Detection and characterization of the electron paramagnetic resonance-silent glutathionyl-5,5-dimethyl-1-pyrroline N-oxide adduct derived from redox cycling of phenoxyl radicals in model systems and HL-60 cells

Rapidly growing knowledge about the nature and behaviour of breast cancer has led to many treatment modalities. Consequently, the possibilities of individualizing the treatment of breast cancer increase. The major tool for the determination of an optimal treatment plan is the estimation of the extent of the disease: in other words, staging. As a consequence, together with the expected result of the treatment, the stage of the disease gives information on the prognosis of the patient. Current staging systems insufficiently describe the clinically important features of breast cancer with respect to management and outcome: local and regional extent, invasiveness, aggressiveness, the state of dissemination, and the effectiveness of different treatment modalities. For staging of the local and regional extent, histology plays a prominent role and should be incorporated in future staging systems. Histological workup therefore needs standardisation. Histological parameters as tumour size, grade, nodal status, and vascular invasion are also the most important prognostic factors. Many so-called biological prognostic factors are related to the invasiveness and aggressiveness (metastatic potential) of the tumour, and therefore to the prognosis of the patient. However, these factors do not necessarily predict the effectiveness of certain systemic treatments. Only if the biological foundation of a prognostic factor is completely clarified can treatment be based on this knowledge, and the factor will become a predictor for the treatment effect. Many "biological" prognostic factors do not fulfil this main criterion and are therefore not useful for clinical decision making. A clinically useful staging system covers three primary aims: (1) to guide locoregional treatment, (2) to prognosticate the chance of survival, and (3) to indicate who needs what kind of adjuvant treatment. For the conception of a new staging system the following steps should be taken: standardization of all aspects of histology, identification of regional nodal involvement, and validation of prognostic factors with respect to their predictive value to treatment outcome.     

Ultrastructural features of cystic and merogonic stages of Hepatozoon sipedon (Apicomplexa: Adeleorina) in northern leopard frogs (Rana pipiens) and northern water snakes (Nerodia sipedon) from Ontario, Canada

This article describes the long-term consequences of successful cardiovascular disease (CVD) prevention and its influence on premature mortality in Finland, with special reference to North Karelia. Active community-based CVD prevention began in 1972 in the province of North Karelia (population, 180,000). Since 1977, active preventive work has been carried out nationwide, taking advantage of the experience from North Karelia, which continued as a demonstration area for integrated prevention of noncommunicable diseases. Comprehensive community-based interventions as part of WHO interhealth and CINDI programmes in North Karelia and nationwide aimed at changing the target risk factors and health behaviours (serum cholesterol, blood pressure, smoking, diet) at the population level. Age-adjusted mortality rates for CVD, coronary heart disease (CHD), cerebrovascular disease, all cancers, lung cancer, accidents and violence, and all causes in the population aged 35-64 years from the pre-programme period (1969-71) to 1995 were the main measures of the outcome. Among men there was a great reduction in deaths from CHD, CVD, cancer, and all causes in the whole country. From 1969-71 to 1995 the age-standardized CHD mortality (per 100,000) decreased in North Karelia by 73% (from 672 to 185) and nationwide by 65% (from 465 to 165). The reduction in CVD mortality was of the same magnitude. Among men, CHD mortality decreased in the 1970s, as did lung cancer mortality in the 1980s and 1990s, significantly more in North Karelia than in all of Finland. Among women there was a great reduction in CVD (including CHD and stroke) mortality and all-causes mortality, but only a small reduction in cancer mortality. These results show that a major reduction in CVD mortality among the working-age population can take place in association with active reduction of major risk factors, with a favourable impact on cancer and all-causes mortality.     

The control of protein release from poly(DL-lactide co-glycolide) microparticles by variation of the external aqueous phase surfactant in the water-in oil-in water method

A unique feature of p21 that distinguishes it from the other cyclin-dependent kinase (CDK) inhibitors is its ability to associate with the proliferating cell nuclear antigen (PCNA), an auxiliary factor for DNA polymerases delta and epsilon. While it is now well established that inhibition of cyclin/CDK complexes by p21 can result in G1 cell cycle arrest, the consequences of p21/PCNA interaction on cell cycle progression have not yet been determined. Here, we show, using a tetracycline-regulated system, that expression of wild-type p21 in p53-deficient DLD1 human colon cancer cells inhibits DNA synthesis and causes G1 and G2 cell cycle arrest. Similar effects are observed in cells expressing p21CDK-, a mutant impaired in the interaction with CDKs, but not in cells expressing p21PCNA-, a mutant deficient for the interaction with PCNA. Analysis of cells treated with a p21-derived PCNA-binding peptide provides additional evidence that the growth inhibitory effects of p21 and p21CDK result from their ability to bind to PCNA. Our results suggest that p21 might inhibit cell cycle progression by two independent mechanisms, inhibition of cyclin/CDK complexes, and inhibition of PCNA function resulting in both G1 and G2 arrest.     

Role of bradykinin B2 receptors in neonatal kidney growth

OBJECTIVES: As the incidence of prostate cancer in the United States exceeds 330,000 in 1997, increasingly more men are faced with treatment choices for which there is no clear approach. At every stage of disease, these treatment choices may involve clinically equivalent modalities that differ in side effects and impact upon quality of life (QOL). Comprehensive, yet efficient, questionnaires are needed to measure QOL in patients with prostate cancer. METHODS: Developed as a disease-specific adjunct to the Functional Assessment of Cancer Therapy (FACT) measurement system, a 12-item prostate cancer subscale (PCS) was developed and tested in three independent samples: a subscale development sample (n = 43), validity sample 1 (n = 34), and validity sample 2 (n = 96). The 12 items ask about symptoms and problems specific to prostate cancer. These questions are added to the general (FACT-G) instrument, thereby comprising a 47-item questionnaire. RESULTS: Internal consistency of the PCS ranged from 0.65 to 0.69, with coefficients for FACT-G subscales and aggregated scores ranging from 0.61 to 0.90. Concurrent validity was confirmed by the ability to discriminate patients by disease stage, performance status, and baseline prostate-specific antigen (PSA) level. Sensitivity to change in performance status and PSA score over a 2-month period suggested that some subscales of the FACT-Prostate (P) (including the PCS) are sensitive to meaningful clinical change. CONCLUSIONS: Our findings support use of the FACT-P as a meaningful component of QOL evaluation in men undergoing therapy for prostate cancer.     

Interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis

Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promoter-human TGF-alpha cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing the interaction of nuclear oncogenes and growth factors in tumorigenesis. Coexpression of c-myc and TGF-alpha as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumors were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. These observations suggest that the interaction of c-myc and TGF-alpha, during development of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases the probability of malignant conversion. These studies have now been extended to examine the interaction of hepatocyte growth factor (HGF) with c-myc during hepatocarcinogenesis in the transgenic mouse model. While sustained overexpression of c-myc in the liver leads to cancer, coexpression of HGF and c-myc in the liver delayed the appearance of preneoplastic lesions and prevented malignant conversion. Similarly, tumor promotion by phenobarbital was completely inhibited in the c-myc/HGF double transgenic mice whereas phenobarbital was an effective tumor promoter in the c-myc single transgenic mice. The results indicate that HGF may function as a tumor suppressor during early stages of liver carcinogenesis, and suggest the possibility of therapeutic application for this cytokine. Furthermore, we show for the first time that interaction of c-myc with HGF or TGF-alpha results in profoundly different outcomes of the neoplastic process in the liver.     

Enalapril-induced renal artery thrombosis in unilateral renal artery stenosis

Intravascular adhesion of leucocytes plays a role in the pathogenesis of acute and chronic vascular disease. Regular aerobic exercise seems to protect against vascular disease. Since leucocyte adhesion is mediated by integrins, we tested the hypothesis that surface expression of the integrin adhesive receptors LFA-1 (cd11a/cd18), MAC-1 (cd11b/cd18), gp 150/95 (cd11c/cd18), and VLA-4 (cd29/cd49) is decreased by moderate endurance exercise. Surface expression of integrins was measured by FACS analysis in 19 healthy subjects (16 males, 3 females, 36.6 +/- 8.7 years, 177.1 +/- 7.5 cm, 70.3 +/- 8.1 kg) before and after submaximal exercise (3 h run) using monoclonal antibodies against cd11a, cd11b, cd11c, cd18, cd29 and cd49. In addition, we compared resting integrin expression in this group with a group of sedentary subjects (19 males, 6 females, 29.3 +/- 5.3 years). White blood cell count increased from 5300 ml(-1) to 9740 ml(-1) during exercise (P < 0.001). Nevertheless, the expression (indicated by the mean log fluorescence) of cd11a (94 +/- 24 vs. 78 +/- 14) and cd18 (128 +/- 31 vs. 102 +/- 21) on lymphocytes and of cd11a (104 +/- 25 vs. 85 +/- 16), cd11c (497 +/- 171 vs. 408 +/- 126) cd29 (109 +/- 16 vs. 89 +/- 16), cd49 (69 +/- 8 vs. 54 +/- 11) on monocytes was decreased after exercise (all P < 0.05). In contrast, integrin expression on granulocytes was not altered by exercise. Comparison of exercising and sedentary subjects showed a significantly decreased expression of integrins in exercising subjects. Our results demonstrate that moderate exercise leads to decreased expression of integrin receptors on leucocytes. This decreased expression of adhesion molecules may result in decreased adhesion and infiltration of leucocytes into the vessel wall. This phenomenon may play a role in the beneficial effect of moderate exercise in prevention of acute and chronic vascular disease.     

Genomic organization of the human TIMP-1 gene. Investigation of a causative role in the pathogenesis of X-linked retinitis pigmentosa 2

PURPOSE: To evaluate the role of TIMP-1 in inherited retinal degeneration. METHODS: The genomic structure of the TIMP-1 gene was established and male patients with x-linked retinitis pigmentosa 2 from five families were screened for sequence alterations by direct sequencing in all exons, exon-intron boundaries, and the 5' upstream region of the gene. RESULTS: TIMP-1 appears to be expressed in the retina at low levels and consists of six exons spanning a genomic region of approximately 4.5 kb on Xp11.23. No disease-specific sequence alterations were identified. A site substitution in exon 5 was observed in samples from control subjects and patients, but it did not alter the amino acid sequence of the protein product. CONCLUSIONS: The results of this study exclude mutations in the TIMP-1 coding sequence, splice sites, and the 5' upstream region as a cause of retinal degeneration in x-linked retinitis pigmentosa 2. However, an as yet unidentified regulatory element that lies outside these intervals may be implicated. The role of this tightly regulated protein in the normal functioning of the retina has yet to be determined.     

Evaluation of the effectiveness of continuous renal replacement therapy in critical patients after cardiovascular surgery

The efficacy of continuous methods of renal substitute therapy (RST) in patients with multiple organ failure is assessed. The patients were divided in 2 groups administered different types of PST. Group 1 were 16 patients subjected to RST by peritoneal dialysis, in group 2 (n = 16) GP and/or GDP were used. Hemodynamics, hematological and biochemical values, and clearance of inflammation mediators were monitored and hemohydrobalance and complications of therapy assessed in the course of RST. Both RST methods proved to be highly effective. The possibility of differentiated use of peritoneal dialysis and GP/GDP permits an individual approach to treatment, and equally high efficacy of both methods solves the problem of treating total renal insufficiency in the majority of patients with multiple organ failure following cardiovascular surgery.