Demonstrating Agreement between Radio and Fluorescence Measurements of the Depth of Maximum of Extensive Air Showers at the Pierre Auger Observatory.

We show, for the first time, radio measurements of the depth of shower maximum (X_{max}) of air showers induced by cosmic rays that are compared to measurements of the established fluorescence method at the same location. Using measurements at the Pierre Auger Observatory we show full compatibility between our radio and the previously published fluorescence dataset, and between a subset of air showers observed simultaneously with both radio and fluorescence techniques, a measurement setup unique to the Pierre Auger Observatory. Furthermore, we show radio X_{max} resolution as a function of energy and demonstrate the ability to make competitive high-resolution X_{max} measurements with even a sparse radio array. With this, we show that the radio technique is capable of cosmic-ray mass composition studies, both at Auger and at other experiments.

Limits to Gauge Coupling in the Dark Sector Set by the Nonobservation of Instanton-Induced Decay of Super-Heavy Dark Matter in the Pierre Auger Observatory Data.

Instantons, which are nonperturbative solutions to Yang-Mills equations, provide a signal for the occurrence of quantum tunneling between distinct classes of vacua. They can give rise to decays of particles otherwise forbidden. Using data collected at the Pierre Auger Observatory, we search for signatures of such instanton-induced processes that would be suggestive of super-heavy particles decaying in the Galactic halo. These particles could have been produced during the post-inflationary epoch and match the relic abundance of dark matter inferred today. The nonobservation of the signatures searched for allows us to derive a bound on the reduced coupling constant of gauge interactions in the dark sector: α_{X}≲0.09, for 10^{9}≲M_{X}/GeV<10^{19}. Conversely, we obtain that, for instance, a reduced coupling constant α_{X}=0.09 excludes masses M_{X}≳3×10^{13} GeV. In the context of dark matter production from gravitational interactions alone, we illustrate how these bounds are complementary to those obtained on the Hubble rate at the end of inflation from the nonobservation of tensor modes in the cosmological microwave background.

First Experimental Characterization of Microwave Emission from Cosmic Ray Air Showers.

We report the first direct measurement of the overall characteristics of microwave radio emission from extensive air showers. Using a trigger provided by the KASCADE-Grande air shower array, the signals of the microwave antennas of the Cosmic-Ray Observation via Microwave Emission experiment have been read out and searched for signatures of radio emission by high-energy air showers in the GHz frequency range. Microwave signals have been detected for more than 30 showers with energies above 3×10^{16} eV. The observations presented in this Letter are consistent with a mainly forward-directed and polarized emission process in the GHz frequency range. The measurements show that microwave radiation offers a new means of studying air showers at E≥10^{17} eV.

Stability of colistimethate sodium in aqueous solution.

Colistimethate sodium, increasingly used to treat multidrug-resistant Gram-negative infections, spontaneously hydrolyzes to form colistin A (polymyxin E1) and B (polymyxin E2/B) when mixed with water. High levels of these active breakdown products at the time of administration have been associated with nephrotoxicity and even death. In this study, reconstituted colistimethate sodium was shown to be stable (<1.0% colistin A/B formation) for up to 24 h when stored at 21, 0, -20, and -70°C.

Group II activators of G-protein signalling and proteins containing a G-protein regulatory motif.

Beyond the core triad of receptor, Gαßγ and effector, there are multiple accessory proteins that provide alternative modes of signal input and regulatory adaptability to G-protein signalling systems. Such accessory proteins may segregate a signalling complex to microdomains of the cell, regulate the basal activity, efficiency and specificity of signal propagation and/or serve as alternative binding partners for Gα or Gßγ independent of the classical heterotrimeric Gαßγ complex. The latter concept led to the postulate that Gα and Gßγ regulate intracellular events distinct from their role as transducers for cell surface seven-transmembrane span receptors. One general class of such accessory proteins is defined by AGS proteins or activators of G-protein signalling that refer to mammalian cDNAs identified in a specific yeast-based functional screen. The discovery of AGS proteins and related entities revealed a number of unexpected mechanisms for regulation of G-protein signalling systems and expanded functional roles for this important signalling system.

Kneelike structure in the spectrum of the heavy component of cosmic rays observed with KASCADE-Grande.

We report the observation of a steepening in the cosmic ray energy spectrum of heavy primary particles at about 8×10(16) eV. This structure is also seen in the all-particle energy spectrum, but is less significant. Whereas the "knee" of the cosmic ray spectrum at 3-5×10(15) eV was assigned to light primary masses by the KASCADE experiment, the new structure found by the KASCADE-Grande experiment is caused by heavy primaries. The result is obtained by independent measurements of the charged particle and muon components of the secondary particles of extensive air showers in the primary energy range of 10(16) to 10(18) eV. The data are analyzed on a single-event basis taking into account also the correlation of the two observables.

Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose.

Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k(e)), elimination half-lives (t(1/2)), and maximum concentration of adducts (C(max)) of the subjects. The mean (+/-SD)k(e) and half-life were 0.486 +/- 0.084 days(-1) and 1.47+/- 0.30 days, respectively, and the C(max) was 1.2 (+/-2.92) nmol/ml serum. The model-derived, predicted adduct value at 48 h (Adduct 48) correlated with adductC(max), adduct T(max), Rumack-Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity.

Analysis of partner of inscuteable (mPins) expression in the developing mouse eye.

PURPOSE: Asymmetric cell division (ACD) is the fundamental mechanism underlying the generation of cellular diversity in invertebrates and vertebrates. During Drosophila neuroblast division, this process involves stabilization of the apical complex and interaction between the Inscuteable (Insc) and Partner of inscuteable (Pins) proteins. Both cell-intrinsic factors and cell-cell interactions seem to contribute to cell fate decisions in the retina. The Pins protein is known to play a major role in the asymmetric segregation of cell fate determinants during development of the central nervous system in general, but its role in asymmetric cell divisions and retinoblast cell fate has never been explored. The primary aim of this study was to determine the spatial distribution and time course of mouse homolog of Drosophila Partner of Inscuteable (mPins) expression in the developing and adult mouse eye. METHODS: The expression pattern of mPins was studied in the mouse eye from embryonic (E) stage E11.5 until adulthood, by semiquantitative RT-PCR, in situ hybridization, and immunohistochemistry. In addition, variations in mRNA and protein levels for mPins were analyzed in the developing postnatal and adult lens, by semiquantitative RT-PCR, western blot analysis, in situ hybridization, and immunohistochemistry. RESULTS: We detected mPins mRNA at early stages of mouse embryonic eye development, particularly in the neuroblastic layer. In early postnatal development, mPins mRNA was still detected in the neuroblastic layer, but also began to be detectable in the ganglion cell layer. Thereafter, mPins mRNA was found throughout the retina. This pattern was maintained in differentiated adult retina. Immunohistochemical studies showed that mPins protein was present in the neuroblastic layer and the ganglion cell layer during the early stages of postnatal retinal development. At these stages, mPins protein was colocalized with Numb protein, a marker of the ACD. At later postnatal stages, mPins protein was present in all retinal nuclear layers and in the inner plexiform layer. It continued to be detected in these layers in the differentiated retina; the outer plexiform layer and the photoreceptor inner segments also began to display positive immunostaining for mPins. In the adult retina, mPins was also detected in the retinal pigment epithelium and choroidal melanocytes. Throughout development, mPins protein was detected in nonretinal tissues, including the cornea, ciliary body, and lens. We focused our attention on lens development and showed that mPins protein was first detected at E14.5. The most striking results obtained concerned the lens, in which mPins protein distribution switched from the anterior to the posterior region of the lens during embryonic development. Interestingly, in the postnatal and adult lens, mPins protein was detected in all lens cells and fibers. CONCLUSIONS: We provide the first demonstration that mPins protein is expressed from embryonic stages until adulthood in the mouse eye. These results suggest that mPins plays important roles in eye development. This work provides preliminary evidence strongly supporting a role for mPins in the asymmetric division of retinoblasts, and in the structure and functions of adult mouse retina. However, the link between the presence of mPins in different ocular compartments and the possible occurrence of asymmetric cell divisions in these compartments remains to be clarified. Further studies are required to elucidate the in vitro and in vivo functions of mPins in the developing and adult human eye.

Potential pharmacokinetic basis for zolpidem dosing in children with sleep difficulties.

The pharmacokinetics of zolpidem was assessed in this open-label, dose-escalation study in children with insomnia. Twenty-one children, seven per age group (2-6, >6 to 12, >12 to 18 years), received a single dose of zolpidem at one of the three dose levels (0.125, 0.25, or 0.50 mg/kg (20 mg maximum dose)). Multiple pharmacokinetic measures were assessed at nine post-dose intervals and pharmacodynamics was assessed by polysomnography and actigraphy. Significant pharmacokinetic effects by dose were observed only as linear increases in maximum concentration (C(max), P<0.001) and area under the plasma concentration-time curve (AUC, P<0.001). Significant pharmacokinetic effects by age group included an increase in AUC (P=0.02), half-life (P=0.04), and mean residence time (P=0.01), whereas total body clearance decreased (P=0.01) and steady-state volume of distribution was variable. Pharmacodynamic measures were independent of the pharmacokinetic estimates. Overall, zolpidem was well tolerated and a pediatric dose of 0.25 mg/kg is recommended for future efficacy studies.

Detection and imaging of atmospheric radio flashes from cosmic ray air showers.

The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10(20) eV remains a mystery. They are likely to be of extragalactic origin, but should be absorbed within approximately 50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this distance from the Galaxy, explanations for UHECRs range from unusual astrophysical sources to exotic string physics. Also unclear is whether UHECRs consist of protons, heavy nuclei, neutrinos or gamma-rays. To resolve these questions, larger detectors with higher duty cycles and which combine multiple detection techniques are needed. Radio emission from UHECRs, on the other hand, is unaffected by attenuation, has a high duty cycle, gives calorimetric measurements and provides high directional accuracy. Here we report the detection of radio flashes from cosmic-ray air showers using low-cost digital radio receivers. We show that the radiation can be understood in terms of the geosynchrotron effect. Our results show that it should be possible to determine the nature and composition of UHECRs with combined radio and particle detectors, and to detect the ultrahigh-energy neutrinos expected from flavour mixing.

Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux.

BACKGROUND: The use of over-the-counter antacids has increased in children under the age of 12 years, and has been followed by an apparent increase in the use of over-the-counter histamine-2 receptor antagonists. However, the pharmacokinetic and pharmacodynamic effects of over-the-counter histamine-2 receptor antagonists in the paediatric population are largely unknown. AIM: To evaluate the pharmacokinetics and pharmacodynamics of a single dose of the over-the-counter histamine-2 receptor antagonist, ranitidine, 75 mg, in children with symptoms of gastro-oesophageal reflux disease. METHODS: Children aged between 4 and 11 years with symptoms of heartburn suspected to be due to gastro-oesophageal reflux disease were recruited at six clinical centres. Following a single dose of either oral ranitidine, 75 mg (n=19), or placebo (n=10), recording of intragastric pH and serial blood sampling were carried out for 6 h. RESULTS: The estimated pharmacokinetic parameters of ranitidine, 75 mg, were as follows: the median Cmax value of 477 ng/mL occurred within a median of 2.5 h after dosing, and the median half-life was 2.0 h. The intragastric pH began to rise approximately 30 min after dosing with ranitidine to a peak of pH; 4. The pH in the ranitidine group remained higher than that in the placebo group throughout the 6-h evaluation period. Adverse events were generally mild. CONCLUSIONS: Ranitidine, 75 mg, significantly increased the intragastric pH in children aged 4-11 years. The pharmacokinetic and pharmacodynamic profiles were similar to those in adults. Ranitidine, 75 mg, appears to be effective for the control of intragastric acidity for 5-6 h in children aged 4-11 years.

The pharmacokinetics of colistin in patients with cystic fibrosis.

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.

Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Linezolid Pediatric Pneumonia Study Group.

OBJECTIVE: To determine the safety, tolerance, pharmacokinetics and efficacy of linezolid, a new oxazolidinone antibiotic in the treatment of community-acquired pneumonia in hospitalized children. DESIGN: A Phase II, open label multicenter study of intravenous linezolid followed by oral linezolid suspension, both at a dose of 10 mg/kg every 12 h. Efficacy was assessed at 7 to 14 days after the last dose of linezolid. PATIENTS: Children 12 months to 17 years old with community-acquired pneumonia admitted to the hospital of 14 participating centers. RESULTS: From July 21, 1998, through May 14, 1999, 79 children were enrolled and 78 received linezolid. Sixty-six children completed treatment and follow-up and were evaluable for clinical outcome. The median age of the evaluable patients was 3 years (range, 1 to 12 years); 47 were 2 to 6 years old. Pathogens were isolated from blood or pleural fluid cultures in 8 children: Streptococcus pneumoniae, 6 (2 penicillin-resistant); Group A Streptococcus, 1; methicillin-resistant Staphylococcus aureus, 1. Chest tubes were placed in 9 patients. The mean total duration of intravenous and oral administration was 12.2 +/- 6.2 days (range, 6 to 41 days). The mean peak and trough plasma concentrations of linezolid were 9.5 +/- 4.8 and 0.8 +/- 1.2 microg/ml, respectively. At the follow-up visit 7 to 14 days after the last dose of linezolid, 61 patients (92.4%) were considered cured including all the patients with proven pneumococcal pneumonia, one failed (methicillin-resistant Staphylococcus aureus) and 4 were considered indeterminate. The most common adverse effects in the intent to treat group were diarrhea (10.3%), neutropenia (6.4%) and elevation in alanine aminotransferase (6.4%). CONCLUSIONS: Linezolid was well-tolerated and could be considered an alternative to vancomycin for treating serious infections caused by antibiotic-resistant Gram-positive cocci in children pending results of additional studies.

Review of the pharmacokinetics of cefepime in children.

BACKGROUND: Because determining the pharmacokinetics of drugs used in pediatric patients allows for appropriate dosing and optimal clinical response, we have reviewed the pharmacokinetic data on the use of cefepime in the pediatric population. METHODS: Three studies encompassing 88 patients ages 2 months to 16 years examined the pharmacokinetics of cefepime given as a single iv dose, as multiple iv doses and by im administration. In all studies serial blood and urine or cerebrospinal fluid (CSF) samples were collected after a single dose and/or at steady state, defined as after at least 2 days of dosing. Pharmacokinetic parameters were generated from concentration-vs.-time curves and were analyzed using noncompartmental methods. RESULTS: In all studies cefepime exhibited a linear pharmacokinetic profile and concentrations declined proportionally over time. Minimal accumulation was observed after multiple dosing. Pharmacokinetic parameters were similar in all studies and appeared to be dose-independent. Mean (range) parameters observed in this review were: t 1/2 = 1.7 h (1.26 to 1.93); volume of distribution at steady state, 0.37 liter/kg (0.33 to 0.40); total body clearance, 3.1 ml/min/kg (1.43 to 4.01); renal total body clearance, 2.3 ml/min/kg (1.86 to 3.05); absolute bioavailability of cefepime after the im dose, 82.3%; and urinary recovery, 72% (57 to 85%). Penetration into CSF appeared to be good, with CSF concentrations averaging 3.3 to 5.7 microg/ml 0.5 and 8 h after administration of the dose, respectively. CONCLUSION: Cefepime displayed a linear pharmacokinetic profile, was well-absorbed via im injection and had adequate penetration into the CSF of patients with bacterial meningitis, compared with other beta-lactams.

Safety of antihistamines in children.

The histamine H1 receptor antagonists (antihistamines) are an important class of medications used for the relief of common symptoms associated with hyperhistaminic conditions occurring in children and adults. This group of drugs may be subdivided into 3 classes, or generations, based upon their propensity to induce sedation and cardiotoxicity. The first generation (classical) antihistamines are highly effective in treating hyperhistaminic conditions. However, they frequently induce sedation and may adversely affect a child's learning ability. First generation antihistamine-induced sedation has been described to occur in more than 50% of patients receiving therapeutic dosages. Serious adverse events are unusual following overdoses of first generation antihistamines although life-threatening adverse events have been described. When the so-called 'second generation' antihistamines terfenadine and astemizole were introduced they were widely embraced and quickly used by clinicians of all specialities, including paediatricians, as nonsedating alternatives to the first generation compounds. These new agents were found to be equally or more effective than first generation antihistamines in relieving symptoms associated with hyperhistaminic conditions without the soporific effects of the first generation agents. Unfortunately, after approximately 10 years of widespread clinical use, disturbing reports of potentially life-threatening dysrhythmias, specifically torsades de pointes, were described. Both terfenadine and astemizole have been shown in vitro to inhibit several ion channels, and in particular the delayed outward rectifier potassium channel in the myocardium, predisposing the heart to dysrhythmias. The potential life-threatening cardiotoxicities of the second generation antihistamines led to the search for noncardiotoxic and nonsedating agents. Loratadine, fexofenadine, mizolastine, ebastine, azelastine and cetirizine are the first of the new third generation antihistamines. These drugs have been shown to be efficacious with few adverse events including no clinically relevant cytochrome P450 mediated metabolic-based drug-drug interactions or QT interval prolongation/cardiac dysrhythmias. Appropriate treatment of an antihistamine overdose depends upon which class of compound has been ingested. There is no specific antidote for antihistamine overdose and treatment is supportive particularly for ingestions of first generation compounds. Ingestion of excessive doses of terfenadine or astemizole requires immediate medical attention. Children who accidentally ingest excessive doses of a third generation compound may usually be adequately managed at home. However, patients ingesting large amounts (approximately >3 to 4 times the normal therapeutic daily dose) should receive medical attention. These patients should be monitored for 2 to 3 hours after the ingestion and patients ingesting cetirizine should be advised about the potential for sedation. The availability of newer generation antihistamine compounds has clearly added to the clinical effectiveness and patient tolerance of a widely prescribed class of drugs. These advances have also been accompanied by improved safety profiles, particularly in the case of third generation antihistamine overdose.

Randomized, double-blind, multicenter trial comparing clinafloxacin with imipenem as empirical monotherapy for febrile granulocytopenic patients.

In a double-blind, multicenter trial, 541 febrile granulocytopenic patients were randomized to receive either intravenous (iv) clinafloxacin (200 mg every 12 h) or i.v. imipenem (500 mg every 6 h) as empirical monotherapy. More baseline pathogens were susceptible to clinafloxacin (259 [99%] of 262 organisms) than to imipenem (253 [95%] of 265; P=.03). Initial favorable clinical response rates for clinafloxacin (88 [32%] of 272 patients) and imipenem (89 [33%] of 269) were similar. After addition of other antimicrobial agents, overall response rates were 259 (95%) of 272 for clinafloxacin and 251 (93%) of 269 for imipenem. During the study, only 13 clinafloxacin (5%) and 18 imipenem (7%) recipients died. Both drugs were generally well tolerated. Drug-related skin rash occurred more often with clinafloxacin (11% vs. 6%; P=.07), whereas nausea (2% vs. 5%; P=.16), Clostridium-difficile-associated diarrhea (3% vs. 8%; P=.02), and seizures (0% vs. 2%; P=.06) occurred more often with imipenem. These results suggest that clinafloxacin and imipenem have similar efficacy as empirical monotherapy in febrile granulocytopenic patients.

The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration.

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.

Exercise-dependent growth hormone release is linked to markers of heightened central adrenergic outflow.

To test the hypothesis that heightened sympathetic outflow precedes and predicts the magnitude of the growth hormone (GH) response to acute exercise (Ex), we studied 10 men [age 26.1 +/- 1.7 (SE) yr] six times in randomly assigned order (control and 5 Ex intensities). During exercise, subjects exercised for 30 min (0900-0930) on each occasion at a single intensity: 25 and 75% of the difference between lactate threshold (LT) and rest (0.25LT, 0.75LT), at LT, and at 25 and 75% of the difference between LT and peak (1.25LT, 1.75LT). Mean values for peak plasma epinephrine (Epi), plasma norepinephrine (NE), and serum GH concentrations were determined [Epi: 328 +/- 93 (SE), 513 +/- 76, 584 +/- 109, 660 +/- 72, and 2,614 +/- 579 pmol/l; NE: 2. 3 +/- 0.2, 3.9 +/- 0.4, 6.9 +/- 1.0, 10.7 +/- 1.6, and 23.9 +/- 3.9 nmol/l; GH: 3.6 +/- 1.5, 6.6 +/- 2.0, 7.0 +/- 2.0, 10.7 +/- 2.4, and 13.7 +/- 2.2 microg/l for 0.25, 0.75, 1.0, 1.25, and 1.75LT, respectively]. In all instances, the time of peak plasma Epi and NE preceded peak GH release. Plasma concentrations of Epi and NE always peaked at 20 min after the onset of Ex, whereas times to peak for GH were 54 +/- 6 (SE), 44 +/- 5, 38 +/- 4, 38 +/- 4, and 37 +/- 2 min after the onset of Ex for 0.25-1.75LT, respectively. ANOVA revealed that intensity of exercise did not affect the foregoing time delay between peak NE or Epi and peak GH (range 17-24 min), with the exception of 0.25LT (P < 0.05). Within-subject linear regression analysis disclosed that, with increasing exercise intensity, change in (Delta) GH was proportionate to both DeltaNE (P = 0.002) and DeltaEpi (P = 0.014). Furthermore, within-subject multiple-regression analysis indicated that the significant GH increment associated with an antecedent rise in NE (P = 0.02) could not be explained by changes in Epi alone (P = 0.77). Our results suggest that exercise intensity and GH release in the human may be coupled mechanistically by central adrenergic activation.