Tumour angiogenesis: vascular growth and survival

Angiogenesis starts at the edge of a malignant epithelial tumour concurrently with tumour cell invasion and stromatogenesis, i.e. the formation of specific connective tissue stroma amenable to easy penetration by endothelial and tumour cells. However, as the tumour continues its growth, the edge becomes the inner tumour area, and a new invading tumour front is formed by the multiplying malignant cells which outflank the initial edge. This process, which repeats itself again and again, forms the "relay race" model of tumour vascular growth and regression. At the heart of the tumour unfavourable environmental conditions prevail -- hypoxia, acidity, lack of nutrients, failure of waste removal, and apoptosis rather than proliferation. Blood vessels and tumour cells are greatly decreased, but do not vanish, as tumour cells are shifting to anaerobic glycolysis, and blood vessels are turning into anti-apoptotic pathways -- vascular survival ability (VSA). Thus, assessing vascular density (VD) by simply counting "hot spots" at the edge of a tumour, where conditions are most favourable, is futile; it may reflect tumour angiogenic activity (TAA), but is not representative of genuine tumour vasculature. By combining vessel counts at the invading tumour front with those of the inner tumour areas a complete picture of tumour VD can be achieved. The thus formed four patterns of vascularization, designated as "edvin" (edge vsinner tumour area), are: edvin 1: low TAA/low VSA; edvin 4: high TAA/high VSA; edvin 2: low TAA/high VSA; and edvin 3: high TAA/low VSA. It is expected that this scheme will prove useful in the field of chemoradiotherapy and anti-angiogenic treatment.     

Classifying clinical severity to help solve problems of stage migration in nonconcurrent comparisons of lung cancer therapy

To compare the effects of stage migration in the "traditional" 3-stage TNM (tumor, node, metastasis) system with those in a new "expanded" 5-stage system, which has two additional stages for the poor prognostic groups, we used both systems to classify a cohort of 178 patients with primary lung cancer. To check for migrations, the stages in both systems were first assigned using only "old" technological information and were then reassigned using all the available "new" as well as old technological data. Although the 5-stage system had more migrations than the 3-stage system, survival rates were relatively unaffected for patients in the two new stages with poor prognosis. In both TNM staging patterns, the effects of stage migration on survival statistics were most impressive in the prognostically better (TNM I and II) stages. A solution to the migration problem is offered by the "clinical severity" (CS) staging system. Like the expanded TNM system, the CS system has 5 stages and a sharp prognostic gradient among stages. The CS system, however, had fewer technology-induced stage migrations than either TNM system, and the migrations had no substantial impact on stage-specific survival results. The excellent prognostic discrimination and secular stability of the CS system make it superior to the TNM system for comparing treatment results from different eras, especially for patients with stage I and II disease.     

Pathogen and resistance spectrum in intraoral infections of the jaw-facial area with special reference to anaerobic bacteria]

The aim of the study was to obtain more knowledge about the aerobic and anaerobic species causing maxillofacial infections and their resistance patterns today. Samples of pus or infectious tissue obtained from 110 patients of maxillofacial surgery were investigated microbiologically by means of aerobic and anaerobic cultivation. After incubation, the cultivated species were isolated and identified. The resistance patterns of all bacteria to penicillin, doxycyclin, and clindamycin were determined. Additionally, the resistance of aerobic species to cefuroxim was documented, and the MICs of cefoxitin and metronidazole to the anaerobic species were assessed. The most frequent disease was periodontitis apicalis (70 patients). Aerobic species alone were found in 23% of the samples, 14% of the infections harbored only anaerobes, but 63% were mixed infections caused by aerobic and anaerobic bacteria. In case of detection of aerobic species, streptococci were always identified. Five patients were infected by Staphylococcus aureus and gram-negative aerobic rods were found in eight patients. Most of the anaerobic species were black pigmented prevotella species (62), nonpigmented prevotellae (56), and fusobacteria (37). Metronidazole and clindamycin were highly efficient to gram-negative anaerobic rods. Most of the oral species were resistant to penicillin and doxycyclin. The indication for applying antibiotics should always be noticed and these drugs should only be used after determination of the pathogenic microorganisms and their susceptibility to the antimicrobials.     

Surface-Attached Polymer Networks Made from Cationic Poly(diitaconates): Synthesis,Surface Characterization,and Bioactivity

Facially amphiphilic polymers carrying cationic and hydrophobic groups on the same repeat unit have shown promising antimicrobial activity and biocompatibility, yet they are prone to suffer from protein adhesion which may induce biofilm formation. To overcome this problem, poly(diitaconate)-based copolymers with cationic/hydrophobic and protein-repellent/charge-neutral repeat units are synthesized. The bioactivity profile of surface-attached polymer networks made from these copolymers depends on the ratio of the cationic and charge-neutral repeat units. In all cases, the protein adhesion is substantially reduced compared to purely cationic polymers. At a 50:50 ratio, the polymer coatings are partially protein-repellent and antimicrobial, yet slightly cell toxic. At an intermediate composition of 30:70, they are still antimicrobial and the cell compatibility is substantially improved. The long-term stability of these materials still has to be determined to judge their suitability for medical applications.     

Inclusion of psychopathologic methods for diagnosis of early neurotoxic effects from lead and organic solvent mixtures

To verify occupational neurotoxic effects it will be necessary to enlist the help of clinical psychologists and psychiatrists. However, no unified professional test battery exists to date. 119 healthy workers (26 lead-exposed, 45 exposed to mixed organic solvents, and 48 controls) were tested using uniformly standardised psychological and psychiatric methods. Long-term lead-exposed employees showed an increased number of psychoneurovegetative symptoms and deficits in attention performance according to the results of the Seeber-PNF and the Brickenkamp-d2-tests. There was no difference between the control group and persons exposed to the organic solvents test. Many parameters correlated to the dose of the toxic agent in the lead-exposed group. SCL-90-R, AMDP, and HAMD merely hinted at differences between the exposed subjects and the controls. Psychological and pathopsychological methods are necessary but will not suffice to detect early effects after long-term exposure to lead or organic solvents.     

Chain length heterogeneity of nucleosomal DNA in mouse liver after dimethylnitrosamine administration

The effect of dimethylnitrosamine on the nucleosomal structure of mouse liver chromatin was studied. After a single oral dose of dimethylnitrosamine (2–75 mg/kg body weight 45 min before sacrifice) liver nuclei were isolated and incubated with micrococcus nuclease. Nucleosomes were separated on sucrose density gradients. There were no differences in nucleosomal sedimentation velocities between preparations from control and dimethylnitrosamine treated animals. The supernatant obtained after centrifugation of the lysed nuclei (2 min at 4,000 g _av) and nucleosomal peak fractions were used for isolation of DNA. DNA was heat denatured in 7 M urea or formamide. After electrophoresis on polyacrylamide gels areas under mononucleosomal DNA and smaller fragments were measured and compared with the total DNA area. The increase in DNA fragmentation was dimethylnitrosamine dose response dependent. When expressed as per cent of controls it amounted to 106% for 2 mg; 115% for 10 mg; 127% for 25 mg; 164% for 75 mg dimethylnitrosamine/kg body weight. A good correlation between mobility and log of chain length of 174 RF DNA-Hae III digest was obtained in nondenaturing 5% polyacrylamide gels and denaturing non-aqueous formamide polyacrylamide gels but not in 12% polyacrylamide gels containing 7 M urea. DNA of mononucleosomal peak fractions contained 200 and that of dinucleosomal peak fractions 400 nucleotides. Fragmentation of DNA was closely related to in vivo dimethylnitrosamine treatment but was not detected in measurements of protein-DNA complexes in the chromatin. It was disclosed on denaturation of DNA followed by polyacrylamide gel electrophoresis.Abbreviations DMN dimethylnitrosamine - SDS sodium dodecyl sulfate The work was supported by Grant Number 1 R0 1 CA26642-01, awarded to A.v.d.D. by the National Cancer Institute, DHEW     

Hashimoto-Enzephalopathie Steroid-sensitive Enzephalopathie bei Hashimoto-Thyreoiditis

Hashimoto's encephalopathy is a steroid-responsive, relapsing or progressive encephalopathy associated with Hashimoto's thyroiditis. Characteristic clinical features are confusion, seizures, alteration in conscious level, stroke-like episodes, myoclonus, and tremulousness. High CSF protein levels without pleocytosis and a diffusely abnormal EEG are typical findings. Brain CT and MRI and cerebral angiogram are usually normal. We present two case reports of Hashimoto's encephalopathy in 55- and 77-year-old patients who both responded well to steroid therapy, and review the literature.     

Induction of partial protection in mice after oral administration of Lactococcus lactis producing Brucella abortus L7/L12 antigen.

The Brucella abortus ribosomal protein L7/L12 is an immunodominant antigen and an interesting candidate for the development of oral live vaccines against brucellosis. Here, a recombinant Lactococcus lactis strain producing L7/L12 under the control of nisin inducible promoter was orally administered to BALB/c mice. Significant levels of anti-L7/L12 specific IgA detected in feces revealed an induced local humoral immune response. However, serum analysis did not reveal any anti-L7/L12 antibodies suggesting the absence of a systemic response. Nevertheless, the vaccinated mice showed a partial protective immunity against B. abortus virulent strain (S2308) challenged by intraperitoneal inoculation.     

Preparticipation cardiovascular screening for US collegiate student-athletes

Context  Sudden death in young competitive athletes due to unsuspected cardiovascular disease has heightened interest in preparticipation screening. Objective  To assess screening practices for detecting potentially lethal cardiovascular diseases in college-aged student-athletes. Design, Setting, and Participants  A total of 1110 National Collegiate Athletic Association member colleges and universities were surveyed between 1995 and 1997, with 879 (79%) responding to the questionnaire. Main Outcome Measures  Information on the administration and scope of the preparticipation screening process was obtained from the team physician or athletic director; preparticipation screening forms were evaluated for content and compared with 12 items recommended by the 1996 American Heart Association (AHA) consensus panel screening guidelines. Results  Preparticipation screening was a requirement at 855 (97%) of 879 schools, was performed on campus at 713 schools (81%), and was required annually by 446 schools (51%). Team physicians were responsible for examinations at 603 (85%) of 713 schools with on-campus screening, although 135 of these schools (19%) also approved nurse practitioners and 244 schools (34%) allowed athletic trainers to perform examinations. Of the history and physical examination screening forms analyzed from 625 institutions, only 163 schools (26%) had forms that contained at least 9 of the recommended 12 AHA screening guidelines and were judged to be adequate, whereas 150 (24%) contained 4 or fewer of these parameters and were considered to be inadequate. Smaller Division III schools were more likely than larger Division I schools to have inadequate screening forms (30% vs 14%; P<.001). Relevant items that were omitted from more than 40% of the screening forms included history of exertional chest pain, dyspnea, or fatigue; familial heart disease or premature sudden death; and physical stigmata or family history of Marfan syndrome. Conclusion  The preparticipation screening process used by many US colleges and universities may have limited potential to detect (or raise the suspicion of) cardiovascular abnormalities capable of causing sudden death in competitive student-athletes.      

Evidence that Tamoxifen Preserves Bone Density in Late Postmenopausal Women with Breast Cancer

Tamoxifen, which is used for treating breast cancer, exhibits estrogenic and antiestrogenic characteristics, depending on the tissue. In the human breast it acts as an antiestrogen, whereas estrogenic effects have been reported on endometrium and bone. The purpose of this study was to determine whether tamoxifen (TAM) prevents bone loss in elderly, postmenopausal women. Bone mineral density of the lumbar spine (SBD) was measured in elderly women (at least 10 years after menopause) 5 years after stage I or II breast cancer (n=111). The results showed that SBD in untreated patients (n=74) was significantly lower (p0.05) than SBD in patients (n=37) treated with TAM over 5 years. In a subgroup of patients (n=24) with positive estrogen receptor status, changes in SBD 12 months after discontinuation of 5-year TAM therapy were measured and compared with the changes of extended TAM treatment over a sixth year. Twelve months after withdrawal of 5-year TAM medication (n