Feedforward correction of nonlinearities in piezoelectric scanner constructions and its experimental verification.

Piezoelectrical actuators widely used in scanning devices for highly resolved displacement generation exhibit a number of known nonlinear effects as hysteresis and creep. This article describes an attempt to minimize those nonlinearities by recognizing the relation between scan range and voltage magnitude in a scanner specific function. In addition, by utilizing a strain gauge sensor system, a forward displacement correction is realized. The mathematical procedure behind the hysteresis correction is described in detail. The dependence of the higher order correction factors on parameters such as scan speed, scan range, or center position is studied carefully to extract their influence on the result. Finally, integral nonlinearities of about 1% are proven in experiments with an atomic force microscope.

In vitro tumor angiogenesis assays: plasminogen lysine binding site 1 inhibits in vitro tumor-induced angiogenesis.

It is generally accepted that tumors are angiogenesis-dependent. For research and clinical purposes it would be very attractive to have a simple in vitro model that allows a rapid screening of the angiogenic potential of tumors and to study the effect of angiogenic inhibitors. In vitro angiogenesis models were developed, based on endothelial sprouting/tube formation on a collagen gel, using both tumor cell lines and tumor biopsies. Best results were obtained using conditioned medium of tumor cell lines. In this model it was found that the plasminogen fragment lysine binding site 1 (LBS-1) inhibited in vitro endothelial cell sprouting. This is the first demonstration that LBS-1, which includes angiostatin, is inhibitory for new vessel formation in an in vitro angiogenesis model. We conclude that the assay system allows for rapid and reliable screening of angiogenesis inhibitors.

Cellular arrangement of human breast cancer cell lines determines hemostatic parameters.

Two in vitro models are compared to investigate whether cellular configuration or composition of the matrix in which the cells are cultured influences growth and/or prognostic parameters. T47D, MCF-7 and Hs578T breast cancer cell lines were cultured on two different matrices (agarose and collagen). Growth curves, biological markers (Ki-67, p53 and bcl-2) and the expression of hemostatic parameters were studied. The tested hemostatic parameters were urokinase-type plasminogen activator, tissue-type plasminogen activator and plasminogen activator inhibitor as fibrinolytic parameters and von Willbrand factor, tissue factor, antithrombin III, factor X and factor Xa as coagulation parameters. We found that T47D and MCF-7 formed spheroids in both matrices. Hs578T did not form spheroids; instead, the cells remained single cells in the agarose matrix and grew invasively through the collagen matrix. Expression of the biological markers was similar for spheroids and monolayers. In contrast, a clear difference in expression of hemostatic factors by spheroids and monolayers was found.

Hemostatic factors and platelet aggregation after a fish-enriched diet or fish oil or docosahexaenoic acid supplementation.

The effects of a fish-enriched diet or dietary supplements consisting of either fish oil or a docosahexaenoic acid-rich oil (DHA-oil) on platelet aggregation and hemostatic factors were studied in healthy male students. After an experimental period of 15 weeks, the levels of tissue factor pathway inhibitor, prothrombin fragment 1+2 and fibrinogen as well as factor VII activity were not changed. Factor X activity was slightly decreased by the fish diet (P < 0.05). Collagen but not ADP-induced maximum platelet aggregation decreased in the fish diet and the fish oil groups (P < 0.05 in both). In the DHA-oil group there was a slight, statistically insignificant, increase of platelet aggregation which correlated significantly with the decrease of plasma triglycerides. Platelet aggregation measured 4 h after a standardized fat meal was lower than in the fasting state and this decrease correlated with the increase of plasma triglycerides. These results show that a fish diet and fish oil, but not DHA-oil, inhibit in vitro platelet aggregation and that hemostatic factors are not affected by moderate n-3 fatty acid supplementation.

Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case-control study of 32,702 veterans.

OBJECTIVE: To determine whether patients with colorectal cancer are less likely than unaffected controls to have had one or more endoscopic procedures (flexible sigmoidoscopy, colonoscopy, or polypectomy) before being diagnosed with cancer. DESIGN: Case-control study. SETTING: Hospitals of the Department of Veterans Affairs. PATIENTS: 8722 and 7629 case-patients with colon and rectal cancer, respectively, and age-, sex-, race-matched controls who were discharged at the same time as the corresponding case-patients. MEASUREMENTS: Number and type of endoscopic procedures of the large bowel done from 1981 until the development of colorectal cancer in each case-patient. The influence of endoscopic procedures on the development of colorectal cancer was tested by conditional multiple logistic regression analysis. RESULTS: Compared with controls, patients with colorectal cancer were less likely to have had an endoscopic procedure of the large bowel before being diagnosed with cancer (odds ratio for colon cancer, 0.51 [95% CI, 0.44 to 0.58]; odds ratio for rectal cancer, 0.55 [CI, 0.47 to 0.64]). In patients who had flexible sigmoidoscopy, colonoscopy, and polypectomy, the odds ratios were even smaller. When analyzed by separate 1-year intervals, patients with cancer had significantly fewer procedures during periods of up to 6 years before their onset of their cancer. Similarly, fewer inpatient and outpatient procedures were done in patients than in controls. CONCLUSIONS: Endoscopic procedures of the large bowel reduce the risk for developing colon and rectal cancer by 50%, their protective influence lasting 6 years.

Protection by endoscopy against death from colorectal cancer. A case-control study among veterans.

BACKGROUND: Although several clinical and epidemiologic studies suggest that timely diagnostic procedures of the large bowel may reduce mortality from colorectal cancer, the evidence for this relationship is primarily circumstantial. METHODS: A case-control study was conducted among hospitalized US military veterans to investigate whether diagnostic procedures of the large bowel were performed in the period preceding the diagnosis of colorectal cancer less frequently in patients dying of colorectal cancer than in control patients. Data files of a total of 4411 veterans dying of colorectal cancer between 1988 and 1992 were extracted from the records of the US Department of Veterans Affairs, Washington, DC. Data of four living control patients and four dead control patients without colorectal cancer were matched by age, sex, and race to each case patient. The case and the two control populations were compared by conditional logistic regression, calculating odds ratios, and their 95% confidence interval. RESULTS: Diagnostic procedures of the large bowel reduced mortality from colorectal cancer, the odds ratio being 0.41 (range, 0.33 to 0.50) for the comparison with living control patients. The protective effects of proctosigmoidoscopy, colonoscopy, and polypectomy lasted for 5 years. The procedures were protective against death from cancer of the colon, as well as cancer of the rectum. The most protective influence was associated with removal of tissue through biopsy, fulguration, and polypectomy. Similar influences were found comparing case patients with dead control patients. CONCLUSION: Removal of tissue represents the most effective means to reduce mortality from cancers of the large bowel. It retains its efficacy over a time period of 5 years.

Evaluation of dyspepsia and functional gastrointestinal disorders: a cost-benefit analysis of different approaches.

OBJECTIVE: To establish a decision rule for diagnostic testing in patients with dyspepsia. DESIGN: Medical decision analysis using a decision-tree model. METHODS: Costs and benefits associated with two alternative strategies are compared. In the first strategy, empirical therapy alone is provided. The second strategy also includes tests to diagnose the cause of dyspepsia. RESULTS: It is more beneficial to test than to employ empirical treatment alone if the a-priori probability P of an organic disease is larger than the ratio of the costs T of testing to the costs C of a missed diagnosis: P > T/C. In most clinical situations, the costs of a missed diagnosis outweigh the costs of testing by a factor of 5-10, for which the cost ratio is 10-20%. CONCLUSION: Diagnostic tests should be performed in patients with dyspepsia, whenever the probability of finding organic disease exceeds the ratio of the cost of testing to the cost of missing this diagnosis.

Membrane related effects in endothelial cells induced by human cytomegalovirus.

Previously, we have reported on the increase in procoagulant activity of human umbilical vein endothelial cells (HUVEC) after infection with human cytomegalovirus (HCMV). When using microvascular endothelial cells from foreskin (MVEC), we also observe a significant increase in membrane perturbation and a concomittant increase in procoagulant activity. This effect is both observed with a laboratory HCMV strain (AD169) with low pathogenicity for endothelium and a HUVEC adapted strain (VHL-E) that readily infects endothelial cells. We compared the membrane perturbation of two types of endothelial cells, HUVEC and MVEC with human embryonal fibroblasts (HEF), being fully permissive for both strains. A membrane effect was only found in endothelial cells. Our results suggest that HCMV induces in MVEC more merocyanine-540 incorporation in the membrane as in HUVEC. The increase in the procoagulant activity induced by HCMV was more pronounced in MVEC than in HUVEC. Inactivated virus, as well as virus pre-incubated with heparin was unable to evoke membrane perturbation. It therefore appears that HCMV induces a rapid membrane response in vascular endothelium and that physical interaction of the virion and the endothelial cell is required to elicit this response.

Diseases preceding colon cancer. A case-control study among veterans.

Patients with regular use of nonsteroidal antiinflammatory drugs (NSAIDs) appear to have a reduced mortality from colon cancer. As NSAID use is associated with gastrointestinal bleeding, endoscopic exploration of patients on NSAID may lead to more efficient screening and frequent detection of colon cancer. A case-control study was conducted among 12,304 veterans with a colon cancer diagnosed between 1988 and 1992. Four controls were matched by age, sex, and race to each case. The frequency distributions of previous discharge diagnoses in cases and controls were compared. Arterial embolism and thrombosis, spondylosis, peripheral vascular disease, angina, osteoarthrosis, and ischemic heart disease protected against future development of colon cancer. On the other hand, atrial fibrillation and flutter, as well as phlebitis and thrombophlebitis, were associated an increased occurrence of colon cancer after 5-10 years. The study contrasts diseases that are treated with aspirin with those that are treated with other anticoagulants. Both cause bleeding, but the reduced risk of colon cancer was seen only in conditions treated with aspirin. The difference between the two disease groups from the same VA patient population suggests that chronic use of NSAID truly protects against future development of colon cancer.

The "institutional colon": a frequent colonic dysmotility in psychiatric and neurologic disease.

OBJECTIVES: The true existence of a disease entity termed "institutional colon" has remained controversial. The present study serves to test whether this entity actually exists and how frequently psychiatric and neurologic diseases are associated with colonic dysmotility. METHODS: Using the hospital discharge records of four million US military veterans, we investigated the comorbid occurrence of volvulus, impaction of intestine, constipation, and megacolon with any neurologic or psychiatric disease. RESULTS: Comorbidity of colonic and neurologic/psychiatric diseases in identical subjects occurred two to three times more often than one would expect from the overall distribution of each group of diseases alone. Presenile dementia and Alzheimer's disease, Parkinson's disease, multiple sclerosis, and quadriplegia were associated significantly with all four colonic diseases. The various forms of schizophrenia coincided mostly with megacolon and constipation. Major depressive disorder was associated only with constipation, but with none of the other colonic diseases. CONCLUSION: Psychiatric and neurologic diseases are frequently associated with colonic dysmotility. The association raises the possibility of a pathophysiologic link involving the neuronal control of colonic motility.

Constipation and cathartics as risk factors of colorectal cancer: a meta-analysis.

Since individual case-control studies have failed to resolve the question whether constipation and use of cathartics represent significant risk factors of colorectal cancer, a meta-analysis was performed. The method by Peto was used to calculate pooled odds ratios of the cancer risk among exposed and unexposed subjects. The analysis of 14 previously published case-control studies revealed statistically significant risks for colorectal cancer associated with both constipation and use of cathartics, the pooled odds ratios and their 95 percent confidence intervals being 1.48 (1.32-1.66) and 1.46 (1.33-1.61), respectively. The increased risk applied similarly to both sexes, it was higher in cancer of the colon than rectum. Since constipation and cathartics are associated with much lower odds ratios than various dietary components, such as fat, meat, alcohol, and low-vegetable or low-residue diets, it appears that their risk reflects the confounding influence of underlying dietary habits.

Tumor spheroid-induced vesicle formation on endothelial cells is associated with procoagulant properties.

Fibrin deposits in tumor beds are an intriguing phenomenon. It has been suggested that fibrin plays a role as a provisional matrix in which the tumor grows and induces development of a vascular network. On the other hand fibrin possibly protects the tumor nodule from host defense mechanisms. We therefore investigate whether tumor cells can induce a procoagulant response in endothelial cells leading to fibrin formation. For our studies we employed a modification of the matrix model of Montesano in which sprouting of endothelial cell aggregates can be followed. This system allows us to study in vitro the involvement of coagulation in tumor growth and angiogenesis. Cocultures of endothelial cell aggregates and avascular tumor spheroids in collagen type I gels results in the appearance of extracellular vesicle-like structures on the endothelial sprouts. The vesicles formed on endothelial cell sprouts upon coculturing with tumor cells exhibit an increased amidolytic activity, suggestive of factor X/Xa activity, not dependent on tissue factor exposure. Experiments using HgCl2 and Iodoacetamide point to the importance of SH groups in the factor X/Xa activity on endothelial cell sprouts.

The procoagulant response of cytomegalovirus infected endothelial cells.

The report describes the effect of an in vitro infection of human umbilical vein endothelial cells with human Cytomegalovirus (CMV). The parameters studied are cellular procoagulant activity, secretion of plasminogen activator inhibitor (PAI-1) and urokinase-type plasminogen activator (u-PA), activation and internalization of factor X and Merocyanine 540 staining. The infection does not result in an increase in PAI-1 and u-PA secretion, but it brings about a procoagulant response, which is relatively rapid compared to the tissue factor mediated response induced by inflammatory mediators. The time course and the coagulation factor dependency suggest a facilitated interaction of coagulation factors on the surface of infected cells. Chromogenic activity measurements after the addition of purified factor X and electron microscopic examination of the cells after addition of colloidal gold-factor X conjugates both point to an internalization of factor X and/or Xa after interaction with the endothelial cell surface. Merocyanine 540 staining suggests that CMV infection leads to membrane perturbations.

The effect of viral infection on eicosanoid formation and procoagulant activity of rat peritoneal macrophages. Role of the dietary fat type.

The effect of dietary manipulation on eicosanoid formation in rat peritoneal macrophages was studied in relation to some of their effector functions: cellular procoagulant activity, production of reactive oxygen species (measured as chemiluminescence), and phagocytosis of antibody-coated erythrocytes. Rats were fed adequate diets for eight weeks containing mackerel oil (MO), sunflowerseed oil (SO) or hydrogenated coconut oil (HCO). The release of eicosanoids from resident macrophages stimulated by opsonized zymosan was significantly lower for the MO group as compared to the other dietary groups. Infection of the animals via intraperitoneal injection with rat cytomegalovirus resulted in a significant decrease in eicosanoid production in all groups, irrespective of dietary fat type. However, in the HCO group a partial restoration of TXB2 and HHT production could be observed at day 10 post infection. Resident macrophages obtained from the mackerel oil fed animals showed a significantly higher procoagulant activity than those from the other diet groups. Infection of the animals resulted in an increase in procoagulant activity in all groups. In contrast, no significant differences in chemiluminescence and in phagocytosis were detected between macrophages obtained from rats fed the different diet groups. It is concluded that peritoneal macrophages obtained from mackerel oil fed rats produce less eicosanoids and are more procoagulant than those from the other dietary groups, but a viral infection eradicates these differences. Therefore, a correlation between eicosanoid formation and effector functions studied could not be established.

The effect of virus infection on the adherence of leukocytes or platelets to endothelial cells.

It has been reported that atherosclerotic lesions contain genomic material belonging to members of the herpes family. This suggests that latent viral infection may be one of the atherogenic triggers. In this study we show that early infection of endothelial cell monolayers with Herpes Simplex virus type 1 (HSV-1) or Cytomegalovirus (CMV) results in an increased monocyte (MC) and polymorphonuclear leukocyte (PMN) adherence, but not in an increased platelet adhesion. Further, is demonstrated that MC and PMN respond differently to virus infected endothelial cell monolayers: PMN adhesion to CMV infected cells is approximately 430% of the control adherence, while the MC adherence is increased to 160%. Also, a difference in virus acting is observed: the adherence of MC or PMN to HSV-1 infected endothelial cells is caused by a secreted adherence promoting factor, while the adherence of MC or PMN to CMV infected endothelial cells seems to be a cell-bound phenomenon. In addition, it was demonstrated that the augmentation of MC or PMN adherence to virus infected endothelial cells is sensitive to tunicamycin, suggesting that both virus infections induce the expression of glycoproteins on the endothelial cell membrane, which is responsible for the MC and PMN adhesion. Thus, HSV-1 and CMV infection of endothelium results in an increased adherence of leukocytes which is suggested, irrespective of the precise nature of the mechanism of virus induced atherosclerosis, to be the earliest event associated with endothelium cell damage.

Effect of a moderate fish intake on haemostatic parameters in healthy males.

This article describes the results of a dietary intervention study performed in three different centers. In the study the effect of a diet enriched with fish on the coagulation tendency of blood was investigated. Two groups of 40 volunteers were given a dietary supplement consisting of 135 g of canned mackerel or meat paste (control) for a 6 weeks period. Compliance, monitored by measuring the urinary excretion of lithium, added to the supplements, was about 80%. Before, during and at the end of the experimental period a number of hemostatic parameters, reflecting the coagulation tendency of blood and the procoagulant activity of monocytes, were measured. The fish supplement did not cause a significant effect on the prothrombin time and on the levels of factor VII, activated factor VII, antithrombin III, von Willebrand factor, fibrinogen, plasminogen and alpha 2-antiplasmin. A slight but transient prolongation in the activated partial thromboplastin time was observed as well as a significant increase in the factor X level, which became more pronounced with prolongation of the experimental period; no activated factor X was found. A tendency towards a stimulation of monocyte procoagulant activity was noticed.

Cytomegalovirus alters the von Willebrand factor content in human endothelial cells.

Cultured human endothelial cells were infected with human cytomegalovirus AD 169 and Kerr. The infection resulted in the appearance of viral antigens in the nuclei of about 10% of the endothelial cells and in the concomitant disappearance of vWF from the infected cells. No differences were observed between endothelial cells from different sources (umbilical cord veins or arteries, adult veins).

Induction of endothelial cell procoagulant activity by cytomegalovirus infection.

Endothelial cells isolated from rat aorta were infected in vitro with rat cytomegalovirus. Viral antigens appeared in nucleus and cytoplasma and newly made extracellular virus was detected in the supernatant. Furthermore, the viral infection caused the appearance of procoagulant activity on the endothelial cells.