Cathepsin K Deficiency Reduces Elastase Perfusion-Induced Abdominal Aortic Aneurysms in Mice

Objective: Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. Methods and Results: Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4 T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3 macrophage accumulation or CD31 microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4 T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. Conclusion: This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities.Other Research Uni

Red Tides in Inshore and Offshore Casco Bay and Their Relationship to Local and Gulf of Maine Physical and Biological Conditions

The objective of this report focuses on the secondary goal of the overall program – to develop a better understanding of A. fundyense bloom dynamics in Casco Bay – by examining bloom origin and development (outside Casco Bay, within Casco Bay or both) and correlations between water quality data, location, and bloom intensity. We analyzed the IPSP monitoring program 2006-2008 data to characterize the blooms (spatially and temporally), and examine correlations between water quality, toxicity and A. fundyense data. Using the IPSP data along with data from other studies, we have examined the role of local and regional physical and biological factors in the larger Gulf of Maine and their potential impact on the onset and temporal and spatial extent of red tide blooms in Casco Bay. We have also examined the role of nutrient availability in the spatial and temporal extent of Casco Bay blooms

Elevation of plasma phospholipid transfer protein increases the risk of atherosclerosis despite lower apolipoprotein B-containing lipoproteins.

Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins and mediates HDL conversion. PLTP-overexpressing mice have increased atherosclerosis. However, mice do not express cholesteryl ester transfer protein (CETP), which is involved in the same metabolic pathways as PLTP. Therefore, we studied atherosclerosis in heterozygous LDL receptor-deficient (LDLR(+/-)) mice expressing both human CETP and human PLTP. We used two transgenic lines with moderately and highly elevated plasma PLTP activity. In LDLR(+/-)/huCETPtg mice, cholesterol is present in both LDL and HDL. Both are decreased in LDLR(+/-)/huCETPtg/huPLTPtg mice (>50%). An atherogenic diet resulted in high levels of VLDL+LDL cholesterol. PLTP expression caused a strong PLTP dose-dependent decrease in VLDL and LDL cholesterol (-26% and -69%) and a decrease in HDL cholesterol (-70%). Surprisingly, atherosclerosis was increased in the two transgenic lines with moderately and highly elevated plasma PLTP activity (1.9-fold and 4.4-fold, respectively), indicating that the adverse effect of the reduction in plasma HDL outweighs the beneficial effect of the reduction in apolipoprotein B (apoB)-containing lipoproteins. The activities of the antiatherogenic enzymes paraoxonase and platelet-activating factor acetyl hydrolase were both PLTP dose-dependently reduced ( approximately -33% and -65%, respectively). We conclude that expression of PLTP in this animal model results in increased atherosclerosis in spite of reduced apoB-containing lipoproteins, by reduction of HDL and of HDL-associated antioxidant enzyme activities

Spending by the Major Charter Management Organizations: Comparing Charter School and Local Public District Financial Resources

Policymakers have long pursued more cost-effective, scalable alternatives for delivering elementary and secondary education. The elusive goal is identifying how to reform educational systems so that children will consistently achieve more academically—at a lesser cost. A frequently heard reform claim of this sort is that charter schools deliver higher performance at a lower cost. While the test score side of this question has been addressed by a great number of studies (with generally mixed findings), the cost side of the question has received far less attention. This study evaluates the cost claim by comparing the per-pupil spending of charter schools operated by major charter management organizations (CMOs) in New York City, Texas and Ohio with district schools. In each context, we assemble three-year panel data sets including information on school level spending per pupil, school size, grade ranges and student populations served for both charter schools and district schools. For charter schools we use both government (and authorizer) reports of spending, and spending as reported on IRS non-profit financial filings (IRS 990). We compare the spending of charters to that of district schools of similar size, serving the same grade levels and similar student populations. Overall, charter spending variation is large as is the spending of traditional public schools. Comparative spending between the two sectors is mixed, with many high-profile charter network schools outspending similar district schools in New York City and Texas, but other charter network schools spending less than similar district schools, particularly in Ohio. We find that in New York City, KIPP, Achievement First and Uncommon Schools charter schools spend substantially more ($2,000 to$4,300 per pupil) than similar district schools. Given that the average spending per pupil was around $12,000 to$14,000 citywide, a nearly $4,000 difference in spending amounts to an increase of some 30%. In Ohio, charters across the board spend less than district schools in the same city. And in Texas, some charter chains such as KIPP spend substantially more per pupil than district schools in the same city and serving similar populations, around 30 to 50% more in some cities (and at the middle school level) based on state reported current expenditures, and 50 to 100% more based on IRS filings. Even in New York where we have the highest degree of confidence in the match between our IRS data and Annual Financial Report Data, we remain unconvinced that we are accounting fully for all charter school expenditures

HUD's Response to Hurricane Katrina

This report discusses the response of the Department of Housing and Urban Development (HUD) to Hurricane Katrina

Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein.

Plasma phospholipid transfer protein (PLTP) is thought to be involved in the remodeling of high density lipoproteins (HDL), which are atheroprotective. It is also involved in the metabolism of very low density lipoproteins (VLDL). Hence, PLTP is thought to be an important factor in lipoprotein metabolism and the development of atherosclerosis. We have overexpressed PLTP in mice heterozygous for the low density lipoprotein (LDL) receptor, a model for atherosclerosis. We show that increased PLTP activity results in a dose-dependent decrease in HDL, and a moderate stimulation of VLDL secretion (</=1.5-fold). The mice were given a high fat, high cholesterol diet, which resulted in hypercholesterolemia in all animals. HDL concentrations were dramatically reduced in PLTP-overexpressing animals when compared with LDL receptor controls, whereas VLDL + LDL cholesterol levels were identical. Susceptibility to atherosclerosis was increased in a PLTP dose-responsive manner. We conclude that PLTP increases susceptibility to atherosclerosis by lowering HDL concentrations, and therefore we suggest that an increase in PLTP is a novel, long term risk factor for atherosclerosis in humans

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK.

PURPOSE: Comparing gonadotrophin-releasing hormone (GnRH) antagonists and agonists as androgen deprivation therapy for advanced prostate cancer (PC). METHODS: This article stems from a round-table meeting in December 2014 to compare the properties of GnRH agonists and antagonists in the published literature in order to identify the patient groups most likely to benefit from GnRH antagonist therapy. A broad PubMed and congress abstract search was carried out in preparation for the meeting to ensure that the latest data and opinion were available for the discussions. RESULTS: In randomised, controlled trials, GnRH antagonist therapy provides more rapid suppression of luteinising hormone, follicle-stimulating hormone and testosterone than GnRH agonist treatment. Compared with the GnRH agonist, there is evidence of improved disease control by a GnRH antagonist, with longer interval to prostate-specific antigen progression and greater reduction of serum alkaline phosphatase. In a post hoc analysis of six randomised trials, the risk of cardiac events within 1 year of initiating therapy was significantly lower among men receiving GnRH antagonist than agonist. Pre-clinical laboratory data suggest a number of mechanisms whereby GnRH antagonist therapy may benefit men with pre-existing cardiovascular disease (CVD), the most plausible hypothesis being that, unlike GnRH agonists, GnRH antagonists do not activate T lymphocytes, which act to increase atherosclerotic plaque rupture. CONCLUSION: When making treatment decisions, clinicians should consider comorbidities, particularly CVD, in addition to effects on PC. GnRH antagonists may be appropriate in patients with significant CV risk, existing osteopenia, lower urinary tract symptoms and significant metastatic disease

Systematic Review of Focal Prostate Brachytherapy and the Future Implementation of Image-Guided Prostate HDR Brachytherapy Using MR-Ultrasound Fusion

Prostate cancer is the most common malignancy found in North American and European men and the second most common cause of cancer related death. Since the practice of PSA screening has become common the disease is most often found early and can have a long indolent course. Current definitive therapy treats the whole gland but has considerable long-term side effects. Focal therapies may be able to target the cancer while decreasing dose to organs at risk. Our objective was to determine if focal prostate brachytherapy could meet target objectives while permitting a decrease in dose to organs at risk in a way that would allow future salvage treatments. Further, we wanted to determine if focal treatment results in less toxicity. Utilizing the Medline repository, dosimetric papers comparing whole gland to partial gland brachytherapy and clinical papers that reported toxicity of focal brachytherapy were selected. A total of 9 dosimetric and 6 clinical papers met these inclusion criteria. Together, these manuscripts suggest that focal brachytherapy may be employed to decrease dose to organs at risk with decreased toxicity. Of current technology, image-guided HDR brachytherapy using MRI registered to transrectal ultrasound offers the flexibility and efficiency to achieve such focal treatments