Two perspectives on equipartition in diffuse elastic fields in three dimensions.

The elastodynamic Green function can be retrieved from the cross correlations of the motions of a diffuse field. To extract the exact Green function, perfect diffuseness of the illuminating field is required. However, the diffuseness of a field relies on the equipartition of energy, which is usually described in terms of the distribution of wave intensity in direction and polarization. In a full three dimensional (3D) elastic space, the transverse and longitudinal waves have energy densities in fixed proportions. On the other hand, there is an alternative point of view that associates equal energies with the independent modes of vibration. These two approaches are equivalent and describe at least two ways in which equipartition occurs. The authors gather theoretical results for diffuse elastic fields in a 3D full-space and extend them to the half-space problem. In that case, the energies undergo conspicuous fluctuations as a function of depth within about one Rayleigh wavelength. The authors derive diffuse energy densities from both approaches and find they are equal. The results derived here are benchmarks, where perfect diffuseness of the illuminating field was assumed. Some practical implications for the normalization of correlations for Green function retrieval arise and they have some bearing for medium imaging.

Scattering fidelity in elastodynamics.

The recent introduction of the concept of scattering fidelity causes us to revisit the experiment by Lobkis and Weaver [Phys. Rev. Lett. 90, 254302 (2003)]. There, the "distortion" of the coda of an acoustic signal is measured under temperature changes. This quantity is, in fact, the negative logarithm of scattering fidelity. We reanalyze their experimental data for two samples, and we find good agreement with random matrix predictions for the standard fidelity. Usually, one may expect such an agreement for chaotic systems, only. While the first sample may indeed be assumed chaotic, for the second sample, a perfect cuboid, such an agreement is surprising. For the first sample, the random matrix analysis yields perturbation strengths compatible with semiclassical predictions. For the cuboid, the measured perturbation strengths are by a common factor of 5/3 too large. Apart from that, the experimental curves for the distortion are well reproduced.

Self-consistent transport dynamics for localized waves.

We find that the Vollhardt and Wolfle self-consistent theory of Anderson localization makes simple predictions for transport dynamics in unbounded one- and two-dimensional media. These predictions are derived and explored and compared with direct numerical simulations.

Ultrasonics without a source: thermal fluctuation correlations at MHz frequencies.

Noise generated in an ultrasonic receiver circuit consisting of transducer and amplifier is usually ignored, or treated as a nuisance. Here it is argued that acoustic thermal fluctuations, with displacement amplitudes of 3 fm, contain substantial ultrasonic information. It is shown that the noise autocorrelation function is the waveform that would be obtained in a direct pulse/echo measurement. That thesis is demonstrated in experiments in which direct measurements are compared to correlation functions. The thermal nature of the elastodynamic noise that generates these correlations is confirmed by an absolute measurement of their strength, essentially a measurement of the sample temperature.

Mode counts in an aluminum foam.

Measurements of the ultrasonic modal density of a disordered elastic frame, a 20 pore-per-inch open-celled aluminum foam, are reported. While the material is dissipative, with a Q only around 700, sufficiently careful signal processing has allowed reliable counts of the modes up through a few hundred, corresponding to wavelengths comparable to the strut lengths. The modal density is found to be essentially constant over this range, and to bear no resemblance to theoretical estimates based on long-wavelength effective moduli.

Observation of equipartition of seismic waves.

Equipartition is a first principle in wave transport, based on the tendency of multiple scattering to homogenize phase space. We report observations of this principle for seismic waves created by earthquakes in Mexico. We find qualitative agreement with an equipartition model that accounts for mode conversions at the Earth's surface.

Antibody-targeted immunotherapy for treatment of malignancy.

Despite testing since the mid-1900s, only in the past three years have some monoclonal antibodies provided sufficient efficacy and safety data to support regulatory approval as cancer therapy. Adjuvant-edrecolomab monoclonal antibody was approved in Germany after demonstration of a statistically significant 32% improvement over observation alone in the seven-year mortality rate for patients with colorectal cancer. Similarly, trastuzumab monoclonal antibody combined with chemotherapy prolonged the median time to the progression of breast cancer compared to chemotherapy alone. Unconjugated monoclonal antibodies investigated for the treatment of hematologic malignancies include anti-idiotype, CAMPATH-1, and rituximab. Rituximab was the first such therapy approved in the United States for relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma after demonstration of an overall response rate of 48% and a duration of response of 11.7 months. The radioisotope-conjugated monoclonal antibodies tested as therapy include anti-B1, LYM-1, LL2, anti-CD33, and ibritumomab tiuxetan. Clearly, the full potential of immunotherapy still lies ahead.

Complex modal statistics in a reverberant dissipative body.

The statistics of the ultrasonic resonance peaks of a finite elastic body are investigated. The distribution of peak phases, and the normalized variance of peak amplitudes, are shown to be consistent with a hypothesis that the modes themselves are complex Gaussian random numbers. A value q = 0.33 for the ratio of the standard deviations of the imaginary and real parts of the modes is found to fit the data, and to bring recent theory of power variances into better accord with measurements.

Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment.

PURPOSE: This phase II trial investigated the safety and efficacy of re-treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with low-grade or follicular non-Hodgkin's lymphoma who relapsed after a response to rituximab therapy. PATIENTS AND METHODS: Fifty-eight patients were enrolled onto this study, and two were re-treated within the study. Patients received an intravenous infusion of 375 mg/m(2) of rituximab weekly for 4 weeks. All patients had at least two prior therapies and had received at least one prior course of rituximab, with a median interval of 14.5 months between rituximab courses. RESULTS: Most adverse experiences (AEs) were transient grade 1 or 2 events occurring during the treatment period. Clinically significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible. No patient developed human antichimeric antibodies after treatment. The type, frequency, and severity of AEs in this study were not apparently different from those reported in the phase III trial of rituximab. The overall response rate in 57 assessable patients was 40% (11% complete response and 30% partial responses). Median time to progression (TTP) in responders and median duration of response (DR) have not been reached, but Kaplan-Meier estimated medians are 17.8 months (range, 5.4+ to 26.6 months) and 16.3 months (range, 3.7+ to 25.1 months), respectively. These estimated medians are longer than the medians achieved in the patients' prior course of rituximab (TTP and DR of 12.4 and 9.8 months, respectively, P: >.1) and in a previously reported phase III trial (TTP in responders and DR of 13.2 and 11.6 months, respectively). Responses are ongoing in seven of 23 responders. CONCLUSION: In this re-treatment population, safety and efficacy were not apparently different from those after initial rituximab exposure.

Population pharmacokinetics of intravenous indomethacin in neonates with symptomatic patent ductus arteriosus.

The population pharmacokinetics of intravenous indomethacin were investigated with 665 indomethacin serum concentrations from 83 neonates (mean +/- SD: gestational age, 28.8 +/- 2.5 weeks; postnatal age, 5.7 +/- 4.7 days; birth weight, 1.13 +/- 0.40 kg) receiving indomethacin for symptomatic patent ductus arteriosus. A one-compartment open model was used for pharmacokinetic analysis. Hypotheses were tested to determine which developmental and demographic data influenced clearance (CL) and volume of distribution (V(area)). In the final regression equation CL and V(area) were modeled as a function of body weight and postnatal age (PNA) from 0 to 20 days. Final estimates were as follows: CL (ml/hr) = 2.63.weight (kg) + 0.244.PNA (days) and V(area) (L) = 0.28.weight (kg) + 0.0041.PNA (days). The coefficients of variation for interindividual variability in CL and V(area) were 77% and 28%, respectively. Intraindividual variability was 19%. These mean population parameter estimates should prove useful in designing dosage regimens to achieve desired indomethacin concentrations for neonates from 0 to 20 days of age with symptomatic patent ductus arteriosus.

Indomethacin pharmacokinetics in neonates: the value of volume of distribution as a marker of permanent patent ductus arteriosus closure.

Indomethacin (INDO) pharmacokinetics were examined in 18 neonates on 19 occasions, before and after patent ductus arteriosus (PDA) closure. Patients received INDO as an initial dose of 0.25 mg/kg intravenously, and INDO serum concentrations were measured 2 and 8 h after the dose. Subsequent doses were individualized based on clinical response, toxicity, and INDO pharmacokinetics. PDA status was confirmed echocardiographically at the start and end of therapy. INDO pharmacokinetic parameters varied from dose-to-dose within the same patient, and wide interpatient variability was also observed. Pre- and post-PDA closure, only INDO volume of distribution differed significantly (p less than 0.001) with mean values of 0.36 (+/- 0.06) L/kg and 0.26 (+/- 0.08) L/kg. The reason for this occurrence remains unclear. However, a new application for pharmacokinetics as a probe of physiology is demonstrated.

Gentamicin in neonates: the need for loading doses.

One hundred eighty-four neonates had gentamicin serum concentrations measured twice after an initial loading dose of 5 mg/kg infused over 1 hour. Gentamicin concentrations immediately postinfusion were calculated using a one-compartment pharmacokinetic model. The extrapolated peak gentamicin concentrations achieved with the 5 mg/kg loading dose was optimal (between 5 and 12 micrograms/ml) in 94% of cases. Had an initial dose of 2.5 mg/kg been given as suggested in most references, peak concentrations 5 mg/kg or higher would only have been achieved in 5% of neonates less than 28 weeks' gestation, 10% of neonates 28 to 30 weeks' gestation, 11% of neonates 31 to 34 weeks' gestation, and 36% of neonates more than 34 weeks' gestation. Our data support the need for greater loading doses of gentamicin in newborns. Our recommendation of 5 mg/kg achieves gentamicin concentrations known to be safe and effective.

Indomethacin for patent ductus arteriosus closure. Application of serum concentrations and pharmacodynamics to improve response.

Indomethacin dosing for patent ductus arteriosus closure has been standardized despite wide interpatient variability in indomethacin pharmacokinetics. We compared a novel indomethacin dosing approach using individual pharmacokinetic and pharmacodynamic information (group A) with a control group from our institution (group B) and a level 3 university-based intensive care nursery (group C) who were dosed using current dosing guidelines. Permanent patent ductus arteriosus closure was achieved in 27 of 28 (96.4%) group A patients, 10 of 16 (62.5%) group B patients, and 7 of 13 (52.8%) group C patients. Success rates were significantly higher in group A than Groups B and C (P less than .02). Renal toxicity was the only toxicity reported in any group. The major manifestations of renal toxicity, ie, urine output below 1 mL/kg/h or increased serum creatinine by greater than or equal to 0.5 mg/dL, occurred in none of the group A patients but in seven (43.8%) group B and eight (61.5%) group C patients. Renal toxicity was significantly greater in groups B and C than group A (P less than .02). A pharmacodynamic concentration versus response curve was developed and proved predictive of patent ductus arteriosus closure rates in previous studies where indomethacin concentration versus response data were available. Serum concentration monitoring is a valuable adjunct to indomethacin therapy for patent ductus arteriosus closure, especially when a pharmacodynamic approach is used.

Effect of phenobarbital administration on theophylline clearance in premature neonates.

The effect of phenobarbital administration on theophylline clearance was studied in 24 premature neonates. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose followed by a maintenance dose of 2.5-5 mg/kg/12 h. Of the 24 neonates studied, 12 received a mean phenobarbital dose of 26.34 mg/kg/d (ranging from 2 mg every 24 h to 25 mg every 12 h) and the mean phenobarbital concentration was 56.12 micrograms/ml (range 22-112 micrograms/ml). The remaining 12 patients did not require phenobarbital therapy but did receive aminophylline alone. The two groups were closely matched for gestational age, 5-min Apgar scores, and sex (p greater than 0.2). Steady-state theophylline clearance was determined at least once a week for four or more separate weeks. The study lasted a minimum of 8 wk and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated an increase in mean theophylline clearance over time (from 15.75 and 16.67 ml/h/kg to 30.33 and 35.42 ml/h/kg for the aminophylline and aminophylline plus phenobarbital groups, respectively). The mean slope, an indicator of the average change in theophylline clearance, was 2.19 for the aminophylline group and 3.27 for the aminophylline plus phenobarbital group (p greater than 0.2), indicating that the theophylline clearance for neonates receiving phenobarbital was not significantly different from that for neonates receiving aminophylline alone. Based on this information, aminophylline does not need to be adjusted solely based on concomitant phenobarbital administration; however, theophylline concentrations should be monitored since theophylline clearance can change rapidly and unpredictably in neonates.

Rapid sequential phenobarbital treatment of neonatal seizures.

The optimal serum concentration of phenobarbital in newborns and its safety at high doses are not well established. The dose response relationship of rapid sequential phenobarbital loading in the newborn was examined and the efficacy of high-dose monotherapy was compared with the addition of a second anticonvulsant for persistent seizure activity. A single loading dose of phenobarbital 15 to 20 mg/kg was initially administered to 120 newborns. Nonresponders received sequential bolus doses of 5 to 10 mg/kg until seizures ceased or a serum concentration of 40 micrograms/mL was obtained. Infants with refractory seizures received additional phenobarbital to a maximum serum concentration of 100 micrograms/mL. The seizures of 48 babies (40%) were controlled after initial loading and 37 of the remaining 72 subjects (51%) responded at serum concentrations of as great as 40 micrograms/mL. The seizures of only seven subjects were controlled at greater concentrations. A second anticonvulsant controlled seizures in 13 of the 28 subjects (46%) whose seizures were refractory to phenobarbital. A gestational age of less than 32 weeks was associated with a significantly better response to phenobarbital. Serum phenobarbital concentrations greater than 50 micrograms/mL produced only occasional feeding difficulty and sedation. It was concluded that sequentially administered IV phenobarbital controls seizures in both term and preterm newborns (77%). This therapeutic effect is dose dependent but plateaus at a serum concentration of 40 micrograms/mL. At greater serum concentrations, unresponsive patients should receive a second antiepileptic agent.

The effect of total parenteral nutrition-induced cholestasis on theophylline clearance in neonates.

The effect of total parenteral nutrition (TPN) induced cholestasis on theophylline clearance was examined in premature neonates. Thirty-six neonates receiving TPN and theophylline concurrently were reviewed. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose, followed by a maintenance dose of 2.5-5 mg/kg every 12 h. Of the 36 neonates reviewed, 18 developed cholestasis (direct bilirubin greater than or equal to 1 mg/100 ml and direct bilirubin greater than or equal to 60% of total bilirubin). The remaining 18 did not develop cholestasis. The two groups were closely matched for gestational age, 5-min apgar score, and sex. The neonates with cholestasis had a mean maximum direct bilirubin of 5.19 mg/100 ml (range 1-13.8 mg/100 ml) as compared to the patients without cholestasis who had a mean maximum direct bilirubin of 0.54 mg/100 ml (range 0.3-0.8 mg/100 ml). Steady-state theophylline clearance was determined at least once a week for at least 4 separate weeks. The study lasted a minimum of 8 weeks, and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated a significant increase in mean theophylline clearance over time (from 16.09 and 18.60 ml/h/kg to 28.65 and 24.73 ml/h/kg for the cholestatic and noncholestatic groups, respectively). The mean slope, an indicator of the average rate of change of theophylline clearance, was 1.4 for the noncholestatic group and 2.5 for the cholestatic group, indicating that the theophylline clearance for neonates with cholestasis was not significantly different from that for neonates with normal liver function (p = 0.61) over time.

In vitro precipitation of calcium phosphate under intracellular conditions: formation of brushite from an amorphous precursor in the absence of ATP.

Release of mitochondrial calcium has been shown to occur concomitant with mineral ion loading of matrix vesicles at the onset of mineralization in epiphyseal growth plate cartilage. Matrix vesicles contain amorphous calcium phosphate (ACP), a mineral form that usually results from rapid precipitation at high initial levels of Ca2+ and/or inorganic P (Pi). Since the cytosol of growth plate chondrocytes has been found to contain high levels of Pi, rapid release of mitochondrial Ca2+ into the cytosol may cause local precipitation of calcium phosphate and thus be coupled with matrix vesicle formation. Studies were carried out to determine the kinetics and nature of mineral formation that occur when small amounts of Ca2+ are added under various conditions to a Pi buffer composed of electrolytes matched in concentrations and pH to that of the cytosol of epiphyseal chondrocytes. Depending on the manner in which Ca2+ was added, ACP, dicalcium phosphate dihydrate (DCPD), or apatite (HA) first formed. In the presence of ATP, ACP was the only solid phase detected, being stable for at least 24 h. However, in its absence, ACP rapidly transformed into DCPD. Increasing the pH of the reaction buffer from 6.9 to 7.5 increased the amount of ACP initially formed, but DCPD was consistently found upon ACP transformation. Yet at pH 8.0, ACP persisted for at least 24 h. The amount of precipitate formed was proportional to the level of added Ca2+; precipitates formed when as little as 1.0 mmole was added per liter of buffer. Our findings support the possibility that rapid release of mitochondrial Ca2+ may cause localized intracellular precipitation of ACP. Since nascent ACP is known to stimulate membrane fusion and blebbing of vesicles, these findings may explain the presence of ACP in matrix vesicles. The rapid conversion of ACP to DCPD in the absence of ATP under these conditions may also explain the reported occurrence of DCPD in samples of early mineralizing tissue.

Gonococcal ventriculitis associated with ventriculoamniotic shunt placement.

Use of a ventriculoamniotic shunt to control fetal hydrocephalus is a new procedure. Early experience suggests possible benefit to the fetus. Complications have been rare. This report describes the first case of Neisseria gonorrhoeae central nervous system infection associated with a ventriculoamniotic shunt and the third case reported in a neonate. On the basis of this clinical experience, we recommend that the mother be monitored closely for cervical pathogens, that delivery be performed prior to amniorrhexis, and that culturing of the shunt and ventricular fluid be carried out at delivery.