Angiostatin overexpression in Morris hepatoma results in decreased tumor growth but increased perfusion and vascularization.

Growth of malignant tumors is dependent on sufficient blood supply. Thus, inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Human angiostatin (hANG) is one of the most potent inhibitors of endothelial cell proliferation, angiogenesis, and tumor growth in vivo. However, its mechanisms operating in vivo are not well understood. METHODS: To obtain more information about functional changes in the angiogenic process, we established Morris hepatoma (MH3924A) cell lines expressing hANG (hANG-MH3924A). The effects of hANG expression on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) were measured in coculture experiments in vitro. To evaluate changes in tumor perfusion and blood volume, H2 15O and 68Ga-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid) were used for PET studies in vivo. Additionally, immunohistologic quantification of vascularization, apoptosis, and proliferation as well as gene array analyses were performed. RESULTS: Our in vitro experiments demonstrate reduced proliferation and increased apoptosis in HUVECs when being cocultured with hANG-MH3924A. In support, tumor growth of hANG-MH3924A is diminished by 95% in vivo. However, tumor perfusion and blood volume are increased in hANG-MH3924A corresponding to an increased microvessel density. Furthermore, hANG-transfected tumors show changes in expression of genes related to apoptosis, stress, signal transduction, and metabolism. CONCLUSION: hANG expression leads to inhibition of tumor growth, increased apoptosis, and changes in the expression of multiple genes involved in stress reactions, signal transduction, and apoptosis, which indicates a multifactorial reaction of tumors. An enhanced microvessel density is seen as part of these reactions and is associated with increased perfusion as measured by PET.     

Initially Accelerated Fractionation of the R1H Tumor of the Rat Increases Local Tumor Control and Might Reduce Impact of Overall Treatment Time

PURPOSE: To study the effect of treatment time prolongation following initial dose acceleration on the response of subcutaneously growing R1H tumor. MATERIAL AND METHODS: Continuous standard fractionation (30 fractions/40 days) was compared to initially accelerated treatment (30 fractions/21 days) followed by five to two fractions per week yielding total treatment times from 40 to 72 days. Local tumor control was assessed as endpoint. RESULTS: Radiation dose to control 50% of the tumors (TCD50%) decreased statistically significant from 83.5 Gy (95% confidence interval [CI]: 78.6 .. 88.4) for standard fractionation to 74.1 Gy (95% CI: 72.7 .. 75.5) determined for all accelerated treatment arms (p = 0.003). Prolongation of treatment time after initial acceleration from 40 to 72 days led to a small but statistically not significant increase in TCD50% from 72.0 Gy (95% CI: 71.0 .. 72.9) to 76.2 Gy (95% CI: 69.9 .. 82.4) corresponding to a repopulated dose of 0.9 Gy per week. This time factor is considerably smaller than for conventional radiation treatment as determined in previous experiments. CONCLUSION: The results indicate that initially accelerated irradiation not only improves local tumor control but also minimizes the negative effect of treatment time prolongation. This might be due to changes in tumor cell repopulation kinetics.     

Muscular activation patterns of healthy persons and low back pain patients performing a functional capacity evaluation test

The results of most reported studies show differences between the muscular activity of low back pain patients and healthy subjects, but the focus has usually been on trunk muscles only, and they have not involved work-related tests or exercises. The reintegration of chronic low back pain patients to job market is a common problem. Therefore assessment systems like the functional capacity evaluation (FCE) according to Isernhagen [S.J. Isernhagen, Work Injury: Management and Prevention, Aspen Publishers Inc., Gaithersburg, MD, 1988] are often used tools to determine the physical abilities and deficits of long-time incapacitated persons. The aim of the present study was to compare the healthy persons and chronic low back pain patients in performing a FCE-test and to analyse their muscular activation and motion patterns. The results indicate differences in the activation patterns of the groups in the test task “floor to waist lift” common in many occupations.     

On language laterality in normal dextrals and sinistrals: Results from the Bilateral Object Naming Latency Task

Rasmussen and Milner [N.Y. Acad. Sci. Vol. 299, pp. 355–379, 1977] published data on late-lesioned (after age 6) epileptic patients who had suffered left hemisphere lesions. They estimated that left hemisphere dominance occurred in 96% of dextrals and 70% of sinistrals. These figures have been regarded as valid estimates for normal dextrals and sinistrals. We administered the Bilateral Object Naming Latency Task, a verbal tachistoscopic task with very good psychometric properties, to 188 dextral and 72 sinistral normals. Results showed that 93.6% of the dextrals and 80.3% of the sinistrals were left hemisphere dominant. A consideration of results from a number of carefully conducted dichotic listening studies suggests, as do present results, that the 70% left-dominance estimate of Rasmussen and Milner for normal sinistrals may be too low by about 10%. It is suggested that ‘bilateral dominance’, present in 15% of the epileptic sinistrals of Rasmussen and Milner, may be much less common in normal sinistrals.     

Impact of randomized trials comparing conventional and endovascular abdominal aortic aneurysm repair on clinical practice.

PURPOSE: To report a retrospective study into the effects of trials on clinical decision-making regarding abdominal aortic aneurysm (AAA) patients suitable for both conventional open (OR) and endovascular aneurysm repair (EVAR). METHODS: A questionnaire was sent to 1400 Dutch surgeons and trainees. Interviewees had to choose between OR and EVAR for AAA patients with and without comorbidity. Specifically, their preferences before and after the publication of 2 randomized trials (EVAR-1 and DREAM) were polled. RESULTS: Of the 524 (37%) questionnaires returned, 223 (43%) respondents treated AAA patients. Before publication of the trials, 160 (72%) preferred OR for the patient without comorbidity and 169 (76%) preferred EVAR for the patient with comorbidity. In total, 72 (32%) respondents changed their preference after the trials were published; however, there was no overall major shift. Focusing on the different cases revealed that the OR preference was significantly enhanced for the patient without comorbidity (p<0.01), while the EVAR preference was significantly enhanced for the patient with comorbidity (p<0.05). CONCLUSION: The randomized trials have not induced major overall changes in surgical decision-making for AAA patients suitable for both EVAR and OR.     

Oral administration of taurolidine ameliorates chronic DSS colitis in mice.

Taurolidine (TRD) has antimicrobial and anti-inflammatory properties. However, the anti-inflammatory effects of TRD in inflammatory bowel diseases (IBD) have not been investigated. Here, we have analyzed the toxicity of TRD after oral long-term application in mice and examined the impact of oral TRD in a dextran sulfate sodium (DSS) model of experimental colitis. Female C57/BL6 mice received TRD in various concentrations (0.1% to 0.4%) for 60 days. Toxicity was evaluated by use of a disease activity index (DAI) and histological examination of major metabolic organs. Furthermore, the impact of 0.2% TRD on a chronic DSS colitis was examined by daily DAI, histological crypt damage score (CDS), bacterial translocation into mesenteric lymph nodes (MLN), and colonic expression of tumor necrosis factor (TNF) alpha, transforming growth factor (TGF) beta, interleukin (IL)-1beta, IL-6, cytochrome oxidase (COX)-2, and monocyte chemotactic protein (MCP)-1 by real-time polymerase chain reaction (PCR). Oral TRD administration for 60 days was well tolerated by the animals and did not show any toxic effects in terms of DAI and histological changes. TRD treatment of DSS colitis led to increased survival of 100%, compared to 33% in the untreated colitis group (p < or = .005). Clinical amelioration was mirrored by significantly reduced DAI and CDS in the TRD treated colitis. Colonic cytokine expression and bacterial translocation into MLN showed no differences between both groups. We thus report for the first time that oral application of TRD results in amelioration of an experimental IBD model. We hypothesize direct intraluminal antimicrobial effects of TRD as well as anti-inflammatory effects during the acute phase of DSS colitis.