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We present an analysis of oscillation mode variability in the hot B subdwarf star EPIC~220422705, a new pulsator discovered from $\sim78$~days of {\em K}2 photometry. The high-quality light curves provide a detection of 66 significant independent frequencies, from which we identified 9 incomplete potential triplets and 3 quintuplets. Those {\sl g-} and {\sl p-}multiplets give rotation periods of $\sim$ 36 and 29 days in the core and at the surface, respectively, potentially suggesting a slightly differential rotation. We derived a period spacing of 268.5\,s and 159.4\,s for the sequence of dipole and quadruple modes, respectively. We characterized the precise patterns of amplitude and frequency modulations (AM and FM) of 22 frequencies with high enough amplitude for our science. Many of them exhibit intrinsic and periodic patterns of AM and FM, with periods on a timescale of months as derived by the best fitting and \texttt{MCMC} test. The nonlinear resonant mode interactions could be a natural interpretation for such AMs and FMs after other mechanisms are ruled out. Our results are the first step to build a bridge between mode variability from {\em K}2 photometry and nonlinear perturbation theory of stellar oscillation., 18 pages,9 figures, 2 tables, accepted in APJ

During Kepler's main mission, nearly 20 pulsating subdwarf B (sdB: extreme horizontal branch stars) were discovered. Many of these stars were observed for three years, accumulating over 1.5 million observations. Only through these extended observations have we been able to identify pulsation modes, applying constraints for structure models. Discoveries include nearly-evenly-spaced asymptotic period overtones which represent the interior structure and rotationally-induced frequency multiplets from which we have learned that rotation periods are long, even when in short-period binaries. This paper reviews progress on observational constraints and highlights some of our discoveries including radially differential rotation, conflicting stratification indicators and mode lifetimes.

The first-dose pharmacokinetics of midazolam and its primary alpha-hydroxymetabolite were studied after single-dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrupformulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t 1/2 was prolonged and CL/F reducedin adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for a-hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The A UC ratios of alpha-hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%-71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its a-hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequateforsuccessful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.

We examine the pulsation properties for 13 members of the pulsating subdwarf B (sdBV, or EC 14026) class of stars. By looking at the pulsation structure of an entire class of stars, it may be possible to determine the various modes of pulsations (O’Brien 1998, Kleinman 1995). Unfortunately, when we examine the ensemble of pulsation periods in EC 14026 stars, we are only able to discern a simple correlation between pulsation period and gravity, and not any structure that might help with mode identification. So we can only report on the lack of structure in the pulsation periods and present some of the work underway, which we hope will identify modes in the future.

High-speed multiplexers, demultiplexers, frequency dividers, mixers, and amplifiers are key electronic components in high-speed fiber-optic communications systems such as SONET/SDH. In this paper, we present several important digital and analog integrated circuits (IC) which have been developed for use in SONET/SDH 10 Gb/s optical communication links. The circuits have been fabricated in MOSAIC 5E, an advanced silicon bipolar technology (f/sub T/=26 GHz). The resulting chipset which amounts to a total of 10 IC's consists of multiplexers, demultiplexers, a regenerative frequency divider (2:1), a dual output limiting amplifier, and two different types of mixers for clock extraction. Specifically, the design and performance of these IC's and a hybrid clock recovery module are discussed. The high performance and potential low cost of this research chipset show that advanced silicon bipolar circuit technology can play an important role in future multigigabit fiber-optic communication systems. >

During the Kepler spacecraft’s first year of operation, its short cadence observations were obtained in a survey mode where targets received one month of nearly continuous observations. Forty eight subdwarf B stars were observed of which 14 were found to be pulsators, 13 having predominantly long (g mode) periods. We applied asymptotic relations to the g-mode pulsations and discovered evenly spaced in period sequences for l = 1 and 2 modes in all of the stars. We were able to associate 222 of 317 measured periods with l = 1 and 2 modes which should provide tight constraints on pulsation models. We use the period spacings to compare with theoretical masses of these stars.

The pressure dependence of the vibrational modes of propan-1- and -2-ol was measured by Raman spectroscopy up to 8 GPa at 300 K. Changes in the observed vibrational spectra indicate that the samples undergo a liquid-to-glass transition at about 4.5 GPa for propan-2-ol and about 5.5 GPa for propan-1-ol. The frequency of the O-H stretching mode (a probe of the degree of hydrogen bonding) was found to decrease as a rate of ca −28 cm −1 GPa −1 for both propan-1- and -2-ol

Background: The purpose of this study was to characterize an Australian cohort of ankylosing spondylitis (AS) patients and examine predictors of important disease outcomes. Methods: Cross-sectional study of first visit data among patients referred to the Austin Spondylitis Clinic from rheumatology or general practices. We obtained clinical and laboratory data and validated composite indices through self-reported questionnaire. Results: Delay in AS diagnosis averaged 8.1 years and was higher among women and younger-onset disease. Cervicothoracic mobility was better in women although they showed more entheseal tender points and greater impairment of quality of life. Those with long-standing AS had similar disease activity to recent onset disease but had greater functional disability. Current smoking was associated with worse outcomes although there was no association between cumulative exposure and AS outcomes. Conclusion: The clinical expression of AS in this first-described Australian cohort is similar to previously described cohorts. We observed greater cervicothoracic mobility and a higher enthesitis index among women perhaps contributing to longer delay to diagnosis.

PG 0014+067 is one of the most promising pulsating subdwarf B stars for seismic analysis, as it has a rich pulsation spectrum. The richness of its pulsations, however, poses a fundamental challenge to understanding the pulsations of these stars, as the mode density is too complex to be explained only with radial and nonradial low degree (l < 3) p-modes without rotational splittings. One proposed solution, for the case of PG 0014+067 in particular, assigns some modes with high degree (l=3). On the other hand, theoretical models of sdB stars suggest that they may retain rapidly rotating cores, and so the high mode density may result from the presence of a few rotationally-split triplet (l=1), quintuplet (l=2) modes, along with radial (l=0) p-modes. To examine alternative theoretical models for these stars, we need better frequency resolution and denser longitude coverage. Therefore, we observed this star with the Whole Earth Telescope for two weeks in October 2004. In this paper we report the results of Whole Earth Telescope observations of the pulsating subdwarf B star PG 0014+067. We find that the frequencies seen in PG 0014+067 do not appear to fit any theoretical model currently available; however, we find a simple empirical relation that is able to match all of the well-determined frequencies in this star., 19 pages, preprint of paper accepted for publication in The Astrophysical Journal

BPM 37093 is the only hydrogen-atmosphere white dwarf currently known which has sufficient mass (~ 1.1 M_sun) to theoretically crystallize while still inside the ZZ Ceti instability strip (T_eff ~ 12,000 K). As a consequence, this star represents our first opportunity to test crystallization theory directly. If the core is substantially crystallized, then the inner boundary for each pulsation mode will be located at the top of the solid core rather than at the center of the star, affecting mainly the average period spacing. This is distinct from the "mode trapping" caused by the stratified surface layers, which modifies the pulsation periods more selectively. In this paper we report on Whole Earth Telescope observations of BPM 37093 obtained in 1998 and 1999. Based on a simple analysis of the average period spacing we conclude that a large fraction of the total stellar mass is likely to be crystallized., Comment: 7 pages, 3 figures, 3 tables, accepted for Astronomy & Astrophysics

WOS: 000182039700036, We have acquired new time series photometry of the two pulsating DB white dwarf stars KUV 05134+2605 and PG 1654+160 with the Whole Earth Telescope. Additional single-site photometry is also presented. We use all these data plus all available archival measurements to study the temporal behaviour of the pulsational amplitudes and frequencies of these stars for the first time. We demonstrate that both KUV 05134+2605 and PG 1654+160 pulsate in many modes, the amplitudes of which are variable in time; some frequency variability of PG 1654+160 is also indicated. Beating of multiple pulsation modes cannot explain our observations; the amplitude variability must therefore be intrinsic. We cannot find stable modes to be used for determinations of the evolutionary period changes of the stars. Some of the modes of PG 1654+160 appear at the same periods whenever detected. The mean spacing of these periods (approximate to40 s) suggests that they are probably caused by non-radial gravity-mode pulsations of spherical degree l = 1. If so, PG 1654+160 has a mass around 0.6 M.. The time-scales of the amplitude variability of both stars (down to two weeks) are consistent with theoretical predictions of resonant mode coupling, a conclusion which might however be affected by the temporal distribution of our data.

MOSAICSE, an advanced silicon bipolar technology (f/sub T/=25 GHz) has been used to develop digital and analog ICs for use in a 10 Gbit/s fiber-optic link. The resulting chipset which amounts to a total of 12 ICs consists of MUXes, DMUXes, a decision circuit (DEC), a dynamic divider (2:1), two different types of limiting amplifiers and mixers for clock extraction. >

Background Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. Methods Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. Results Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. Conclusion Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

The selection and titration of pharmacologic agents are essential in the treatment of asthma. This Article focuses on the primary medications used in the treatment of reactive airway disease. The recent advances in the technology of devices used to administer aerosolized medications are also reviewed.

As can be discerned from this article, antipsychotics are commonly prescribed, and they are not used to treat only psychosis. Although some data support the use of typical antipsychotics in pediatric patients with a variety of psychiatric syndromes, concerns about the safety and tolerability of these agents often complicated their use and probably even interfered with case identification. A fundamentally new group of medications, the atypicals, have now become available and may not only have improved tolerability but also may have greater ability to reduce some target symptoms. Because of their superior side-effect profile in adults, some of these atypical treatments probably will be commonly prescribed despite a relative paucity of data about their use in the young. Moreover, although frequently prescribed in this age group, the overall prescription rate for antipsychotics will probably increase because of the putative improved safety profile of the newer agents. However, it is possible that serious side effects, such as tardive dyskinesia or neuroleptic malignant syndrome, may occur with these atypical agents. For this reason, the enthusiasm for prescribing these newer treatments should be tempered with the understanding that these agents, although they may in some ways be superior to their predecessors, still possess the potential for significant adverse events. Four atypical antipsychotics are currently marketed in the United States (see Table 2). One additional agent, ziprasodone, is undergoing clinical investigation. Ziprasodone has been shown to be superior to placebo in adults suffering from schizophrenia. Ziprasodone will probably be marketed in the United States in the near future. Whether all of these atypical drugs will have a place in the clinical armamentarium of the pediatric psychopharmacologist remains to be determined. Because the receptor binding profile of the atypical agents differ, it is not possible to assume that what is true for one of these agents is true for the others. Although results from most preliminary studies with atypical antipsychotics indicate that these are promising agents for pediatric patients, further research is needed to define just how these medications may be most judiciously used.

Since the discovery of pulsating subdwarf (sdB) stars in 1997 (the EC 14026 class), nearly 40 members have been discovered. After nearly a decade, many of these have had significant follow-up observations to resolve their pulsation spectra and to discern their pulsation properties. In this work we compare and contrast the frequency content in terms of richness and range and the amplitudes and phases for 23 sdB pulsators. We draw no conclusions but merely show the incredible variety of pulsations emanating from seemingly similar stars. Pulsation properties Figure 1 shows some of the tests we have applied to the resolved pulsators. Panel A compares the ratio of high-amplitude (with A≥Amax/5) to total frequencies for individual pulsators with gravity. Note that this ratio is lowest for stars with lower gravity (i.e. less even-amplitudes) while all of the H/T=1 values (roughly equal amplitude pulsations) occur for higher gravity, though there are exceptions. Panel B compares the summed pulsation amplitudes (solid lines with the top line representing the lowest-amplitude 90% of frequencies, and subsequent lines indicating the fractional amplitudes of the lowest 70%, 50%, and 10%, respectively) while the dashed line indicates the fractional amplitude of the highest-amplitude frequency. The stars are ordered by, but not scaled with gravity. Like panel A, this indicates a general trend for lower gravity stars to have relatively few pulsation frequencies that contain nearly all of the pulsation power. But it also indicates the large variety observed as stars near log g ∼ 5.7 have a complete range of values. Panel C shows the frequency density compared to gravity with the dotted line indicating the limit for ≤ 2, m = 0 and the dashed line indicating the limit for ≤ 2, all possible m values. For several stars, ≥ 3 values are required to explain the observed density. Panel D shows the amplitude deviations divided by the average amplitude as a measure of pulsation stability. The open circles indicate frequencies known to be phasestable over time, filled triangles indicate non-phase-stable frequencies, and squares indicate frequencies for which the stability of phases is unknown. The dashed line is σA/〈A〉 = 0.52, a value indicative of stochastic oscillations and the horizontal bar is the average error. For the full comparison, see our paper in MNRAS, which is coming soon. Acknowledgments. Support for DMT came in part from funds provided by the Ohio State University Department of Astronomy. Support for MDR is from the National Science Foundation under Grant Number AST007480, the American Astronomical Society and Missouri State University. Travel for JRE was supported by the Missouri Space Grant Consortium. 270 Observations of 23 EC 14026-type pulsating subdwarf B stars Figure 1: Group properties of sdBV pulsators. Mike Reed and Dave Kilkenny finding some time to relax.

Social scientists have long been interested in the study of grief and bereavement, but only recently has research focused on the aftereffects of sudden loss. Theory and research alike suggest that grief is multidimensional and that specific grief reactions have a unique set of predictors. The purpose of this study is to examine the relative contribution of risk factors in explaining variations in specific grief reactions following a sudden death. Data for this study come from medical examiners' reports and mail-back surveys of survivors of sudden loss from suicide or accident. The results indicate that several characteristics of the survivor, mode of death, and social support are important determinants of grief symptomatology. This research concludes by directing future theoretical and empirical endeavors to examine more fully the role of relational factors in influencing grief experiences following bereavement.

Propylene glycol (PG) is present in many pharmaceutical products, lotions, ointments, and cosmetics. Although considered to be a relatively safe substance, overdoses have been associated with serious adverse effects. Propylene glycol intoxication occurred in a child and caused central nervous system depression and a severe metabolic acidosis. Initial assessment revealed an elevated serum anion gap, a slight increase in measured serum osmolality, and a normal osmolal gap. The child's acidosis was due to increased concentrations of lactate and pyruvate. The possibility of serious PG intoxication should be considered in any patient with an unexplained serious metabolic acidosis.

To determine whether any advantage exists using racemic epinephrine instead of the more potent and less expensive levo(1)-epinephrine in the treatment of postextubation laryngeal edema.Prospective, double-blind, randomized study.Pediatric intensive care unit in a university teaching hospital.Twenty-eight patients with stridor during the immediate postextubation period.After extubation, patients demonstrating clinically important stridor were randomized in a double-blind fashion to receive an aerosol containing either 2.25% racemic or 1% l-epinephrine.Heart rate, respiratory rate, blood pressure, and stridor score were determined at 20, 40, and 60 mins and 4 and 8 hrs after the initial aerosol administration. Patients in both groups demonstrated significant (p.01) reductions in stridor score after aerosol administration. No significant differences were observed between treatment groups in improvement in stridor score or the number of subsequent aerosols required. Respiratory rate decreased significantly 40 and 60 mins after l-epinephrine but not after racemic epinephrine. No significant change in heart rate or blood pressure occurred after aerosol administration in either group.These data suggest that aerosolized l-epinephrine is as effective as aerosolized racemic epinephrine in the treatment of postextubation laryngeal edema without additional adverse side effects. When dosed appropriately, l-epinephrine is a less expensive and more widely available alternative to racemic epinephrine for the treatment of postextubation laryngeal edema.

The study of sudden bereavement focuses almost exclusively on its impact on psychological well-being. This research broadens our understanding of bereavement outcomes by exploring the effect of grief on family detachment following sudden bereavement. Moreover, this study examines the relative contributions of resources in alleviating grief symptoms and reducing detachment. Data are collected from medical examiner records and mail-back surveys from family members of victims of suicide and accidental deaths in a large metropolitan area of the United States. A covariance structural equation model allowing for correlated measurement error is estimated using LISREL VII. The results indicate that the most grief-stricken survivors are more detached from family than those who are least grief-stricken. Examination of the direct and indirect influences of resources on bereavement outcomes reveals that self-esteem is the strongest predictor of grief and that it also plays a decisive role in mediating the influences of religious participation and exercise on grief. Expressive support exerts direct effects on both grief and detachment. This research concludes by directing future research to examine more fully the impact of sudden bereavement on marital and family relationships.

Ceftibuten (CFB), a new broad-spectrum cephalosporin for oral administration, possesses potent activity in vitro against a wide range of gram-negative and certain gram-positive pathogens frequently encountered in pediatric patients. Its antimicrobial spectrum and dosage formulation suggest a use for CFB in the treatment of otitis media and upper and lower respiratory and urinary tract infections in infants and children. To assess the pharmacokinetic characteristics of CFB in pediatric patients, we completed a multicenter investigation of 49 children (26 females) between the ages of 6 months and 17 years who had normal hepatic and renal functions and no evidence of chronic disease. Pharmacokinetic parameters were determined from repeated blood samples (n = 12) and, when possible, quantitative urine collections (n = 7) obtained over a 12- to 24-h period following a single oral CFB dose of either 4.5 or 9.0 mg/kg of body weight. CFB was quantitated from plasma and urine samples by using a sensitive, microanalytical high-pressure liquid chromatography method. The drug was rapidly absorbed (mean time to maximum concentration in serum = 140 min) and produced apparent peak concentrations in plasma (Cmax) ranging from 5.0 to 19.0 mg/liter. Average CFB pharmacokinetic parameters (+/- standard deviations) were as follows: apparent elimination half-life, 2.0 +/- 0.5 h; mean residence time, 3.9 +/- 1.1 h; apparent steady-state volume of distribution, 0.4 +/- 0.2 liter/kg; and apparent total plasma clearance (CL/F), 2.5 +/- 0.9 ml/min/kg. No significant differences in any of the pharmacokinetic parameters were observed between the two dosing groups. Significant (P < 0.05) negative correlations were found between patient age and CFB elimination half-life and CL/F and between the estimated creatinine clearance and renal clearance and CL/F. Apparent age dependence of CFB disposition was also reflected by a greater CL/F in children from 0.5 to less than or equal 5 years of age (3.1 +/- 1.1 ml/min/kg) than in children > 10 years of age (2.0 +/- 0.6 ml/min/kg; P < 0.005). The increased CL/f for CFB (3.0 +/- 0.5 ml/min/kg) was corroborated by a validation study performed with 11 infants (1.0 +/- 0.5 ml/min/kg) with CL/F for 19 subjects suggested that appreciable nonrenal clearance (1.3 +/- 0.6 ml/min/kg) of CFB occurred in children, a finding different from preliminary data for adults.

The pharmacology and history of development of nondepolarizing neuromuscular blocking agents are presented, and the pharmacokinetics and pharmacodynamics of these agents, administration guidelines for mechanically ventilated patients, adverse effects, factors affecting paralysis, and methods for blockade reversal are reviewed. Nondepolarizing neuromuscular blocking agents (tubocurarine, metocurine, pancuronium, vecuronium, and atracurium) are frequently used to induce prolonged pharmacologic paralysis in patients in the intensive-care unit (ICU). These agents are poorly absorbed after oral administration and must be administered by injection, preferably by the i.v. route. Individualized adjustment of the dose is necessary to maintain the desired degree of paralysis. Dosing modifications may be necessary in patients with underlying renal or hepatic diseases and in pediatric and geriatric patients. Patients with thermal burns require larger doses of these drugs than other patients. These agents can cause several important adverse effects, including histamine release, cardiovascular changes, and muscle atrophy. Pathophysiologic variables and drug interactions can affect the degree of paralysis. Generally, patients no longer requiring paralysis in the ICU will be allowed to spontaneously regain muscle function after drug therapy has been discontinued. If the effects of the nondepolarizing neuromuscular blocking agents must be reversed more rapidly, acetylcholinesterase-inhibiting agents such as physostigmine, neostigmine, pyridostigmine, and edrophonium can be used. Nondepolarizing neuromuscular blocking agents can be used to paralyze mechanically ventilated patients, facilitating optimal oxygenation and ventilation.

This research examines the significance of the survivor-victim relationship in understanding grief following sudden death bereavement. Data for this study come from medical examiner's reports and mailed self-report surveys of survivors of suicide and accidental death. In general, the results show that survivor-victim attachment is more important than survivor's status in explaining grief reactions. Also, suicide survivors experience significantly less emotional distress and shock, but greater feelings of guilt/shame and rejection, than survivors of accidental death. This paper concludes by directing future research to explore more fully the importance of survivor-victim relationships in understanding grief following bereavement.

Several cooperative radio systems for avoiding aircraft collisions are considered from the standpoints of technical requirements, feasibility, and cost. The system with the broadest potential application is selected. In basic form, the selected system utilizes the upper UHF region to communicate altitude and heading information, and vertical maneuvers are defined by the altitude information. In expanded form this system determines relative bearing and heading, to predict collision hazard in both the vertical and horizontal planes. Potentially, a reduction in unintentional collisions of 100: 1 can be achieved with the selected approach. The applicability of this system to collision avoidance problems of military, commercial, and private aircraft, and to related problems of navigation and air traffic control is outlined.

Two adolescents with serum theophylline concentrations in excess of 100 mg/L were treated with continuous nasogastric infusion of activated charcoal after an intentional overdose. In both cases, nasogastric boluses of 20 to 50 gm of charcoal resulted in prompt emesis of stomach contents despite the presence of a functional nasogastric tube. For nasogastric infusion, activated charcoal was diluted in 0.9% sodium chloride and infused at a rate of 0.25 to 0.5 gm/kg/hr up to a maximal rate of 50 gm/hr. Despite the high initial serum concentrations, the theophylline elimination half-lives during the first 20 hours after the start of charcoal were 7.7 and 13.5 hours. Subsequently, this decreased to 2.6 and 3.2 hours. No serious neurologic, cardiovascular, or metabolic derangements were observed. Continuous nasogastric infusions of activated charcoal may be safe and effective alternatives to charcoal hemoperfusion in patients with theophylline overdose.

A case of salicylate hepatitis in a seven-week-old boy with Kawasaki's disease, mucocutaneous lymph node syndrome, is reported. The infant was admitted to the hospital with fever and a diffuse maculopapular petechial rash. He was treated with antibiotics for 72 hours for presumed septicemia. His condition deteriorated and he developed mucous membrane lesions and edema in his hands and feet. When the cultures of spinal fluid, blood, and urine were found to be negative, the antimicrobial therapy was discontinued; however, the cyanosis of his extremities progressed and gangrenous regions developed in his toe and finger pads. Oral aspirin therapy was started at a dosage of 100 mg/kg/day, every six hours. After five days, the rash, membrane lesions, and swelling in his hands and feet resolved. The cyanosis regressed. Liver enzyme tests revealed mild elevations of SGOT and LDH, and on the 12th hospital day these values peaked to a level consistent with salicylate hepatitis. The aspirin therapy was discontinued and within four days the liver function test results were normal. Aspirin therapy was reinstituted at a single daily dose of 30 mg/kg with no recurrence of hepatitis. The careful monitoring of liver function tests is recommended for children with Kawasaki's disease receiving aspirin therapy to avoid salicylate-induced hepatitis.

Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood. The ontogeny of drug absorption, distribution, metabolism, and elimination are addressed in this review. Drug absorption from any site depends upon both the physicochemical properties of the drug and a variety of patient factors. Absorption of orally administered drugs may be affected by changes in gastric acidity and emptying time as well as by bile salt pool size, bacterial colonisation, and extraintestinal disease states such as congestive heart failure. Factors affecting drug absorption following intramuscular, percutaneous, and rectal administration are also discussed. Drug distribution in the neonate is influenced by a variety of important and predictable age-dependent factors. The developmental aspects of protein binding and body water compartments are described. Additionally, hepatic drug metabolism assumes an important role in understanding the pharmacokinetic and pharmacodynamic properties of many compounds. Certain biotransformation pathways, including hydroxylation by the P450 mono-oxygenase system and glucuronidation, demonstrate only limited activity at birth, while other pathways, such as sulphate or glycine conjugation, appear very efficient at birth. Elimination of drugs excreted unchanged in the urine is dramatically reduced in the newborn, compared with older infants and children, due to immaturity of both glomerular filtration and tubular secretory processes. The glomerular filtration rate remains markedly reduced prior to 34 weeks gestational age, increasing as a function of post-conceptual age until adult values are achieved by approximately 2.5 to 5 months of age. Tubular secretory capacity is also limited at birth, approaching adult values by approximately 7 months of age. Published reports describing the pharmacokinetics and pharmacodynamics of commonly used drugs in the neonatal period, as well as differences in drug biodisposition among premature infants, full term neonates, and older infants and children, are reviewed. Our recommendations for neonatal drug therapy are based upon a critical interpretation of these data, an understanding of fetal development and maturational processes, and an understanding of how disease states may affect drug biodisposition in the neonate.

Pharmacokinetic variables were studied in children with central nervous system infections who received a single dose of ceftriaxone sodium. After initial lumbar puncture of children with documented or suspected bacterial meningitis, ventriculitis, or both, therapy was initiated with i.v. ampicillin and chloramphenicol. Children were randomly selected to receive a single i.v. dose of ceftriaxone. Concentrations of ceftriaxone were measured in plasma at intervals from 0 to 720 minutes after the beginning of the infusion and in cerebrospinal fluid (CSF) at one to five hours after the dose. Blood samples were obtained immediately after the second lumbar puncture for assessment of drug penetration into CSF. Elimination rate constant, elimination half-life, apparent volume of distribution, and plasma clearance were determined from samples obtained 30-720 minutes after the start of the infusion. In two children with ventriculoperitoneal shunts, serial determinations of ceftriaxone in CSF were obtained. All eight children who received 75 mg/kg and five of eight who received 50 mg/kg had positive CSF cultures. Volume of distribution was less after the 50 mg/kg dose than after the 75 mg/kg dose. In the children with shunts, adequate CSF drug concentrations were maintained throughout 12 hours of testing. These data support a 12-hour dosage interval, but clinical studies are needed to evaluate efficacy of the drug at both 12-hour and 24-hour dosage regimens.

Nine children underwent ten bone marrow transplants for malignancies and were supported by parenteral alimentation administered in cyclic fashion 18 hours daily. Children received cyclic parenteral nutrition for an average of 29 days, which provided a caloric intake (mean +/- SD) of 55.9 +/- 18.1 Kcal/kg/day, and a nitrogen intake of 0.28 +/- 0.08 g/kg/day. Nutritional status was assessed using nitrogen balance, creatinine-height index, and visceral protein concentrations including serum albumin, transferrin, and prealbumin. Minimal transient elevation in tests of liver function were observed without marked derangement in blood glucose, electrolytes, or osmolality. Unlike prealbumin, determinations of nitrogen balance, creatinine-height index, serum albumin and transferrin concentrations did not parallel changes in clinical status. Cyclic parenteral alimentation is a practical approach to the maintenance of nutrition during intensive antitumor therapy and provides an infusion-free period for the administration of drugs and blood transfusions without interfering with nutritional support. Prealbumin accurately reflects changes in the patient's clinical status at any point and is easily and reliably determined.

THe stability of an extemporaneous formulation of injectable cholecalciferol 40,000 IU/ml was assessed. A preparation of cholecalciferol 40,000 IU/ml in a solution of propylene glycol with ethanol 10% was prepared. The solution was stored at 4 degrees C in 2-ml sterile glass vials protected from light. Cholecalciferol content was measured initially and periodically for 199 days using a high-pressure liquid chromatography technique. A 7.3% loss of cholecalciferol potency from baseline was observed over the 199-day period. In contrast to currently available preparations, this extemporaneous formulation of injectable cholecalciferol potentially offers a versatile dosage form for therapeutic or prophylactic therapy of vitamin D deficiency. It was easily prepared and retained more than 90% potency of cholecalciferol for at least six months. The addition of this formulation to large-volume parenteral or parenteral nutrition solutions is not recommended, however, because compatibility data are not available. In addition, the biological activity of the preparation has not been assessed.

The authors discuss two areas of therapeutics employed commonly in office practice, namely, anti-infective therapy and therapy for disorders of micturition. In anti-infective therapy, the pharmacodynamic aspects of drug action, as exemplified by the in-vitro susceptibility of various pathogens to antibiotics, are often known before the drug is administered to the patient. Thus, therapeutic failures generally result from a lack of knowledge of the individual patient's pharmacokinetics. In contrast, drug therapy for disorders of micturition is directed against a variety of often conflicting mechanisms and is seldom based on any pharmacokinetic tenets.

Ciprofloxacin has potent in vitro activity against Pseudomonas aeruginosa and Pseudomonas cepacia strains isolated from cystic fibrosis patients. Our previous single-dose pharmacokinetic and pharmacodynamic studies identified important differences between cystic fibrosis patients and age- and sex-matched controls. Based on these data, 30 acutely ill cystic fibrosis patients (aged 18 to 44 years) received 750 mg of ciprofloxacin orally every eight hours for 21 days. Multiple timed serum, urine, and sputum samples for pharmacokinetic analysis were obtained on Days 3, 12, 14, and 21 of the study. Estimates of steady-state pharmacokinetic parameters averaged (+/- SD): t1/2 beta, 3.8 (1) hours; Vd/F, 4.4 (2) liters/kg; Cl/F, 772.9 (301) ml/minute/1.73 m2; Fe, 46 percent; peak, 5.4 (2) mg/liter; and trough, 1.8 (0.8) mg/liter. Serum ciprofloxacin concentrations and pharmacokinetic estimates remained unchanged throughout the study. Sputum ciprofloxacin concentrations exceeded those observed in serum. Sputum cultures revealed 43 P. aeruginosa (MIC90 = 2 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml) strains. Sputum ciprofloxacin concentrations exceeded the MIC90 for P. aeruginosa approximately fivefold, yet only eight isolates were fully suppressed. Posttreatment sputum cultures revealed 35 P. aeruginosa (MIC90 = 16 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml). All patients showed clinical improvement based upon the results of pulmonary function tests and an acute clinical efficacy score (median pre 49/post 60). No patients experienced drug-related toxicity. Ciprofloxacin monotherapy is effective for the acute treatment of cystic fibrosis patients. The development of pathogen resistance during oral therapy may limit its utility in ambulatory patients.

The epidemiology and incidence, etiology, pathogenesis and pathophysiology, clinical presentation, diagnosis, principles of therapy, and treatment of bacterial meningitis in infants and children are reviewed. Bacterial meningitis is a major cause of morbidity and mortality, and most cases occur in children less than five years old. Haemophilus influenzae type b, Neisseria meningitidis, and Streptococcus pneumoniae are the major pathogens involved. Bacteremia or colonization of the upper-respiratory-tract epithelium often precedes meningitis. Defense mechanisms are poor in the cerebrospinal fluid; once an organism penetrates the blood-brain barrier, infection may follow quickly. Clinical signs and symptoms are somewhat nonspecific, with lethargy, restlessness, and poor feeding prominent; diagnosis often relies on the patient history along with preliminary results of lumbar punctures. Therapy is based on pharmacologic and pharmacodynamic principles concerning the available antimicrobial agents, the blood-brain barrier, and supportive therapy. Effective antimicrobial therapy requires attainment of adequate bactericidal activity in the cerebrospinal fluid; penetration of agents into the brain depends on their physico-chemical characteristics. Antibiotic therapy must generally be started before culture results are available, making empiric therapy based on the child's age, history, and underlying conditions important. Established therapeutic agents include penicillins, aminoglycosides, and chloramphenicol, though newer expanded-spectrum cephalosporins such as cefuroxime, ceftriaxone, and cefotaxime are being used with increasing frequency. However, the use of these newer, more potent antimicrobial agents have not appreciably altered associated morbidity and mortality. Aggressive supportive care and evaluation of newer nonantibiotic treatments should be addressed in future studies of bacterial meningitis in infants and children.

Twenty-five patients with malignancies resistant to conventional chemoradiation therapy or for which no effective therapy is known were treated with escalating doses of thiotepa (135-1215 mg/m2 iv over 3 days) followed by reinfusion of previously cryopreserved autologous bone marrow. The hematological and nonhematological toxic effects, therapeutic effects, and pharmacokinetics of this regimen were evaluated. Granulocyte (greater than 500/microliter) and platelet (greater than 20,000/microliter) count recovery occurred at a median of 16 (range, 11-38) and 18.5 (range, 11-40) days after marrow reinfusion, respectively. Six patients experienced severe infection, four of which were fatal. One patient died due to intracranial hemorrhage. Toxicity to the gastrointestinal and central nervous systems was dose-limiting, and the maximum tolerated dose of thiotepa was 1005 mg/m2. Objective tumor regression occurred in six of the patients. Serum thiotepa concentration peaked immediately after infusion and declined rapidly in a biphasic manner. No relationship between thiotepa serum concentration or pharmacokinetic parameter estimates was observed for tumor response or toxicity. High-dose thiotepa and autologous bone marrow transplantation may represent an alternative therapeutic modality for patients with advanced cancer.

The mechanism of action, antibacterial spectrum, pharmacokinetics, current dosage recommendations, adverse reactions, therapeutic uses, and pharmaceutical considerations of moxalactam disodium are reviewed. Moxalactam is a synthetically derived, structurally unique beta-lactam antibiotic. Its antimicrobial activity encompasses a wide spectrum and includes some strains of pseudomonal species. Administered by i.v. or i.m. injection, moxalactam is widely distributed to body fluids and tissues. Its elimination half-life is longer than those of first- and second-generation cephalosporins. Usually administered in two or three divided doses daily, moxalactam has been shown to be effective against specific organisms in a variety of infections, including lower respiratory, urinary-tract, intra-abdominal, central nervous system, skin and skin-structure, and bone and joint infections, and bacterial septicemia. Adverse reactions associated with moxalactam administration have been limited and appear similar to those experienced following the use of other beta-lactam antibiotics. Because of its wide spectrum of activity, colonization of resistant organisms and (to a lesser extent) superinfection may complicate therapy. Early clinical experience indicates that moxalactam is effective for the treatment of a number of bacterial infections, including those involving the abdominal cavity and respiratory and urinary tracts. More experience is necessary to delineate its most appropriate roles in specific infectious processes.