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Biomedical subjects

H Levine

Publications and source records attributed to H Levine.

At least 19 recordsLinked to original sources
PubMed2004

Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men.

OBJECTIVE: A phase I single centre, open label study of the pharmacokinetics and tolerability of a buccal testosterone tablet (COL 1621) was carried out. DESIGN: Twelve testosterone-deficient males were treated with the buccal tablet twice daily for 7 consecutive days. Multiple blood samples were drawn for testosterone, dihydrotestosterone (DHT), bioavailable testosterone and sex hormone-binding globulin (SHBG). RESULTS: After COL 1621, means+/-S.D. serum testosterone level increased to a peak concentration of 26.6+/-5.8 nmol/l (7.7+/-1.7 ng/ml) at 4.8+/-5.8 h and stayed in the eugonadal range. Steady state was achieved within the first 24 h and was maintained in the normal range. The bioavailable testosterone, DHT and free testosterone index followed a pattern very similar to that of testosterone. The mean serum testosterone to DHT ratio was within the normal male range throughout treatment. There was only one treatment-related adverse event (headache). Two-thirds of patients indicated that treatment with COL 1621 was acceptable and that the tablet was convenient to use. Six patients (50.0%) preferred COL 1621 to their previous testosterone replacement therapy, two patients gave preference to their previous treatment and three patients found both treatments to be equally acceptable. Data for one patient was not available. CONCLUSION: We conclude that COL 1621 can efficiently elevate serum testosterone and DHT levels in hypogonadal men within the first day of application, achieve a steady state within 24 h and maintain serum testosterone in the normal range with a twice-daily treatment regimen. COL 1621 provides an effective alternative oral testosterone replacement therapy that gives physiological levels of testosterone and is well tolerated by the patients.

Administration, Buccal↗
PubMed2003

Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence.

Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Spatiotemporal dynamics of HIV propagation.

Although viral propagation is a localized process, mathematical models of viral replication kinetics have been limited to systems of ordinary differential equations describing spatially averaged behavior. In this paper, we introduce a cellular automaton model of viral propagation based on the known biophysical properties of HIV. In particular, we include the competition between viral lability and Brownian motion. The model predicts three testable effects not present in previous descriptions. First, we find a profound dependence of viral infectivity on cell concentration; virion instability decreases infectivity more than 100-fold under typical experimental conditions, resulting in misleading estimates of the number of infectious particles. Second, we find that, in a large parameter regime, infection extinguishes itself due to insufficient target cell replenishment. Finally, we find that propagation is limited by viral stability at low cell density and by geometry at high cell density. The geometry-limited regime can be modulated by downregulation of CD4. These different properties are analysed quantitatively and compared with previous experimental results.

Animals↗
PubMed2001

Phase-field model of mode III dynamic fracture.

We introduce a phenomenological continuum model for the mode III dynamic fracture that is based on the phase-field methodology used extensively to model interfacial pattern formation. We couple a scalar field, which distinguishes between "broken" and "unbroken" states of the system, to the displacement field in a way that consistently includes both macroscopic elasticity and a simple rotationally invariant short-scale description of breaking. We report two-dimensional simulations that yield steady-state crack motion in a strip geometry above the Griffith threshold.

Journal Article↗
PubMed2001

Microscopic selection of fluid fingering patterns.

We study the issue of the selection of viscous fingering patterns in the limit of small surface tension. Through detailed simulations of anisotropic fingering, we demonstrate conclusively that no selection independent of the small-scale cutoff (macroscopic selection) occurs in this system. Rather, the small-scale cutoff completely controls the pattern, even on short time scales, in accordance with the theory of microscopic solvability. We demonstrate that ordered patterns are dynamically selected only for not too small surface tensions. For extremely small surface tensions, the system exhibits chaotic behavior and no regular pattern is realized.

Journal Article↗
PubMed2001

Acoustical cavity excitation.

A tutorial exposition is given of cavity excitations and it is shown that relatively simple analytical solutions for the excitation of acoustic fields in cavities with lossy walls can be obtained for a broad class of such cavities. The standard analytic procedure whereby one expresses the acoustic field as a sum over the eigenmodes of the cavity is reviewed and its limitations are pointed out. An alternate procedure is to seek to make use of Green's functions depending on a single coordinate and to not express such Green's functions as sums over eigenfunctions. Instead, one expresses the Green's function as a closed form function that has a discontinuous slope at the value of the coordinate corresponding to the source location. Although the class of cavities for which this approach is possible is limited, it is sufficiently broad to be of intrinsic interest and the results may be helpful to those seeking benchmark solutions and analytic insight. Displayed examples are for cavities whose shapes are spheres and cylinders, with interior monopole, dipole, line, and distributed sources. The formulation yields simple expressions for the total power absorbed by the cavity walls.

Journal Article↗
PubMed2000

Nonlinear lattice model of viscoelastic mode III fracture.

We study the effect of general nonlinear force laws in viscoelastic lattice models of fracture, focusing on the existence and stability of steady-state mode III cracks. We show that the hysteretic behavior at small driving is very sensitive to the smoothness of the force law. At large driving, we find a Hopf bifurcation to a straight crack whose velocity is periodic in time. The frequency of the unstable bifurcating mode depends on the smoothness of the potential, but is very close to an exact period-doubling instability. Slightly above the onset of the instability, the system settles into a exactly period-doubled state, presumably connected to the aforementioned bifurcation structure. We explicitly solve for this new state and map out its velocity-driving relation.

Journal Article↗
PubMed2000

Self-organization in systems of self-propelled particles.

We investigate a discrete model consisting of self-propelled particles that obey simple interaction rules. We show that this model can self-organize and exhibit coherent localized solutions in one- and in two-dimensions. In one-dimension, the self-organized solution is a localized flock of finite extent in which the density abruptly drops to zero at the edges. In two-dimensions, we focus on the vortex solution in which the particles rotate around a common center and show that this solution can be obtained from random initial conditions, even in the absence of a confining boundary. Furthermore, we develop a continuum version of our discrete model and demonstrate that the agreement between the discrete and the continuum model is excellent.

Animals↗
PubMed2000

How does a beta -hairpin fold/unfold? competition between topology and heterogeneity in a solvable model.

We study the competition between topological effects and sequence inhomogeneities in determining the thermodynamics and the un/folding kinetics of a beta-hairpin. Our work utilizes a new exactly solvable model that allows for arbitrary configurations of native contacts. In general, the competition between heterogeneity and topology results in a crossover of the dominant transition state. Interestingly, near this crossover, the single reaction coordinate picture can be seriously misleading. Our results also suggest that inferring the folding pathway from unfolding simulations is not always justified.

Animals↗
PubMed2000

Discrete stochastic modeling of calcium channel dynamics.

We propose a discrete stochastic model for calcium dynamics in living cells. A set of probabilities for the opening/closing of calcium channels is assumed to depend on the calcium concentration. We study this model in one dimension, analytically in the limit of a large number of channels per site N, and numerically for small N. As the number of channels per site is increased, the transition from a nonpropagating region of activity to a propagating one changes from one described by directed percolation to that of deterministic depinning in a spatially discrete system. Also, for a small number of channels a propagating calcium wave can leave behind a novel fluctuation-driven state.

Calcium Channels↗
PubMed2000

Two state behavior in a solvable model of beta-hairpin folding.

Understanding the mechanism of protein secondary structure formation is an essential part of the protein-folding puzzle. Here we describe a simple model for the formation of a beta hairpin, motivated by the fact that folding of a beta hairpin captures much of the basic physics of protein folding. The modeled hairpin is composed of two interacting Gaussian chains with one pairwise (two-body) and two many-body interactions. We show that these many-body interactions, arising from side chain packing effects, are responsible for producing an "all-or-none" folding transition. We also estimate the (single exponential) folding/unfolding rate via calculating the thermodynamic weight of the "critical" droplet/bubble.

Kinetics↗
PubMed2000

Comparison of the pharmacokinetics of crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women(3).

OBJECTIVE: Compare the pharmacokinetics of vaginal progesterone gel (Crinone 8%, 90 mg) with that of oral progesterone (Prometrium, 100 mg). DESIGN: Open-label, randomized, parallel-group protocol. SETTING: Outpatient clinic. PATIENT(S): Twelve healthy postmenopausal women. INTERVENTION(S): Six subjects each were randomized to receive progesterone, which was administered either as 90 mg of progesterone gel (Crinone 8%) given vaginally or 100 mg progesterone in a capsule (Prometrium) given orally. MAIN OUTCOME MEASUREMENT(S): Serum progesterone levels were measured by both radioimmunoassay (RIA) and liquid chromatography-mass spectrometry (LC-MS). RESULT(S): Progesterone given vaginally resulted in greater bioavailability with less relative variability in absorption than oral progesterone (mean AUC(0-24) = 1.48 +/- 0.16 ng. h/mL per milligram vs. 0.035 +/- 0.0052 ng. h/mL per milligram). Mean C(max) for oral progesterone was much lower than that of vaginal progesterone (i.e., 2.20 +/- 3. 06 ng/mL vs. 10.51 +/- 0.46 ng/mL). Mean T(max) occurred earlier for oral progesterone than for Crinone (1.00 +/- 0.41 hours vs. 7.67 +/- 3.67 hours). Radioimmunoassay is inappropriate for determining serum progesterone levels after oral administration, because it provided erroneously high values that were approximately eightfold higher than those obtained with LC-MS. CONCLUSION(S): Crinone (progesterone gel) given vaginally results in greater bioavailability with less relative variability than oral progesterone, thus providing more reliable delivery of progesterone, compared with oral progesterone. Measuring circulating progesterone with use of direct RIA is not appropriate after oral progesterone administration.

Administration, Intravaginal↗
PubMed2000

Developmental competence of juvenile calf oocytes in vitro and in vivo: influence of donor animal variation and repeated gonadotropin stimulation.

Juvenile calf oocytes represent an untapped source of germ plasm for reproduction. Reports on the developmental competence of calf oocytes have been controversial. In this research, oocytes were recovered after gonadotropin stimulation from Holstein calves (N = 10) at 2-3 mo of age (2-mo cycle) and again at 4-5 mo of age (4-mo cycle). The in vitro developmental competence was measured, and prestimulation follicle numbers (for 2-mo cycle) and poststimulation follicle numbers (both cycles) were obtained. The number of antral follicles doubled after stimulation (23.4 +/- 6.1 vs. 55.1 +/- 16.1) for the 2-mo cycle and for the 4-mo cycle (47.4 +/- 12.4). The number of follicles observed prior to stimulation in the 2-mo cycle was found to be highly correlated with the poststimulation oocyte recovery for both collection cycles (r = 0.95, 2-mo cycle; r = 0.81, 4-mo cycle). The majority (90-96%) of recovered oocytes were found to be usable for in vitro maturation and fertilization; of these, 41-42% cleaved and 10-11% developed to morulae or blastocysts. Eighty-four in vitro-produced embryos were transferred to synchronized recipients and resulted in 11 pregnancies, leading to 7 live (4 males, 3 females) and 2 dead (one male, one female) calves at full term. No significant differences were observed between the 2-mo and 4-mo collection cycles; however, 73% of the total pregnancies resulted from the 2-mo cycle. All pregnancies resulted from embryos of high-responding donors. The high correlation between the number of follicles prior to stimulation and the poststimulation response suggests the possibility of screening calves prior to stimulation for routine embryo production.

Aging↗
PubMed2000

Nutrient chemotaxis suppression of a diffusive instability in bacterial colony dynamics.

Bacteria grown on a semisolid agar surface have been observed to form branching patterns as the colony envelope propagates outward. The fundamental cause of this instability relates to the need for limited nutrient to diffuse towards the colony. Here, we investigate the effect on this instability of allowing the bacteria to move chemotactically in response to the nutrient gradient. Our results show that this additional effect has a tendency to suppress the instability. Our calculations are done within the context of a simple "cutoff" model of colony dynamics, but presumably remain valid for more complex and hence more realistic approaches.

Bacteria↗
PubMed2000

Stochastic spreading of intracellular Ca(2+) release.

We study the spreading of calcium-induced calcium release with the stochastic DeYoung-Keizer-model of the inositol 1,4,5-trisphosphate receptor channel. The model shows a transition from isolated release events to steadily propagating waves with increasing IP3 concentration. A state--stochastic backfiring--was found in the regime of steady propagation. The model can be reduced by an adiabatic elimination of the partial differential equation for the Ca(2+) concentration to a lattice of stochastic channel clusters.

Calcium↗