Lovastatin-induced apoptosis in prostate stromal cells

Benign prostatic hyperplasia (BPH) is a common disease of aging men. Current medical treatment for this condition is only partially effective, therefore many patients must undergo surgery for symptomatic relief. BPH is caused by an increase in prostate epithelial and stromal cells, especially the latter. Since BPH stromal cells have a long life span and are not very responsive to androgen withdrawal, cultured BPH stromal cells were used to explore the feasibility of pharmacologically inducing apoptosis in these cells. We obtained BPH tissue during surgery, and stromal cells were isolated and maintained in culture. After cells achieved confluence, we induced apoptosis with the HMGCoA reductase inhibitor, lovastatin (30 micromol/L). The effects of testosterone (100 micromol/L), dihydrotestosterone (DHT; 100 micromol/L) and finasteride (100 micromol/L) on lovastatin-induced apoptosis were studied on cells grown in media containing charcoal stripped serum. Similarly, we examined the effect of the cholesterol pathway metabolites, mevalonic acid (30 micromol/L), geranyl geraniol (30 micromol/L), farnesol (10 micromol/L), squalene (30 micromol/L) and 7-ketocholesterol (3 micromol/L) on lovastatin-induced apoptosis. We demonstrated apoptosis by DNA laddering in agarose gels, by fluorescence microscopy following acridine orange staining, and by flow cytometry after end-labeling of DNA strand breaks with biotin-16-dUTP using deoxynucleotidyl exotransferase (TdT). Lovastatin at 30 micromol/L, but not at lower concentrations, induced apoptosis in BPH prostate stromal cells. This was seen (by flow cytometry) in 16.6 +/- 7.3% (mean +/- SD) of BPH cells treated with lovastatin at 72 h vs. 2.5 +/- 1.2% of cells treated with ethanol. Lovastatin-induced apoptosis was not increased in stripped serum or by the addition finasteride, and was not inhibited by testosterone or DHT. Only mevalonate and geranyl geraniol, prevented lovastatin-induced apoptosis whereas farnesol, squalene, or 7-ketocholesterol did not. We conclude that lovastatin can induce apoptosis in BPH stromal cells in vitro, and this is not affected by androgen withdrawal or stimulation. It is unlikely that lovastatin, per se, will be an effective treatment for BPH in vivo, but it does provide a means for inducing apoptosis in vitro. Understanding the apoptotic process in BPH stromal cells ultimately may lead to new therapeutic strategies for BPH.     

Isolation and characterization of Bordetella bronchiseptica from cats in southern Louisiana

The role of Bordetella bronchiseptica in respiratory disease of domestic cats is currently being explored. Clinical and experimental studies in the United Kingdom have shown Bordetella bronchiseptica to be a primary respiratory pathogen in cats; similar studies in the United States are limited. The purpose of this study is to report on the isolation, seroprevalence, and partial characterization of Bordetella bronchiseptica from shelter cats in southern Louisiana. A total of 614 cats from four local shelters were studied. All cats appeared to be asymptomatic for signs of respiratory disease. Bordetella bronchiseptica was isolated in 19/614 (3.1%) cats by oropharyngeal swab and in 6/614 cats by bronchial lavage. Using an antibody capture ELISA method, 148/614 (24.1%) cats were seropositive for Bordetella bronchiseptica. The 25 isolates of Bordetella bronchiseptica were further characterized by ribotype analysis, and a total of 17 different ribotypes were identified. Specific pathogen-free kittens were experimentally infected with five of the isolates, and four of the five isolates induced clinical signs typical of feline bordetellosis. It is concluded that Bordetella bronchiseptica is present in the cat population in southern Louisiana, the organism can be isolated from asymptomatic cats, some of these isolates can produce disease in specific pathogen-free kittens, and that Bordetella bronchiseptica isolates from cats in a relatively small geographic area are genetically diverse. This and other studies indicate that Bordetella bronchiseptica should be considered in cases of feline respiratory disease.     

Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice

To investigate the role of plasmin(ogen) in mammary tumor development and progression, plasminogen-deficient mice were crossed with transgenic mice expressing Polyoma middle T antigen under the control of the mouse mammary tumor virus long terminal repeat. Virgin females carrying the Polyoma middle T antigen uniformly developed multiple, bilateral mammary tumors, regardless of the presence or absence of circulating plasminogen. Both the age at which these tumors became palpable and subsequent tumor growth were indistinguishable between plasminogen-deficient mice and plasminogen-expressing littermates. However, plasminogen was found to greatly modify the metastatic potential in this model system; lung metastasis in plasminogen-deficient mice was significantly reduced as compared to littermate controls with respect to frequency of occurrence, total number of metastases, and total metastatic tumor burden. Plasminogen activators, as well as other key factors that govern the conversion of plasminogen to plasmin, were expressed within the mammary tumors, suggesting that the plasminogen/plasmin system may promote metastasis by contributing to tumor-associated extracellular proteolysis. The data provide direct evidence that plasmin(ogen) is a tumor progression factor in PymT-induced mammary cancer, and support the hypothesis that hemostatic factors play an important role in tumor biology.     

Accurate determination of effective lens position and lens-capsule distance with 4 intraocular lenses

PURPOSE: To measure effective lens position (ELP) of 4 intraocular lenses (IOLs) using high precision and high resolution dual-beam partial coherence interferometry (PCI) and to assess the tendency of these IOLs to produce a lens-capsule distance (LCD), a possible risk factor for posterior capsule opacification. SETTING: Department of Ophthalmology, Vienna General Hospital; Institute of Medical Physics, University of Vienna, Austria. METHODS: In a retrospective study, PCI was used to measure ELP and LCD in 139 pseudophakic eyes of 110 patients with 4 IOLs: acrylic 3-piece IOL (AcrySof MA60BM); silicone 3-piece IOL without a capsular tension ring (PhacoFlex SI30) and with a capsular tension ring (PhacoFlex SI30 and Morcher Type 14); silicone plate-haptic IOL (Staar AA4203VF); and a hydrogel plate-haptic IOL (logel 1103). RESULTS: The ELP and LCD were determined with a precision of approximately 3 to 4 microns. An LCD was detected in 21% eyes with the AcrySof, 20% of eyes with the SI30 without a capsular tension ring, 10% of eyes with a capsular tension ring, 21% of eyes with the Staar, and 17% of eyes with the logel. The LCDs detected by PCI, but not by slitlamp examination, were significantly smaller than those detected by both. CONCLUSION: The amount of LCD detected by PCI was approximately the same with all IOL types (approximately 20%) except the PhacoFlex SI30 with a capsular tension ring (10%).     

Plasma concentrations of inactive renin in adult life are related to indicators of foetal growth

OBJECTIVES: To determine whether plasma concentrations of inactive and active renin in adult life are related to foetal development. DESIGN: A follow-up study of a group of men and women whose weight and other measurements of body size had been recorded at birth. SETTING: Sheffield, England. SUBJECTS: In total 148 men and women born in the Jessop Hospital, Sheffield, during 1939-40 and now aged 50-53 years. MAIN OUTCOME MEASUREMENT: Plasma concentrations of inactive and active renin in adult life. RESULTS: Plasma concentrations of inactive and active renin in adult life tended to be higher in people who had been large at birth. The strongest relationship was between concentrations of inactive renin and abdominal circumference at birth; the median plasma concentration of inactive renin was 88.5 mu/ml in people whose abdominal circumference at birth had been 13 inches (33.02 cm) or more compared with 61 mu/ml in people whose abdomens had measured 11.5 inches (29.21 cm) or less. CONCLUSION: Impairment of foetal growth is associated with lower plasma concentrations of inactive renin in adult life. Alterations in the activity of the renin-angiotensin system may be a mechanism by which reduced foetal growth leads to raised adult blood pressure.     

Race, resource use, and survival in seriously ill hospitalized adults. The SUPPORT Investigators

OBJECTIVE: To examine the association between patient race and hospital resource use. DESIGN: Prospective cohort study. SETTING: Five geographically diverse teaching hospitals. PATIENTS: Patients were 9,105 hospitalized adults with one of nine illnesses associated with an average 6-month mortality of 50%. MEASUREMENTS AND MAIN RESULTS: Measures of resource use included: a modified version of the Therapeutic Intervention Scoring System (TISS); performance of any of five procedures (operation, dialysis, pulmonary artery catheterization, endoscopy, and bronchoscopy); and hospital charges, adjusted by the Medicare cost-to-charge ratio per cost center at each participating hospital. The median patient age was 65; 79% were white, 16% African-American, 3% Hispanic, and 2% other races; 47% died within 6 months. After adjusting for other sociodemographic factors, severity of illness, functional status, and study site, African-Americans were less likely to receive any of five procedures on study day 1 and 3 (adjusted odds ratio [OR] 0.70; 95% confidence interval [CI] 0.60, 0.81). In addition, African-Americans had lower TISS scores on study day 1 and 3 (OR -1.8; 95% CI-1.3, -2.4) and lower estimated costs of hospitalization (OR (-)$2,805; 95% CI (-)$1,672, (-)$3,883). Results were similar after adjustment for patients' preferences and physicians' prognostic estimates. Differences in resource use were less marked after adjusting for the specialty of the attending physician but remained significant. In a subset analysis, cardiologists were less likely to care for African-Americans with congestive heart failure (p < .001), and cardiologists used more resources (p < .001). After adjustment for other sociodemographic factors, severity of illness, functional status, and study site, survival was slightly better for African-American patients (hazard ratio 0.91; 95% CI 0.84, 0.98) than for white or other race patients. CONCLUSIONS: Seriously ill African-Americans received less resource-intensive care than other patients after adjustment for other sociodemographic factors and for severity of illness. Some of these differences may be due to differential use of subspecialists. The observed differences in resource use were not associated with a survival advantage for white or other race patients.     

Phase II study of dual 131I-labeled monoclonal antibody therapy with interferon in patients with metastatic colorectal cancer

The combination of COL-1 (anti-CEA) and CC49 (anti-TAG-72) has shown an increase in binding and distribution in colon cancer by immunoperoxidase staining compared to either antibody alone. To overcome tumor heterogeneity and allow delivery of higher radiation dose, 131I-labeled COL-1 and CC49 at a total dose of 75 mCi/m2 (2775 MBq/m2) were simultaneously administered to 14 patients with metastatic colon cancer. alpha-IFN (3 x 10(6) IU) was given s.c. on days -5 to +3 to increase carcinoembryonic antigen and TAG-72 antigen expression. Most patients had mild symptoms during IFN therapy, including mild neutropenia, fever, and malaise, which rapidly subsided after IFN cessation. No acute allergic reactions occurred with radioimmunotherapy; two patients experienced transient, delayed grade 2 arthralgias. Transient neutropenia and/or thrombocytopenia, which was maximal at 4-6 weeks, were consistent side effects without adverse events. All patients had tumor localization, and 13 of 14 patients achieved 4+ (highest grade) localization readings to at least one known site of disease. No objective responses occurred; 4 patients were stable and 10 progressed. Tumor dose estimates varied from 393 to 1327 cGy, including liver and extrahepatic sites. Combining two complementary antibodies and IFN administration appeared to increase localization intensity and radiation doses at tumor sites as compared to historical controls. The amount of radiation delivered to tumor sites was still below that required to cause tumor regressions in metastatic colorectal cancer.