First dark matter results from the XENON100 experiment.

The XENON100 experiment, in operation at the Laboratori Nazionali del Gran Sasso in Italy, is designed to search for dark matter weakly interacting massive particles (WIMPs) scattering off 62 kg of liquid xenon in an ultralow background dual-phase time projection chamber. In this Letter, we present first dark matter results from the analysis of 11.17 live days of nonblind data, acquired in October and November 2009. In the selected fiducial target of 40 kg, and within the predefined signal region, we observe no events and hence exclude spin-independent WIMP-nucleon elastic scattering cross sections above 3.4 × 10⁻44 cm² for 55 GeV/c² WIMPs at 90% confidence level. Below 20 GeV/c², this result constrains the interpretation of the CoGeNT and DAMA signals as being due to spin-independent, elastic, light mass WIMP interactions.

Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth.

We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth. alpha(1)-adrenergic agonist-induced hypertrophy of cardiac myocytes in culture resulted in a significant decrease in palmitate oxidation rates and a reduction in the expression of the gene encoding muscle carnitine palmitoyltransferase I (M-CPT I), an enzyme involved in mitochondrial fatty acid uptake. Cardiac myocyte transfection studies demonstrated that M-CPT I promoter activity is repressed during cardiac myocyte hypertrophic growth, an effect that mapped to a peroxisome proliferator-activated receptor-alpha (PPARalpha) response element. Ventricular pressure overload studies in mice, together with PPARalpha overexpression studies in cardiac myocytes, demonstrated that, during hypertrophic growth, cardiac PPARalpha gene expression falls and its activity is altered at the posttranscriptional level via the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. Hypertrophied myocytes exhibited reduced capacity for cellular lipid homeostasis, as evidenced by intracellular fat accumulation in response to oleate loading. These results indicate that during cardiac hypertrophic growth, PPARalpha is deactivated at several levels, leading to diminished capacity for myocardial lipid and energy homeostasis.

A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator- activated receptor alpha- deficient mice.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPARalpha is activated as a component of the cellular lipid homeostatic response, the expression of PPARalpha target genes was characterized in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPARalpha target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPARalpha (PPARalpha-/-), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female PPARalpha-/- mice. The metabolic phenotype of male PPARalpha-/- mice was rescued by a 2-wk pretreatment with beta-estradiol. These results demonstrate a pivotal role for PPARalpha in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism.

RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload.

RGS family members are GTPase-activating proteins (GAPs) for heterotrimeric G proteins. There is evidence that altered RGS gene expression may contribute to the pathogenesis of cardiac hypertrophy and failure. We investigated the ability of RGS4 to modulate cardiac physiology using a transgenic mouse model. Overexpression of RGS4 in postnatal ventricular tissue did not affect cardiac morphology or basal cardiac function, but markedly compromised the ability of the heart to adapt to transverse aortic constriction (TAC). In contrast to wild-type mice, the transgenic animals developed significantly reduced ventricular hypertrophy in response to pressure overload and also did not exhibit induction of the cardiac "fetal" gene program. TAC of the transgenic mice caused a rapid decompensation in most animals characterized by left ventricular dilatation, depressed systolic function, and increased postoperative mortality when compared with nontransgenic littermates. These results implicate RGS proteins as a crucial component of the signaling pathway involved in both the cardiac response to acute ventricular pressure overload and the cardiac hypertrophic program.

Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography.

Noninvasive measurement of myocardial blood flow in absolute terms (i.e., milliliters per gram per min) has been difficult to accomplish despite the intrinsically quantitative power of positron emission tomography because of the nonphysiologic nature of tracers that have been employed conventionally as well as the limited spatial resolution of currently available instruments. It was previously demonstrated that myocardial blood flow in animals can be quantitated accurately with the diffusible tracer oxygen-15-labeled water (H2(15)O) when the arterial input function and myocardial radiotracer concentration were measured directly. To extend the approach for completely noninvasive measurement of blood flow, a parameter estimation procedure was developed whereby effects of limited tomographic spatial resolution and cardiac motion were compensated for within the operational flow model. In validation studies in 18 dogs, myocardial blood flow measured with positron emission tomography after intravenously administered H2(15)O correlated closely with flow measured with concomitantly administered radiolabeled microspheres over the range of 0.29 to 5.04 ml/g per min (r = 0.95). Although regional ischemia was clearly identifiable tomographically, absolute flow could not be determined accurately in ischemic regions in four dogs because of poor count statistics related to wall thinning. Subsequently, myocardial blood flow was measured in 11 normal human subjects. Flow was homogeneous throughout the myocardium, averaged 0.90 +/- 0.22 ml/g per min at rest and increased to 3.55 +/- 1.15 ml/g per min after intravenous administration of dipyridamole. Therefore, positron emission tomography with H2 15O and the approach developed permits noninvasive measurement of myocardial blood flow in absolute terms in humans and should facilitate objective assessment of interventions designed to enhance nutritive perfusion.

Pretreatment with buflomedil enhances ventricular function by reducing the dysfunctional area after transient coronary artery occlusion.

OBJECTIVE: The aim was to evaluate whether buflomedil (a drug used to treat peripheral vascular disease and which has a number of pharmacological actions potentially beneficial to dysfunctional myocardium) would preserve myocardial function after transient coronary artery occlusion followed by reperfusion. METHODS: The physiological response to a 15 min balloon occlusion of the left anterior descending coronary artery followed by 1 h of reperfusion was monitored in 17 placebo treated dogs and compared with that of 15 dogs which received 10 mg.kg-1 of buflomedil. Buflomedil or its vehicle were given intravenously. Myocardial blood flow was assessed with radiolabelled microspheres and cardiac function was evaluated with quantitative contrast left ventriculography. RESULTS: Buflomedil did not affect baseline haemodynamic variables or contractile function. At the end of occlusion, there was no difference between dogs receiving vehicle compared with those receiving drug with respect to ejection fraction [33(SD 11)% v 34(11)%] or transmural blood flow [0.23(0.11) v 0.28(0.14) ml.g-1 x min-1]. However, at 30 min after reperfusion, ejection fraction was 89% of normal in the buflomedil group compared with 69% of normal in the placebo group (p < 0.03). This difference was sustained 60 min after reperfusion, and was due in part to slightly enhanced flow during reperfusion and a decrease in the dysfunctional area (16 compared with 28 chords lower than -2 SD from the mean, p < 0.04) in the hearts of dogs receiving buflomedil. Areas at risk were equivalent (15.9% and 15.8% of the left ventricle, respectively). CONCLUSIONS: The results suggest that buflomedil and agents with similar modes of action may be beneficial in preserving ventricular function after transient ischaemia followed by reperfusion.

Determination of the separation efficiencies of a single-stage cryogenic distillation setup to remove krypton out of xenon by using a (83m)Kr tracer method.

The separation of krypton and xenon is of particular importance for the field of direct dark matter search with liquid xenon detectors. The intrinsic contamination of the xenon with radioactive (85)Kr makes a significant background for these kinds of low count-rate experiments and has to be removed beforehand. This can be achieved by cryogenic distillation, a technique widely used in industry, using the different vapor pressures of krypton and xenon. In this paper, we present an investigation on the separation performance of a single stage distillation system using a radioactive (83m)Kr-tracer method. The separation characteristics under different operation conditions are determined for very low concentrations of krypton in xenon at the level of (83m)Kr/Xe = 1.9 ⋅ 10(-15), demonstrating, that cryogenic distillation in this regime is working. The observed separation is in agreement with the expectation from the different volatilities of krypton and xenon. This cryogenic distillation station is the first step on the way to a multi-stage cryogenic distillation column for the next generation of direct dark matter experiment XENON1T.

Quantitation of myocardial fatty acid metabolism using PET.

UNLABELLED: Abnormalities of fatty acid metabolism in the heart presage contractile dysfunction and arrhythmias. This study was performed to determine whether myocardial fatty acid metabolism could be quantified noninvasively using PET and 1-(11)C-palmitate. METHODS: Anesthetized dogs were studied during control conditions; during administration of dobutamine; after oxfenicine; and during infusion of glucose. Dynamic PET data after administration of 1-(11)C-palmitate were fitted to a four-compartment mathematical model. RESULTS: Modeled rates of palmitate utilization correlated closely with directly measured myocardial palmitate and total long-chain fatty acid utilization (r = 0.93 and 0.96, respectively, p < 0.001 for each) over a wide range of arterial fatty acid levels and altered patterns of myocardial substrate use (fatty acid extraction fraction ranging from 1% to 56%, glucose extraction fraction from 1% to 16% and myocardial fatty acid utilization from 1 to 484 nmole/g/ min). The percent of fatty acid undergoing oxidation could also be measured. CONCLUSION: The results demonstrate the ability to quantify myocardial fatty acid utilization with PET. The approach is readily applicable for the determination of fatty acid metabolism noninvasively in patients.

Noninvasive estimation of regional myocardial oxygen consumption by positron emission tomography with carbon-11 acetate in patients with myocardial infarction.

We previously demonstrated in experimental studies that myocardial oxygen consumption (MVO2) can be estimated noninvasively with positron emission tomography (PET) from analysis of the myocardial turnover rate constant (k) after administration of carbon-11 (11C) acetate. To determine regional k in healthy human subjects and to estimate alterations in MVO2 accompanying myocardial ischemia, we administered [11C]acetate to five healthy human volunteers and to six patients with myocardial infarction. Extraction of [11C]acetate by the myocardium was avid and clearance from the blood-pool rapid yielding myocardial images of excellent quality. Regional k was homogeneous in myocardium of healthy volunteers (coefficient variation = 11%). In patients, k in regions remote from the area of infarction was not different from values in myocardium of healthy human volunteers (0.061 +/- 0.025 compared with 0.057 +/- 0.008 min-1). In contrast, MVO2 in the center of the infarct region was only 6% of that in remote regions (p less than 0.01). In four patients studied within 48 hr of infarction and again more than seven days after the acute event, regional k and MVO2 did not change. The approach developed should facilitate evaluation of the efficacy of interventions designed to enhance recovery of jeopardized myocardium and permit estimation of regional MVO2 and metabolic reserve underlying cardiac disease of diverse etiologies.

The role of the peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac lipid metabolism.

The postnatal mammalian heart uses mitochondrial fatty acid oxidation (FAO) as the chief source of energy to meet the high energy demands necessary for pump function. Flux through the cardiac FAO pathway is tightly controlled in accordance with energy demands dictated by diverse physiologic and dietary conditions. In this report, we demonstrate that the lipid-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), regulates the expression of several key enzymes involved in cardiac mitochondrial FAO. In response to the metabolic stress imposed by pharmacologic inhibition of mitochondrial long-chain fatty acid import with etomoxir, PPARa serves as a molecular 'lipostat' factor by inducing the expression of target genes involved in fatty acid utilization including enzymes involved in mitochondrial and peroxisomal beta-oxidation pathways. In mice lacking PPARalpha (PPARalpha-/- mice), etomoxir precipitates a cardiac phenotype characterized by myocyte lipid accumulation. Surprisingly, this metabolic regulatory response is influenced by gender as demonstrated by the observation that male PPARalpha-/- mice are more susceptible to the metabolic stress compared to female animals. These results identify an important role for PPARalpha in the control of cardiac lipid metabolism.

Evaluation of copper-labeled bifunctional chelate-albumin conjugates for blood pool imaging.

62Cu(T1/2 = 9.8 min) is a generator-produced positron-emitting radionuclide with a half-life amenable to blood-pool imaging with PET. Three bifunctional chelates [cyclic anhydride of diethylenetriaminepentaacetic acid (cDTPAA), 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane-N,N ',N", N"'-tetraacetic acid (BAT), and p-carboxyethylphenylglyoxal-bis-(4N-methyl-thiosemicarbazone (CE-DTS)] were conjugated to HSA and labeled with 67Cu. The labeling efficiency of 67Cu-DTS-HSA was > 90%, whereas the labeling yields of 67Cu-DTPA-HSA and 67Cu-benzyl-TETA-HSA were less than 70%. Blood clearance and biodistribution of these three 67Cu-labeled conjugates were determined in rats. Of the three 67Cu-labeled bifunctional chelate-HSA conjugates, 67Cu-benzyl-TETA-HSA remained in the blood pool the longest, achieving stable blood levels at times longer than 24 h post-injection. The 67Cu radioactivity cleared the blood within 60 min post-injection of 67Cu-DTS-HSA, and within 10 min after administration of 67Cu-DTPA-HSA, indicating the dissociation of Cu2+ from these conjugates. Copper-labeled DTS-HSA achieved stable blood concentrations for at least 30 min post-injection and was therefore evaluated as a vascular imaging agent. DTS-HSA and benzyl-TETA-HSA were labeled with 62Cu and administered to a dog for blood-pool imaging using PET. Images were nearly identical to an image taken after administration of C15O. Because of the high labeling efficiency, DTS-HSA can be labeled with 62Cu without purification, making it more practical than 62Cu-benzyl-TETA-HSA as a blood-pool imaging agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological properties of hybrid plasminogen activators.

A number of hybrid plasminogen activator genes were constructed from the t-PA and u-PA cDNAs and expressed using a bovine papilloma virus vector and mouse C-127 cells. Hybrid A was constructed by replacing the finger (F) and EGF domains of t-PA with the EGF and Ku domains of u-PA, while hybrids B and C had an extra Ku inserted before or after the double kringle (K1-K2) region of t-PA respectively. While all the hybrids showed comparable enzymatic activities towards a small substrate (S-2288), they had different activities in binding to fibrin clots as well in the fibrin-dependent plasminogen activation, the order of activities being: t-PA greater than or equal to hybrid B greater than hybrid C greater than hybrid A. Carbohydrate analysis showed that while hybrid C, like rt-PA, had at least one high-mannose type sugar chain (probably at residue 117 in K1), the other hybrids had only complex-type carbohydrates suggesting that domain interaction in t-PA might influence glycan processing. Pharmacokinetic studies in dog showed that hybrid B had a significantly longer plasma half-life than rt-PA. Thrombolytic efficacies of hybrid B and rt-PA were compared in dog model using an artificially induced coronary thrombus. Complete thrombolysis was achieved with 18 mg and 50 mg dosages for hybrid B and rt-PA respectively. These data show the superior pharmacokinetic and thrombolytic properties of hybrid B compared to rt-PA.

Ellipsometry with polarisation analysis at cryogenic temperatures inside a vacuum chamber.

In this paper we describe a new variant of null ellipsometry to determine thicknesses and optical properties of thin films on a substrate at cryogenic temperatures. In the PCSA arrangement of ellipsometry the polarizer and the compensator are placed before the substrate and the analyzer after it. Usually, in the null ellipsometry the polarizer and the analyzer are rotated to find the searched minimum in intensity. In our variant we rotate the polarizer and the compensator instead, both being placed in the incoming beam before the substrate. Therefore the polarisation analysis of the reflected beam can be realized by an analyzer at fixed orientation. We developed this method for investigations of thin cryogenic films inside a vacuum chamber where the analyzer and detector had to be placed inside the cold shield at a temperature of T ≈ 90 K close to the substrate. All other optical components were installed at the incoming beam line outside the vacuum chamber, including all components which need to be rotated during the measurements. Our null ellipsometry variant has been tested with condensed krypton films on a highly oriented pyrolytic graphite substrate (HOPG) at a temperature of T ≈ 25 K. We show that it is possible to determine the indices of refraction of condensed krypton and of the HOPG substrate as well as thickness of krypton films with reasonable accuracy.

A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders.

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARalpha (PPARalpha-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARalpha+/+ mice, fasting induced the hepatic and cardiac expression of PPARalpha target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPARalpha target genes was not induced by fasting in PPARalpha-/- mice. These results define a critical role for PPARalpha in a transcriptional regulatory response to fasting and identify the PPARalpha-/- mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.

Noninvasive quantification of regional myocardial perfusion with rubidium-82 and positron emission tomography. Exploration of a mathematical model.

Positron emission tomography (PET) centers without cyclotrons use generator-produced rubidium-82 (82Rb) for assessment of myocardial perfusion. The aim of the present study was to determine whether myocardial blood flow could be assessed quantitatively with 82Rb and PET. Because the myocardial extraction fraction of 82Rb varies inversely and nonlinearly with flow and cannot be measured conveniently with PET, we used an experimentally derived mathematical function defining the relation between single-pass extraction fraction of 82Rb and flow to obviate the necessity of measuring the extraction fraction directly. Myocardial blood flow in absolute terms (ml/g/min) was estimated from dynamic PET scans after intravenous administration of 82Rb in intact dogs and compared with flows measured with radiolabeled microspheres. In 36 comparisons in 13 dogs studied at rest, or after coronary occlusion, reperfusion, or after coronary hyperemia induced with intravenous dipyridamole, over the flow range from 0.2 to 2.0 ml/g/min, estimates of perfusion with rubidium correlated well with flows measured concomitantly with microspheres, although there was a slight underestimation of flow with rubidium (flow by 82Rb = 0.92 x flow by microspheres-0.021, r = 0.83). In general, estimates of flow in ischemic regions were less reliable than estimates for regions with normal flow. Thus, although the relation between myocardial extraction and retention of 82Rb and flow can vary under a variety of physiological and pathophysiological conditions, this study demonstrates the ability to obtain quantitative estimates of myocardial blood flow with 82Rb and PET under carefully defined conditions without measuring the extraction fraction directly.