Search Results - (Author, Cooperation:M. A. Young)

2012-01-13

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Antineoplastic Agents/adverse effects/therapeutic use ; Clonal Evolution/*genetics ; Clone Cells/drug effects/metabolism/pathology ; DNA Damage/drug effects ; DNA Mutational Analysis ; Genes, Neoplasm/genetics ; Genome, Human/drug effects/*genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Leukemia, Myeloid, Acute/drug therapy/*genetics/*pathology ; Mutagenesis/drug effects/genetics ; Recurrence ; Reproducibility of Results

1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

The first excited electronic state (S1) vibrational dynamics of aniline(Ar)1 and aniline(CH4)1 van der Waals (vdW) clusters have been studied using molecular jet and time resolved emission spectroscopic techniques. The rates of intramolecular vibrational energy redistribution (IVR) and vibrational predissociation (VP) as functions of vibrational energy are reported for both clusters. For vibrational energy in excess of the cluster binding energy, both clusters are observed to dissociate. The dispersed emission spectra of these clusters demonstrate that aniline(Ar)1 dissociates to all energetically accessible bare molecule states and that aniline(CH4)1 dissociates selectively to only the bare molecule vibrationless state. The emission kinetics show that in the aniline(Ar)1 case, the initially excited states have nanosecond lifetimes, and intermediate cluster states have very short lifetimes. In contrast, the initially excited aniline(CH4)1 states and other intermediate vibrationally excited cluster states are very short lived (〈100 ps), and the intermediate cluster 00 state is observed. These results can be understood semiquantitatively in terms of an overall serial IVR/VP mechanism which consists of the following: (1) the rates of chromophore to vdW mode IVR are given by Fermi's golden rule, and the density of vdW vibrational states is the most important factor in determining the relative [aniline(Ar)1 vs aniline(CH4)1] rates of IVR; (2) IVR among the vdW modes is rapid; and (3) VP rates can be calculated by a restricted vdW mode phase space Rice–Ramsberger–Kassel–Marcus theory. Since the density of vdW states is three orders of magnitude greater for aniline(CH4)1 than aniline(Ar)1 at 700 cm−1, the model predicts that IVR is slow and rate limiting in aniline(Ar)1, whereas VP is slow and rate limiting in aniline(CH4)1. The agreement of these predictions with the experimental results is very good and is discussed in detail.

Electronic Resource

1089-7623

AIP Digital Archive

Physics

Electrical Engineering, Measurement and Control Technology

A broadband detection scheme for a time-resolved infrared absorption spectrometer, based on a multielement mercury-cadmium-telluride (MCT) array, has been successfully implemented. The spectrometer achieves a resolution on the 10-ns time scale despite the much larger time constant characteristic of the MCT elements. Our signal-collection circuitry takes advantage of the slow decay by integrating the detector response to pulsed IR radiation. The dynamic range is 100–1 and the resultant noise level is near the detector limit. Data acquisition for the 120 elements is fast enough to allow scan rates of 30–40 Hz. The completed electronics are sufficiently compact to be situated local to the array detector, and the design is relatively inexpensive to construct using commonly found electronic components.

Electronic Resource

1089-7623

AIP Digital Archive

Physics

Electrical Engineering, Measurement and Control Technology

An amplified tunable picosecond dye laser has been constructed which is pumped by an active-passive mode-locked Nd:YAG laser. The laser is tunable from 555 nm to 〉700 nm. It provides a maximum of 2-mJ pulses with pulse widths of ∼17 ps (FWHM). The tuning range can be extended by frequency doubling and/or mixing with the residual 1064-nm pulses. The dye laser is very stable and relatively inexpensive to construct.

Electronic Resource

1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

We have investigated the photofragmentation spectroscopy of Mg2(CO2)+1,2 in a reflectron time-of-flight mass spectrometer. For the linear bimolecular complex Mg2(CO2)+, we have observed three distinct molecular absorption bands, in the red, the green, and the near uv spectral regions. In each band both Mg+ and Mg+2 fragments are observed, although with different action spectra. In the uv band, we also observe reactive fragmentation to form the chemical product Mg2O+. As an initial step in investigating the dissociation mechanism and the dynamical effects which determine the final state branching, we have carried out preliminary calculations of the low lying Mg2(CO2)+ potential energy curves in collinear geometry. Photofragmentation of the complex Mg2(CO2)+2 occurs over a broad spectral range in the visible. We have found that the addition of the second solvent molecule dramatically enhances the solvent cage effect, as evidenced by a large increase in the Mg+2/Mg+ branching ratio throughout this spectral region. © 1995 American Institute of Physics.

Electronic Resource

1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

We have investigated the spectroscopy and photochemistry of Zn+(C2H4) in an angular reflectron time-of-flight mass spectrometer. We identify four absorption bands in the spectral range 220–550 nm. These bands are assigned to radiative transitions in the bimolecular complex correlating with Zn-centered and ethylene-centered absorptions, and with Zn–ethylene photo-induced charge transfer processes. The lowest energy band, assigned as 1 2B2←1 2A1, is a weak continuum consistent with a large geometry change and fast predissociation. The higher energy 1 2B1←1 2A1 band shows a long progression in the intermolecular stretch with a mode frequency of ωe=333.7 cm−1. The spectroscopic results, including partially resolved rotational structure, are consistent with a weakly bound, π-bonded complex in C2v symmetry. A Birge–Sponer analysis gave an estimate for the dissociation energies of the excited 1 2B1 state as De′=2.76 eV and the ground 1 2A1 state as De″=0.86 eV. A second structured band at still higher energies is tentatively assigned as 2 2B2←1 2A1 and shows activation of higher frequency intramolecular ethylene modes. Zn+ and C2H4+ fragment ions are observed over most of the spectral range. At higher energies (λ〈250 nm) we also see a significant branching to reactive products C2H2+ and C2H3+ that result from charge transfer accompanied by C–H bond cleavage. We propose a reaction mechanism that involves coupling through an excited charge-transfer state followed by C–H bond insertion. © 2001 American Institute of Physics.

Electronic Resource

1432-0428

Keywords Insulin secretion ; C-peptide kinetics ; normal subjects ; type 2 diabetes ; mathematical modelling.

Springer Online Journal Archives 1860-2000

Medicine

Summary The accuracy of calculations of pre-hepatic insulin secretion were investigated, to provide independent validation of a population model of C-peptide kinetics. The effects of sampling frequency were also assessed. Five normal subjects (aged 28 to 43 years; BMI (kg/m2) 20.5 to 24.5) and five subjects with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone (aged 34 to 57 years; BMI 22.6 to 25.6) were given a variable intravenous infusion of biosynthetic human C-peptide (BHCP) (t = –60 to 240 min) mimicking meal stimulated C-peptide secretion, with short-term oscillations (peak approximately every 12 min) superimposed on the infusion profile. Plasma C-peptide was measured every 5 min (t = 0 to 240 min). The BHCP infusion was reconstructed from C-peptide measurements using a population model of C-peptide kinetics and a deconvolution method. Bias, defined as the percentage difference between the total amount of calculated BHCP and the total amount of infused BHCP (t = 0 to 240 min), indicated that overall C-peptide secretion can be measured with 14 % [95 % confidence interval (CI) –11 to 39 %] and 21 % (95 % CI –3 to 45 %) accuracy in normal subjects and subjects with NIDDM respectively. Accuracy was not reduced by reducing the sampling frequency to every 30 min. The root mean square error, measuring the average deviation between the infused and normalised calculated BHCP profiles, was also independent of the sampling frequency [mean (95 % CI) 0.9 (0.3 to 1.6) pmol/kg per min in normal subjects; 1.0 (0.9 to 1.1) pmol/kg per min in subjects with NIDDM]. Deconvolution employing a population model of C-peptide kinetics can be used to estimate postprandial total C-peptide secretion with biases of 14 % and 22 % respectively in normal subjects and subjects with NIDDM. Plasma C-peptide samples need only be drawn every 30 minutes. [Diabetologia (1998) 41: 548–554]

Electronic Resource

1432-1041

Key words Troglitazone ; Hepatic insufficiency

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Abstract Objective: Troglitazone is an agonist of the peroxisome proliferator-activated receptor-γ (PPAR-γ), which has been shown to improve the metabolic control of type 2 diabetes. Troglitazone undergoes hepatic metabolism to an inactive sulphate conjugate and an oxidative quinone metabolite with minor activity. The objective of this study was to compare the pharmacokinetics of troglitazone in patients with hepatic insufficiency and normal subjects. Methods: Three groups of eight subjects with normal liver function and moderate or severe hepatic impairment (Pugh-Child classification) completed this open study. Subjects received a single 400-mg dose of troglitazone 30 min after breakfast. Plasma concentrations of troglitazone and its metabolites were measured and standard pharmacokinetic parameters derived. Results: A 46% increase in area under the plasma concentration-time curve (AUClast) was observed for troglitazone, together with a 154% increase for the quinone metabolite in the patients with moderate hepatic impairment compared with normal subjects, but these did not reach statistical significance. Corresponding increases of 18% and 53% in the severe group also failed to reach statistical significance. For the sulphate conjugate, the AUClast values for both moderate and severe hepatic impairment were in the order of fourfold higher than those in the normal group. There were reductions in the maximum observed plasma concentration (Cmax) of troglitazone to 61% of the normal group in the severe group for troglitazone, and twofold increases in sulphate metabolite Cmax in the moderate and severe groups. There was an approximately threefold increase in the half-life of the sulphate conjugate in subjects with both moderate and severe impairment of liver function compared with normal individuals. First times to maximum concentrations of troglitazone, its sulphate conjugate and the quinone metabolite were significantly longer in all severely impaired subjects compared with those with normal hepatic function, although the range was wide in all cases. Plasma protein binding was high in all subjects measured (mean unbound fraction range 0.7–5.1%), but there were insufficient samples to compare across groups. Conclusion: The formation of metabolites of troglitazone following a single dose is not impaired in the presence of reduced liver function although the capacity to eliminate the metabolites is altered. The clinical significance of the effect of liver disease on the conjugates is not clear.

Electronic Resource

1432-1041

indapamide ; hypertension ; cardiovascular reflexes ; diuretic effect ; blood pressure variability

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Summary Nine elderly and 11 young hypertensives underwent continuous ambulatory monitoring of blood pressure (BP), assessment of cardiovascular reflexes and M-mode echocardiography as hospital in-patients prior to treatment with once-daily indapamide (2.5 mg). They were followed as out-patients for 4 months during which time casual BP was measured at monthly intervals. The patients were then readmitted to hospital and studied using the same protocol under similar standardised conditions. The results showed that indapamide reduced casual and ambulatory BP in both young and elderly although the most marked effect was seen on systolic BP. Assessment of cardiovascular reflexes indicates that at least part of the hypotensive action of indapamide is due to a diuretic effect. Treatment with indapamide has comparable results on both young and elderly.

Electronic Resource

1572-8951

MD ; DNA ; protein-DNA ; simulation ; solvent ; lambda repressor ; operator ; GROMOS ; reduced charge model

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Abstract The results of a recent nanosecond (ns) molecular dynamics (MD) simulation of the d(CGCGAATTCGCG) double helix in water and a 100 ps MD study of the λ repressor-operator complex are described. The DNA simulations are analyzed in terms of the structural dynamics, fluctuations in the groove width and bending of the helical axis. The results indicate that the ns dynamical trajectory progresses through a series of three substates of B form DNA, with lifetimes of the order of hundreds of picoseconds (ps). An incipient dynamical equilibrium is evident. A comparison of the calculated axis bending with that observed in corresponding crystal structure data is presented. Simulation of the DNA in complex with the protein and that of the free DNA in solution, starting from the crystal conformation, reveal the dynamical changes that occur on complex formation.

Electronic Resource