Time-resolved near backscatter imaging system on Laser MegaJoule.

The newly operating near-backscattering imaging (NBI) system on the Laser MegaJoule (LMJ) is briefly described with emphasis on the temporally resolved measurements and their synchronization with the LMJ laser pulse through target shots taken as part of the diagnostic commissioning campaign. The NBI measures the stimulated Brillouin and Raman scattered light around two quadruplets (one inner and one outer) of the upper LMJ hemisphere. The temporal resolution is achieved with a unique system: a specifically designed wide-open optical lens images 40 points of a diffuser onto an array of optical fibers with the scattered light recorded on a multiplexed photodiode array.

Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.

Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val(158)Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (P<0.0001, n=95). In COMT Val/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.

The tetrapeptide AcSDKP reduces the sensitivity of murine CFU-MK and CFU-GM progenitors to aracytine in vitro and in vivo.

The tetrapeptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) has been described as an inhibitor of CFU-S entry into DNA synthesis; as a result, its administration can protect mice against lethal doses of cytosine arabinoside (Ara-C). In the present study, we tested the protective effect of AcSDKP on CFU-MK and CFU-GM progenitor cells in mice treated at lower doses of Ara-C more relevant to human clinical situations. Firstly, we report for the first time that in vitro pre-incubation of murine BM MNC with AcSDKP at concentrations of 10(-10) and 10(-9) M for 48 h decreased CFU-MK, in parallel to CFU-GM, progenitor growth. This resulted in an increase of recovery of these progenitors after exposure to Ara-C. Secondly, we tested the effect of AcSDKP on progenitor cells in vivo in different conditions in Ara-C treated mice. We show that the administration of AcSDKP before starting Ara-C treatment resulted in a significant increase in progenitor CFU-GM, CFU-MK and mature MK numbers, 6 and 8 days after the first Ara-C injection. Interestingly, no difference was observed whether AcSDKP was started 24 or 48 h before Ara-C. In a protocol in which AcSDKP was administered for 8 days starting 48 h before Ara-C treatment, the dose did not appear to be critical at least within the range tested (4 vs. 40 micrograms/injection). In addition, the administration of AcSDKP at 64 micrograms/kg per injection for 5 days and stopping it 3 days before the end of Ara-C treatment, i.e. five instead of eight applications, further increased its protective effect. Thus our results demonstrate protective effect of AcSDKP for progenitors during a fractionated protocol of Ara-C treatment and indicates an importance of the dose and the schedule of administration of AcSDKP in designing future clinical trials.

Guinea pig blood: a model for the pharmacologic modulation of the GPIb/IX-vWF axis.

Antithrombotic activity of two recombinant GPIb-binding fragments of vWF, RG12986 (residues 445-733), and VCL (residues 504-728), were assessed in an ex vivo capillary perfusion chamber exposing human type III collagen to native nonanticoagulated guinea pig blood. Platelet adhesion and thrombus formation were evaluated by computer assisted morphometry for two shear rates (650 and 1800 s-1) and for two perfusion times (1.5 and 4 min). At 1800 s-1 and 4 min of perfusion, platelet adhesion decreased from 63 +/- 7% for control, to 46 +/- 4% for 20 mg/kg RG12986, and to 29 +/- 5% for 4 mg/kg VCL, and the mean thrombus height dropped from 40 +/- 8 microns to 24 +/- 3 microns and 7.5 +/- 1 microns, respectively. The two doses did not change bleeding time values. Our results suggest that guinea pig blood and the circular perfusion chamber represent a good model for the evaluation of limited amount of GPIb/IX-vWF axis inhibitors.

Optimal antagonism of GPIIb/IIIa favors platelet adhesion by inhibiting thrombus growth. An ex vivo capillary perfusion chamber study in the guinea pig.

To evaluate the involvement of the glycoprotein (GP) IIb/IIIa-dependent process in platelet deposition and thrombus growth on capillaries coated with human type III collagen, the effects of incremental doses of Lamifiban, a potent specific synthetic GPIIb/IIIa antagonist, were studied in ex vivo capillary perfusion chambers using guinea pig blood. In this model, nonanticoagulated blood was perfused for 4.5 minutes at three shear rates: 100, 650, and 1600 s-1. Platelet deposition was quantified by computer-assisted morphometry and expressed as platelet adhesion (percentage of capillary surface covered with spread and contact platelets and platelets implicated in thrombus), mean thrombus height, and total thrombus cross-sectional area. In control untreated guinea pigs, platelet adhesion and thrombus height were 63% and 2.5 microns at 100 s-1, 60.5% and 13.8 microns at 650 s-1, and 45% and 28.1 microns at 1600 s-1, respectively. At 100 s-1, Lamifiban had no effect on platelet deposition at any of the three doses administered to the guinea pigs (0.3, 1, and 3 mg/kg). At 0.3 mg/kg and shear rates of 650 and 1600 s-1, Lamifiban had no effect on platelet adhesion or thrombus size, but at 1 and 3 mg/kg and shear rates of 650 and 1600 s-1, it significantly reduced thrombus size. At 1600 s-1, 1 mg/kg Lamifiban significantly increased platelet adhesion from 45% to 62.5%, whereas at 3 mg/kg it induced a significant overall decrease from 45% to 25% and qualitatively increased the ratio of contact to spread platelets. These data suggest that at high shear rates, GPIIb/IIIa participates in platelet spreading and that there is a balance between platelet involvement in adhesion to the thrombogenic surface and the growth of the already formed thrombus. This indicates that important clinical implications of an optimal therapeutic degree of GPIIb/IIIa antagonism could be expected.