Factors Affecting Steady-state Plasma Concentrations of Enantiomeric Mirtazapine and its Desmethylated Metabolites in Japanese Psychiatric Patients.

INTRODUCTION: This study evaluated the effects of the CYP2D6*10 genotype on steady-state plasma concentrations of enantiomeric mirtazapine (MIR) and N-desmethylmirtazapine (DMIR) in Japanese patients. METHODS: Subjects were 77 Japanese patients treated with racemic MIR. Steady-state plasma concentrations of MIR and DMIR enantiomers were measured using stereoselective liquid chromatography. Polymerase chain reaction was used to determine the CYP2D6 genotypes. RESULTS: After correcting for dose and body weight, smokers (n=15) had significantly lower S-(+)-MIR than nonsmokers (n=55) (15.1±17.8 vs. 23.9±17.8 ng/mL/mg/kg, Kruskal-Wallis test, p=0.034). One-way analysis of variance revealed that CYP2D6*10 homozygotes had significantly higher corrected plasma concentrations of S-(+)-MIR than the no-variant allele group (p=0.034). Multiple regression analysis revealed a significant positive correlation between the number of CYP2D6*10 alleles and corrected plasma concentrations of S-(+)-MIR. These results yielded the following final model: corrected plasma concentration of S-(+)-MIR=15.9+7.30×(number of CYP2D6*10 alleles) (R=0.279, p=0.023, coefficient of determination (R(2))=0.078). CONCLUSION: Homozygous CYP2D6*10 alleles and smoking have a significant impact on the metabolism of S-(+)-MIR in Japanese patients.

Study on micro-structure and morphological evolution of Fe/Pt nano-magnetic film.

One of the vertical magnetic recordings medium materials of the hard disk drive (HDD) is a Fe/Pt thin film. The development of ultra-high density magnetic recording medium in next generation is expected the magnetic disks such as HDD with capacity enlargement of the data. In order to study effectiveness of the proposed sputtering method, we evaluated micro structure, magnetic and the mechanical properties of a Fe/Pt thin film by some sputtering process conditions. From research results, effect sputtering conditions on micro-structure and mechanical properties of Fe/Pt nano film are verified.

Vacuum-assisted closure for bilateral severe ischemic foot after revascularization: a case report.

Vacuum-assisted closure (VAC) therapy is a unique system that helps promote wound healing. We report a case of severe ischemic foot in which VAC therapy markedly improved wound healing. A 73-year-old man underwent left axillopopliteal bypass and left 3rd, 4th , and 5th digital amputations for gangrene. Although his amputation stumps were complicated with methicillin-resistant Staphylococcus aureus (MRSA) infection, the stumps were successfully healed by VAC. He also had gangrene in his right 1st toe, which could not healed by VAC alone, and we performed right femoropopliteal bypass and right 1st digital amputation. The stump with MRSA infection was also successfully healed by VAC. Histopathologic examination revealed a lot of microvessels in the increased granulation tissue.

A new method of diagnosing gastric intestinal metaplasia: narrow-band imaging with magnifying endoscopy.

BACKGROUND AND STUDY AIMS: With endoscopy, there is a high rate of interobserver variability in the identification of gastric intestinal metaplasia, and the endoscopic findings correlate poorly with the histological findings. Previous studies by our group investigating the use of a narrow-band imaging system with magnifying endoscopy (NBI-ME) in the gastric mucosa suggested that the appearance of a light blue crest (LBC) on the epithelial surface may be a distinctive endoscopic finding associated with the presence of intestinal metaplasia. The aim of the present study was to clarify the value of NBI-ME for diagnosing gastric intestinal metaplasia. PATIENTS AND METHODS: The LBC was defined as a fine, blue-white line on the crests of the epithelial surface/gyri. To investigate the histology underlying the appearance of LBC, 44 biopsy specimens were obtained from regions containing LBC and 44 from non-LBC mucosa in 34 patients with atrophic gastritis. Three endoscopists then carried out NBI-ME in 107 consecutive patients to validate the diagnostic accuracy of the novel endoscopic technique. The degree of correlation between the LBC grading and the histological parameters of intestinal metaplasia was then assessed. RESULTS: The LBC grading correlated with cells that were positive for CD10 ( P = 0.0001) and Alcian blue ( P = 0.036). The appearance of LBC correlated with histological evidence of intestinal metaplasia with a sensitivity of 89 % (95 % CI, 83 - 96 %), a specificity of 93 % (95 % CI, 88 - 97 %), a positive predictive value of 91 % (95 % CI, 85 - 96 %), a negative predictive value of 92 % (95 % CI, 87 - 97 %), and an accuracy of 91 % (95 % CI, 88 - 95 %). CONCLUSIONS: In narrow-band imaging with magnifying endoscopy, observation of a light blue crest on the epithelial surface in the gastric mucosa is a highly accurate sign of the presence of histological intestinal metaplasia.

The human renal lymphatics under normal and pathological conditions.

AIMS: The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. METHODS AND RESULTS: Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. CONCLUSIONS: Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics.

Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression.

BACKGROUND: The loss of sonic hedgehog is an early change that occurs in the mucosa prior to neoplastic transformation and correlates with the type of intestinal metaplasia. Aberrant expression of CDX has also been shown to correlate with the development of intestinal metaplasia. AIM: To examine CDX2 expression in the non-cancerous mucosa of patients with gastric cancer and compared it to CDX2 expression in controls with intestinal metaplasia. METHODS: Sixty patients who had undergone endoscopic mucosal resection for early gastric cancer and 60 gender- and age-matched controls were studied. Two specimens each were obtained from the greater and lesser curves of the corpus and from the greater curve of the antrum. Expression of CDX2 and sonic hedgehog were evaluated by immunostaining. RESULTS: Gastric cancer was associated with a higher frequency of incomplete intestinal metaplasia (OR = 8.3; 95%CI, 3.7-18.9, P < 0.001). CDX2 negatively correlated with sonic hedgehog expression, however, multivariate analysis revealed that CDX2 correlated with the intestinal metaplasia scores. Sonic hedgehog indices were lower and CDX2 staining in the corpus lesser curve was higher in the cancer group than in the controls. Sonic hedgehog indices in the corpus decreased and CDX2 indices in both areas increased in patients in the ascending order of those without intestinal metaplasia, those with complete intestinal metaplasia and those with incomplete intestinal metaplasia (P < 0.001). CONCLUSIONS: Loss of sonic hedgehog expression and aberrant expression of CDX2 correlates with the type of intestinal metaplasia and may play a role in carcinogenesis.

Direct acceleration of solid-density plasma bunch by ultraintense laser.

The interaction of a petawatt laser with a small solid-density plasma bunch is studied by particle-in-cell simulation. It is shown that when irradiated by a laser of intensity >10(21) W/cm2, a dense plasma bunch of micrometer size can be efficiently accelerated. The kinetic energy of the ions in the high-density region of the plasma bunch can exceed ten MeV at a density in the 10(23)-cm(-3) level. Having a flux density orders of magnitude higher than that of the traditional charged-particle pulses, the laser-accelerated plasma bunch can have a wide range of applications. In particular, such a dense energetic plasma bunch impinging on the compressed fuel in inertial fusion can significantly enhance the nuclear-reaction cross section and is thus a promising alternative for fast ignition.

In vitro application of endotoxin enhances nitric oxide production in thoracic aortas from Mg-deficient rats.

Since endotoxin-induced vascular hyporeactivity to phenylephrine is enhanced in Mg-deficient rats, this study was designed to determine whether endotoxin directly enhances nitric oxide (NO) production in thoracic aortas isolated from Mg-deficient rats in vitro. Thoracic aortas isolated from Mg-deficient and control rats were cultured for 6 h with or without endotoxin (LPS). LPS (0.01-1.0 microg) increased NO production in a concentration-dependent manner. NO production in the presence of 0.1 and 1.0 microg/mL LPS was significantly higher in Mg-deficient rat aortas compared to aortas from control rats. The enhanced NO production was not significantly affected by endothelium-denudation. LPS-stimulated NO production was fully inhibited by a selective iNOS inhibitor, 1400W (0.1, 1.0 microM), in control rat aortas, but in Mg-deficient rat aortas inhibition by 1400W was only partial. A similar inhibitory effect was observed with anti-CD14 and anti-TLR4 antibodies. These results suggest that endotoxin enhances NO production in Mg-deficient rat aortas directly, and that endotoxin receptors might, at least in part, contribute to this enhancement.

Outcome of 51 nonmalignant nodules in the liver: usefulness of aspiration cytology for diagnosis of dysplastic nodules.

Pathologic diagnostic criteria for intrahepatic nonmalignant nodules using needle biopsy are controversial. To evaluate the cytodiagnostic criteria for dysplastic nodules using aspiration biopsy, a follow-up study of nonmalignant nodules was performed. Fifty-one intrahepatic nodules diagnosed histologically and cytologically as nonmalignant using an aspiration biopsy in 39 patients were followed up without treatment. The outcomes of the nodules were investigated using the Kaplan-Meier method and Cox's multivariate analysis. The cumulative rates of development to HCC at the 2nd year were 0%, 18%, and 53% in the non-dysplastic nodules, the low-grade dysplastic nodules, and the high-grade dysplastic nodules, respectively; and significant differences were seen among them (P= 0.0001). Multivariate analysis showed that cytologic grade was a significant risk factor for development to HCC (P=0.020). In conclusion, aspiration cytology was useful for diagnosis of the dysplastic nodules to predict risks of development to HCC.

Endoscopic resection with a two-channel videoendoscope for gastric carcinoid tumors.

BACKGROUND/AIMS: Endoscopic resection has been used to treat hypergastrinemia-associated early carcinoid tumors of the stomach. However, indications for endoscopic treatment of these tumors have not been established. Moreover, endoscopic resection of these tumors is often difficult with conventional polypectomy, because these tumors are often located in the submucosal layer. To completely remove these tumors, we used a two-channel videoendoscope with which both grasping forceps and a polypectomy snare could be used simultaneously. METHODOLOGY: At Osaka Medical Center for Cancer and Cardiovascular Diseases, eight carcinoid tumors in six patients were removed with a two-channel videoendoscope. Reports of early carcinoid tumor in Japanese literature were reviewed to analyze the relationship between lymph node metastasis and the size and depth of involvement of these tumors. RESULTS: Six carcinoid tumors were completely removed "en bloc", but two tumors were incompletely removed. In these two patients, submucosal tumor invasion was observed on the excision line. To completely remove these tumors, the oral side, but not the top, of the tumor should be strongly grasped and pulled toward the center of the lumen as far as possible by the grasping forceps, which had been passed through the snare loop. Endoscopic follow-up studies showed no local recurrence in any patients with and without complete tumor resection during the average observation period of 30 months. A review of histological reports in Japanese literature showed that lymph node metastasis did not occur when the tumors were less than 10 mm in diameter, and could be completely removed by an endoscope. CONCLUSIONS: Endoscopic resection with a two-channel videoendoscope is a useful and safe method for resection of small carcinoid tumors of the stomach.

[Off-pump heart surgery for the removal of a ruptured, detached, and entrapped cutting balloon].

A 84-year-old female with a ruptured, detached, and entrapped cutting balloon was successfully undergone the surgical removal under beating heart. But the left anterior descending coronary artery (LAD) was severely dissected by ruptured cutting balloon. So we had to anastomose left internal thoracic artery (LITA) to the distal part of LAD. Postoperative coronary angiography showed the narrowing of LAD and the effective revascularization was not obtained. We must recognize that the intima of the coronary artery is impaired by the ruptured cutting balloon more severely than we expected.

Stimulated electron-acoustic-wave scattering in a laser plasma.

Intense laser-plasma interaction can be a source of various electronic instabilities. Recently, stimulated backscattering from a trapped electron-acoustic wave (SEAS) [Montgomery et al., Phys. Rev. Lett. 87, 155001 (2001)] was proposed to reinterpret spectra previously attributed to stimulated Raman scattering (SRS) from unrealistically low densities. By particle simulations in a uniform plasma layer, which is overdense for ordinary SRS, strong reflection by SEAS at the electron plasma frequency is found. Transient SEAS reflectivity pulsations are followed by strong relativistic heating of electrons. Physical conditions are explained by three-wave parametric coupling between laser light, standing backscattered wave and slow electron-acoustic wave. Regions in which SEAS reflection can dominate over SRS are singled out.

Frequent expression of smooth muscle markers in malignant fibrous histiocytoma of bone.

BACKGROUND/AIMS: Malignant fibrous histiocytoma (MFH) of bone, a relatively rare primary malignant bone tumour, is a distinct clinicopathological entity as opposed to MFH derived from soft tissue. Although the true histogenesis of this condition is still controversial, a considerable number of cases of MFH in soft tissue show positive immunohistochemical reactivity for muscle markers such as desmin, common muscle actin (HHF35), and alpha smooth muscle actin (SMA), suggesting that MFH cells are myofibroblastic in nature. METHODS: This study investigated immunoreactivity for several different muscle markers in 19 cases of MFH of bone together with reverse transcription polymerase chain reaction (RT-PCR) analysis on frozen tissue samples that were available in four cases, and compared the data with those found in 11 cases of osteosarcoma and 11 cases of soft tissue MFH treated over the same period. RESULTS: Immunohistochemistry revealed that MFH of bone showed relatively frequent expression of smooth muscle markers, including calponin (nine cases), alpha-SMA (nine cases), and SM22alpha (18 cases), and this was confirmed by RT-PCR analysis. However, only one, two, and three cases of MFH of bone showed positive staining for desmin, MyoD1, and HHF35, respectively. Similarly, 11 osteosarcoma cases were relatively frequently positive for alpha-SMA (five cases), calponin (four cases), and SM22alpha (seven cases), and less frequently positive for desmin (one case), MyoD1 (none), and HHF35 (none). In contrast, very few MFH of soft tissue cases (n = 11) showed positive reactivity for all of these muscle markers. It has recently been reported that human bone marrow stromal cells also express various kinds of smooth muscle markers including alpha-SMA and calponin. CONCLUSIONS: These results suggested that MFH of bone may derive from mesenchymal stromal cells in bone marrow and has a more myofibroblastic differentiation than soft tissue MFH.

Hepatic angiomyolipoma: radiologic and histopathologic correlation.

We present two cases of hepatic angiomyolipoma. Histologic analysis showed that mature adipose tissue occupied 79.0% of the area on the largest cut surface in the first case and 40.2% in the second case. We suggest that the difference in the ratio of adipose tissue volume to its distribution is reflected on diagnostic images.

Malignant mesenchymoma of the lower leg.

A 24 year old man had a two year history of a painless mass on his right popliteal region. Magnetic resonance imaging demonstrated a 6 x 8 cm tumour mass in the lateral gastrocnemius. Histological examination of the tumour resected by radical surgery revealed that it consisted of myoblastic sarcoma and chondrosarcoma. Immunohistochemical studies were positive for Ki-67 and p53 throughout the area and for S-100 protein in the chondrosarcomatous area; in addition, they showed partial positivity for muscle common actin (HHF-35), smooth muscle actin, and myoglobin in the spindle cells. The percentages of Ki-67, p53, and p21/WAF1 positive cells in the spindle cell component were 34%, 65.7%, and < 0.1%, respectively. In addition, staining was negative for pancytokeratin, desmin, and glial fibrillary acidic protein. The SYT-SSX, TLS-CHOP, and EWS-FLI1 fusion genes were not detected using the reverse transcription polymerase chain reaction. Given the results, the definitive histological diagnosis is malignant mesenchymoma. This is the first report of malignant mesenchymoma of the lower leg with immunohistochemical and molecular studies.

Reduced expression of focal adhesion kinase in liver metastases compared with matched primary human colorectal adenocarcinomas.

The focal adhesion kinase (FAK) is implicated in integrin-mediated signal transduction pathways used in cell adhesion, cell motility, apoptosis, and anchorage-independent growth. Because cancer invasion and metastasis are thought to be associated with alterations in cellular adhesive and motile properties, we studied the expression of four focal adhesion proteins including FAK in matched samples of human normal colorectal mucosa (N), primary colorectal adenocarcinomas (T) and liver metastases (M) from 10 patients by Western blot analysis. This gave us the advantage of directly comparing levels of focal adhesion protein expression within the same genetic background. Average FAK expression level was significantly higher in T than in N and it was significantly lower in M than in T. Average paxillin expression level was also significantly higher in T than in N, but it was not significantly different between T and M. Similar results were obtained by immunohistochemical analyses of FAK and paxillin expression. Average vinculin and talin expression levels showed no significant differences among these three samples (N, T, and M). These data demonstrate that the FAK expression level increases in primary tumors compared with normal mucosa and decreases in liver metastases to the level of normal mucosa in the majority of human colorectal adenocarcinomas. Up- and down-regulation of FAK protein expression observed in this study may have a profound effect on the signal transduction.

The DEFECTIVE IN ANTHER DEHISCIENCE gene encodes a novel phospholipase A1 catalyzing the initial step of jasmonic acid biosynthesis, which synchronizes pollen maturation, anther dehiscence, and flower opening in Arabidopsis.

The Arabidopsis mutant defective in anther dehiscence1 (dad1) shows defects in anther dehiscence, pollen maturation, and flower opening. The defects were rescued by the exogenous application of jasmonic acid (JA) or linolenic acid, which is consistent with the reduced accumulation of JA in the dad1 flower buds. We identified the DAD1 gene by T-DNA tagging, which is characteristic to a putative N-terminal transit peptide and a conserved motif found in lipase active sites. DAD1 protein expressed in Escherichia coli hydrolyzed phospholipids in an sn-1-specific manner, and DAD1-green fluorescent protein fusion protein expressed in leaf epidermal cells localized predominantly in chloroplasts. These results indicate that the DAD1 protein is a chloroplastic phospholipase A1 that catalyzes the initial step of JA biosynthesis. DAD1 promoter::beta-glucuronidase analysis revealed that the expression of DAD1 is restricted in the stamen filaments. A model is presented in which JA synthesized in the filaments regulates the water transport in stamens and petals.

Evaluation of epithelial cell proliferation rate in normal-appearing colonic mucosa as a high-risk marker for colorectal cancer.

To determine whether the colonic epithelial proliferation rate is useful as a marker for colorectal cancer, we measured the Ki-67 labeling index (LI) in normal-appearing mucosa from the sigmoid and ascending colon in patients with two or more tumors (early cancers, which are defined as tumors the depth of invasion of which is limited to mucosal layer or submucosal layer, adenomas, or both). The association of baseline LI with the risk of development of colon tumors 2 years after endoscopic removal was assessed by cohort analysis. The presence of two or more tumors was defined as occurrence. One hundred and six specimens from the sigmoid colon and 130 from the ascending colon from 246 subjects (203 males and 43 females) were used for analysis. The patients with higher upper-third LI in the normal-appearing mucosa in the sigmoid colon, but not in the ascending colon, had significantly more tumors at follow-up colonoscopy 2 years later (risk ratio, 3.6; 95% confidence interval, 1.2-10.6). Moreover, multivariate analysis showed that it was an independent factor. We concluded that the higher upper-third Ki-67 LI of normal-appearing mucosa in the sigmoid colon indicates a high risk for colorectal cancer.

Human stomach-specific gene, CA11, is down-regulated in gastric cancer.

To reveal the implication in gastric cancer pathogenesis of the novel human gene referred to as CA11, which was recently isolated by a differential display technique using normal gastric mucosa and gastric cancer tissue, we examined CA11 expression in 50 primary gastric cancers and also introduced the CA11 gene into gastric cancer cells. RNA dot blot analysis against various human organs and developmental stages demonstrated that CA11 was intensively expressed especially in normal stomach tissue. Northern blot analysis showed that expression of the CA11 gene in cancer tissue was down-regulated compared with normal tissue. Semi-quantitative RT-PCR also demonstrated that CA11 gene expression was decreased in 41 out of 50 (82%) of the gastric cancer tissues, when compared with normal stomach tissues, while no relationship was found between CA11 expression and various clinicopathological characteristics including histological type, depth of invasion, lymph node metastasis, and clinical stage. Immunohistochemical analysis with anti CA11 antibody showed that CA11-positive staining was observed in the surface regions of normal gastric epithelium, but was found faintly or not at all in cancer tissues. CA11 transfected MKN28 cells also displayed a marked decrease in the number of colony formations when compared to double normal controls. These findings suggest that the loss of CA11 expression in gastric tissues may play an important role in gastric carcinogenesis.