Valsartan Improves Insulin Sensitivity without Altering Vascular Function in Healthy Overweight Adults without the Metabolic Syndrome

Background. We investigated hyperactivity of the renin-angiotensin system (RAS) as a cause of endothelial dysfunction in obese humans. Methods. Thirty five healthy overweight (BMI = 33.6 ± 6.6 kg m −2) adults (33 ± 10 years old) without cardiovascular risk factors received valsartan (160 mg) orally daily or a matching placebo for 6 weeks each. Results. Baseline flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) were not altered by placebo or valsartan. However, fasting plasma insulin was significantly decreased by valsartan compared to placebo (−4.6 ± 16.0 μUmL−1 versus −0.4 ± 11.6 μUmL−1, P = 0.032) with no changes in glucose. A secondary analysis in patients with elevated waist to hip ratios (ÿ0.85, n = 18) showed an increase in FMD with valsartan. Conclusions. Our findings suggest that angiotensin 2 receptor blockade may aid in the prevention of diabetes even at the earliest stages of risk due solely to uncomplicated obesity. The lack of an improvement in FMD does not support a central role of RAS-hyperactivity in the etiology of the vascular dysfunction due solely to obesity. However, it is possible that obese patients with central adiposity may improve FMD with RAS blockade, and future investigation is warranted in this subgroup.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63259/1/met.2007.0002.pd

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC500 h) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC500 h using only two timed samples: AUC500 h=(6.588×C2.5 h)+(146.4×C49.5 h)+15.53, where C2.5 h and C49.5 h are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan

Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite.

Transmission of the malaria parasite from the mammalian host to the mosquito vector requires the formation of adequately adapted parasite forms and stage-specific organelles. Here we show that formation of the crystalloid-a unique and short-lived organelle of the Plasmodium ookinete and oocyst stage required for sporogony-is dependent on the precisely timed expression of the S-acyl-transferase DHHC10. DHHC10, translationally repressed in female Plasmodium berghei gametocytes, is activated translationally during ookinete formation, where the protein is essential for the formation of the crystalloid, the correct targeting of crystalloid-resident protein LAP2, and malaria parasite transmission

FLUTE, a linac based THz source

We propose a versatile THz source named FLUTE (Ferninfrarot Linac- Und Test-Experiment) based on a 30 - 50 MeV S-band linac with bunch compressor, that aimsat not only producing high field THz pulses but also at serving as a test facility to study accelerator physics issues. This source is an important step towards the planned ultra-broadband THz to mid infrared user facility TBONE. Special emphasis is put on studies of bunch compression as a function of bunch charge (0.1-5 nC) and of different generation mechanisms of coherent radiation (CSR, CER, CTR). This paper describes the design and layout of the proposed FLUTE machine and presents results of beam dynamic calculations with the tracking programs ASTRA and CSRtrack. In addition, calculations for the achievable peak electrical field and spectral characteristics for one version of the FLUTE layout are shown