Musculoskeletal Simulation for Determining Influences of the Magnitude of Sensory Noise and Stiffness on the Selection of Hip or Ankle Movement Strategies.

While standing, the elderly exhibit different move- ment behaviors compared to young people. However, the causes of these differences remain clear. The purpose of this study was to verify a hypothesis that only the magnitude of sensory noise and stiffness can reproducibly determine trends in the hip or ankle movement strategies. Simulations of postural control of a musculoskeletal model for three noise conditions and three stiffness conditions were performed. Variations in the angles of the hip and ankle suggested that the sensory noise amplitude had no influence on the selection. However, the ankle strategy tended to be selected with the increase of stiffness. Strategy shifts of elderly may be derived from other components; muscle weakness, increase of neurological time delay, or learning based on other evaluation index.

Functional role of ALK-related signal cascades on modulation of epithelial-mesenchymal transition and apoptosis in uterine carcinosarcoma.

BACKGROUND: Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Recently, the deregulated expression of full-length ALK has been observed in some primary solid tumors, but little is known about its involvement in the tumorigenesis of uterine carcinosarcomas (UCSs). Here we examined the functional role of the ALK gene in UCSs. METHODS: Regulation and function of the ALK gene were assessed using two endometrial carcinoma cell lines. Expression of ALK and its related molecules were also investigated using clinical samples of UCSs. RESULTS: In cell lines, ALK promoter activity was significantly increased by transfection of Sox11 and N-myc, which are known to contribute to neuronal properties. Cells stably overexpressing full-length ALK showed an enhancement of EMT properties mediated by TGF-ß1 and HGF, along with an increase in phosphorylated (p) Akt and nuclear p65. Overexpression of p65 also led to transactivation of Twist1 gene, known as an EMT inducer. Finally, treatment of the stable ALK-overexpressing cells with doxorubicin resulted in inhibition of apoptosis with progressive increase in the expression ratio of both pAkt and bcl2 relative to total Akt and bax, respectively. In clinical samples, strong cytoplasmic ALK immunoreactivity and mRNA signals without rearrangement or amplification of the ALK locus were frequently observed in UCSs, particularly in the sarcomatous components. Further, ALK IHC score was found to be positively correlated with Sox11, N-myc, Twist1, and bcl2 scores. CONCLUSION: ALK-related signal cascades containing Akt, NF-κB, Twist1, and bcl2 may participate in initial signaling for divergent sarcomatous differentiation driven from carcinomatous components in UCSs through induction of the EMT process and inhibition of apoptotic features.

Action of physiologically active materials in human semen during aging.

We examined the activities of some physiologically active substances (enzymes) in human seminal plasma from subjects in their 20s, 30s, and 40s. The average volume of semen per ejaculation in this investigation did not differ significantly depending on the age of the subject. Two age dependent patterns of decrease of substances in semen were observed, and the substances including tissue kallikrein and prostate specific antigen (PSA) basic arginine amidase in human seminal plasma showing the first pattern (a significant decrease in the 40s as compared to the 30s) might be initially secreted from the prostate gland, and whereas the glands secreting the other group of substances including active form coagulation factor X (FXa) and plasminogen are not now known. The levels of these substances in semen decrease in the subjects in their 30s. The coagulation and liquefaction times of human semen from older subjects were both prolonged with those of semen from younger subjects, and that such alteractions ultimately cause the age dependent declines of the motility of sperm and the ability of fertility.

Blood coagulation factor X (FX) in human seminal plasma.

The active form of human blood coagulation factor X (FXa, EC 3.4.21.6) showing N-alpha-Benzoyl-L-isoleucyl-L-glutamyl-L-glycyl-L-arginine- p-nitroanilide (S-2222) hydrolyzing activity was first detected in human semen (seminal plasma) by affinity chromatography using anti-human coagulation factor X, and this enzyme activity was inhibited by anti-human FX. This enzyme has been associated with the human coagulation factor X (FX) in human semen (seminal plasma) by Western blot analysis, and the molecular mass of mature FX was also estimated to be 59 KDa by SDS-PAGE and Western blot analysis.

Effects of dermatan and dextran sulfates on arginine amidase activity released from isolated rabbit arteries.

We examined the levels of arginine amidase secreted from isolated rabbit arteries treated with dermatan and dextran sulfates, and the relation between the secretion of arginine amidase activity and the concentration of dermatan sulfate added to these arteries. The results showed that while dextran sulfate tended to accelerate the release of arginine amidase activity from the isolated rabbit ear artery, the induction was not significant. There was a significant increase in the level of arginine amidase released from the lower portion of isolated rabbit aorta (p<0.05), but no significant change in the upper portion of the aorta. In contrast, the addition of dermatan sulfate significantly increased the level of arginine amidase activity released from the isolated rabbit ear artery and the upper and lower portions of the aorta (p<0.05). Linear dose-response relationships were observed between the level of arginine amidase activity released from the isolated rabbit ear artery and aorta and the concentration of dermatan sulfate added.

[A case of systemic lupus erythematosus with hemophagocytic syndrome and cytophagic histiocytic panniculitis].

A 23-year-old man, admitted because of high fever, polyarthralgia, butterfly rash and chest pain, was diagnosed as systemic lupus erythematosus (SLE) from the findings of positive antinuclear antibody and anti-DNA antibody. He was treated with 60 mg prednisolone daily, but as reducing the dose, white blood cell counts and platelet counts were decreased and fever, polyarthralgia, decrease of complements, increase of ferritin, hepato-splenomegaly and liver dysfunction were observed. Bone marrow specimen revealed phagocytosis of blood cells by histiocytes and he was diagnosed as hemophagocytic syndrome(HPS) due to active SLE. Methylprednisolone pulse therapy was effective temporarily, HPS recurred while reducing steroid, and cyclosporin was added. After a temporary remission, marked extensive swelling in the face appeared suddenly. Facial skin biopsy showed necrosis of fat cells and hemophagocytosis by histiocytes. Accordingly, he was diagnosed as panniculitis due to HPS and was treated successfully with intravenous cyclophosphamide pulse therapy and high dose of gammaglobulin. Several cases of HPS due to SLE have been reported recently, but this is a rare case of cytophagic histiocytic panniculitis (CHP) due to SLE.

Genes encoding nitrilase-like proteins from tobacco.

Nitrilase (nitrile aminohydrolase, EC 3.5.5.1) catalyzes the hydrolysis of indole-3-acetonitrile (IAN) to indole-3-acetic acid (IAA). Arabidopsis thaliana genome has four nitrilase genes (NIT1, NIT2, NIT3 and NIT4). Three (NIT1, NIT2 and NIT3) of the four genes have high similarity. We have cloned two NIT4 homologs (TNIT4A and TNIT4B) from tobacco (Nicotiana tabacum). Genomic Southern hybridization, among other experiments, strongly suggests that tobacco has NIT4 homologs but not NIT1 to NIT3 homologs. Introduction of Arabidopsis NIT2 into tobacco conferred IAN-mediated growth inhibition, probably due to hydrolysis of IAN to IAA, while ectopic expression of TNIT4A had little effect on the sensitivity of transgenic plants to IAN. Nitrilase activity of TNIT4 proteins is discussed.

A case-control study evaluating occult blood screening for colorectal cancer with hemoccult test and an immunochemical hemagglutination test.

A case control study to evaluate the occult blood screening for colorectal cancer was conducted in a town where colorectal cancer screening had been performed by Hemoccult test during the early years and subsequently by an immunochemical hemagglutination test. All residents aged >/=40 years had been offered the annual screening. Case series consisted of 51 subjects with fatal colorectal cancer. Three controls per case were selected from the list of residents who were alive at the time of diagnosis of the corresponding case and had been living in the town, matched by gender and by age. The odds ratio (OR) of dying of colorectal cancer for those having their most recent screening histories with Hemoccult test or the immunochemical test during the preceding 1 year and 1-2 year segment before case diagnosis were 0.20 [95% confidence interval (CI): 0.08-0.49] and 0. 17 (95% CI: 0.04-0.75), respectively. The OR increased towards 1.0 as the number of years since the most recent screening increased. The OR of dying of colorectal cancer was calculated to be 0.19 (95% CI: 0.05-0.70) for those screened with the immunochemical test alone during the preceding 1 year after adjustment for previous screening histories with the Hemoccult test. Corresponding OR was 0.36 (95% CI: 0.11-1.17) for those screened with Hemoccult test during the preceding 1 year. These results suggest that screening for colorectal cancer by fecal occult blood testings or immunochemical test alone would reduce mortality and that efficacy of the screening would be higher for the immunochemical test than for Hemoccult test.

Total number and size distribution of hepatic metastases of carcinoma.

OBJECTIVE: To quantify the susceptibility of carcinoma to hepatic metastases by studying autopsy livers with carcinoma metastases, the primary sites of which were mostly the digestive organs. STUDY DESIGN: We developed a stereologic method of estimating the total number, N, and the size distribution of metastatic tumors in the liver based on a geometric model of spherical nodules with varying radii, r. This method proved to be sufficiently reliable by disector analysis simultaneously performed in some cases; it gave an approximate result. This method was applied to the 31 autopsy cases. Correlation and regression analyses were performed among N, the mean radius of nodules, rmean, and conventional pathologic features of the primary tumor. RESULTS: The estimates of N ranged from 10 to 3.2 x 10(5). A close negative correlation was confirmed between N and rmean. Neither significant correlation nor regression was observed among N and the other pathologic factors of the primary tumors. CONCLUSION: N turned out to serve as a useful index for evaluating the metastatic potential of a carcinoma. However, investigation has yet to be made to determine biologic factors in the primary tumor closely associated with N.

Ligation of CD31 (PECAM-1) on endothelial cells increases adhesive function of alphavbeta3 integrin and enhances beta1 integrin-mediated adhesion of eosinophils to endothelial cells.

We determined the role of the heterophilic interaction of alphavbeta3 integrin on endothelial cells with CD31 on leukocytes in mediating leukocyte-endothelial cell interactions. Preincubation of interleukin-4 (IL-4)-stimulated human umbilical vein endothelial cells (HUVECs) with anti-CD31 monoclonal antibodies (MoAbs) enhanced eosinophil adhesion to the IL-4-stimulated HUVECs, and the endothelial CD31-induced enhancement of eosinophil adhesion to IL-4-stimulated HUVECs was prevented by anti-vascular cell adhesion molecule-1 (VCAM-1) MoAb and anti-very late activation antigen-4 (VLA-4) MoAb, but not by anti-intercellular adhesion molecule-1 (ICAM-1) MoAb, anti-lymphocyte function-associated antigen-1 (LFA-1) MoAb, anti-P-selectin MoAb, or anti-E-selectin MoAb. CD31 stimulation of HUVECs increased the adhesive function of alphavbeta3 integrin to its ligand RGD peptide, the binding of which reached a maximum at 10 minutes after the stimulation, and the CD31-induced alphavbeta3 integrin activation on HUVECs was inhibited by inhibitors of protein kinase C and phosphatidylinositol 3 kinase (PI3-kinase). Furthermore, anti-alphavbeta3 integrin MoAb and RGD peptide as well as soluble CD31 inhibited endothelial CD31-induced enhancement of eosinophil adhesion to IL-4-stimulated HUVECs. However, anti-alphavbeta3 integrin MoAb had no significant inhibitory effect on the eosinophil adhesion to IL-4-stimulated or unstimulated HUVECs without CD31 stimulation of HUVECs. Finally, CD31 stimulation of eosinophils increased the adhesive function of alpha4beta1 integrin (VLA-4) to its ligand fibronectin and their adhesion to IL-4-stimulated HUVECs in a VLA-4-dependent manner. These results indicate that CD31-mediated inside-out signaling activates alphavbeta3 integrin on endothelial cells, that the heterophilic alphavbeta3 integrin/CD31 interaction induces beta1 integrin-mediated adhesion of eosinophils to endothelial cells, and that the heterophilic interaction itself is not significantly involved in firm adhesion of eosinophils to endothelial cells.

Effects of Nd:YAG laser irradiation on morphometry and lung function in elastase-induced emphysema in rats.

BACKGROUND & OBJECTIVE: Although thoracoscopic laser ablation therapy has been hailed as an effective surgical treatment for diffuse emphysema, no one has as yet made an in-depth study of the efficacy of this treatment. This investigation was undertaken to research the effects of laser pneumoplasty on an animal model of emphysema. STUDY DESIGN/MATERIALS AND METHODS: Eight weeks after elastase treatment, the rats' left lungs were irradiated using contact Nd:YAG laser. Pulmonary function tests were performed 4 weeks after irradiation and the lungs were prepared for histologic examination. RESULTS: Dense fibrous scars beneath the pleura were observed at 4 weeks after irradiation. Although mean linear intercept values of irradiated lungs were not much lower than those in the non-irradiated elastase-treated group, laser irradiation caused a significant decrease in lung volume. While there was no significant difference in quasistatic compliance, elastic recoil pressure of the lung increased to control levels at total lung capacity volume. CONCLUSION: We conclude that laser therapy does not cause normalization of compliance, or improvement in the deeper part of the emphysematous lung, but rather a peripheral volume reduction and "encasement effect" on the lungs as a result of fibrotic scars.

Cross-linking of intercellular adhesion molecule-1 induces interleukin-8 and RANTES production through the activation of MAP kinases in human vascular endothelial cells.

We investigated whether intercellular adhesion molecule-1 (ICAM-1) transduces outside-in signals for the production of chemokines IL-8 and RANTES in endothelial cells. Cross-linking of ICAM-1 induced IL-8 and RANTES mRNA expressions and increased their protein synthesis and secretions in endothelial cells. Furthermore, ICAM-1 cross-linking activated 44- and 42-kDa mitogen-activated protein (MAP) kinases (ERK1 and ERK2) in endothelial cells, as indicated by the electrophoretic mobility shift of MAP kinases on SDS-polyacrylamide gels. Finally, the specific MEK inhibitor PD98059 inhibited ICAM-1-induced IL-8 and RANTES production in endothelial cells. Taken together, these results indicate that stimulation of ICAM-1 induces IL-8 and RANTES production through the activation of 44- and 42-kDa MAP kinases in endothelial cells, suggesting that ICAM-1-induced chemokine production in endothelial cells would further attract and activate leukocytes to induce intense inflammation.

Two-D distance distribution analysis: an application to HBcAg-positive hepatocytes and its relation to septum formation in cirrhosis.

The morphogenesis of cirrhotic septa in chronic hepatitis B was studied assuming that they arise at the sites of hepatocellular necrosis invoked by host immune reaction against HBcAg-expressing hepatocytes. Sections from three livers with chronic hepatitis B, all in cirrhotic stage, were immunostained with HBcAg and subjected to morphometry to analyze the distribution of HBcAg(+) hepatocytes and its relation with septa. HBcAg(+) cells were not distributed randomly over the nodules but forming focal areas. The septum formation along these foci was shown by 2-D distance distribution analysis, a technique we devised. Upon a sheet of color microphotograph of immunostained section, hundreds of test points each 400 microns apart were arranged by overlaying a tessellated grid. From each of the points hitting the nodules, the distance to the nearest nodulo-septal border D(min) was measured. Measurement was performed on a total of 2,585 test points. It was shown that the mean D(min) in the HBcAg(+) areas was significantly smaller than in HBcAg(-) areas. Thus, the cirrhotic septa are considered to arise at the places of HBcAg(+) foci, connecting them by postnecrotic collapsing.

[Histological effects of short term endocrine therapy on prostatic cancer].

BACKGROUND: The objective of this study is to investigate the pathological changes which occurred in prostatic cancer shortly after the commencement of endocrine therapy. METHODS: Fourty-three patients underwent radical prostatectomy immediately after the short term endocrine therapy (treatment period was within one month) and the histological pictures of operative specimens were compared to those obtained from the pretreatment biopsy specimens. RESULTS: Degenerative changes of cancer cells, such as nuclear and cytoplasmic vacuole, collapse of the cytoplasm and the appearance of naked hyperchromatic nucleus were noticed after the short term endocrine therapy. Especially in the cases which were histologically evaluated to be poorly differentiated in the biopsy specimens, not only degenerative changes but also destruction of cancer nests caused by cell death were observed. The histological effects affected by short term endocrine treatment had no relation to the prognosis, but in the cases of stage D2, the pathological grade judged by post-therapeutic specimens were found to be useful for the prediction of prognosis. CONCLUSION: Endocrine therapy induces remarkable pathological changes in prostatic cancer within a very short time after beginning treatment.

Papillary adenoma of type II pneumocytes might have malignant potential.

Papillary adenoma of type II pneumocytes is a rare tumour. It is considered to be a benign neoplasm and is derived from immature cells in the bronchioloalveolar epithelium, however, its biological nature has not been elucidated. We report a case of an adenomatous tumour; a papillary adenoma of type II pneumocytes, which we regard as possessing malignant potential. Light microscopically, as well circumscribed, papillary tumour of predominantly cuboidal cells resembling type II pneumocytes was found, but Clara type and ciliated cells were also present. Immunohistochemically, the tumour cells reacted positively with antibodies to surfactant apoproteins (A, B), carcinoembryonic antigen, cytochrome P-450 1A1-2 and 2B1-2. Ultrastructurally, many osmiophilic lamellar bodies and electron-dense granules were demonstrated. Semi-serial sections revealed signs of transbronchial dissemination and vascular invasion. Morphometry using 12-dimensional cluster analysis disclosed features of the tumour cells which resembled those of pneumocyte type II adenocarcinoma. These findings suggest that the present case has some malignant characteristics and originates from immature bronchiolar or alveolar cells, with a potential to develop into both type II pneumocyte and Clara cell type adenocarcinomas.

Atypical adenomatous hyperplasia and adenocarcinoma of the human lung: their heterology in form and analogy in immunohistochemical characteristics.

BACKGROUND: In a previous study, morphometry and multivariate cluster analysis was performed on 97 lesions. These consisted of atypical adenomatous hyperplasia (AAH), considered to be an important lesion corresponding to a step of carcinogenesis for adenocarcinoma of the human lung, Clara cell type, and type 2 pneumocyte type adenocarcinomas. Although AAH and the two types of adenocarcinoma were re-classified into three clusters and AAH was defined in clear morphologic terms, the biologic nature of AAH has yet to be clarified. In the present study, immunohistochemical analysis was performed to gain a deeper understanding of the relationship between AAH and the two types of adenocarcinoma, and to compare the results with those obtained by morphometry. METHODS: The 97 lesions analyzed by morphometry were submitted to immunohistochemical analyses using antibodies against surfactant apoprotein A, urine protein 1, carcinoembryonic antigen and cytochrome P-450s (1A1-2, 2B1-2, 2E1). Also examined, as controls, were 17 lesions with adenomatous hyperplasia (AH), a non-neoplastic reactive change of bronchiolo-alveolar cells, 30 areas of normal Clara cells, and 36 areas of normal type 2 pneumocytes. The immunoreactivity was graded by introducing a semi-quantitative scoring system. RESULTS: Immunohistochemically, AAHs behaved quite similarly to the lesions classified as Clara cell type or type 2 pneumocyte type adenocarcinomas. For any of the antibodies employed, no significant difference in immunoreactivity was demonstrated among these lesions. CONCLUSIONS: The results suggest, in accordance with our previous morphometry, that AAH is a lesion closely related with Clara cell type and type 2 pneumocyte type adenocarcinomas, probably as their common precursor. However, the two types of adenocarcinomas, despite their characteristic morphologic features, are indistinguishable using the biological indicators applied in this study.

Computer-assisted pathology of intraepithelial adenocarcinoma and related lesions: 3-D distribution, structural aberration and discrimination.

To discriminate among intraepithelial neoplasms, we have been relying on tissue microscopy, but pathologists' subjectivity sometimes impairs diagnosis. Even an individual pathologist is sometimes unable to reproduce exactly his or her own previous diagnosis. Are various atypical lesions classifiable in a reproducible way, and if they are, how? The reliability of a diagnosis will be strengthened if we can define the "natural" categories inherent in cells and tissues. Morphometry and statistical analysis using a computer can provide answers. Atypia, a morphological feature of carcinoma, is essentially multivariate. Quantification of a tissue feature requires reducing it to a set of ten or more quantities, including size, shape and position of the nucleus, nucleolus, and the cell itself. The grade of aberration from the norm can be assessed only by a synthetic approach, using a computer for multivariate cluster analysis. This classification has been attempted in adenocarcinoma and related lesions of the lung and pancreas. The categories thus established are reproducible, because the lesions fall into divisions according to their forms. We can also examine the organ distribution of intraepithelial neoplasms by three dimensional (3-D) computer-assisted mapping. To reach a higher level of reliability, as many meaningful features as possible should be taken into account. Particularly, we emphasize the significance of architectural pattern as a biomarker for intraepithelial glandular neoplasms. Computer-aided 3-D structural analysis visualizes the basic skeleton of these neoplasms around which the cells adhere. Instead of the dichotomous tree pattern of normal glands, the tumors basically harbor a 3-D network, tubular or porous, which increasingly deviates from the norm along with the transition from adenoma to well to moderately to poorly differentiated adenocarcinoma. This structural aberration, if recognizable on 2-D sectional images, will serve as a surrogate endpoint biomarker for glandular tumors.

Quantitative cytopathology of endometrial lesions.

Morphometric and multivariate statistical methods were used to discriminate endometrial carcinoma from benign cells in cytologic studies. Clumps of epithelial cells that appeared most diagnostically relevant were selected from aspirated samples of 70 endometrial cancer patients. The cells' cytologic character was reduced to a combination of five quantitative parameters--nuclear size, degree of anisokaryosis, nuclear from index, homogeneity of nuclear chromatin texture, and regularity of nuclear arrangement. The 5-variate cluster analysis demonstrated that the 70 cases could be classified into three definite groups: Group A (17 cases) was characterized by cells of small nuclear size, slight anisokaryosis, homogeneous chromatin texture, and regular nuclear arrangement; Group C (12 cases) by cells of large nuclear size, marked anisokaryosis, heterogeneous chromatin texture, and irregular nuclear arrangement; and Group B (41 cases) by cells of intermediate parameter values. Group C was derived from 10 cases of adenocarcinoma and 2 of atypical hyperplasia, while Groups A and B were not derived from any cases of malignancy. The computer-assisted morphometric statistical method can objectively classify the endometrial cells into malignant and benign, with improved validity and reproducibility. The cytopathologic finding, if detected by this method, may serve as a surrogate endpoint biomarker.

Phase-change optical disks compatible with a two-wavelength laser beam.

Three types of multiple-layer structure are proposed for a two-wavelength-compatible phase-change optical disk that uses an 830-nm beam for writing and erasing and a 670-nm beam for reading. Each disk with an optimized structure exhibits high-enough carrier-to-noise and erasing ratios at 830 nm and 670 nm for practical use. One of the disks has a lower erasing ratio at 670 nm than at 830 nm for the same erased marks. This difference is explained by optical characteristics that stem from the multiple-layer structure of the disks.

Morphometric and multivariate statistical detection of cancer cells in endometrial cytology.

Endometrial carcinoma was discriminated in cytologic studies using morphometric and multivariate statistical methods. On aspirated samples from 70 cases (10 well-differentiated adenocarcinomas, 4 hyperplasias and 56 normal controls), clumps of epithelial cells that could be regarded as the most diagnostically relevant were selected in each case. Their cytologic character was reduced to a combination of five quantitative parameters (nuclear size, degree of anisokaryosis, nuclear form index, homogeneity of nuclear chromatin texture and regularity of nuclear arrangement). The five-variate cluster analysis demonstrated that the 70 cases could be classified into three groups: group A (17 cases) was characterized by cells with small nuclear size, slight anisokaryosis, homogeneous chromatin texture and regular nuclear arrangement; group C (12) by cells with large nuclear size, marked anisokaryosis, heterogeneous chromatin texture and irregular nuclear arrangement; and group B (41) by cells with intermediate parameter values. Group C was derived from 10 cases of adenocarcinoma and 2 of atypical hyperplasia, while groups A and B were not derived from any cases of malignancy. This preliminary study indicated that morphometric-statistical classification can be of great help in improving the cytodiagnostic validity and reproducibility of endometrial carcinoma, and it awaits further, practical testing within a significantly larger series of malignancy cases.