Improving aeration control at the Ljubljana wastewater treatment plant.

This paper describes an improvement to the aeration control at the Ljubljana wastewater treatment plant. Several changes were made to the existing aeration control. An adjustment to the parameters of the common air pressure controller contributes to a more responsive operation of the compressors. The introduction of the air pressure set-point controller adjusts the air pressure in the common air rail according to the changes in the plant load. The introduction of the airflow controllers reduces the variation in the oxygen concentrations in the aerobic reactors and, consequently, enables a reduction in the oxygen set-points. With the improved aeration control, savings of up to 10% in the electricity used for aeration are achieved on a yearly basis.

Impact of "early intervention" parent workshops on outcomes for caregivers of children with neurodisabilities: a mixed-methods study.

PURPOSE: This study explored the feasibility, impact and parent experiences of ENVISAGE (ENabling VISions And Growing Expectations)-Families, a parent-researcher co-designed and co-led program for parents/caregivers raising children with early-onset neurodisabilities. METHODS: Parents/caregivers of a child with a neurodisability aged ≤6 years, recruited in Australia and Canada, participated in five weekly online workshops with other parents. Self-report measures were collected at baseline, immediately after, and 3 months post-ENVISAGE-Families; interviews were done following program completion. Quantitative data were analyzed with generalized estimating equations and qualitative data using interpretive description methodology. RESULTS: Sixty-five parents (86% mothers) were recruited and 60 (92%) completed the program. Strong evidence was found of effects on family empowerment and parent confidence (all p ≤ 0.05 after the program and maintained at 3-month follow-up). The ENVISAGE-Families program was relevant to parents' needs for: information, connection, support, wellbeing, and preparing for the future. Participants experienced opportunities to reflect on and/or validate their perspectives of disability and development, and how these perspectives related to themselves, their children and family, and their service providers. CONCLUSIONS: ENVISAGE was feasible and acceptable for parent/caregivers. The program inspired parents to think, feel and do things differently with their child, family and the people who work with them.Implications for rehabilitationENVISAGE (ENabling VISions And Growing Expectations)-Families is a co-designed, validated parent/researcher "early intervention and orientation" program for caregivers raising a child with neurodevelopmental disabilities (NDDs).ENVISAGE-Families empowered parents' strengths-based approaches to their child, family, disability, and parenting.ENVISAGE-Families increased caregivers' confidence in parenting children with NDD's and provided them tools to support connection, collaboration, and wellbeing.Raising children with NDD can have a profound impact on caregivers, who can benefit from strengths-based, future focused supports early in their parenting experience.

Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer.

It is unclear whether disseminated tumour cells detected in bone marrow in early stages of solid cancers indicate a subclinical systemic disease component determining the patient's fate or simply represent mainly irrelevant shed cells. Moreover, characteristics differentiating high and low metastatic potential of disseminated tumour cells are not defined. We performed repeated serial bone marrow biopsies during follow-up in operated gastric cancer patients. Most patients with later tumour relapse revealed either an increase or a constantly high number of tumour cells. In contrast, in patients without recurrence, either clearance of tumour cells or negative or low cell counts were seen. Urokinase plasminogen activator (uPA)-receptor expression on disseminated tumour cells was significantly correlated with increasing tumour cell counts and clinical prognosis. These results demonstrate a systemic component in early solid cancer, indicated by early systemically disseminated tumour cells, which may predict individual disease development.

Urokinase plasminogen activator receptor (uPA-R): one potential characteristic of metastatic phenotypes in minimal residual tumor disease.

Evidence of dynamic development of cytokeratin (CK) 18-positive disseminated tumor cells in bone marrow of curatively resected cancer patients has implicated a subclinical minimal residual disease as a biologically relevant component in solid cancer. However, differentiation between irrelevant shed cells and those cells potentially capable of causing later recurrence has not yet been made. In parallel, accumulating data show functional association of the urokinase plasminogen activator (uPA) system and the membranous uPA receptor (uPA-R) with the capacity of a tumor cell for invasion and metastasis. The present study was designed to find descriptive evidence in vivo concerning whether uPA-R could be one potential characteristic for metastatically relevant phenotypes of disseminated tumor cells. An immunocytochemical double staining for uPA-R and CK18 (immunogold/alkaline phosphatase anti-alkaline phosphatase) was performed on perioperative and follow-up bone marrow aspirations of 78 curatively resected gastric cancer patients, if positive tumor cell status had been shown previously with the single alkaline phosphatase anti-alkaline phosphatase method. Bone marrow cells (10(6)) were examined in each assay. Postoperative qualitative and quantitative development of uPA-R-expressing disseminated tumor cells was followed in relation to uPA-R-negative cells and correlated with later clinical relapse. Double staining could be performed perioperatively or in follow-up, or both, in 58 of 78 patients. Expression of uPA-R on perioperatively disseminated tumor cells significantly correlated with later quantitative increases of tumor cells (P = 0.0009). Overall median tumor cell numbers with uPA-R expression significantly increased during follow-up from a median value of 5.5 to 10.0 in 10(6) cells (P = 0.008), and the mean relative percentage of uPA-R-positive, compared with uPA-R-negative, disseminated tumor cells also increased, from 47.9% at surgery to 68.6% in follow-up (P < 0.001). This was mainly due to patients with later tumor relapse (increase from 63.9 to 80.7%, P = 0.001). Patients without relapse showed slight increases at lower percentage levels (5.7% at surgery, 7.4% in follow-up). Differences for relapsing patients were significant (surgery, P = 0.006; follow-up, P < 0.001). Our results suggest from an in vivo model that uPA-R may be one antigen that enables identification and follow-up observations of metastatically relevant phenotypes of disseminated tumor cells, differentiating their individual potential for causing relapse.

Fibrin-fibronectin compounds in human ovarian tumor ascites and their possible relation to the tumor stroma.

Covalently linked heterogeneous fibrin-fibronectin compounds were detected in ascitic fluid of 31 patients with advanced ovarian cystadenocarcinoma by means of enzyme-linked immunosorbent assay techniques, immunoaffinity chromatography, and Western blot analysis. Deposition of fibrin and fibronectin could also be demonstrated immunohistochemically in Carnoy-fixed tissue sections. Fibrin and fibronectin were found in the tumor stroma within tumor nests and more prominently in stroma surrounding the tumor nests. The association of fibrin and fibronectin was especially pronounced in the stroma surrounding the tumor islands. Fibronectin was also found to be associated with stroma cells. Areas within the tumor stroma showed superimposed staining for both fibrin and fibronectin supporting the assumption that the covalently linked fibrin-fibronectin conjugates found in ascitic fluid may stem from the provisional tumor stroma by proteolytic release.

c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems.

PURPOSE: The c-erbB-2 gene (encoding the protein p185) is overexpressed in diverse human cancers and has been implicated to be of prognostic value in gastric cancer. Recent studies suggest a role of p185 in tumor progression by specifically promoting the invasive capacity of tumor cells. Therefore, the present study was conducted with the following three objectives: (1) to support the prognostic value of c-erbB-2 in gastric cancer in a large prospective series using a monoclonal antibody and a highly sensitive immunohistochemical method; (2) to determine the association of c-erbB-2 expression with the expression of invasion-related genes; and (3) to perform the first overall multivariate analysis including c-erbB-2 and the invasion-related tumor-associated protease systems. PATIENTS AND METHODS: In a consecutive prospective series of 203 gastric cancer patients (median follow-up, 42 months), expression of c-erbB-2 and a panel of tumor-associated proteases and inhibitors by tumor cells were evaluated semiquantitatively (score 0 to 3) and analyzed for correlation (chi(2) test, Bonferroni-corrected). Kaplan-Meier survival analysis and multivariate Cox analysis were performed to determine the relative prognostic impact of c-erbB-2 and the invasion-related parameters. RESULTS: Kaplan-Meier analysis (log-rank statistics) revealed a significant association of increasing expression of c-erbB-2 with shorter disease-free (P =. 0023) and overall survival (P =.0160). High amounts of p185 were significantly associated with a high expression of urokinase-type plasminogen activator (uPA) (P <.010), uPA-receptor (P =.030), type-1 plasminogen activator inhibitor (PAI) (P <.010), type-2 PAI (P =.021), cathepsin D (P =.036), matrix metalloproteinase-2 (P =. 024), alpha-1-antichymotrypsin (P =.025), and alpha-2-macroglobulin (P =.017). Multivariate analysis considering these proteases/protease inhibitors, in addition to alpha-1-antitrypsin, tissue plasminogen activator, plasminogen, alpha-2-antiplasmin, and antithrombin III, and established prognostic parameters revealed that, in addition to surgical curability, pT stage, pN stage, and PAI-1, c-erbB-2 is an independent prognostic factor for overall survival of curatively resected patients (n = 139; P =.049; relative risk, 1.54; 95% confidence interval, 1.08 to 1.67) and all patients (P =.028; relative risk 1.33; 95% CI, 1.28 to 1.38). CONCLUSION: c-erbB-2 is confirmed as a new independent, functional prognostic parameter for overall survival in gastric cancer, even when a panel of invasion-related factors, including the strong prognostic parameter PAI-1, are considered. The significant correlation of p185 with several tumor-associated proteases supports the hypothesis that c-erbB-2 is a promoter of invasion and metastasis. This strongly suggests that c-erbB-2 may be a promising target for anti-invasive therapy in gastric cancer.

Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system.

PURPOSE: The significance of tumor-associated proteolysis as reflected by parameters of the urokinase-type plasminogen activator (uPA) system for prognosis in cancer patients has been proposed because of evidence for its central role in basic mechanisms of invasion and metastasis. The aim of the present study was to evaluate whether the expression of the uPA parameters might be of clinical value in gastric cancer as a tumor/biologically defined risk factor. PATIENTS AND METHODS: In a consecutive series of 203 patients resected for primary gastric cancer, the expression of uPA, uPA-receptor (uPA-R), plasminogen activator inhibitor (PAI)-1, and PAI-2 was determined immunohistochemically. The results were classified semiquantitatively (0 to 3). Patients were followed-up prospectively for a median of 31 months (range, 9 to 56 months). Disease-free and overall survival were analyzed according to Kaplan-Meier and with univariate and multivariate Cox analyses in relation to conventional prognostic factors. RESULTS: Univariate analyses revealed a highly significant inverse correlation of uPA, uPA-R, and PAI-1 expression with survival time (P = .0008, P = .0002, and P = .0002, respectively), whereas PAI-2 demonstrated only a weak correlation. In multivariate analyses, PAI-1 was an independent and strong prognostic factor (P = .005; relative risk, 1.47 per staining degree; 95% confidence interval [CI], 1.31 to 1.64). In pT1/2 tumors and in Laurén's diffuse and mixed types, uPA, uPA-R, and PAI-1 added significant prognostic information. PAI-1 was also associated with survival in the subgroup of lymph node-positive patients. CONCLUSION: PAI-1, uPA, and uPA-R are new functional risk factors reflecting clinical prognosis. In particular, PAI-1 is a new independent variable for the identification of patients at high risk after tumor resection. Our results support the hypothesis that the uPA system probably is of general importance for prognosis of patients with malignant disease, indicating an individual tumor's capacity for invasion and metastasis.

Prognostic significance of bone marrow micrometastases in patients with gastric cancer.

BACKGROUND: Monoclonal antibodies (mabs) against components of the cytoskeleton such as cytokeratins allow single disseminated epithelial carcinoma cells to be detected in the bone marrow. The aim of this study was to examine the prognostic relevance of these cells in patients with gastric cancer and to evaluate by multivariate analysis their predictive value compared with conventional risk factors. PATIENTS AND METHODS: A total of 1 x 10(6) cells from bone marrow aspirates were screened immunoctochemically for the presence and absolute number of disseminated tumor cells using mab CK2 to cytokeratin component no. 18. Patients were monitored prospectively for 30.6 +/- 15.2 months. RESULTS: Between one and 122 CK2-positive cells per 1 million mononuclear bone marrow cells were present in 95 of 180 patients (53%). A similar prevalence of 51% was found in curatively operated patients (55 of 109). Comparison with conventional prognostic risk factors showed a correlation of cell dissemination with pathohistologic tumor (pT) stage (P = .07) and Bormann classification (P = .022). Tumor-cell content in the bone marrow predicted disease-free and overall survival in curatively resected patients (P = .007 and P = .049, respectively). Multivariate analysis, which included established risk factors, showed that extent of tumor-cell dissemination was an independent prognostic parameter for disease-free survival in T1/2 tumors (P = .014; relative risk [RR], 1.84; 95% confidence interval [CI], 1.35 to 2.52), in intestinal type carcinomas according to Laurén (P = .008; RR, 1.62; 95% CI, 1.23 to 2.12), and in patients without lymph node involvement (P = .004; RR, 2.43; 95% CI, 1.22 to 4.82). CONCLUSION: Presence of disseminated tumor cells in bone marrow is indicative of systemic disease even in early-stage gastric cancer. The extent of tumor-cell presence in bone marrow correlates with prognosis in curatively resected patients. Therefore, a positive bone marrow finding may be a selection criteria for adjuvant treatment because of minimal residual tumor load.

Dipyridamole-dobutamine echocardiography: a novel test for the detection of milder forms of coronary artery disease.

OBJECTIVES: This study was designed to assess the clinical, hemodynamic and diagnostic effects of the addition of dobutamine to dipyridamole echocardiography. BACKGROUND: Pharmacologic stress echocardiography with either dipyridamole or dobutamine has gained acceptance because of its safety, feasibility, diagnostic accuracy and prognostic power. The main limitation of the two tests is a less than ideal sensitivity in some patient subsets, such as those with limited coronary artery disease. We hypothesized that two pharmacologic stresses might act synergistically in the induction of ischemia by combining the mechanisms of inappropriate coronary vasodilation (with dipyridamole) and an increase in myocardial oxygen consumption (with dobutamine). METHODS: One hundred fifty patients (mean [+/- SD] age 51 +/- 11 years) referred for stress echocardiography were initially studied by dipyridamole-dobutamine echocardiography. The test was stopped during the dipyridamole step in 95 patients for achievement of a predetermined end point (obvious dyssynergy induced by lower or higher dipyridamole dose), and dipyridamole-dobutamine tests were performed in 55 patients (negative dipyridamole echocardiographic test). In the same 150 patients the dobutamine echocardiographic test (up to 40 micrograms/kg body weight per min) was performed on a separate day. RESULTS: Significant coronary artery disease (> 50% diameter stenosis of at least one major coronary vessel by quantitative coronary arteriography) was present in 131 patients (one vessel in 115; two vessels in 10, three vessels in 6), with normal coronary arteriography in 19. The feasibility of the dipyridamole-dobutamine test was 96%. Self-limiting side effects occurred in 5% of patients. The peak rate-pressure product was lowest during the dipyridamole test (132 +/- 30) and was comparable during the dobutamine (186 +/- 59) and dipyridamole-dobutamine tests (179 +/- 45, p = NS vs. dobutamine; p < 0.01 vs. dipyridamole). Sensitivity was 71% for dipyridamole, 75% for dobutamine and 92% for dipyridamole-dobutamine echocardiography (dipyridamole vs. dipyridamole-dobutamine, p < 0.01; dobutamine vs. dipyridamole-dobutamine, p < 0.01; dipyridamole vs. dobutamine, p = NS), whereas specificity was 89% for dipyridamole, 79% for dobutamine and 89% for dipyridamole-dobutamine echocardiography (p = NS for all). CONCLUSIONS: Routine dobutamine addition to dipyridamole stress testing is clinically useful and well tolerated. It expands the spectrum of the disease detectable by pharmacologic stress echocardiography and allows documentation of milder forms of coronary artery disease that can be missed by conventional dipyridamole or dobutamine stress echocardiography.

High dose adenosine stress echocardiography for noninvasive detection of coronary artery disease.

OBJECTIVES: The aim of this study was to assess the tolerability and incremental diagnostic value of high adenosine doses in stress echocardiography testing in patients with coronary artery disease (CAD). BACKGROUND: In comparison with other pharmacologic stress echocardiography tests, standard dose adenosine stress has sub-optimal sensitivity for detecting milder forms of CAD. METHODS: Adenosine stress echocardiography was performed in 58 patients using a starting dose of 100 micrograms/kg body weight per min over 3 min followed by 140 micrograms/kg per min over 4 min (standard dose). If no new wall motion abnormality appeared, the dose was increased to 200 micrograms/kg per min over 4 min (high dose). All patients underwent coronary angiography. Significant CAD was defined as > or = 50% diameter stenosis in at least one major coronary artery. Thirty-three patients had one-vessel and seven had multivessel CAD. Coronary angiographic findings were normal in 18 patients. RESULTS: The high adenosine dose caused a slight but significant increase over baseline values in rate-pressure product. Limiting side effects occurred in two patients during the standard dose protocol and in one patient receiving the high dose regimen. The test was stopped in 30 patients after the standard adenosine dose regimen because of a provoked new wall motion abnormality. The sensitivity of adenosine echocardiography with the standard dose was 75% (95% confidence interval [CI] 63% to 87%). After completion of the standard dose protocol, 28 patients continued testing with the high dose adenosine protocol. The overall sensitivity of adenosine echocardiography, calculated as cumulative, increased to 92% (95% CI 84% to 100%) with the high dose (p < 0.05). The specificity of adenosine testing was 100% and 88%, respectively, with the standard and high dose regimen (p = 0.617). CONCLUSIONS: We believe that use of a higher than usual adenosine dose protocol for stress testing may improve the diagnostic value of adenosine echocardiography, mainly by increasing sensitivity in patients with single-vessel disease without deterioration of the safety profile and with only a mild reduction in specificity.

Integrated evaluation of relation between coronary lesion features and stress echocardiography results: the importance of coronary lesion morphology.

OBJECTIVES: The aim of this study was to analyze, in the same group of patients, the relationship between multiple variables of coronary lesion and results of exercise, dobutamine and dipyridamole stress echocardiography tests. BACKGROUND: Integrated evaluation of the relation between stress echocardiography results and angiographic variables should include not only the assessment of stenosis severity but also evaluation of other quantitative and qualitative features of coronary stenosis. METHODS: Study population consisted of 168 (138 male, 30 female, mean age 51+/-9 years) patients, on whom exercise (Bruce treadmill protocol), dobutamine (up to 40 mcg/kg/min) and dipyridamole (0.84 mg/kg over 10 min) stress echocardiography tests were performed. Stress echocardiography test was considered positive for myocardial ischemia when a new wall motion abnormality was observed. One-vessel coronary stenosis ranging from mild stenosis to complete obstruction of the vessel was present in 153 patients, and 15 patients had normal coronary arteries. The observed angiographic variables included particular coronary vessel, stenosis location, the presence of collaterals, plaque morphology according to Ambrose classification, percent diameter stenosis and obstruction diameter as assessed by quantitative coronary arteriography. RESULTS: Covariates significantly associated with the results of physical and pharmacological stress tests included for all three stress modalities presence of collateral circulation, percent diameter stenosis and obstruction diameter, as well as lesion morphology (p < 0.05 for all, except collaterals for dobutamine stress test, p = 0.06). By stepwise multiple logistic regression analysis, the strongest predictor of the outcome of exercise echocardiography test was only percent diameter stenosis (p = 0.0002). However, both dobutamine and particularly dipyridamole stress echocardiography results were associated not only with stenosis severity - percent diameter stenosis (dobutamine, p = 0.04; dipyridamole, p = 0.003) - but also, and even more strongly, with lesion morphology (dobutamine, p = 0.006; dipyridamole, p = 0.0009). As all of stress echocardiography results were significantly associated with percent diameter stenosis, the best angiographic cutoff in relation to the results of stress echocardiography test was: exercise, 54%; dobutamine, 58% and dipyridamole, 60% (p < 0.05 vs. exercise). CONCLUSIONS: Integrated evaluation of angiographic variables have shown that the results of dobutamine and dipyridamole stress echocardiography are not only influenced by stenosis severity but also, and even more importantly, by plaque morphology. The results of exercise stress echocardiography, although separately influenced by plaque morphology, are predominantly influenced by stenosis severity, due to a stronger exercise capacity in provoking myocardial ischemia in milder forms of coronary stenosis.

Endometrial stromal sarcoma arising in extrauterine endometriosis: a case report.

We report a rare case of a 46-year-old woman developing endometrial stromal sarcoma (ESS) on the grounds of extrauterine endometriosis. The patient presented with symptoms of stenosis of the rectosygmoid colon. The tissue samples were submitted to histological and immunohistochemical analyses using antibodies for indirect staining. The trial showed multiple foci of endometriosis and mesenchymal malignant tissue described as ESS in the bowel wall, mesentery and in the remnants of the left adnexae. According to our findings, we suspect that ESS might have arisen in colon endometriosis.

Ventricular and vascular remodelling effects of the angiotensin II receptor blocker telmisartan and/or the angiotensin-converting enzyme inhibitor ramipril in hypertensive patients.

Angiotensin II induces inflammatory activation of vascular smooth muscle cells and can cause left ventricular hypertrophy (LVH). Telmisartan is an angiotensin II receptor blocker with demonstrated beneficial effects on cardiac and vascular structure and function in animal models. The angiotensin-converting enzyme inhibitor ramipril also reduces ventricular and vascular remodelling. The open-label study observed 75 treatment-naive, moderately or severely hypertensive (systolic blood pressure 160-190 mmHg, diastolic blood pressure 90-110 mmHg) patients (age range, 42-58 years) treated with once-daily telmisartan 40 mg force-titrated to 80 mg after 1 month (n=25), once-daily ramipril 2.5 mg force-titrated to 5 mg after 1 month (n=25), or once-daily telmisartan 40 mg plus ramipril 2.5 mg (n=25); the total duration of treatment was 6 months. At baseline, blood pressure, left ventricular mass index (LVMI), carotid intima-media thickness (IMT) and carotid cross-sectional intima-media area (CSA) were measured. Measurements were repeated 1, 3 and 6 months after initiation of treatment. After 6 months, comparable blood pressure reductions were achieved with the three treatments. Reductions in LVMI after 6 months' treatment were 11.4%, 9.9% and 15.6% with telmisartan, ramipril, and telmisartan plus ramipril, respectively. Respective reductions in IMT were 14.6%, 12.0% and 18.2%, and for CSA were 7.8%, 4.3% and 11.5%. In conclusion, treatment with telmisartan or ramipril for 6 months resulted in regression of LVH and vascular remodelling. When a combination of telmisartan and ramipril was administered, additional regression and remodelling occurred.

Tumor-associated proteases and inhibitors in gastric cancer: analysis of prognostic impact and individual risk protease patterns.

Expression of proteolytic parameters of the urokinase-type plasminogen activator (uPA) system [uPA receptor (uPA-R), plasminogen activator inhibitor (PAI)-1] has been proven to be an independent prognostic parameter in cancer. However, it has not been considered that the uPA system is interacting with several other protease/inhibitor systems, neither has a comparable prognostic role of these factors been investigated. Moreover, studies evaluating specific protease patterns indicating high individual risk are missing completely. Therefore, in a consecutive prospective series of 203 gastric cancer patients, the expression of activators (plasminogen, tPA, MMP-2, cathepsin D, antithrombin 3) and inhibitors (alpha-2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitrypsin, alpha-1-antichymotrypsin) of proteolysis was studied immunohistochemically in the tumor epithelium semiquantitatively (score 0-3) in addition to the uPA system. Kaplan-Meier analysis (median time of follow-up 31 months) revealed a significant association of cathepsin D (P=0.0042), alpha-2-macroglobulin (P=0.0281) and antitrypsin (P=0.0372) with disease-free survival and of cathepsin D (P=0.0018), antitrypsin (P=0.0112) and antichymotrypsin (P=0.0002) with overall survival. Multivariate Cox analysis performed to correct these results for relative impact of the uPA system and established prognostic factors showed PAI-1 (disease-free survival: P=0.002, relative risk 1.86; overall survival: P=0.005, relative risk 1.39), pT and pN as independent parameters. Cathepsin D was shown to have an independent impact on disease-free survival (P=0.020, relative risk 2.98). Comparative chi-square analysis of cases with poor and good prognoses revealed that in patients with good clinical outcome, inhibitors of proteolysis are correlated significantly, whereas in patients with poor prognosis activators of proteolysis are significantly associated preferentially and significant correlations with the uPA-R are dominant. For detailed pattern analysis, stepwise overall Kaplan-Meier analyses were performed in subgroups of high uPA-R-, uPA-, PAI1- and cathepsin D expression for two additional proteases each. From these analyses, the combination of high (score 2/3) expression of uPA-R, PAI-1, antichymotrypsin and alpha-2-macroglobulin was identified as a high-risk pattern, representing parameters known to be essential for uPA-R internalization and recycling. This suggests some of the uPA-associated proteases and inhibitors investigated as univariate prognostic parameters in gastric cancer. Cathepsin D is a new independent parameter for disease-free survival. The study further demonstrates that a protease pattern promoting uPA-R recycling in tumor cells especially indicates high individual risk tumors in gastric cancer.

The contribution of endothelial cells to hyperacute rejection in xenogeneic perfused working hearts.

The mechanisms leading to the hyperacute rejection of a vascularized xenograft are still incompletely understood. The first stage of the rejection process is when blood of the recipient comes into contact with the endothelium of the xenograft. A working heart model was used to examine endothelium-related processes and their impact on organ function. Pig hearts were perfused with porcine (autologous) or human (xenogeneic) blood. Cardiac function was evaluated by calculating the stroke work index, arteriovenous oxygen, coronary flow, and resistance. PgF1a as a marker of endothelial activation, its antagonist TXB2, and myoglobin reflecting myocardial damage were measured in the hemoperfusate. H&E and PAS staining and immunohistological demonstration of factor VIII-related antigen was performed. Xenogeneic perfused porcine hearts showed significantly less stroke work, a higher arteriovenous oxygen difference, and an increased coronary resistance. Factor VIII-related antigen could not be demonstrated immunohistologically on the endothelium after xenogeneic perfusion. PgF1a levels were significantly higher in the xenogeneic hemoperfusate, indicating endothelial cell activation. The concentration of myoglobin in the hemoperfusate remained within normal values and was similar during autologous and xenogeneic perfusion. Therefore endothelium-related processes are likely to affect the coronary circulation--thus being one mechanism leading to diminished cardiac performance during hyperacute rejection.

Immunocytochemical phenotyping of disseminated tumor cells in bone marrow by uPA receptor and CK18: investigation of sensitivity and specificity of an immunogold/alkaline phosphatase double staining protocol.

Phenotyping of cytokeratin (CK)18-positive cells in bone marrow is gaining increasing importance for future prognostic screening of carcinoma patients. Urokinase-type plasminogen activator receptor (uPA-R) is one example of a potential aggressive marker for those cells. However, a valid and reliable double staining method is needed. Using monoclonal antibodies against uPA-R and CK18, we modified an immunogold/alkaline phosphatase double staining protocol. UPA-R/CK18-positive tumor cell controls exhibited black uPA-R staining in 15-80% of cases and red CK18 staining in almost 100% of tumor cells. Isotype- and cross-matched controls were completely negative. Bone marrow from healthy donors was always CK18-negative. Reproducibility of CK18-positive cell detection was estimated in a series of specimens from 61 gastric cancer patients comparatively stained with the single alkaline phosphatase-anti-alkaline phosphatase (APAAP) and our double staining method (10(6) bone marrow cells/patient). In four cases, double staining could not reproduce CK18-positive cells. In 34 cases it revealed fewer or equal numbers, and in 23 cases more CK18-positive cells than the APAAP method. Overall quantitative analysis of detected cell numbers (838 in APAAP, range 1-280 in 10(6); double staining 808, range 0-253) demonstrated relative reproducibility of APAAP results by double staining of 97%. Correlation of results between both methods was significant (p < 0.001, linear regression). Sensitivity of double staining tested in logarithmic tumor cell dilutions was one CK18-positive cell in 300,000. Specific uPA-R staining was seen on CK18-positive cells in bone marrow from 29 of 61 patients, and also on single surrounding bone marrow cells. To test the specificity of this staining, bone marrow cytospins from 10 patients without tumor disease were stained for uPA-R with the APAAP method. uPA-R expression was confirmed in all 10 cases, with a mean of 6.5% uPA-R-positive cells in 1000 bone marrow cells (SEM 1.2%). These results suggest that our double staining protocol is a sensitive, reproducible, and specific method for routine uPA-R phenotyping of disseminated CK18-positive cells in bone marrow of carcinoma patients.

The special role of rimes in the description, use, and acquisition of English orthography.

The links between spellings and sounds in a large set of English words with consonant-vowel-consonant phonological structure were examined. orthographic rimes, or units consisting of a vowel grapheme and a final consonant grapheme, had more stable pronunciations than either individual vowels or initial consonant-plus-vowel units. In 2 large-scale studies of word pronunciation, the consistency of pronunciation of the orthographic rime accounted for variance in latencies and errors beyond that contributed by the consistency of pronunciation of the individual graphemes and by other factors. In 3 experiments, as well, children and adults made more errors on words with less consistently pronounced orthographic rimes than on words with more consistently pronounced orthographic rimes. Relations between spellings and sounds in the simple monomorphemic words of English are more predictable when the level of onsets and rimes is taken into account than when only graphemes and phonemes are considered.

An investigation of young infants' perceptual representations of speech sounds.

The present study examined the ability of newborns and 2-month-olds to detect phonetic differences between syllables. By relying on the modified high-amplitude sucking procedure, which did not permit the infants to use a simple same-different response, the present experiments tapped the perceptual representations of the speech sounds. Infants as young as a few days old displayed some capacity to represent differences in a set of syllables varying in their phonetic composition, although there was no convincing evidence that their representations were structured in terms of phonetic segments. Finally, evidence of developmental changes in speech processing were noted for the first time with infants in this age range. The change noted was a tendency from global toward more specific representations on the part of the older infants.

Bridging to transplant: allogeneic heart transplantation after xenografting.

Xenografting seems to be a solution to use to bridge time intervals when desperately needed allograft cannot be obtained. A following allograft was never ventured. Nine dogs (weight, 20 to 25 kg; age, 2 years) underwent right cervical heart transplantation. Donors were silver foxes (3 to 4 kg). The animals were treated by triple-drug therapy consisting of cyclosporine, methylprednisolone, and azathioprine in clinical dosages. For control, six recipients received only allogeneic hearts and the identical immunosuppression. After rejection of the xenograft, a second allogeneic heart was anastomosed subsequently to the same right cervical vessels. Routine histologic and immunohistologic examinations were performed. Thromboxane B2 and 6-keto-prostaglandin F1 alpha were determined daily in peripheral blood. After final rejection the sensitization of the recipient was controlled by hemagglutination test. Survival time of the xenografts was 9.6 +/- 1.2 days; the subsequent allogeneic hearts under the same therapy beat for 4.5 +/- 5.0 days. The average survival time of control hearts was 18 +/- 1.9 days. The five hyperacute second allografts showed signs of humoral rejection by absence of inflammation. The release of thromboxane B2 was different in hyperacute, accelerated, or cellular rejection. In contrast to the long-functioning grafts, thromboxane B2 persisted during hyperacute rejection at a high level. However, 6-keto-prostaglandin F1 alpha showed no significant differences between longtime survivors and hyperacute rejecting hearts. After xenogeneic transplantation, all recipients showed hemagglutinating titers between 1:4 and 1:16. Allogeneic grafts have a different kinetics of rejection after xenogeneic heart transplantation compared with control hearts. Thromboxane B2 seems to be an important mediator in hyperacute rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of ventricular arrhythmias with left ventricular remodelling after myocardial infarction.

OBJECTIVE: To assess the relation between ventricular arrhythmias after myocardial infarction and left ventricular remodelling. DESIGN: Prospective study with consecutive patients. METHODS: 97 patients with acute myocardial infarction underwent serial echocardiographic examinations (days 1, 2, 3, and 7, and after 3 weeks) to determine end diastolic volume, end systolic volume, and ejection fraction; volumes were normalised for body surface area and expressed as indices. Holter monitoring was performed on the day of the final echocardiogram. Coronary angiography was performed in 88 patients before hospital discharge. RESULTS: Complex ventricular arrhythmias (defined as Lown class 3-5) were found in 16 of 97 patients. In logistic regression models, variables predictive of complex ventricular arrhythmias were end systolic volume index on admission (b = 0.054, P = 0.015) and end diastolic volume index after three weeks (b = 0.034, P = 0.012). Complex arrhythmias were also related to the increase of end diastolic and end systolic volume indices throughout the study (F = 5.62, P = 0.046, and F = 6.42, P = 0.017, respectively by MANOVA). A two stage linear regression model of ventricular volume versus time from infarct showed that both intercept (initial volume) and slope (rate of increase) were higher for patients with complex arrhythmias in both diastole and systole (P < 0.001 for all). CONCLUSIONS: Complex ventricular arrhythmias after myocardial infarction are related to the increase of left ventricular volume rather than to depressed ejection fraction. Complex arrhythmias may be an aetiological factor linking left ventricular remodelling with higher mortality, but larger follow up studies of patients with progressive left ventricular dilatation after myocardial infarction are necessary to answer these questions.