Publisher Correction: Groundwater Throughflow and Seawater Intrusion in High Quality Coastal Aquifers.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Groundwater Throughflow and Seawater Intrusion in High Quality Coastal Aquifers.

High quality coastal aquifer systems provide vast quantities of potable groundwater for millions of people worldwide. Managing this setting has economic and environmental consequences. Specific knowledge of the dynamic relationship between fresh terrestrial groundwater discharging to the ocean and seawater intrusion is necessary. We present multi- disciplinary research that assesses the relationships between groundwater throughflow and seawater intrusion. This combines numerical simulation, geophysics, and analysis of more than 30 years of data from a seawater intrusion monitoring site. The monitoring wells are set in a shallow karstic aquifer system located along the southwest coast of Western Australia, where hundreds of gigalitres of fresh groundwater flow into the ocean annually. There is clear evidence for seawater intrusion along this coastal margin. We demonstrate how hydraulic anisotropy will impact on the landward extent of seawater for a given groundwater throughflow. Our examples show how the distance between the ocean and the seawater interface toe can shrink by over 100% after increasing the rotation angle of hydraulic conductivity anisotropy when compared to a homogeneous aquifer. We observe extreme variability in the properties of the shallow aquifer from ground penetrating radar, hand samples, and hydraulic parameters estimated from field measurements. This motived us to complete numerical experiments with sets of spatially correlated random hydraulic conductivity fields, representative of karstic aquifers. The hydraulic conductivity proximal to the zone of submarine groundwater discharge is shown to be significant in determining the overall geometry and landward extent of the seawater interface. Electrical resistivity imaging (ERI) data was acquired and assessed for its ability to recover the seawater interface. Imaging outcomes from field ERI data are compared with simulated ERI outcomes derived from transport modelling with a range of hydraulic conductivity distributions. This process allows for interpretation of the approximate geometry of the seawater interface, however recovery of an accurate resistivity distribution across the wedge and mixing zone remains challenging. We reveal extremes in groundwater velocity, particularly where fresh terrestrial groundwater discharges to the ocean, and across the seawater recirculation cell. An overarching conclusion is that conventional seawater intrusion monitoring wells may not be suitable to constrain numerical simulation of the seawater intrusion. Based on these lessons, we present future options for groundwater monitoring that are specifically designed to quantify the distribution of; (i) high vertical and horizontal pressure gradients, (ii) sharp variations in subsurface flow velocity, (iii) extremes in hydraulic properties, and (iv) rapid changes in groundwater chemistry. These extremes in parameter distribution are common in karstic aquifer systems at the transition from land to ocean. Our research provides new insights into the behaviour of groundwater in dynamic, densely populated, and ecologically sensitive coastal environments found worldwide.

A reduction in cardiac arrests and duration of clinical instability after implementation of a paediatric rapid response system.

OBJECTIVE: To determine the effects of a multifaceted paediatric rapid response system on the duration of predefined clinical instability and the subsequent rate of cardiac arrests. METHODS: An interrupted time series study coupled with a retrospective chart review to evaluate the effects of implementing a four component paediatric rapid response system. All patients in a 136-bed university-affiliated paediatric hospital from August 2003 to May 2007 were considered. The main outcome measures included rate of cardiac arrests as indicated by the number of patient days between ward paediatric cardiac arrests and duration of predefined clinical instability before evaluation by critical care personnel. RESULTS: The mean time interval between cardiac arrests increased significantly with the establishment of the rapid response system from a baseline of 2512 to 9418 patient days. The median duration of clinical instability decreased from 9 h 55 min to 4 h 15 min post intervention (p=0.028). CONCLUSIONS: The implementation of a paediatric rapid response system is associated with a significant reduction in the rate of cardiac arrests and duration of clinical instability before evaluation by critical care personnel. This study provides evidence that implementation of a rapid response system brings emergency personnel to deteriorating patients earlier, thus preventing cardiac arrests.

A reduction in cardiac arrests and duration of clinical instability after implementation of a paediatric rapid response system.

OBJECTIVE: To determine the effects of a multifaceted paediatric rapid response system on the duration of predefined clinical instability and the subsequent rate of cardiac arrests. METHODS: An interrupted time series study coupled with a retrospective chart review to evaluate the effects of implementing a four component paediatric rapid response system. All patients in a 136-bed university-affiliated paediatric hospital from August 2003 to May 2007 were considered. The main outcome measures included rate of cardiac arrests as indicated by the number of patient days between ward paediatric cardiac arrests and duration of predefined clinical instability before evaluation by critical care personnel. RESULTS: The mean time interval between cardiac arrests increased significantly with the establishment of the rapid response system from a baseline of 2512 to 9418 patient days. The median duration of clinical instability decreased from 9 h 55 min to 4 h 15 min post intervention (p = 0.028). CONCLUSIONS: The implementation of a paediatric rapid response system is associated with a significant reduction in the rate of cardiac arrests and duration of clinical instability before evaluation by critical care personnel. This study provides evidence that implementation of a rapid response system brings emergency personnel to deteriorating patients earlier, thus preventing cardiac arrests.

Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity.

Muscle carnosine synthesis is limited by the availability of beta-alanine. Thirteen male subjects were supplemented with beta-alanine (CarnoSyn) for 4 wks, 8 of these for 10 wks. A biopsy of the vastus lateralis was obtained from 6 of the 8 at 0, 4 and 10 wks. Subjects undertook a cycle capacity test to determine total work done (TWD) at 110% (CCT(110%)) of their maximum power (Wmax). Twelve matched subjects received a placebo. Eleven of these completed the CCT(110%) at 0 and 4 wks, and 8, 10 wks. Muscle biopsies were obtained from 5 of the 8 and one additional subject. Muscle carnosine was significantly increased by +58.8% and +80.1% after 4 and 10 wks beta-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres. No increase was seen in control subjects. Taurine was unchanged by 10 wks of supplementation. 4 wks beta-alanine supplementation resulted in a significant increase in TWD (+13.0%); with a further +3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.

New and emerging therapies in infectious diseases.

Infectious diseases account for one-third of all deaths worldwide. The last decade has yielded significant advances in the treatment of infectious skin diseases. This article highlights emerging therapies for viral, fungal, bacterial, and parasitic skin cutaneous infections.

Dizocilpine attenuates streptomycin-induced vestibulotoxicity in rats.

NMDA receptor mediated excitotoxicity contributes substantially to aminoglycoside antibiotic-induced cochlear damage. Since vestibular as well as cochlear hair cells have glutamatergic synapses, aminoglycoside-induced vestibulotoxicity may also have an excitotoxic component. This hypothesis was tested by examining the effects of the uncompetitive NMDA receptor antagonist dizocilpine on streptomycin-induced vestibulotoxicity. Streptomycin-treated rats exhibited almost complete destruction of sensory hair cells in the crista ampullaris, vestibular impairment in the drop test, and hyperkinesia. Concurrent treatment with dizocilpine not only rescued a substantial population of sensory hair cells in the cristae, but prevented the attendant hyperkinesis and vestibular impairments. These results indicate that excitotoxic mechanisms contribute to aminoglycoside-induced vestibulotoxicity and that NMDA antagonists may be useful in attenuating aminoglycoside ototoxicity.

Pigmented purpuric dermatosis in a young male.

The pigmented purpuric dermatoses (PPD) are a group of disorders that most often occur on the lower extremities of middle-aged adults as asymptomatic, yellow-orange patches with petechiae. The PPD represent a benign, often chronic, capillaritis of unknown cause. We present a case of PPD on the abdomen of a young male and emphasize careful observation in such a patient to reveal possible progression to purpuric mycosis fungoides.

Aminoglycoside neurotoxicity involves NMDA receptor activation.

Previous studies have led to the hypothesis that the ototoxicity produced by aminoglycoside antibiotics involves the excitotoxic activation of cochlear NMDA receptors. If this hypothesis is correct, then these antibiotics should also injure neurons within the brain. Because aminoglycosides do not readily penetrate the blood brain barrier, we examined the effects of the aminoglycoside neomycin following intrastriatal injection. Neomycin (10-250 nmol) produced dose-dependent striatal damage manifested as an increased gliosis as measured by: (1) [3H]PK-11195 binding, (2) staining for the astrocytic marker glial fibrillary acidic protein (GFAP) and (3) staining for OX-6, an MHC class II antigen expressed by microglia and macrophages. Co-injection of subthreshhold doses of NMDA potentiates the striatal damage produced by neomycin (10 nmol). Moreover, neomycin-induced striatal damage is attenuated by a combination of the NMDA antagonists ifenprodil and 5, 7-dichlorokynurenic acid. Intrastriatal administration of compounds structurally related to neomycin, but devoid of modulatory actions at NMDA receptors (paromamine and 2-deoxystreptamine), fail to produce neuronal damage. These data support the hypothesis that aminoglycoside-induced ototoxicity is, in part, an excitotoxic process involving the activation of NMDA receptors. Moreover, aminoglycosides may damage the central nervous system in individuals with compromised blood brain barriers.

Stereoselective actions of halothane at GABA(A) receptors.

Isoflurane anesthesia exhibits stereoselectivity, and a corresponding stereoselectivity ((+)->(-)-isomer) has been reported at GABA(A) receptors in vitro. The objective of the present study was to determine if the positive modulatory actions of halothane at GABA(A) receptors exhibited a similar stereoselectivity. Both (R)- and (S)-halothane ((+)- and (-)- isomers, respectively) enhanced [3H]flunitrazepam binding to brain membranes in a concentration dependent manner without a significant difference in either potency (EC50) or efficacy (Emax). While both (R)- and (S)-halothane enhanced [3H]muscimol binding, the potency of the (+)-isomer was slightly greater than the corresponding (-)-isomer (0.91 +/- 0.17 versus 1.45 +/- 0.04% atmospheres, respectively (P < 0.02)). Thus, subtle structural differences between inhalational anesthetics can have a significant impact on the degree of stereoselectivity at the receptor level and may provide insights for the development of more specific drugs.

Contribution of "diazepam-insensitive" GABAA receptors to the alcohol antagonist properties of Ro 15-4513 and related imidazobenzodiazepines.

Both in vivo and in vitro studies have shown that Ro 15-4513 can antagonize many of the pharmacologic actions of ethanol. In contrast to many benzodiazepine receptor (BzR) ligands, Ro 15-4513 binds with high affinity to a novel GABAA receptor subtype, referred to as "diazepam-insensitive" (DI). This study examined the contribution of DI GABAA receptors to the modulation of ethanol-induced sleep time by Ro 15-4513 and related imidazobenzodiazepines [e.g., Ro 19-4603, Ro 16-6028, and ZG-63 (t-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-imidazo[1,5,a] [1,4]benzodiazepine-3-carboxylate)] that possess high affinities for this GABAA receptor subtype. Ro 15-4513 (0.6-5 mg/kg) significantly reduced ethanol (3.5 g/kg, i.p.) sleep time in mice (p < 0.001, analysis of variance). This effect was not blocked by BzR antagonists ZK 93426 (5 mg/kg) and Ro 14-7437 (5 mg/kg), which possess low affinities for DI but bind with high affinities to other "diazepam-sensitive" (DS) GABAA receptor isoforms. Although Ro 19-4603 (2.5 mg/kg) also reduced ethanol sleep time (p < 0.01), this effect was attenuated by coadministration of ZK 93426 (2.5 mg/kg). Ro 16-6028 (2.5 mg/kg) prolonged (p < 0.01) ethanol sleep time. However, in the presence of either Ro 19-7437 (5 mg/kg) or ZK 93426 (2.5 mg/kg) ethanol-induced sleep time was reduced to values approaching those obtained with ethanol in the presence of Ro 15-4513. A low dose (2.5 mg/kg) of ZG-63 did not significantly affect alcohol sleep time. However, in the presence of ZK 93426, ZG-63 increased sleep time (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Different subunit requirements for volatile and nonvolatile anesthetics at gamma-aminobutyric acid type A receptors.

The ability of volatile (halothane and isoflurane) and nonvolatile (alphaxalone and pentobarbital) general anesthetics to modulate radioligand binding to gamma-aminobutyric acid (GABA)A receptors was examined in an immortalized cell line (WSS-1) expressing rat alpha 1 and gamma 2 subunits. Volatile anesthetics enhance [3H]flunitrazepam binding to WSS-1 cells in a concentration-dependent manner, with potencies and efficacies comparable to those found with native GABAA receptors. Transfection of these cells with cDNAs encoding rat beta 2 or beta 3 subunits had a significant influence on anesthetic efficacy but not potency in this assay. Thus, transfection with the beta 2 subunit reduced the efficacy of both isoflurane and halothane, whereas transfection with the beta 3 subunit increased the efficacy of isoflurane but not halothane, compared with values obtained in WSS-1 cells. In contrast, alpha-xalone (an anesthetic steroid) had no effect, whereas at high concentrations pentobarbital (an anesthetic barbiturate) produced a modest inhibition of [3H]flunitrazepam binding to GABAA receptors in WSS-1 cells. Transfection of WSS-1 cells with cDNAs encoding either beta 2 or beta 3 subunits resulted in a concentration-dependent enhancement of [3H]flunitrazepam binding by these nonvolatile anesthetics. Moreover, pentobarbital was significantly more potent in enhancing [3H]flunitrazepam binding to WSS-1 cells transfected with the beta 2 subunit, compared with the beta 3 subunit. The difference in subunit requirements between volatile and nonvolatile anesthetics for enhancement of [3H]flunitrazepam binding indicates that these classes of agents affect GABAA receptor function at distinct loci. These studies also provide evidence that the beta subunit is required for these nonvolatile anesthetics to positively modulate GABAA receptors.

The potential for safer anaesthesia using stereoselective anaesthetics.

The molecular mechanisms by which inhalational agents produce anaesthesia remains a subject of controversy, despite a history of clinical use spanning two centuries. The demonstration of a significant difference in the anaesthetic potencies of (+)- and (-)-isoflurane provides compelling evidence for the hypothesis that proteins, rather than lipids, are the primary sites of anaesthetic action. Moreover, the optically active isomers of volatile anaesthetics provide new tools to discriminate among putative molecular targets of anaesthesia. A difference in the anaesthetic potencies of (+)- and (-)-isoflurane, together with an apparent lack of stereoselectivity in their myocardial suppression, raises the possibility that an optically active volatile agent may have clinical advantages over currently available racemic mixtures.

Volatile anesthetics bidirectionally and stereospecifically modulate ligand binding to GABA receptors.

Pharmacologically relevant concentrations of volatile anesthetics can bidirectionally modulate radioligand binding to GABAA receptors. In mouse cerebral cortex, halothane (a prototypic volatile anesthetic) increased [3H]muscimol (a GABA receptor agonist) binding while inhibiting the binding of a GABA receptor antagonist ([3H]SR 95531). These bidirectional effects of inhalational anesthetics on ligand binding to GABA receptors are effected through changes in the Bmax with no significant alterations in the KD of these radioligands. Moreover, the concentration dependent, bidirectional modulation of radioligand binding to GABA receptors by volatile anesthetics exhibited stereoselectivity. Thus, (+)-isoflurane was about twice as potent as the (-)-enantiomer in enhancing [3H]muscimol binding and approximately 50% more potent as an inhibitor of [3H]SR 95531 binding, respectively. The demonstration of a bidirectional, stereospecific modulation of radioligand binding to GABA receptors by inhalational agents is consistent with the presence of specific recognition sites for inhalational anesthetics on the GABAA receptor complex.

Stereospecific actions of the inhalation anesthetic isoflurane at the GABAA receptor complex.

The inhalation anesthetic isoflurane stereoselectively modulates ligand binding to the GABAA receptor complex. The (+)-isomer of isoflurane was more potent and efficacious than the (-)-isomer in enhancing [3H]flunitrazepam binding to benzodiazepine receptors. For example, concentration effect curves for Cl- enhancement of [3H]flunitrazepam binding were significantly different (P < 0.001) in the presence of (+)- and (-)-isoflurane (0.44 and 0.88 mM). At the higher anesthetic concentration, they potency of Cl- to increase [3H]flunitrazepam binding was increased 3.2- and 1.45-fold by (+)- and (-)-isoflurane, respectively (P < 0.05). Likewise, concentration-effect curves for (+) isoflurane-enhanced [3H]flunitrazepam binding were significantly different (P < 0.05-P < 0.001) from the (-)-isomer in the presence of 0-200 mM Cl-. Stereoselectivity was not observed with respect to the potencies of these enantiomers as inhibitors of [35S]t-butylbicyclophosphorothionate (TBPS) binding to sites within the Cl- ionophore. In this measure, the isomers had similar potencies (P > 0.05), although at higher concentrations (> 0.1 mM) (+)-isoflurane produced significantly more inhibition than (-)-isoflurane. While the absolute potency differences between isomers were modest (< or = 2-fold) and measure dependent, these effects were manifested at clinically relevant concentrations of isoflurane and are consistent with in vivo studies demonstrating (+)-isoflurane is a more effective anesthetic than the (-)-isomer. This is the first demonstration of an inhalation anesthetic producing a stereoselective perturbation of the GABAA receptor complex.

Linkage analysis of the monoamine A and B genes using newly-defined polymorphisms.

The monoamine oxidase A (MAOA) and B (MAOB) genes have been localized to chromosome Xp11.3. Recently-defined polymorphisms and linkage analysis have shown tight linkage between MAOA and MAOB, with a distance of approximately 2.7 cM between them.