High-frequency pulsations in DFB lasers with amplified feedback

We describe the basic ideas behind the concept of distributed feedback (DFB) lasers with short optical feedback for the generation of high-frequency self-pulsations and show the theoretical background describing realized devices. It is predicted by theory that the self-pulsation frequency increases with increasing feedback strength. To provide evidence for this, we propose a novel device design which employs an amplifier section in the integrated feedback cavity of a DFB laser. We present results from numerical simulations and experiments. It has been shown experimentally that a continuous tuning of the self-pulsation frequency from 12 to 45 GHz can be adjusted via the control of the feedback strength. The numerical simulations, which are in good accordance with experimental investigations, give an explanation for a self-stabilizing effect of the self-pulsations due to the additional carrier dynamic in the integrated feedback cavity.     

Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting

PURPOSE: To determine the maximum-tolerated doses (MTD), the principal toxicities, and the pharmacologic behavior of high doses of Taxol (paclitaxel; Bristol-Myers Squibb, New York, NY) combined with cisplatin and granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: Untreated and minimally pretreated solid-tumor patients received 24-hour infusions of Taxol on day 1 followed by cisplatin on day 2 and G-CSF, 5 micrograms/kg/d subcutaneously (SC), beginning on day 3. Treatment was repeated every 3 weeks. Starting doses of Taxol and cisplatin were 135 and 75 mg/m2, respectively. RESULTS: The development of a severe peripheral neuropathy and/or severe myalgias precluded the chronic administration of Taxol and cisplatin with G-CSF at doses greater than 250 mg/m2 and 75 mg/m2, respectively. At this dose, the mean Taxol steady-state plasma concentration (Css) exceeds concentrations capable of inducing pertinent antimicrotubule effects in vitro. The severity of the neuropathy was related to the cumulative dose of Taxol, the magnitude of the dose administered during each treatment, and the presence of a pre-existing medical disorder associated with peripheral neuropathy. A proximal myopathy of modest severity also was documented. Although severe neutropenia occurred frequently, especially at the MTD, it was rarely associated with fever (8% of courses), and absolute neutrophil counts (ANCs) less than 500/microL never persisted for more than 5 days. Responses were noted in non-small-cell lung cancer (NSCLC) and head and neck, breast, and esophageal cancers. CONCLUSION: Taxol and cisplatin doses of 250 mg/m2 and 75 mg/m2, respectively, can be administered repetitively with G-CSF to untreated and minimally pretreated patients. However, these doses are not recommended for patients with pre-existing neuropathies until additional experience in high-risk patients is obtained. Although this Taxol dose is nearly 85% higher than the dose that can be combined with cisplatin in the absence of G-CSF, this high-dose regimen should not be used outside the investigational setting until a dose-response relationship has been demonstrated for Taxol in randomized clinical trials.     

Dispersive self-Q-switching in self-pulsating DFB lasers

Self-pulsations reproducibly achieved in newly developed lasers with two distributed feedback sections and with an additional phase tuning section are investigated. The existence of the dispersive self-Q-switching mechanism for generating the high-frequency self-pulsations is verified experimentally for the first time. This effect is clearly distinguished from other possible self-pulsation mechanisms by detecting the single-mode type of the self-pulsation and the operation of one section near the transparency current density using it as a reflector with dispersive feedback. The operating conditions for generating this self-pulsation type are analyzed. It is revealed that the required critical detuning of the Bragg wavelengths of the two DFB sections is achieved by a combination of electronic wavelength tuning and current-induced heating. The previous reproducibility problems of self-pulsations in two-section DFB lasers operated at, in principle, suited current conditions are discussed, and the essential role of an electrical phase-control section for achieving reproducible device properties is pointed out. Furthermore, it is demonstrated that phase tuning can be used for extending the self-pulsation regime and for optimizing the frequency stability of the self-pulsation. Improved performance of the devices applied as optical clocks thus can be expected     

Modeling of mode control and noise in self-pulsating PhaseCOMB lasers

Self-pulsations (SPs) in phase-controlled mode beating lasers (PhaseCOMB) are very attractive for all-optical clock recovery at ultra-high bit rates. In this paper, we apply the comprehensive simulation tool Longitudinal Dynamics in Semiconductor Lasers, developed by us, for studying the SP features of PhaseCOMB lasers, considering the effects of spontaneous emission noise, longitudinal spatial hole burning, and gain dispersion. In particular, the importance of mode control for adjusting the PhaseCOMB operating conditions is pointed out. The simulation results are confirmed by measurements on fabricated devices.     

Myosin heavy chains IIa and IId are functionally distinct in the mouse

Myosin in adult murine skeletal muscle is composed primarily of three adult fast myosin heavy chain (MyHC) isoforms. These isoforms, MyHC-IIa, -IId, and -IIb, are >93% identical at the amino acid level and are broadly expressed in numerous muscles, and their genes are tightly linked. Mice with a null mutation in the MyHC-IId gene have phenotypes that include growth inhibition, muscle weakness, histological abnormalities, kyphosis (spinal curvature), and aberrant kinetics of muscle contraction and relaxation. Despite the lack of MyHC-IId, IId null mice have normal amounts of myosin in their muscles because of compensation by the MyHC-IIa gene. In each muscle examined from IId null mice, there was an increase in MyHC-IIa- containing fibers. MyHC-IIb content was unaffected in all muscles except the masseter, where its expression was extinguished in the IId null mice. Cross-sectional fiber areas, total muscle cross-sectional area, and total fiber number were affected in ways particular to each muscle. Developmental expression of adult MyHC genes remained unchanged in IId null mice. Despite this universal compensation of MyHC-IIa expression, IId null mice have severe phenotypes. We conclude that despite the similarity in sequence, MyHC-IIa and -IId have unique roles in the development and function of skeletal muscle.     

Dispersive self-Q-switching in DFB lasers-theory versus experiment

The single-mode model of dispersive self-Q-switching is extended to lasers containing a phase tuning section. The parameter set used for modeling is taken from independent measurements on existing self-pulsating devices. Detuning of the Bragg wavelengths by current induced heating is found, and this effect is included in the model. Calculated self-pulsation characteristics were compared quantitatively with experimental results on the device. A very good correspondence between theory and experiment is obtained, e.g., for conditions generating self-pulsations and for the frequency-current dependence. Dispersive self-Q-switching thus is confirmed as the responsible mechanism for high frequency DFB type self-pulsations. The modeling further shows that the delay between the stimulated emission within the device and the radiation of photons from the facets plays an important role for keeping the pulsations running     

Phase I and pharmacologic study of topotecan in patients with impaired renal function

PURPOSE: To determine the toxicities, pharmacokinetics, and recommended doses of the topoisomerase I inhibitor, topotecan, in patients with varying degrees of renal excretory dysfunction. PATIENTS AND METHODS: Fourteen patients with normal renal function [creatinine clearance (CrCl) > or = 60 mL/min] and 28 patients with varying degrees of renal dysfunction were treated with topotecan 0.4 to 2.0 mg/m2/d as a 30-minute infusion for 5 consecutive days every 3 weeks. Plasma and urine samples were obtained to determine the disposition of topotecan. RESULTS: In patients with mild renal dysfunction (CrCl = 40 to 59 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1.0 mg/m2/d and in two of five patients receiving topotecan 1.5 mg/m2/d. In patients with moderate renal dysfunction (CrCl = 20 to 39 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients who received topotecan 0.5 mg/m2/d, and in two of four patients receiving topotecan 1.0 mg/m2/d; these events were more frequently observed in extensively pretreated patients. Pharmacokinetic analyses showed significant correlations between CrCl and the plasma clearance of both total topotecan [Spearman's correlation coefficient (r2) = 0.65, P = .00001] and topotecan lactone (r2 = 0.65, P = .00003). Mean systemic plasma clearance of total topotecan was significantly reduced in patients with mild (P = .04) and moderate (P = .00006) renal dysfunction. There was no evidence of changes in the pharmacodynamic relationship between topotecan exposure (AUC) and myelotoxicity. CONCLUSION: Dose adjustments are required in patients with moderate, but not mild, renal impairment. For patients with moderate renal dysfunction, the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks. Moreover, extensively pretreated patients need further dose reductions.