Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation.

BACKGROUND: Ischemia followed by reperfusion (I/R) causes apoptosis, inflammation, and tissue damage leading to organ malfunction. Ischemic preconditioning can protect against such injury. This study investigates the contribution of the acute phase proteins alpha(1)-acid glycoprotein (AGP) and alpha(1)-antitrypsin (AAT) to the protective effect of ischemic preconditioning in the kidney. METHODS AND RESULTS: Exogenous AGP and AAT inhibited apoptosis and inflammation after 45 minutes of renal I/R in a murine model. AGP and AAT administered at reperfusion prevented apoptosis at 2 hours and 24 hours, as evaluated by the presence of internucleosomal DNA cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, and the determination of renal caspase-1- and caspase-3-like activity. AGP and AAT exerted anti-inflammatory effects, as reflected by reduced renal tumor necrosis factor-alpha expression and neutrophil influx after 24 hours. In general, these agents improved renal function. Similar effects were observed when AGP and AAT were administered 2 hours after reperfusion but to a lesser extent and without functional improvement. Moreover, I/R elicited an acute phase response, as reflected by elevated serum AGP and serum amyloid P (SAP) levels after 24 hours, and increased hepatic acute phase protein mRNA levels after 18 hours of renal reperfusion. CONCLUSIONS: We propose that the antiapoptotic and anti-inflammatory effects of AGP and AAT contribute to the delayed type of protection associated with ischemic preconditioning and other insults. This mechanism is potentially involved in the course of many clinical conditions associated with I/R injury. Moreover, exogenous administration of these proteins may provide new therapeutic means of treatmen

Type 2 Diabetes Mellitus: New Genetic Insights will Lead to New Therapeutics

Type 2 diabetes is a disorder of dysregulated glucose homeostasis. Normal glucose homeostasis is a complex process involving several interacting mechanisms, such as insulin secretion, insulin sensitivity, glucose production, and glucose uptake. The dysregulation of one or more of these mechanisms due to environmental and/or genetic factors, can lead to a defective glucose homeostasis. Hyperglycemia is managed by augmenting insulin secretion and/or interaction with hepatic glucose production, as well as by decreasing dietary caloric intake and raising glucose metabolism through exercise. Although these interventions can delay disease progression and correct blood glucose levels, they are not able to cure the disease or stop its progression entirely. Better management of type 2 diabetes is sorely needed. Advances in genotyping techniques and the availability of large patient cohorts have made it possible to identify common genetic variants associated with type 2 diabetes through genome-wide association studies (GWAS). So far, genetic variants on 19 loci have been identified. Most of these loci contain or lie close to genes that were not previously linked to diabetes and they may thus harbor targets for new drugs. It is also hoped that further genetic studies will pave the way for predictive genetic screening. The newly discovered type 2 diabetes genes can be classified based on their presumed molecular function, and we discuss the relation between these gene classes and current treatments. We go on to consider whether the new genes provide opportunities for developing alternative drug therapies

Effectiveness of customary use of phytosterol/-stanol enriched margarines on blood cholesterol lowering.

Postlaunch monitoring of functional foods can encompass monitoring of effectiveness under conditions of customary use. To this end, the effectiveness of phytosterol/-stanol enriched margarine consumption in free-living conditions was investigated with data from the Dutch "Doetinchem cohort study". In total, 4,505 subjects (aged 26-70 years) were examined in 1994-1998 and re-examined during 1999-2003. A general and a food frequency questionnaire and non-fasting blood samples for total and HDL cholesterol determination were obtained. Subjects were stratified into phytosterol/-stanol enriched margarine users (n = 84) and non-users (n = 4,421) based on the re-examination data, as these margarines were available on the Dutch market from 1999 onwards. Mean spontaneous daily use (g +/- SD) of phytosterol-containing margarine (n = 71) was 15 +/- 8 and of phytostanol-containing margarine (n = 13) 9+/-6. After five years, total blood cholesterol had increased with 0.26 mmol/l in non-users while it had not significantly changed in users. The difference in total blood cholesterol change in users versus non-users was -0.30 mmol/l (p < 0.001). The beneficial effect of the phytosterol/-stanol enriched margarine, used under customary conditions can be characterized as a stabilization of cholesterol levels. This is the first report finding a modest beneficial effect on blood cholesterol level under customary conditions thereby partly confirming findings from clinical trials

Inverting Time-Dependent Harmonic Oscillator Potential by a Unitary Transformation and a New Class of Exactly Solvable Oscillators

A time-dependent unitary (canonical) transformation is found which maps the Hamiltonian for a harmonic oscillator with time-dependent real mass and real frequency to that of a generalized harmonic oscillator with time-dependent real mass and imaginary frequency. The latter may be reduced to an ordinary harmonic oscillator by means of another unitary (canonical) transformation. A simple analysis of the resulting system leads to the identification of a previously unknown class of exactly solvable time-dependent oscillators. Furthermore, it is shown how one can apply these results to establish a canonical equivalence between some real and imaginary frequency oscillators. In particular it is shown that a harmonic oscillator whose frequency is constant and whose mass grows linearly in time is canonically equivalent with an oscillator whose frequency changes from being real to imaginary and vice versa repeatedly.Comment: 7 pages, 1 figure include

The human somatostatin receptor type 2 as an imaging and suicide reporter gene for pluripotent stem cell-derived therapy of myocardial infarction

Rationale: Pluripotent stem cells (PSCs) are being investigated as a cell source for regenerative medicine since they provide an infinitive pool of cells that are able to differentiate towards every cell type of the body. One possible therapeutic application involves the use of these cells to treat myocardial infarction (MI), a condition where billions of cardiomyocytes (CMs) are lost. Although several protocols have been developed to differentiate PSCs towards CMs, none of these provide a completely pure population, thereby still posing a risk for neoplastic teratoma formation. Therefore, we developed a strategy to (i) monitor cell behavior noninvasively via site-specific integration of firefly luciferase (Fluc) and the human positron emission tomography (PET) imaging reporter genes, sodium iodide symporter (hNIS) and somatostatin receptor type 2 (hSSTr2), and (ii) perform hSSTr2-mediated suicide gene therapy via the clinically used radiopharmacon 177Lu-DOTATATE. Methods: Human embryonic stem cells (ESCs) were gene-edited via zinc finger nucleases to express Fluc and either hNIS or hSSTr2 in the safe harbor locus, adeno-associated virus integration site 1. Firstly, these cells were exposed to 4.8 MBq 177Lu-DOTATATE in vitro and cell survival was monitored via bioluminescence imaging (BLI). Afterwards, hNIS+ and hSSTr2+ ESCs were transplanted subcutaneously and teratomas were allowed to form. At day 59, baseline 124I and 68Ga-DOTATATE PET and BLI scans were performed. The day after, animals received either saline or 55 MBq 177Lu-DOTATATE. Weekly BLI scans were performed, accompanied by 124I and 68Ga-DOTATATE PET scans at days 87 and 88, respectively. Finally, hSSTr2+ ESCs were differentiated towards CMs and transplanted intramyocardially in the border zone of an infarct that was induced by left anterior descending coronary artery ligation. After transplantation, the animals were monitored via BLI and PET, while global cardiac function was evaluated using cardiac magnetic resonance imaging. Results: Teratoma growth of both hNIS+ and hSSTr2+ ESCs could be followed noninvasively over time by both PET and BLI. After 177Lu-DOTATATE administration, successful cell killing of the hSSTr2+ ESCs was achieved both in vitro and in vivo, indicated by reductions in total tracer lesion uptake, BLI signal and teratoma volume. As undifferentiated hSSTr2+ ESCs are not therapeutically relevant, they were differentiated towards CMs and injected in immune-deficient mice with a MI. Long-term cell survival could be monitored without uncontrolled cell proliferation. However, no improvement in the left ventricular ejection fraction was observed.Conclusion: We developed isogenic hSSTr2-expressing ESCs that allow noninvasive cell monitoring in the context of PSC-derived regenerative therapy. Furthermore, we are the first to use the hSSTr2 not only as an imaging reporter gene, but also as a suicide mechanism for radionuclide therapy in the setting of PSC-derived cell treatment

Measurement of single electron emission in two-phase xenon

We present the first measurements of the electroluminescence response to the emission of single electrons in a two-phase noble gas detector. Single ionization electrons generated in liquid xenon are detected in a thin gas layer during the 31-day background run of the ZEPLIN-II experiment, a two-phase xenon detector for WIMP dark matter searches. Both the pressure dependence and magnitude of the single-electron response are in agreement with previous measurements of electroluminescence yield in xenon. We discuss different photoionization processes as possible cause for the sample of single electrons studied in this work. This observation may have implications for the design and operation of future large-scale two-phase systems.Comment: 11 pages, 6 figure