Increase of [(18)F]FLT tumor uptake in vivo mediated by FdUrd: toward improving cell proliferation positron emission tomography.

PURPOSE: 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2'-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [(18)F]FLT in tumor xenografts. METHODS: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[(125)I]iodo-2'-deoxyuridine biodistribution measurements. In [(18)F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection. [(18)F]FLT biodistributions were measured 1 to 3 h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [(18)F]FDG tumor uptake. Using microPET, the dynamic distribution of [(18)F]FLT was followed for 1.5 h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation. RESULTS: FdUrd induced an immediate increase in tumor uptake of 5-[(125)I]iodo-2'-deoxyuridine, that vanished after 6 h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [(18)F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [(18)F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [(18)F]FLT uptake in all tumors increased steadily up to 1.5 h. MRI showed a well-vascularized homogenous lymphoma with high [(18)F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis. CONCLUSION: We showed a reliable and significant uptake increase of [(18)F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [(18)F]FLT PET.

Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice.

Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic vaccines have had limited clinical efficacy to date. Here, we report that intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased ∼fivefold the number of vaccine-specific interferon-γ-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG treatment locally increased both E7-specific and total CD8 T cells, but not CD4 T cells. This previously unreported selective recruitment of CD8 T cells from the periphery by IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/melanoma differentiation-associated gene 5 signaling pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, IVAG CpG-ODN following vaccination led to complete regression of large genital HPV tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.Mucosal Immunology advance online publication 12 September 2012; doi:10.1038/mi.2012.83.

Cerebral extracellular lactate increase is predominantly non ischemic in patients with severe traumatic brain injury

Le cerveau est l'organe avec les besoins en énergie les plus élevés du corps humain, et le glucose est un substrat énergétique cérébral essentiel. Ces dernières décennies, la compréhension de la neuroénergétique a beaucoup évolué et un rôle du lactate comme substrat énergétique important a été mis en évidence, notamment suite à l'introduction du modèle de l'ANLS (astrocyte-neuron lactate shuttle). Selon celui-ci, les astrocytes convertissent le glucose en lactate par réaction de glycolyse, puis il est transporté jusqu'aux neurones qui l'utilisent comme source d'énergie à travers le cycle de Krebs. Chez l'homme, divers travaux récents ont montré que le lactate peut servir de « carburant » cérébral chez le sujet sain, après effort intense ou chez le patient diabétique. La régulation métabolique et le rôle du lactate après lésion cérébrale aiguë sont encore peu connus. Présentation de l'article Le but de ce travail a été d'étudier le métabolisme cérébral du lactate chez les patients atteints de traumatisme crânien (TCC) sévère. Nous avons émis l'hypothèse que l'augmentation du lactate cérébral chez ces patients n'était pas associée de manière prédominante à une hypoxie ou une ischémie mais plutôt à une glycolyse aérobie, et également à une perfusion cérébrale normale. L'étude a porté sur une cohorte prospective de 24 patients avec TCC sévère admis au service de médecine intensive du CHUV (centre hospitalier universitaire vaudois), monitorés par un système combinant microdialyse cérébrale (outil permettant de mesurer divers métabolites cérébraux, tels que le lactate, le pyruvate et le glucose), mesure de la pression cérébrale en oxygène et de la pression intracrânienne. Cet outil nous a permis de déterminer si l'élévation du lactate était principalement associée à une glycolyse active ou plutôt à une hypoxie. L'utilisation du CTde perfusion a permis d'évaluer la relation entre les deux patterns d'élévation du lactate (glycolytique ou hypoxique) et la perfusion cérébrale globale. Nos résultats ont montré que l'augmentation du lactate cérébral chez les patients avec TCC sévère était associée de manière prédominante à une glycolyse aérobie plutôt qu'à une hypoxie/ischémie. D'autre part, nous avons pu confirmer que les épisodes de lactate glycolytique étaient toujours associés à une perfusion cérébrale normale ou augmentée, alors que les épisodes de lactate hypoxique étaient associés à une hypoperfusion cérébrale. Conclusions et perspectives Nos résultats, qui ont permis de mieux comprendre le métabolisme cérébral du lactate chez les patients avec TCC sévère, soutiennent le concept que le lactate est produit dans des conditions aérobes et pourrait donc être utilisé comme source d'énergie par le cerveau lésé pour subvenir à des besoins augmentas. Etant donné que la dysfonction énergétique est une des probables causes de perte neuronale après traumatisme crânien, ces résultats ouvrent des perspectives thérapeutiques nouvelles après agression cérébrale chez l'homme, visant à tester un potentiel effet neuroprotecteur via l'administration de lactate exogène.

Study of Iowa's Current Road Use Tax Funds (RUTF) and Future Road Maintenance and Construction Needs, 2006

The 81st General Assembly of the Iowa Legislature, in Section 85 of House File 868, required the Iowa Department of Transportation (DOT) to conduct a study of current Road Use Tax Fund (RUTF)revenues, and projected roadway construction and maintenance needs.

Study of Iowa’s Current Road Use Tax Funds (RUTF) and Future Road Maintenance and Construction Needs, 2006

The 81st General Assembly of the Iowa legislature, in Section 85 of House File 868, required the Iowa Department of Transportation (Iowa DOT) to conduct a study of current Road Use Tax Fund (RUTF) revenues, and projected roadway construction and maintenance needs. With input from Iowa’s cities, counties and other interested groups, the Iowa DOT completed this report for submittal to the legislature.

Study of Iowa’s Current Road Use Tax Funds (RUTF) and Future Road Maintenance and Construction Needs, 2006

The 81st General Assembly of the Iowa legislature, in Section 85 of House File 868, required the Iowa Department of Transportation (Iowa DOT) to conduct a study of current Road Use Tax Fund (RUTF) revenues, and projected roadway construction and maintenance needs.

Vacuum assisted venous drainage does not increase trauma to blood cells.

Although gravity drainage has been the standard technique for cardiopulmonary bypass (CPB), the development of min imally invasive techniques for cardiac surgery has renewed interest in using vacuum assisted venous drainage (VAVD) Dideco (Mirandola, Italy) has modified the D903 Avant oxygenator to apply a vacuum to its venous reservoir. The impact of VAVD on blood damage with this device is analyzed. Six calves (mean body weight, 71.3 +/- 4.1 kg) were con nected to CPB by jugular venous and carotid arterial cannu lation, with a flow rate of 4-4.51 L/min for 6 h. They were assigned to gravity drainage (standard D903 Avant oxygen ator, n = 3) or VAVD (modified D903 Avant oxygenator, n = 3). The animals were allowed to survive for 7 days. A standard battery of blood samples was taken before bypass, throughout bypass, and 24 h, 48 h, and 7 days after bypass. Analysis of variance was used for repeated measurements. Thrombocyte and white blood cell counts, corrected by hematocrit and normalized by prebypass values, were not significantly different between groups throughout all study periods. The same holds true for hemolytic parameters (lactate dehydrogenase [LDH] and plasma hemoglobin). Both peaked at 24 hr in the standard and VAVD groups: LDH, 2,845 +/- 974 IU/L vs. 2,537 +/- 476 IU/L (p = 0.65), respectively; and plasma hemoglobin, 115 +/- 31 mg/L vs. 89 +/- 455 mg/L (p = 0.45), respectively. In this experimental setup with prolonged perfusion time, VAVD does not increase trauma to blood cells in comparison with standard gravity drainage.

Audit report on applying agreed-upon procedures for the City of Linden’s compliance with road use tax requirements for the period July 1, 1999 through June 30, 2004

Audit report on applying agreed-upon procedures for the City of Linden’s compliance with road use tax requirements for the period July 1, 1999 through June 30, 2004

Emerging Biofuels: Outlook of Effects on U.S. Grain, Oilseed, and Livestock Markets, 2007

Projections of U.S. ethanol production and its impacts on planted acreage, crop prices, livestock production and prices, trade, and retail food costs are presented under the assumption that current tax credits and trade policies are maintained. The projections were made using a multi-product, multi-country deterministic partial equilibrium model. The impacts of higher oil prices, a drought combined with an ethanol mandate, and removal of land from the Conservation Reserve Program (CRP) relative to baseline projections are also presented. The results indicate that expanded U.S. ethanol production will cause long-run crop prices to increase. In response to higher feed costs, livestock farmgate prices will increase enough to cover the feed cost increases. Retail meat, egg, and dairy prices will also increase. If oil prices are permanently $10-per-barrel higher than assumed in the baseline projections, U.S. ethanol will expand significantly. The magnitude of the expansion will depend on the future makeup of the U.S. automobile fleet. If sufficient demand for E-85 from flex-fuel vehicles is available, corn-based ethanol production is projected to increase to over 30 billion gallons per year with the higher oil prices. The direct effect of higher feed costs is that U.S. food prices would increase by a minimum of 1.1% over baseline levels. Results of a model of a 1988-type drought combined with a large mandate for continued ethanol production show sharply higher crop prices, a drop in livestock production, and higher food prices. Corn exports would drop significantly, and feed costs would rise. Wheat feed use would rise sharply. Taking additional land out of the CRP would lower crop prices in the short run. But because long-run corn prices are determined by ethanol prices and not by corn acreage, the long-run impacts on commodity prices and food prices of a smaller CRP are modest. Cellulosic ethanol from switchgrass and biodiesel from soybeans do not become economically viable in the Corn Belt under any of the scenarios. This is so because high energy costs that increase the prices of biodiesel and switchgrass ethanol also increase the price of cornbased ethanol. So long as producers can choose between soybeans for biodiesel, switchgrass for ethanol, and corn for ethanol, they will choose to grow corn. Cellulosic ethanol from corn stover does not enter into any scenario because of the high cost of collecting and transporting corn stover over the large distances required to supply a commercial-sized ethanol facility.

Investigation of County Treasurers' Tax-Sale Registration Fees, June 2007

On January 2, 2007, the Ombudsman received a complaint regarding the fee that county treasurers charge registrants at annual tax sales. The complainant said generally that many of the state’s counties, especially larger ones, appeared to be charging higher fees than was thought to be allowed by law. Investigation The investigation was conducted by Assistant Ombudsman Bert Dalmer. For purposes of this report, all investigative actions are ascribed to the Ombudsman. In early 2007, the Ombudsman surveyed tax-sale registration fees in 10 of the state’s 99 counties. Interviews of 10 county treasurers and/or some of their deputies were conducted. In addition, the Ombudsman researched the Iowa Code and relevant case law. The Ombudsman also consulted with the Iowa State Auditor and the president of the Iowa State County Treasurers Association.

From severance pay to self-insurance: Effects of severance payments savings accounts in Colombia

In 1990 Colombia replaced its traditional system of severance paymentswith a new system of severance payments savings accounts (SPSAs). Althoughseverance payments often are justified on the grounds that they provideinsurance against earnings loss, they also increase costs for employersand distort employment decisions. The impact of severance payments dependslargely on how much of the costs to employers can be shifted to workers.The theoretical analysis in this paper shows that, in contrast to atraditional system of severance payments, the system of SPSAs facilitatesthe shifting of severance payments costs to workers in the form of lowerwages. Empirical results using the Colombian National Household Surveysindicate that the introduction of SPSAs shifted around 80% of the totalseverance payments contributions to wages and had a positive effect onweekly hours. Results using the 1997 Colombian Living Standards MeasurementSurvey suggest that, although SPSAs in part replaced employer insurancewith self-insurance, SPSAs continue to play a consumption smoothing rolefor the non-employed.

Tenofovir use is associated with an increase in serum alkaline phosphatase in the Swiss HIV Cohort Study.

BACKGROUND: Tenofovir (TDF) use has been associated with proximal renal tubulopathy, reduced calculated glomerular filtration rates (cGFR) and losses in bone mineral density. Bone resorption could result in a compensatory osteoblast activation indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP. METHODS: We analysed sAP dynamics in patients initiating (n = 657), reinitiating (n = 361) and discontinuing (n = 73) combined antiretroviral therapy with and without TDF and assessed correlations with clinical and epidemiological parameters. RESULTS: TDF use was associated with a significant increase of sAP from a median of 74 U/I (interquartile range 60-98) to a plateau of 99 U/I (82-123) after 6 months (P < 0.0001), with a prompt return to baseline upon TDF discontinuation. No change occurred in TDF-sparing regimes. Univariable and multivariable linear regression analyses revealed a positive correlation between sAP and TDF use (P < or = 0.003), but no correlation with baseline cGFR, TDF-related cGFR reduction, changes in serum alanine aminotransferase (sALT) or active hepatitis C. CONCLUSIONS: We document a highly significant association between TDF use and increased sAP in a large observational cohort. The lack of correlation between TDF use and sALT suggests that the increase in sAP is because of the bone isoenzyme and indicates stimulated bone turnover. This finding, together with published data on TDF-related renal phosphate losses, this finding raises concerns that TDF use could result in osteomalacia with a loss in bone mineral density at least in a subset of patients. This potentially severe long-term toxicity should be addressed in future studies.

Determinants of organizational form: Transaction costs and institutions in the European trucking industry

We explain why European trucking carriers are much smaller and rely more heavily on owner-operators(as opposed to employee drivers) than their US counterparts. Our analysis begins by ruling outdifferences in technology as the source of those disparities and confirms that standard hypothesesin organizational economics, which have been shown to explain the choice of organizational form inUS industry, also apply in Europe. We then argue that the preference for subcontracting oververtical integration in Europe is the result of European institutions particularly, labor regulationand tax laws that increase the costs of vertical integration.