased. Chronic hemodialysis patients who take niceritrol every day showed the highest nicotinic acid serum concentration (500-1,000 ng/ml) on the day without hemodialysis and the serum level decreased with dialysis for 4 hrs to 25-80%. There was no significant difference in the nicotinic acid level in the serum between healthy controls (n = 10), chronic glomerulonephritis patients (n = 7), chronic renal failure patients (n = 8) and chronic hemodialysis patients (n = 17). Lp(a) concentration in the serum, however, was increased with greater severity of renal dysfunction, The side effect was not observed in any cases administered niceritrol. These data suggest nicotinate derivatives are effective for hemodialysis patients. High nicotinic acid level in the serum after treatment with niceritrol was lowered by dialysis. It is plausible that the nicotinate level in patients without niceritrol treatment did not influence the Lp(a) concentration, because there was no increase in the nicotinate level of the serum even if the patients had renal dysfunction.

An absorbed dose in the narrow beam is calculated based on the depth dose distribution and a field factor. The field factor has to be measured with especially high accuracy because it is highly variable. The field factor was calculated when detection size was changed, by using Monte Carlo simulation, which had no energy dependency or geometrical error. Then the relation between field factor and detection size in the narrow beam was investigated. An absorbed dose in peak depth and reference depth according to detection size was calculated for each field size. Detection size dependency was recognized in the case of measuring a field factor, because the absorbed dose tended to decrease as detection size increased. The absorbed dose in the narrow beam has to be calculated within a change of +/- 2%. The change in peak depth according to detection size was eliminated, and then the relation between an absorbed dose at the ideal detection size of 0 mm phi by extrapolation and detection size which has a deference of 2% from it, were acquired. In addition, the maximum usable detection size was estimated in the case of measuring the field factor.