Plasma urokinase antigen and plasminogen activator inhibitor-1 antigen levels predict angiographic coronary restenosis.

BACKGROUND: The fibrinolytic system is intimately involved in several processes that contribute to restenosis, including clot dissolution, cell migration, and tissue remodeling. However, the role of the individual activators (urokinase [uPA] and tissue plasminogen [tPA] activators) and inhibitors (plasminogen activator inhibitor [PAI-1]) of the fibrinolytic system in maintaining patency after coronary artery angioplasty and stenting is unclear. METHODS AND RESULTS: We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty (n=110) or stenting (n=49) of de novo native coronary artery lesions. Plasma samples were drawn at baseline (before angioplasty) and serially after angioplasty (immediately afterward and 6 hours, 24 hours, 3 days, 7 days, 1 month, 3 months, and 6 months afterward). Antigen and activity assays were performed for uPA, tPA, and PAI-1. Follow-up quantitative coronary angiography was performed in 92% of eligible patients. The overall angiographic restenosis rate (diameter stenosis >50%) was 31% (37% in PTCA patients, 17% in stented patients). At all time periods, including baseline, uPA antigen levels were significantly higher and PAI-1 antigen levels were significantly lower in patients with restenosis. Restenosis rates for patients in the upper tertile of baseline uPA antigen levels were 2-fold higher than for those in the lower 2 tertiles (46% versus 24% and 22%, respectively; P<0.004). In a stepwise regression multivariate analysis, obstruction diameter after the procedure and uPA antigen were significant predictors of follow-up diameter stenosis. CONCLUSIONS: Plasma uPA antigen levels and PAI-1 antigen levels identify patients at increased risk for restenosis after percutaneous coronary revascularization.

Arterial elastase activity after balloon angioplasty and effects of elafin, an elastase inhibitor.

Increased proteolytic activity may be a factor in intimal hyperplasia after balloon angioplasty (BA). The objectives of this study were to assess elastase activity after BA in a rabbit arterial double-injury model and the effects of elastase inhibition. Elastase activity increased immediately after BA, reached an 8-fold peak at 1 week, and declined to baseline levels by 4 weeks. Elastin zymography showed that the elastase activity was associated predominantly with a molecular mass of 25 kDa. Elastase activity was significantly inhibited in vitro by elafin and phenylmethylsulfonyl fluoride, selective inhibitors of serine elastases. A second group of animals was transfected after BA with a plasmid containing the cDNA for either elafin or a control (chloramphenicol acetyltransferase, CAT) construct by using a hemagglutinating virus of Japan-liposome transfection technique. Arterial segments were obtained at 48 hours, 1 week, and 4 weeks to assess transgene expression, arterial wall elastase activity, and intimal cross-sectional area, respectively. Elafin transgene expression was evident at 48 hours and resulted in a significant (80%) inhibition of elastase activity compared with chloramphenicol acetyltransferase-transfected arteries. There was a 43% reduction in intimal cross-sectional area in elafin-transfected arteries (0.28+/-0.22 versus 0.16+/-0.07 mm(2) for CAT-transfected versus elafin-transfected arteries, respectively; P<0.05). These data suggest that an early increase in serine elastase activity after BA contributes to intimal hyperplasia. Serine elastase inhibition may be a potential therapeutic approach to inhibit intimal hyperplasia.

Administration of exogenous endothelin-1 following vascular balloon injury: early and late effects on intimal hyperplasia.

Administration of exogenous endothelin-1 (ET-1) has been shown to stimulate neointimal hyperplasia following arterial balloon angioplasty (BA). However, the specific effects of ET-1 on the cellular and extracellular matrix response of the vessel wall after balloon injury and the persistence of these ET-1 effects have not been studied. The objectives of this study were to determine the acute (1 week) and long term (10 weeks) effects of administering exogenous ET-1 after arterial BA on neointimal hyperplasia, collagen synthesis and content, cellular proliferation, and ET(A) and ET(B) receptor expression. Thirty-one rabbits were randomized to receive subcutaneous ET-1 (500 pmol/kg/day for 1 week) or placebo time-release pellets and sacrificed at either 1 or 10 weeks after BA. At 1 week, there was a significant two-fold increase in intimal cross-sectional area (CSA) in ET-1 treated animals compared with placebo. ET-1 treated animals showed significant increases in collagen synthesis (ten-fold) and collagen content (three-fold) compared to placebo treated animals. ET-1 treated animals also had a significant increase (two-fold) in proliferation rates. In addition, ET(A) and ET(B) receptor expression were significantly upregulated in ET-1 treated animals. By 10 weeks these stimulatory effects on intimal CSA and collagen content were no longer evident with a 'catch up' phenomenon observed in the placebo treated animals. Similarly, ET(A) and ET(B) mRNA levels had declined significantly in both groups. Therefore, exogenous ET-1 acutely stimulates extracellular and cellular processes including increased expression of ET(A) and ET(B) receptors contributing to intimal hyperplasia. However, these effects are transient and not maintained long term after withdrawal of exogenous ET-1 stimulation.

Canine rabies in Australia: a review of preparedness and research needs.

Australia is unique as a populated continent in that canine rabies is exotic, with only one likely incursion in 1867. This is despite the presence of a widespread free-ranging dog population, which includes the naturalized dingo, feral domestic dogs and dingo-dog cross-breeds. To Australia's immediate north, rabies has recently spread within the Indonesian archipelago, with outbreaks occurring in historically free islands to the east including Bali, Flores, Ambon and the Tanimbar Islands. Australia depends on strict quarantine protocols to prevent importation of a rabid animal, but the risk of illegal animal movements by fishing and recreational vessels circumventing quarantine remains. Predicting where rabies will enter Australia is important, but understanding dog population dynamics and interactions, including contact rates in and around human populations, is essential for rabies preparedness. The interactions among and between Australia's large populations of wild, free-roaming and restrained domestic dogs require quantification for rabies incursions to be detected and controlled. The imminent risk of rabies breaching Australian borders makes the development of disease spread models that will assist in the deployment of cost-effective surveillance, improve preventive strategies and guide disease management protocols vitally important. Here, we critically review Australia's preparedness for rabies, discuss prevailing assumptions and models, identify knowledge deficits in free-roaming dog ecology relating to rabies maintenance and speculate on the likely consequences of endemic rabies for Australia.

Recognition of progressive atlanto-occipital dislocation (by a changing neurologic status and clinical deformity).

We present a case of progressive atlanto-occipital dislocation, recognized by a new onset of positive neurologic findings. We discuss the anatomic relationship of the lower four cranial nerves to the foramen magnum and the atlanto-occipital joint. The importance of careful assessment of the cranial nerves prior to choosing a treatment algorithm is emphasized.

Infrapatellar ganglion that developed from infrapatellar fat and had minimal intraarticular extension.

Ganglia of the knee joint are rare and are mostly an incidental finding during arthroscopy or MRI examinations. Usually their origin is intraarticular, arising from the menisci or ACL or PCL. Ganglia arising from the infrapatellar fat pad are rare and only few are mentioned in the literature. We report a case of infrapattellar ganglion in a 41-year-old female, which developed from the infrapattellar fad pad and with minimal intraarticular extension.

The effect of residual moisture in lyophilized smallpox vaccine on its stability at different temperatures.

In a study of the influence of residual moisture on the potency of freeze-dried smallpox vaccine, vaccine lots with moisture contents between 0.36% and 6.7% were used. These lots were stored at 4 degrees C, 24 degrees C, and 37 degrees C for up to 6 months, or were exposed to 100 degrees C for up to 3 hours, and were sampled at regular time intervals for assay. No loss in potency occurred at 4 degrees C where the moisture content was 4.8% or less. At 24 degrees C the critical moisture level was 2.5%, and at 37 degrees C it was 0.36%. At 100 degrees C the potency loss was more rapid and there were significant losses after 1 hour at a moisture level of 2.4% or more. A residual moisture content of less than 1% seems to be essential for satisfactory storage of freeze-dried smallpox vaccine.

Stability of BCG vaccine (intravesical) Theracys/BCG therapeutic ImmuCyst and its importance in clinical efficacy.

The manufacture of Therapeutic BCG can and should be a controlled process, to ensure adequate treatment doses are received by CIS patients. Standardization of production methods and CFU potency testing methods are essential to ensure continued successful treatment of CIS. Stability data can be used to validate assumptions about Therapeutic BCG potency used in clinical trials. Accelerated heat degradation studies of Therapeutic BCG should not be used for predictions of shelf life, but can be used for comparative purposes.

Evaluation of clinical data in bladder cancer immunotherapy with Connaught BCG (ImmuCyst).

Treatment of superficial bladder carcinoma in situ with Connaught BCG (ImmuCyst) significantly increased complete response rate and extended the disease-free interval when compared with Doxorubicin (DOX) chemotherapy. In 54 patients treated with ImmuCyst, 74% showed complete response compared with 42% of 60 patients treated with DOX. The median disease-free time was 48.2 months for BCG and 5.9 months for DOX treatment. Types and severity of adverse reactions were similar for both treatments and within tolerable ranges.

Antibody and immunoglobulin response to antirabies vaccination in man.

Serum neutralization antibody and immunoglobulin responses in 30 individuals were studied in paired serum samples which had been obtained before and 2 to 3 weeks after the administration of a recall dose of rabies tissue culture vaccine. The immune reaction consisted of a predominantly immunoglobulin G (IgG) antibody response. Also, a significant increase in neutralizing antibody titers was observed, but without a consistently correlated change of the IgG levels in the individual serum samples. The radial immunodiffusion test appears to contain the elements necessary for the development of a routine test to determine rabies antibody in single serum samples.

Rat immunogenicity assay of inactivated poliovirus.

A rat immunogenicity assay for IPV potency was validated and applied to routine vaccine testing as a potential alternative to the CFR Monkey Potency Assay. Potencies of pure trivalent polio, various combinations and experimental vaccines were tested with a view of producing a single dilution assay.

Trends in the frequency and predictive value of reporting high grade abnormalities in cervical smears.

BACKGROUND: The "organized approach" to cervical screening in Australia includes standardized quality assurance measures for laboratories. This study examines changes in the frequency and the positive predictive value of reporting severe abnormalities in cervical smears over a 3-year period as a guide to the effects of implementing these measures. METHODS: The results of screening in 6-month periods from January 1995 to December 1997 were determined. Biopsy follow-up for results in the high grade epithelial abnormality ("HGEA") and "inconclusive: possible HGEA" categories was obtained from the Western Australian Cervical Cytology Registry (CCR). RESULTS: Approximately 40,000 smears were examined in each 6-month period. The frequencies of reporting HGEA were 0.47%, 0.59%, 0.79%, 0.85%, and 0.84%, and 0.91% for the study periods (P < 0.001). For the inconclusive category, they were 0.24%, 0.18%, 0.24%, 0.31%, 0.38%, and 0.35% (P < 0.001). Biopsy follow-up was available for 83. 9%, 80.5%, 89.9%, 92.4%, 93.1%, and 90.3% of the HGEA results and for 78.6%, 71.7%, 80.5%, 75.0%, 87.1%, and 85.9% of the inconclusive results over the study periods. The yield of high grade lesions for the biopsied cases was 82.6%, 82.3%, 83.1%, 79.5%, 80.9%, and 79% for HGEA cases and 58.2%, 41.9%, 60.6%, 52.8%, 47.5%, and 54.1% for inconclusive cases. CONCLUSIONS: There was a doubling in the reporting of HGEA results, whereas the positive predictive value for biopsied cases remained at about 80%. Reporting rates for inconclusive: possible HGEA cases also doubled, but the yield of biopsy-proven, high grade lesions remained at about 50%. These changes occurred in the absence of ancillary testing and with targeted rescreening methods. A high rate of reporting HGEA, in combination with a high positive predictive value, is among the most important indicators of cervical cytology laboratory performance. Large improvements in results may occur using conventional methods of quality assurance. Cancer (Cancer Cytopathol)

Homocysteine, lipoprotein(a), and restenosis after percutaneous transluminal coronary angioplasty: a prospective study.

BACKGROUND: Restenosis complicates 30% to 40% of angioplasty procedures and may be unrelated to traditional coronary risk factors. Homocysteine, lipoprotein(a), and methylenetetrahydrofolate reductase (MTHFR 677T) (a genetic determinant of plasma homocysteine concentrations) are novel risk factors for coronary artery disease. Their roles in restenosis are unclear, and the potential synergism between homocysteine and lipoprotein(a) has not previously been studied. The objective of this study was to determine the relations among homocysteine, lipoprotein (a), MTHFR 677T, and restenosis after percutaneous transluminal coronary angioplasty. METHODS: This prospective study enrolled patients with successful elective percutaneous transluminal coronary angioplasty or stenting of a single, de novo, native coronary lesion. Fasting blood was drawn the morning of the procedure for homocysteine, lipoprotein(a), and MTHFR 677T. Follow-up angiography was performed 6 months after the procedure or earlier if clinically indicated. All cineangiograms were analyzed quantitatively. RESULTS: A total of 144 (92%) of 156 eligible patients underwent follow-up coronary angiography. The overall angiographic restenosis rate (residual stenosis >50%) was 31%. Mean homocysteine concentration was 10.1 +/- 3.7 micromol/L. Plasma homocysteine concentrations were not significantly different in patients with or without angiographic restenosis (9.6 +/- 3.3 vs 10.3 +/- 3.8 micromol/L; P =.31). Mean lipoprotein(a) concentration was 21.2 +/- 20.1 mg/dL. Plasma lipoprotein(a) concentrations were not significantly different in patients with or without restenosis (21.9 +/- 21.8 vs 20.9 +/- 19.5 mg/dL). Homozygosity for MTHFR 677T was present in 6.5% and was not associated with increased restenosis. No interaction between homocysteine and lipoprotein(a) was detected. CONCLUSIONS: Homocysteine, lipoprotein(a), and MTHFR 677T are not associated with restenosis after percutaneous transluminal coronary angioplasty.