Synchronization of delay-coupled oscillators: a study of semiconductor lasers.

Two delay-coupled semiconductor lasers are studied in the regime where the coupling delay is comparable to the time scales of the internal laser oscillations. Detuning the optical frequency between the two lasers, novel delay-induced scenarios leading from optical frequency locking to successive states of periodic intensity pulsations are observed. We demonstrate and analyze these dynamical phenomena experimentally using two distinct laser configurations. A theoretical treatment reveals the universal character of our findings for delay-coupled systems.

Delay dynamics of semiconductor lasers with short external cavities: bifurcation scenarios and mechanisms.

We present a comprehensive study of the emission dynamics of semiconductor lasers induced by delayed optical feedback from a short external cavity. Our analysis includes experiments, numerical modeling, and bifurcation analysis by means of computing unstable manifolds. This provides a unique overview and a detailed insight into the dynamics of this technologically important system and into the mechanisms leading to delayed feedback instabilities. By varying the external cavity phase, we find a cyclic scenario leading from stable intensity emission via periodic behavior to regular and irregular pulse packages, and finally back to stable emission. We reveal the underlying interplay of localized dynamics and global bifurcations.

Dynamics of semiconductor lasers subject to delayed optical feedback: the short cavity regime.

We give experimental and numerical evidence for a new dynamical regime in the operation of semiconductor lasers subject to delayed optical feedback occurring for short delay times. This short cavity regime is dominated by a striking dynamical phenomenon: regular pulse packages forming a robust low-frequency state with underlying fast, regular intensity pulsations. We demonstrate that these regular pulse packages correspond to trajectories moving on global orbits comprising several destabilized fixed points within the complicated phase space structure of this delay system.

Chaos synchronization and spontaneous symmetry-breaking in symmetrically delay-coupled semiconductor lasers.

We present experimental and numerical investigations of the dynamics of two device-identical, optically coupled semiconductor lasers exhibiting a delay in the coupling. Our results give evidence for subnanosecond coupling-induced synchronized chaotic dynamics in conjunction with a spontaneous symmetry-breaking: we find a well-defined time lag between the dynamics of the two lasers, and an asymmetric physical role of the subsystems. We demonstrate that the leading laser synchronizes its lagging counterpart, whereas the synchronized lagging laser drives the coupling-induced instabilities.

Amplitude-squeezed emission from a transverse single-mode vertical-cavity surface-emitting laser with weakly anticorrelated polarization modes.

We discuss the polarization-resolved intensity noise characteristics of a transverse single-mode vertical-cavity surface-emitting laser (VCSEL). Measurements by a sensitivity-enhanced lock-in amplifier detection scheme yield only an imperfect anticorrelation between the strong and the weak orthogonally polarized fundamental modes. Yet the total emission shows amplitude squeezing of 0.4 dB below the shot-noise level. Unlike for transverse two-mode emission, a perfect anticorrelation between the two polarization modes is not necessary for generation of amplitude-squeezed emission in a transverse single-mode VCSEL, in agreement with theoretical predictions.

Long-term stable mode locking of a visible diode laser with phase-conjugate feedback.

We present a new method to obtain long-term stable phase-conjugate feedback (pcf) with a photorefractive crystal for a mode-locked semiconductor laser. The phase-conjugate mirror is a barium titanate crystal in a self-pumped internal reflection configuration, and the laser is a visible, antireflection-coated AlGaInP diode. We describe a new dynamic writing procedure for growth of an index grating in the photorefractive crystal that leads to stable pcf and discuss the reasons for this stability, which is the major advantage of this method over previously reported ones. Using this superior method, we achieve stable mode-locked operation of the laser with pulse widths of ~30 ps and a timing jitter of less than 2 ps.

Synergistic inhibition of AZT-resistant HIV by AZT combined with poly(I):poly(C12U), without synergistic toxicity to bone marrow progenitor cell elements.

Mutation of human immunodeficiency virus (HIV) to drug resistance is an obstacle to HIV containment, and may account for the transitory nature of the improvement in CD4 cell counts of patients receiving azidothymidine (AZT). The emergence of AZT-resistant (AZTR) virus might be suppressed if a second therapeutic could be added; however, such a regimen would have to confer not only additional control over HIV replication but also no additional toxicity, especially to bone marrow progenitor cells. In the present study, HIV was isolated from patients receiving AZT alone and was studied for sensitivity to the mismatched double-stranded RNA, poly(I):poly(C12U) (ampligen). In addition, the combination of poly(I):poly(C12U) plus AZT was studied in vitro for toxicity to bone marrow CFU-GM and in patients receiving combined therapy for bone marrow toxicity. HIV isolated from patients receiving AZT alone showed higher resistance to AZT than wildtype virus, but remained sensitive to poly(I):poly(C12U). Poly(I):poly(C12U) and AZT were synergistic in inhibiting all isolates of HIV tested, regardless of their AZTR phenotype. Furthermore, the combination of poly(I):poly(C12U) and AZT showed no toxicity in vitro to bone marrow CFU-GM compared to AZT alone. In 11 HIV infected individuals receiving the combinational regimen, bone marrow function gradually improved. These results indicate that poly(I):poly(C12U) was active against AZTR HIV, synergistic with AZT and did not convey added toxicity.

A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a physically debilitating illness associated with immunologic abnormalities, viral reactivation, and impairment of cognition. In a randomized, multicenter, placebo-controlled, double-blind study of 92 patients meeting the CFS case definition of the Centers for Disease Control and Prevention, the response of several laboratory and clinical variables to an antiviral and immunomodulatory drug, poly(I).poly(C12U), was determined. Measures of clinical response included Karnofsky performance score, a cognition scale derived from a self-administered instrument assessing symptomatology (SCL-90-R), an activities of daily living scale, and exercise treadmill performance. After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo. In particular, patients given poly(I).poly(C12U) had increased Karnofsky performance scores (P < .03), exhibited a greater ability to do work during exercise treadmill testing (P = .01), displayed an enhanced capacity to perform the activities of daily living (P < .04), had a reduced cognitive deficit (P = .05), and required less use of other medications (P < .05).

Elimination of flecainide as a function of urinary flow rate and pH.

In order to evaluate the influence of urinary flow rate at different pH values on the pharmacokinetics of the basic antiarrhythmic drug flecainide 7 healthy men received 50 mg flecainide under 4 different conditions: 1. acidic urine (pH 5) and a high fluid load (125 ml.h-1) 2. acidic urine (pH 5) and a low fluid load (25 ml.h-1) 3. alkaline urine (pH 8) and a high fluid load (125 ml.h-1) 4. alkaline urine (pH 8) and a low fluid load (25 ml.h-1) At acidic pH the half-life, the amount of unchanged drug in the urine (Ae), renal clearance (CLR) and area under the curve (AUC) were independent of the fluid load. At alkaline pH Ae (5.8 vs 2.6 mg) and CLR (73 vs 33 ml.min-1) were significantly affected by fluid load (high vs low), whereas half-life and AUC were not different (15.7 vs 16.0 h, 1480 vs 1540 ng.ml-1.h). When comparing acidic and alkaline urinary pH conditions, half-life, Ae, CLR, and AUC were different. For a high fluid load the values at acidic vs alkaline pH were half-life 10.0 vs 15.7 h; Ae 15.9 vs 5.8 mg; CLR 288 vs 73 ml.min-1; AUC 976 vs 1480 ng.ml-1.h. For a low fluid load the corresponding values at acidic vs alkaline pH were half-life 10.1 vs 16.0 h; Ae 15.9 vs 2.6 mg; CLR 267 vs 33 ml.min-1; AUC 1045 vs 1540 ng.ml-1.h. It is concluded that urinary pH affects flecainide pharmacokinetics independently of urinary flow rate, and that a high flow enhances the elimination of flecainide only with an alkaline urine. This effect of flow rate does not appear to be of clinical relevance.

Nonamphoteric isoelectric focusing: II. Stability of borate-glycerol pH gradients in recycling isoelectric focusing.

By complexing polyols with borate in recycling isoelectric focusing and by varying the ratio of polyol to borate over the useful pH range of 4.0-6.0, it is possible to control pH. Twelve solutions of 0.1 M boric acid and varying glycerol concentration were used to vary pH in a twelve-compartment commercial recycling isoelectric focusing (RIEF) system. Various concentrations of boric acid were tested as anolyte, and various Tris(hydroxymethylamino)methane-borate buffer systems were tested as catholyte. Electroosmosis, hydrogen ion flow, and fluid balancing were characterized in two glycerol gradients; one was maintained at 0.06 pH/fraction and the other at 0.12 pH/fraction. In the latter case, ovalbumin (pI4.70) migrated to the pH 4.61 and 4.72 compartments. It is concluded that the borate-glycerol system can be adequately stabilized in RIEF for isoelectric purification of certain proteins.

Nonlinear optical interaction in semiconductor lasers due to population pulsations.

Population pulsations are demonstrated as a basic mechanism for nonlinear optical interaction in a semiconductor laser by detecting the optical beat frequency in the noise spectrum of the injection current.

Enoxacin--a potent inhibitor of theophylline metabolism.

The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.

Outline of a theory of cellular heterogeneity.

In the effort to advance toward a theory of cellular function that is not completely mechanistic, I have encountered a variable whose significance is often overlooked. This is the degree of heterogeneity of organic tissue, which may vary from highly homogeneous conditions to quite large degrees of heterogeneity, primarily with respect ot chemical bonding. For several decades, I have dealt with the theoretical analysis of this type of problem, and here I give a condensed outline of the conceptual changes to which such an analysis is likely to lead. I believe the time is ripe to compare these theoretical arguments with observations. The data that occasion this note are those of Rubin [Rubin, H. (1984) Proc. Natl. Acad. Sci. USA 81, 5121-5125]; they and numerous similar observations suggest the possibility of an advance toward a nonreductionist model of cellular function along lines that are here indicated; the theoretical model is thought of as operating entirely within the framework of quantum mechanics.

Biological application of the statistical concepts used in the Second Law.

The idea that living things violate the Second Law has been suggested many times. We point out that any mathematical formalism can be applied to a variety of physical processes; here to all molecules on the one hand (Boltzmann) and to messages of the genetic code on the other. The latter is an application of what is known as Shannon's law of communications theory. One application can be valid without the other, in particular if we suspect Shannon's law, this does not imply a breakdown of the molecular law leading to thermodynamics. To avoid a defect of Shannon's law, a widening of the representative "space" of the genome is proposed; the new space, called here the "polymeric space" is found to have properties that make it particularly suitable as a vehicle of biological description. We find that in this manner an apparent violation of Shannon's law can be accounted for.