Alpine and pre-Alpine magmatism in the root-zone of the western Central Alps

The highest grade of metamorphism and associated structural elements in orogenic belts may be inherited from earlier orogenic events. We illustrate this point using magmatic and metamorphic rocks from the southern steep belt of the Lepontine Gneiss Dome (Central Alps). The U-Pb zircon ages from an anatectic granite at Verampio and migmatites at Corcapolo and Lavertezzo yield 280-290 Ma, i.e., Hercynian ages. These ages indicate that the highest grade of metamorphism in several crystalline nappes of the Lepontine Gneiss Dome is pre-Alpine. Alpine metamorphism reached sufficiently high grade to reset the Rb-Sr and K-Ar systematics of mica and amphibole, but generally did not result in crustal melting, except in the steep belt to the north of the Insubric Line, where numerous 29 to 26 Ma old pegmatites and aplites had intruded syn- and post-kinematically into gneisses of the ductile Simplon Shear Zone. The emplacement age of these pegmatites gives a minimum estimate for the age of the Alpine metamorphic peak in the Monte Rosa nappe. The U-Pb titanite ages of 33 to 31 Ma from felsic porphyritic veins represent a minimum-age estimate for Alpine metamorphism in the Sesia Zone. A porphyric vein emplaced at 448 +/- 5 Ma (U-Pb monazite) demonstrates that there existed a consolidated Caledonian basement in the Sesia Zone.

Rapid transgene expression in multiple precursor cell types of adult rat subventricular zone mediated by adeno-associated type 1 vectors.

Abstract The adult rat brain subventricular zone (SVZ) contains proliferative precursors that migrate to the olfactory bulb (OB) and differentiate into mature neurons. Recruitment of precursors constitutes a potential avenue for brain repair. We have investigated the kinetics and cellular specificity of transgene expression mediated by AAV2/1 vectors (i.e., adeno-associated virus type 2 pseudotyped with AAV1 capsid) in the SVZ. Self-complementary (sc) and single-stranded (ss) AAV2/1 vectors mediated efficient GFP expression, respectively, at 17 and 24 hr postinjection. Transgene expression was efficient in all the rapidly proliferating cells types, that is, Mash1(+) precursors (30% of the GFP(+) cells), Dlx2(+) neuronal progenitors (55%), Olig2(+) oligodendrocyte progenitors (35%), and doublecortin-positive (Dcx(+)) migrating cells (40%), but not in the slowly proliferating glial fibrillary acidic protein-positive (GFAP(+)) neural stem cell pool (5%). Because cell cycle arrest by wild-type and recombinant AAV has been described in primary cultures, we examined SVZ proliferative activity after vector injection. Indeed, cell proliferation was reduced immediately after vector injection but was normal after 1 month. In contrast, migration and differentiation of GFP(+) precursors were unaltered. Indeed, the proportion of Dcx(+) cells was similar in the injected and contralateral hemispheres. Furthermore, 1 month after vector injection into the SVZ, GFP(+) cells, found, as expected, in the OB granular cell layer, were mature GABAergic neurons. In conclusion, the rapid and efficient transgene expression in SVZ neural precursors mediated by scAAV2/1 vectors underlines their potential usefulness for brain repair via recruitment of immature cells. The observed transient precursor proliferation inhibition, not affecting their migration and differentiation, will likely not compromise this strategy.

Trying to define Free Will : a cognitive and fonctional model proposal

The debate about Free Will has been in the human mind for centuries, but has become even more intense with the recent scientific findings adding new lights on the problem. This interdisciplinary explosion of interest for the topic has brought many insightful knowledge, but also a great deal of epistemological problems. We think that those epistemological problems are deeply related to the very definition of Free Will and how this definition interacts with the interpretations of experimental results. We will thus outline a few of these problems and then propose a definition of Free Will which takes into account those epistemological pitfalls.

Identification of secretory IgA, free secretory piece and serum IgA in the ovine and caprine species.

Caprine and ovine IgA were identified by cross-reaction with anti-human and anti-bovine IgA sera in colostrum, mature milk, saliva, urine and serum. Secretory component (SC) was shown in the free form and associated with polymeric serum IgA in secretions. Mean molecular weights were determined for the IgA and the free secretory components. The high IgA content of saliva suggested that it was a major secretory immunoglobulin in these species. Traces of secretory IgA were also found in normal sera but most of the serum IgA had no secretory determinant. Secretory IgA, serum IgA and free secretory component were purified. Levels of the sheep and goat immunoglobulins were measured in various fluids.

The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF.

The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the T-independent IgG3, but not IgM, response was impaired in the TACI-IgxBcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.

Neurogenic subventricular zone stem/progenitor cells are notch1-dependent in their active but not quiescent state.

The adult mammalian forebrain contains neural stem/progenitor cells (NSCs) that generate neurons throughout life. As in other somatic stem cell systems, NSCs are proposed to be predominantly quiescent and proliferate only sporadically to produce more committed progeny. However, quiescence has recently been shown not to be an essential criterion for stem cells. It is not known whether NSCs show differences in molecular dependence based on their proliferation state. The subventricular zone (SVZ) of the adult mouse brain has a remarkable capacity for repair by activation of NSCs. The molecular interplay controlling adult NSCs during neurogenesis or regeneration is not clear but resolving these interactions is critical in order to understand brain homeostasis and repair. Using conditional genetics and fate mapping, we show that Notch signaling is essential for neurogenesis in the SVZ. By mosaic analysis, we uncovered a surprising difference in Notch dependence between active neurogenic and regenerative NSCs. While both active and regenerative NSCs depend upon canonical Notch signaling, Notch1-deletion results in a selective loss of active NSCs (aNSCs). In sharp contrast, quiescent NSCs (qNSCs) remain after Notch1 ablation until induced during regeneration or aging, whereupon they become Notch1-dependent and fail to fully reinstate neurogenesis. Our results suggest that Notch1 is a key component of the adult SVZ niche, promoting maintenance of aNSCs, and that this function is compensated in qNSCs. Therefore, we confirm the importance of Notch signaling for maintaining NSCs and neurogenesis in the adult SVZ and reveal that NSCs display a selective reliance on Notch1 that may be dictated by mitotic state.

hMMP9 as predictive factor for response and progression free survival in breast cancer patients treated with bevacizumab and pegylated liposomal doxorubicin (PLD)

Background: The anti-angiogenic drug, bevacizumab (Bv), is currently used in the treatment of different malignancies including breast cancer. Many angiogenesis-associated molecules are found in the circulation of cancer patients. Until now, there are no prognostic or predictive factors identified in breast cancer patients treated with Bv. We present here the first results of the prospective monitoring of 6 angiogenesis-related molecules in the peripheral blood of breast cancer patients treated with a combination of Bv and PLD in the phase II trial, SAKK 24/06. Methods: Patients were treated with PLD (20 mg/m2) and Bv (10 mg/kg) on days 1 and 15 of each 4-week cycle for a maximum of 6 cycles, followed by Bv monotherapy maintenance (10 mg/m2 q2 weeks) until progression or severe toxicity. Plasma and serum samples were collected at baseline, after 2 months of therapy, then every 3 months and at treatment discontinuation. Enzyme-linked immunosorbent assays (Quantikine, R&D Systems and Reliatech) were used to measure the expression levels of human vascular endothelial growth factor (hVEGF), placental growth factor (hPlGF), matrix metalloproteinase 9 (hMMP9) and soluble VEGF receptors hsVEGFR-1, hsVEGFR-2 and hsVEGFR-3. The log-transformed data (to reduce the skewness) for each marker was analyzed using an analysis of variance (ANOVA) model to determine if there was a difference between the mean of the subgroups of interest (where α = 0.05). The untransformed data was also analyzed in the same manner as a "sensitivity" check. Results: 132 blood samples were collected in 41 out of 43 enrolled patients. Baseline levels of the molecules were compared to disease status according to RECIST. There was a statistically significant difference in the mean of the log-transformed levels of hMMP9 between responders [CR+PR] versus the mean in patients with PD (p-value=0.0004, log fold change=0.7536), and between patients with disease control [CR+PR+SD] and those with PD (p-value=<0.0001, log fold change=0.81559), with the log-transformed level of hMMP9 being higher for the responder group. The mean of the log-transformed levels of hsVEGFR-1 was statistically significantly different between patients with disease control [CR+PR+SD] and those with PD (p-value=0.0068, log fold change=-0.6089), where the log-transformed level of hsVEGFR-1 was lower for the responder group. The log-transformed level of hMMP9 at baseline was identified as a significant prognostic factor in terms of progression free survival (PFS): p-value=0.0417, hazard ratio (HR)=0.574 with a corresponding 95% confidence interval (0.336 - 0.979)). No strong correlation was shown either between the log-transformed levels of hsVEGF, hPlGF, hsVEGFR-2 or hsVEGFR-3 and clinical response or the occurrence of severe toxicity, or between the levels of the different molecules. Conclusions: Our results suggest that baseline plasma level of the matrix metalloproteinase, hMMP9, could predict tumor response and PFS in patients treated with a combination of Bv and PLD. These data justify further investigation in breast cancer patients treated with anti-angiogenic therapy.

Characterizing emission and breathing-zone concentrations following exposure cases to fluororesin-based waterproofing spray mists.

Measurements and simulations were performed to assess workers' exposure to solvent vapors and aerosols during the waterproofing of a tiled surface. This investigation followed two recent incidents in the same company where workers experienced acute respiratory illness after spraying a stain-repellent resin containing fluorinated polymers on stone-tiled walls and floors. Because the waterproofing activity had been done for years at the tile company without encountering any exposure problems prior to these cases, it was strongly suspected that the incidents were linked to a recent change in the composition of the coating mixture. Experimental measurements and simulations indicated that the emission rate of particles smaller than 10 microm may be estimated at 0.66 mg/sec (SD 0.10) for the old resin and at 0.37 mg/sec (SD 0.04) for the new one. The measurement of the solvent emission rate from surfaces coated with the two resins indicated that shortly after spraying, the emission was in the range of 18 to 20 mg/sec x m2 and was similar for both products. Solvent and overspray emission rates were introduced in a two-zone compartment model. The results obtained in the near-field indicate significant exposure to overspray mist (7 and 34 mg/m3 for new resin) and solvent vapors (80 to 350 ppm for the new resin). It was also shown that the introduction of the new resin tended to significantly decrease the levels of solvents and particulates in the workers' breathing zone. These results strongly suggest that cases of acute respiratory illness are related to the specific toxicity of the fluorinated polymer itself. The fact that the same polymer is used in various commercial products raises concern regarding other possible occupational and domestic exposures.

Lifetime of an ocean island volcano feeder zone: constraints from U-Pb dating on coexisting zircon and baddeleyite, and 40Ar/39Ar age determinations, Fuerteventura, Canary Islands

High-precision isotope dilution - thermal ionization mass spectrometry (ID-TIMS) U-Pb zircon and baddeleyite ages from the PX1 vertically layered mafic intrusion Fuerteventura, Canary Islands, indicate initiation of magma crystallization at 22.10 +/- 0.07 Ma. The magmatic activity lasted a minimum of 0.52 Ma. Ar-40/Ar-39 amphibole dating yielded ages from 21.9 +/- 0.6 to 21.8 +/- 0.3, identical within errors to the U-Pb ages, despite the expected 1% theoretical bias between Ar-40/Ar-39 and U-Pb dates. This overlap could result from (i) rapid cooling of the intrusion (i. e., less than the 0.3 to 0.6 Ma 40Ar/39Ar age uncertainties) from closure temperatures (T-c) of zircon (699-988 degrees C) to amphibole (500-600 degrees C); (ii) lead loss affecting the youngest zircons; or (iii) excess argon shifting the plateau ages towards older values. The combination of the Ar-40/Ar-39 and U/Pb datasets implies that the maximum amount of time PX1 intrusion took to cool below amphibole T-c is 0.8 Ma, suggesting PX1 lifetime of 520 000 to 800 000 Ma. Age disparities among coexisting baddeleyite and zircon (22.10 +/- 0.07/0.08/0.15 Ma and 21.58 +/- 0.15/0.16/0.31 Ma) in a gabbro sample from the pluton margin suggest complex genetic relationships between phases. Baddeleyite is found preserved in plagioclase cores and crystallized early from low silica activity magma. Zircon crystallized later in a higher silica activity environment and is found in secondary scapolite and is found close to calcite veins, in secondary scapolite that recrystallised from plagioclase. close to calcite veins. Oxygen isotope delta O-18 values of altered plagioclase are high (+7.7), indicating interaction with fluids derived from host-rock carbonatites. The coexistence of baddeleyite and zircon is ascribed to interaction of the PX1 gabbro with CO2-rich carbonatite-derived fluids released during contact metamorphism.

Physiological traits affecting the distribution and wintering strategy of the bat Tadarida teniotis

The ability to enter torpor at low ambient temperature, which enables insectivorous bats to survive seasonal food shortage, is often seen as a prerequisite for colonizing cold environments. Free-tailed bats (Molossidae) show a distribution with a maximum latitudinal extension that appears to be intermediate between truly tropical and temperate-zone bat families. We therefore tested the hypothesis that Tadarida teniotis, the molossid species reaching the highest latitude worldwide (46 degrees N), lacks the extreme physiological adaptations to cold that enable other sympatric bats to enter further into the temperate zone. We studied the metabolism of individuals subjected to various ambient temperatures in the laboratory by respirometry, and we monitored the body temperature of free-ranging individuals in winter and early spring in the Swiss Alps using temperature-sensitive radio-tags. For comparison, metabolic data were obtained from Nyctalus noctula, a typically hibernating vespertilionid bat of similar body size and convergent foraging tactics. The metabolic data support the hypothesis that T. teniotis cannot experience such low ambient temperatures as sympatric temperate-zone vespertilionid bats without incurring much higher energetic costs for thermogenesis. The minimum rate of metabolism in torpor was obtained at 7.5 degrees-10 degrees C in T. teniotis, as compared to 2.5 degrees-5 degrees C in N. noctula. Field data showed that T. teniotis behaves as a classic thermo-conforming hibernator in the Alps, with torpor bouts lasting up to 8 d. This contradicts the widely accepted opinion that Molossidae are nonhibernating bars. However, average body temperature (10 degrees-13 degrees C) and mean arousal frequency (3.4 d in one bat in January) appear to be markedly higher than in other temperate-zone bat species. At the northern border of its range T. teniotis selects relatively warm roosts (crevices in tall, south-exposed limestone cliffs) in winter where temperatures oscillate around 10 degrees C. By this means, T. teniotis apparently avoids the risk of prolonged exposure to energetically critical ambient temperatures in torpor (<6.5 degrees-7.5 degrees C) during cold spells. Possibly shared by other Molossidae, the physiological pattern observed in T. teniotis may clearly be linked to the intermediate latitudinal extension of this bat family.

Physical activity under confinement and free-living conditions.

The objective of this study was to investigate the relationship between the physical activity (PA) and its related variables under confinement and in free-living conditions in Asian individuals, where no such information presently exists. The subjects consisted of eighty-six Japanese individuals with a mean age of 38+/-12 years. Under confinement in a large respiratory chamber, the energy expenditure (EE) was measured for 24h. In addition, two moderate walking exercises of 30 min each on a horizontal treadmill were assigned. Free-living measurements of 7 days were also performed using a validated accelerometer. The PA level in the chamber (1.47+/-0.11), expressed as a multiple of the basal EE, was lower than that in free-living conditions (1.53+/-0.12) (p<0.001). However, the two values were closely correlated (r=0.744, p<0.001). Conversely, a residual analysis showed a wide variation in the mean difference for both conditions and revealed a significant systematic error (r=-0.548, p<0.001), thus indicating an increased gap with increasing PA levels in free-living conditions. Similar results were obtained following the exclusion of the imposed exercise sessions. In contrast, the daily step counts under both conditions did not show any correlation. The PA level in the chamber (including and excluding imposed walking exercises) is compatible with the PA level in free-living conditions at the group level, although the daily step counts are unrelated. Thus, the PA level in the chamber may provide valuable information to help us achieve a better understanding of human PA in daily life as it is related to behavioral research.

Real-time motion correction in navigator-gated free-breathing double-oblique submillimeter 3D right coronary artery magnetic resonance angiography.

RATIONALE AND OBJECTIVES: The purpose of this study was the investigation of the impact of real-time adaptive motion correction on image quality in navigator-gated, free-breathing, double-oblique three-dimensional (3D) submillimeter right coronary magnetic resonance angiography (MRA). MATERIALS AND METHODS: Free-breathing 3D right coronary MRA with real-time navigator technology was performed in 10 healthy adult subjects with an in-plane spatial resolution of 700 x 700 microm. Identical double-oblique coronary MR-angiograms were performed with navigator gating alone and combined navigator gating and real-time adaptive motion correction. Quantitative objective parameters of contrast-to-noise ratio (CNR) and vessel sharpness and subjective image quality scores were compared. RESULTS: Superior vessel sharpness, increased CNR, and superior image quality scores were found with combined navigator gating and real-time adaptive motion correction (vs. navigator gating alone; P < 0.01 for all comparisons). CONCLUSION: Real-time adaptive motion correction objectively and subjectively improves image quality in 3D navigator-gated free-breathing double-oblique submillimeter right coronary MRA.

Free conjunctival autologous graft for bleb repair and bleb reduction after trabeculectomy and nonpenetrating filtering surgery.

PURPOSE: To describe methods and outcomes of excisional revision of a filtering bleb (bleb revision) using free conjunctival autologous graft either for bleb repair or for bleb reduction after trabeculectomy and deep sclerectomy with an implant. METHODS: Retrospective medical records were reviewed for a consecutive non-comparative case series comprising patients who underwent excisional revision of a filtering bleb between May 1998-January 2001. Excisional revision using free conjunctival autologous graft (bleb revision) was performed either for bleb repair, to treat early and late leaks and hypotony with maculopathy, or for bleb reduction, to improve ocular pain, discomfort, burning, foreign body sensation, tearing, and fluctuations of visual acuity. The revision consisted of bleb excision and free conjunctival autologous graft. The bleb histopathology was analyzed in patients who underwent bleb repair. RESULTS: Sixteen patients were included in the study, consisting of nine patients who had a trabeculectomy and seven patients who had a deep sclerectomy with an implant. Bleb revision was necessary in 14 patients due to leaking filtering bleb (bleb repair), and in 2 patients due to bleb dysesthesia (bleb reduction). After a follow-up of 15.1 +/- 8.4 months, the mean intraocular pressure (IOP) rose from 7.8 +/- 6.3 mm Hg to 14.3 +/- 6.5 mm Hg, and the visual acuity from 0.4 +/- 0.3 to 0.7 +/- 0.3, with a P value of 0.008 and 0.03, respectively. The complete success rate at 32 months, according to the Kaplan-Meier survival curve, was 38.3%, and the qualified success rate was 83.3%. Four patients (25%) required additional suturing for persistent bleb leak. To control IOP, antiglaucoma medical therapy was needed for six patients (37.5%) and repeated glaucoma surgery was needed for one patient. CONCLUSION: Free conjunctival autologous graft is a safe and successful procedure for bleb repair and bleb reduction. However, patients should be aware of the postoperative possibility of requiring medical or surgical intervention for IOP control after revision.