Low-lying excited states and nonradiative processes of 9-methyl-2-aminopurine

he UV spectrum of the adenine analogue 9-methyl-2-aminopurine (9M-2AP) is investigated with one- and two-color resonant two-photon ionization spectroscopy at 0.3 and 0.05 cm−1 resolution in a supersonic jet. The electronic origin at 32 252 cm−1 exhibits methyl torsional subbands that originate from the 0A′′1 (l = 0) and 1E ″ (l = ±1) torsional levels. These and further torsional bands that appear up to 000+230 cm−1 allow to fit the threefold (V 3) barriers of the torsional potentials as ∣∣V′′3∣∣=50 cm−1 in the S 0 and ∣∣V′3∣∣=126 cm−1 in the S 1 state. Using the B3LYP density functional and correlated approximate second-order coupled cluster CC2 methods, the methyl orientation is calculated to be symmetric relative to the 2AP plane in both states, with barriers of V′′3=20 cm−1 and V′3=115 cm−1. The 000 rotational band contour is 75% in-plane (a/b) polarized, characteristic for a dominantly long-axis 1ππ* excitation. The residual 25% c-axis polarization may indicate coupling of the 1ππ* to the close-lying 1 nπ* state, calculated at 4.00 and 4.01 eV with the CC2 method. However, the CC2 calculated 1 nπ oscillator strength is only 6% of that of the 1ππ* transition. The 1ππ* vibronic spectrum is very complex, showing about 40 bands within the lowest 500 cm−1. The methyl torsion and the low-frequency out-of-plane ν′1 and ν′2 vibrations are strongly coupled in the 1ππ* state. This gives rise to many torsion-vibration combination bands built on out-of-plane fundamentals, which are without precedence in the 1ππ* spectrum of 9H-2-aminopurine [S. Lobsiger, R. K. Sinha, M. Trachsel, and S. Leutwyler, J. Chem. Phys.134, 114307 (2011)]. From the Lorentzian broadening needed to fit the 000 contour of 9M-2AP, the 1ππ* lifetime is τ ⩾ 120 ps, reflecting a rapid nonradiative transition.

Total Tumor Volume and Alpha Fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation.

The selection of liver transplant candidates with hepatocellular carcinoma (HCC) is currently validated based on Milan criteria. The use of extended criteria has remained a matter of debate, mainly because of the absence of prospective validation. The present prospective study recruited patients according to the previously proposed Total Tumor Volume (TTV ≤115 cm(3) )/alpha fetoprotein (AFP ≤400 ng/ml) score. Patients with AFP >400 ng/ml were excluded, and as such the Milan group was modified to include only patients with AFP <400 ng/ml; these patients were compared to patients beyond Milan, but within TTV/AFP. From January 2007 to March 2013, 233 patients with HCC were listed for liver transplantation. Of them, 195 patients were within Milan, and 38 beyond Milan but within TTV/AFP. The average follow-up from listing was 33,9 ±24,9 months. The risk of drop-out was higher for patients beyond Milan but within TTV/AFP (16/38, 42,1%), than for patients within Milan (49/195, 25,1%, p=0,033). In parallel, intent-to-treat survival from listing was lower in the patients beyond Milan (53,8% vs. 71,6% at four years, p<0,001). After a median waiting time of 8 months, 166 patients were transplanted, 134 patients within Milan criteria, and 32 beyond Milan but within TTV/AFP. They demonstrated acceptable and similar recurrence rates (4,5% vs. 9,4%, p=0,138) and post-transplant survivals (78,7% vs. 74,6% at four years, p=0,932). CONCLUSION Based on the present prospective study, HCC liver transplant candidate selection could be expanded to the TTV (≤115 cm(3) )/AFP (≤400 ng/ml) criteria in centers with at least 8-month waiting time. An increased risk of drop-out on the waiting list can be expected but with equivalent and satisfactory post-transplant survival. This article is protected by copyright. All rights reserved.

Processing-dependent and -independent pathways for recognition of iodinated contrast media by specific human T cells

One to three percent of patients exposed to intravenously injected iodinated contrast media (CM) develop delayed hypersensitivity reactions. Positive patch test reactions, immunohistological findings, and CM-specific proliferation of T cells in vitro suggest a pathogenetic role for T cells. We have previously demonstrated that CM-specific T cell clones (TCCs) show a broad range of cross-reactivity to different CM. However, the mechanism of specific CM recognition by T cell receptors (TCRs) has not been analysed so far.

(106)Ruthenium brachytherapy for ciliary recurrence with supraciliary effusion in retinoblastoma

A 2-year-old boy with syndromic bilateral retinoblastoma resulting from a (del(13)(q12.3q14.3)) developed a recurrent tumor measuring 2.3 X 2.3 mm at the ora serrata 15 months following last treatment.

Generation and characterization of stable, highly concentrated titanium dioxide nanoparticle aerosols for rodent inhalation studies

The intensive use of nano-sized titanium dioxide (TiO2) particles in many different applications necessitates studies on their risk assessment as there are still open questions on their safe handling and utilization. For reliable risk assessment, the interaction of TiO2 nanoparticles (NP) with biological systems ideally needs to be investigated using physico-chemically uniform and well-characterized NP. In this article, we describe the reproducible production of TiO2 NP aerosols using spark ignition technology. Because currently no data are available on inhaled NP in the 10–50 nm diameter range, the emphasis was to generate NP as small as 20 nm for inhalation studies in rodents. For anticipated in vivo dosimetry analyses, TiO2 NP were radiolabeled with 48V by proton irradiation of the titanium electrodes of the spark generator. The dissolution rate of the 48V label was about 1% within the first day. The highly concentrated, polydisperse TiO2 NP aerosol (3–6 × 106 cm−3) proved to be constant over several hours in terms of its count median mobility diameter, its geometric standard deviation, and number concentration. Extensive characterization of NP chemical composition, physical structure, morphology, and specific surface area was performed. The originally generated amorphous TiO2 NP were converted into crystalline anatase TiO2 NP by thermal annealing at 950 °C. Both crystalline and amorphous 20-nm TiO2 NP were chain agglomerated/aggregated, consisting of primary particles in the range of 5 nm. Disintegration of the deposited TiO2 NP in lung tissue was not detectable within 24 h.

Intermolecular Clamping by Hydrogen Bonds: 2-Pyridone center dot NH3

A combined spectroscopic and ab initio theoretical study of the doubly hydrogen-bonded complex of 2-pyridone (2PY) with NH3 has been performed. The S-1 <- S-0 spectrum extends up to approximate to 1200 cm(-1) above the 0(0)(0) band, close to twice the range observed for 2PY. The S-1 state nonradiative decay for vibrations above approximate to 300 cm(-1) in the NH3 complex is dramatically slowed down relative to bare 2PY. Also, the Delta v=2,4,... overtone bands of the v(1)' and v(2)' out-of-plane vibrations that dominate the low-energy spectral region of 2PY are much weaker or missing for 2PY center dot NH3, which implies that the bridging (2PY)NH center dot center dot center dot NH3 and H2NH center dot center dot center dot O=C H-bonds clamp the 2PY at a planar geometry in the S-1 state. The mass-resolved UV vibronic spectra of jet-cooled 2PY center dot NH3 and its H/D mixed isotopomers are measured using two-color resonant two-photon ionization spectroscopy. The S-0 and S-1 equilibrium structures and normal-mode frequencies are calculated by density functional (B3LYP) and correlated ab initio methods (MP2 and approximate second-order coupled-cluster, CC2). The S-1 <- S-0 vibronic assignments are based on configuration interaction singles (CIS) and CC2 calculations. A doubly H-bonded bridged structure of C-S symmetry is predicted, in agreement with that of Held and Pratt [J. Am. Chem. Soc. 1993, 115, 9718]. While the B3LYP and MP2 calculated rotational constants are in very good agreement with experiment, the calculated H2NH center dot center dot center dot O=C H-bond distance is approximate to 0.7 angstrom shorter than that derived by Held and Pratt. On the other hand, this underlines their observation that ammonia can act as a strong H-bond donor when built into an H-bonded bridge. The CC2 calculations predict the H2NH center dot center dot center dot O distance to increase by 0.2 angstrom upon S-1 <- S-0 electronic excitation, while the (2PY)NH center dot center dot center dot NH3 H-bond remains nearly unchanged. Thus, the expansion of the doubly H-bonded bridge in the excited state is asymmetric and almost wholly due to the weakening of the interaction of ammonia with the keto acceptor group.

S-0 and S-1 State Structure, Methyl Torsional Barrier Heights, and Fast Intersystem Crossing Dynamics of 5-Methyl-2-hydroxypyrimidine

We report the analysis of the SI So rotational band contours of jet-cooled 5-methyl-2-hydroxypyrimidine (5M2HP), the enol form of deoxythymine. Unlike thymine, which exhibits a structureless spectrum, the vibronic spectrum of 5M2HP is well structured, allowing us to determine the rotational constants and the methyl group torsional barriers in the S-0 and S-1 states. The 0(0)(0), 6a(0)(1), 6b(0)(1), and 14(0)(1) band contours were measured at 900 MHz (0.03 cm(-1)) resolution using mass-specific two-color resonant two-photon ionization (2C-R2PI) spectroscopy. All four bands are polarized perpendicular to the pyrimidine plane (>90% c type), identifying the S-1 <- S-0 excitation of 5M2HP as a 1n pi* transition. All contours exhibit two methyl rotor subbands that arise from the lowest 5-methyl torsional states 0A '' and 1E ''. The S-0 and S-1 state torsional barriers were extracted from fits to the torsional subbands. The 3-fold barriers are V-3 '' = 13 cm(-1) and V3' = SI cm(-1); the 6-fold barrier contributions V-6 '' and V-6' are in the range of 2-3 cm(-1) and are positive in both states. The changes of A, B, and C rotational constants upon S-1 <- S-0 excitation were extracted from the contours and reflect an "anti-quinoidal" distortion. The 0(0)(0) contour can only be simulated if a 3 GHz Lorentzian line shape is included, which implies that the S-1(1n pi*) lifetime is similar to 55 ps. For the 6a(0)(1) and 6b(0)(1) bands, the Lorentzian component increases to 5.5 GHz, reflecting a lifetime decrease to similar to 30 ps. The short lifetimes are consistent with the absence of fluorescence from the 1n pi* state. Combining these measurements with the previous observation of efficient intersystem crossing (ISC) from the Si state to a long-lived T-1((3)n pi*) state that lies similar to 2200 cm(-1) below [S. Lobsiger, S. et al. Phys. Chem. Chem. Phys. 2010, 12, 5032] implies that the broadening arises from fast intersystem crossing with k(ISC) approximate to 2 x 10(10) s(-1). In comparison to 5-methylpyrimidine, the ISC rate is enhanced by at least 10 000 by the additional hydroxy group in position 2.

Vibronic Spectra of Jet-Cooled 2-Aminopurine center dot H2O Clusters Studied by UV Resonant Two-Photon Ionization Spectroscopy and Quantum Chemical Calculations

For understanding the major- and minor-groove hydration patterns of DNAs and RNAs, it is important to understand the local solvation of individual nucleobases at the molecular level. We have investigated the 2-aminopurine center dot H2O. monohydrate by two-color resonant two-photon ionization and UV/UV hole-burning spectroscopies, which reveal two isomers, denoted A and B. The electronic spectral shift delta nu of the S-1 <- S-0 transition relative to bare 9H-2-aminopurine (9H-2AP) is small for isomer A (-70 cm(-1)), while that of isomer B is much larger (delta nu = 889 cm(-1)). B3LYP geometry optimizations with the TZVP basis set predict four cluster isomers, of which three are doubly H-bonded, with H2O acting as an acceptor to a N-H or -NH2 group and as a donor to either of the pyrimidine N sites. The "sugar-edge" isomer A is calculated to be the most stable form with binding energy D-e = 56.4 kJ/mol. Isomers B and C are H-bonded between the -NH2 group and pyrimidine moieties and are 2.5 and 6.9 kJ/mol less stable, respectively. Time-dependent (TD) B3LYP/TZVP calculations predict the adiabatic energies of the lowest (1)pi pi* states of A and B in excellent agreement with the observed 0(0)(0) bands; also, the relative intensities of the A and B origin bands agree well with the calculated S-0 state relative energies. This allows unequivocal identification of the isomers. The R2PI spectra of 9H-2AP and of isomer A exhibit intense low-frequency out-of-plane overtone and combination bands, which is interpreted as a coupling of the optically excited (1)pi pi* state to the lower-lying (1)n pi* dark state. In contrast, these overtone and combination bands are much weaker for isomer B, implying that the (1)pi pi* state of B is planar and decoupled from the (1)n pi* state. These observations agree with the calculations, which predict the (1)n pi* above the (1)pi pi* state for isomer B but below the (1)pi pi* for both 9H-2AP and isomer A.

Treatment of soft tissue recessions at titanium implants using a resorbable collagen matrix: a pilot study

OBJECTIVES: To histologically assess the effectiveness of a porcine-derived collagen matrix (CM) and a subepithelial connective tissue graft (CTG) for the coverage of single mucosal recessions at osseointegrated dental implants. MATERIALS AND METHODS: Chronic-type mucosal Miller Class I-like recessions (mean clinical defect height: 0.67 ± 0.33-1.16 ± 0.19 mm) were established at the buccal aspect of titanium implants with platform switch in six beagle dogs. The defects were randomly allocated to either (1) coronally advanced flap surgery (CAF) + CM, (2) CAF + CTG or (3) CAF alone. At 12 weeks, histomorphometrical measurements were made (e.g.) between the implant shoulder (IS) and the mucosal margin (PM) and IS and the outer contour of the adjacent soft tissue (mucosal thickness [MT]). RESULTS: All treatment procedures investigated were associated with an almost complete soft tissue coverage of the defect area (i.e. coronal positioning of PM relative to IS). Mean IS-PM and MT values tended to be increased in both CAF + CM (1.04 ± 0.74 mm/0.71 ± 0.55 mm) and CAF + CTG (0.88 ± 1.23 mm/0.62 ± 0.66 mm) groups when compared with CAF (0.16 ± 0.28 mm/0.34 ± 0.23 mm) alone. These differences, however, did not reach statistical significance. CONCLUSIONS: Within the limits of this pilot study, it was concluded that all treatment procedures investigated were effective in covering soft tissue recessions at titanium implants.

Improved water vapour spectroscopy in the 4174-4300 cm-1 region and its impact on SCIAMACHY HDO/H2O measurements

The relative abundance of the heavy water isotopologue HDO provides a deeper insight into the atmospheric hydrological cycle. The SCanning Imaging Absorption spectroMeter for Atmospheric CartograpHY (SCIAMACHY) allows for global retrievals of the ratio HDO/H2O in the 2.3 micron wavelength range. However, the spectroscopy of water lines in this region remains a large source of uncertainty for these retrievals. We therefore evaluate and improve the water spectroscopy in the range 4174–4300 cm−1 and test if this reduces systematic uncertainties in the SCIAMACHY retrievals of HDO/H2O. We use a laboratory spectrum of water vapour to fit line intensity, air broadening and wavelength shift parameters. The improved spectroscopy is tested on a series of ground-based high resolution FTS spectra as well as on SCIAMACHY retrievals of H2O and the ratio HDO/H2O. We find that the improved spectroscopy leads to lower residuals in the FTS spectra compared to HITRAN 2008 and Jenouvrier et al. (2007) spectroscopy, and the retrievals become more robust against changes in the retrieval window. For both the FTS and SCIAMACHY measurements, the retrieved total H2O columns decrease by 2–4% and we find a negative shift of the HDO/H2O ratio, which for SCIAMACHY is partly compensated by changes in the retrieval setup and calibration software. The updated SCIAMACHY HDO/H2O product shows somewhat steeper latitudinal and temporal gradients and a steeper Rayleigh distillation curve, strengthening previous conclusions that current isotope-enabled general circulation models underestimate the variability in the near-surface HDO/H2O ratio.

Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation

BACKGROUND: Stent thrombosis may occur late after drug-eluting stent (DES) implantation, and its cause remains unknown. The present study investigated differences of the stented segment between patients with and without very late stent thrombosis with the use of intravascular ultrasound. METHODS AND RESULTS: Since January 2004, patients presenting with very late stent thrombosis (> 1 year) after DES implantation underwent intravascular ultrasound. Findings in patients with very late stent thrombosis were compared with intravascular ultrasound routinely obtained 8 months after DES implantation in 144 control patients, who did not experience stent thrombosis for > or = 2 years. Very late stent thrombosis was encountered in 13 patients at a mean of 630+/-166 days after DES implantation. Compared with DES controls, patients with very late stent thrombosis had longer lesions (23.9+/-16.0 versus 13.3+/-7.9 mm; P<0.001) and stents (34.6+/-22.4 versus 18.6+/-9.5 mm; P<0.001), more stents per lesion (1.6+/-0.9 versus 1.1+/-0.4; P<0.001), and stent overlap (39% versus 8%; P<0.001). Vessel cross-sectional area was similar for the reference segment (cross-sectional area of the external elastic membrane: 18.9+/-6.9 versus 20.4+/-7.2 mm2; P=0.46) but significantly larger for the in-stent segment (28.6+/-11.9 versus 20.1+/-6.7 mm2; P=0.03) in very late stent thrombosis patients compared with DES controls. Incomplete stent apposition was more frequent (77% versus 12%; P<0.001) and maximal incomplete stent apposition area was larger (8.3+/-7.5 versus 4.0+/-3.8 mm2; P=0.03) in patients with very late stent thrombosis compared with controls. CONCLUSIONS: Incomplete stent apposition is highly prevalent in patients with very late stent thrombosis after DES implantation, suggesting a role in the pathogenesis of this adverse event.

Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications

Although rare, stent thrombosis remains a severe complication after stent implantation owing to its high morbidity and mortality. Since the introduction of drug-eluting stents (DES), most interventional centers have noted stent thrombosis up to 3 years after implantation, a complication rarely seen with bare-metal stents. Some data from large registries and meta-analyses of randomized trials indicate a higher risk for DES thrombosis, whereas others suggest an absence of such a risk. Several factors are associated with an increased risk of stent thrombosis, including the procedure itself (stent malapposition and/or underexpansion, number of implanted stents, stent length, persistent slow coronary blood flow, and dissections), patient and lesion characteristics, stent design, and premature cessation of antiplatelet drugs. Drugs released from DES exert distinct biological effects, such as activation of signal transduction pathways and inhibition of cell proliferation. As a result, although primarily aimed at preventing vascular smooth muscle cell proliferation and migration (ie, key factors in the development of restenosis), they also impair reendothelialization, which leads to delayed arterial healing, and induce tissue factor expression, which results in a prothrombogenic environment. In the same way, polymers used to load these drugs have been associated with DES thrombosis. Finally, DES impair endothelial function of the coronary artery distal to the stent, which potentially promotes the risk of ischemia and coronary occlusion. Although several reports raise the possibility of a substantially higher risk of stent thrombosis in DES, evidence remains inconclusive; as a consequence, both large-scale and long-term clinical trials, as well as further mechanistic studies, are needed. The present review focuses on the pathophysiological mechanisms and pathological findings of stent thrombosis in DES.

Clinical end points in coronary stent trials: a case for standardized definitions

BACKGROUND: Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end points, differences in definitions and timing of assessment have created confusion in interpretation. METHODS AND RESULTS: The Academic Research Consortium is an informal collaboration between academic research organizations in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006, sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs, were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of considerations from historical legacy to key pathophysiological mechanisms and relevance to clinical interpretability, criteria for assessment of death, myocardial infarction, repeat revascularization, and stent thrombosis were developed. The broadly based consensus end point definitions in this document may be usefully applied or recognized for regulatory and clinical trial purposes. CONCLUSION: Although consensus criteria will inevitably include certain arbitrary features, consensus criteria for clinical end points provide consistency across studies that can facilitate the evaluation of safety and effectiveness of these devices.