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While chlorine loadings in the atmosphere are expected to decrease towards pre-ozone-hole levels by 2060, the greenhouse gases (GHGs) burden is rising continuously and may in turn significantly modify the stratospheric ozone layer. In this study, use is made of the new interactively coupled chemistry–general-circulation model IGCMFASTOC to investigate in detail the response of stratospheric ozone to a specified increase in GHG concentrations between 1979 and 2060. The Intermediate General Circulation Model (IGCM) is a relatively fast general-circulation model with parametrizations of an intermediate level of complexity, and the new chemistry scheme Fast STratospheric Ozone Chemistry (FASTOC) is an efficient input-output model composed of pre-computed nonlinear functions. A total of seven 14-year time-slice simulations are performed to allow for the separation of individual processes and the analysis of sensitivity to methane and stratospheric water-vapour scenarios. In a basic scenario where all GHG concentrations increase (except stratospheric H2O) the total ozone column is found to increase at a global rate of 0.27 DU decade−1 with maxima in late winter–spring poles. This increase is merely the result of two opposing effects: (i) An increase of ozone concentration in the summer and tropical stratospheric region near 30–40 km which is passively advected into the polar-night vortex between 40 and 20 km. This ozone increase is due to the slowing down of the NOx catalytic cycle caused by the cooling of the stratosphere resulting from increased GHG concentrations in the stratosphere. (ii) A decrease of ozone concentration in the same region which is also advected into the polar-night vortex, due to enhanced NOx concentrations caused by the increased N2O concentrations. These two opposing effects are additive to a large degree, i.e. the sum of their individual effects is a good approximation of their total effect when the processes are acting together. A significant deviation from this additivity occurs inside the northern polar-night vortex and to a lesser extent in the southern polar-night vortex. Our analysis suggests that methane is mainly responsible for this feature. The impact of methane increase on ozone is confined to the high latitudes and is found to have a negative sign in the northern polar vortex when the stratospheric cooling is taken into account, and a positive sign when no stratospheric cooling is taken into account. The scenario where methane is kept at its 1979 level produces a global rate of increase of the ozone column of 9% above the basic scenario. The scenario where stratospheric H2O is increased by 50% leads to a global rate of increase of the ozone column of 70% above the basic scenario. Finally, in a scenario where CO2 is reduced to its 1979 level and the other GHGs involved in the ozone chemistry are increased as in the basic scenario, the global effect of GHGs on the ozone layer is to decrease it at a rate of 0.37 DU decade−1. Copyright © 2005 Royal Meteorological Society

Simulation of future climate-composition changes requires simulations of coupled dynamical-radiative-chemical models of many decades in length. Yet, to assure the generality of the simulation's results against uncertainties in emissions, unforced year-to-year variability and dependence on initial conditions, it is necessary to repeat them a significant number of times. The computational cost of such an exercise is still too large when using complex three-dimensional coupled models. We introduce in this paper a computationally efficient chemical scheme, the FAst STratospheric Ozone Chemistry (FASTOC) scheme, which has advantages over many existing fast methods, as it does not rely on relaxation to assumed conditions, does not rely on tuning parameters, and does not rely on linearization approximations. The scheme is nevertheless three orders of magnitude faster than a stiff kinetic equations solver. Part I of the paper gives a detailed description of the FASTOC model and some performance evaluations when incorporated in a general-circulation model (GCM). In Part II, the FASTOC model, coupled to a GCM, is specifically applied to study the impact of climate–chemistry interactions on stratospheric ozone in the middle of the twenty-first century. Copyright © 2005 Royal Meteorological Society

Criteria for slice health and factors that affect slice health were discussed by many of the participants in the conference. In addition to the standard parameters of slice health (energy metabolism, morphology, electrophysiological responsiveness) more subtle but possibly equally important manifestations of slice health were discussed. These included protein synthesis, and more subtle changes, of which we are becoming increasingly aware. The latter include synthesis of stress-related proteins, altered levels of phosphorylation, altered levels of proteolysis. These last were only touched on, but it is becoming apparent they do in fact constitute important manifestations of differences between the slice preparation and the in vivo tissue. They may well lead to quite different responses in slices from those that occur in vivo. While many ways of optimizing slice wellness were discussed, there was a fair consensus that certain adjustments will optimize the most widely measured aspects of cell function. These include the following, wherever possible. Use of young animals, use of the interface chamber, preparing slices with the vibratome, pre-treating animals with ice-cold cardiac perfusion before sacrificing, using pre-incubation media which reduce NMDA receptor activation, free radical formation and cell swelling. When possible these treatments should perhaps be continued into the normal incubation. This being said, many viewpoints were actually expressed in the discussion, and it should be read to get a feel for the usefulness of the different approaches.

Sawmills in the Canadian province of Alberta were surveyed in order to identify occupations at greatest risk and to guide compliance measures. Two hundred and ten wood dust samples (inhalable) were collected from nine Alberta sawmills using Institute of Occupational Medicine (IOM) personal samplers. Nine percent of samples exceeded 5 mg/m3 8-hour time-weighted average (TWA) for total dust. There was a significant statistical difference (p < .001) between the median and geometric mean inhalable particulate matter (IPM) dust levels for 4 aggregated occupational groups. Levels were highest for cleanup workers (3.5 mg/m3), followed by the maintenance, planermill, and sawmill occupational groups, as were other measures of dust levels. In response to these findings, the Alberta Forest Products Association undertook a program to train sawmill managers to implement these recommendations on engineering controls, administrative controls, and personal protective equipment.

The term “neuroprotection” means the pharmacologic prevention of the rapid (hours) or slower neuronal cell death caused by impaired blood flow or head trauma. Typically, neuroprotection is studied by acute drug treatment shortly after the insult in animal models of stroke, brain ischemia, or head trauma. The study of neuroprotection with organic cation channel blockers probably begins with nimodipine. This drug is a 1,4-dihydropyridine compound closely related to nitrendipine and other drugs used to treat hypertension by relaxing arterial smooth muscles. Subsequently, other compounds with varying specificity for blocking Ca2+ and Na+ channels have proven to be neuroprotective in various animal models. Several of these have been studied in placebo-controlled clinical trials. Unfortunately, to date, none of these compounds has unequivocally reduced human brain damage from stroke, cardiac arrest, or head trauma.

A patient being treated for sickle cell crisis developed swollen, painful, indurated, discoloured thighs after several days in hospital. Imaging revealed the presence of multiple small abscesses in the muscle and methicillin resistant Staphylococcus aureus (MRSA) was cultured from aspirated fluid. Pyomyositis usually occurs in association with damaged muscle and impaired host defences. Staphylococcus is the most frequent organism involved. It is not a common complication of sickle cell disease, although it may be under diagnosed. Availability of advanced imaging techniques facilitates early diagnosis of pyomyositis.

Several novel N-type voltage sensitive calcium channel blockers showed high affinity in the IMR32 assay and efficacy in the anti-writhing model. Herein, we describe the design, synthesis, SAR studies, biological data, physicochemical properties and pharmacokinetics of this 4-piperidinylaniline series.

Exploration of the SAR around the leucine side chain in a series of N,N-dialkyldipeptidylamines with potent functional activity at N-type VSCC is presented. A novel analog is disclosed which possesses improved aqueous solubility, in vivo activity in an audiogenic seizure model, and reversible blockade in electrophysiological assays.

We report a family with hereditary spherocytosis in whom there is, in addition, a cluster of genetic predispositions to thrombosis. Although inherited prothrombotic abnormalities are prevalent in the general population, the likelihood of this combination of abnormalities being found in a single family is extremely low. The management of such high risk individuals is discussed.

It is clear that in coming years, many interesting new compounds will emerge from these and other strategies for drug discovery. In previous strategies of anticonvulsant discovery, whole-animal models of seizures were utilized from the initial stages; however, with the newer strategies, it will become necessary to select promising drug targets for clinical trials in epilepsy that have well-defined molecular targets of action but poorly defined actions in various animal seizure models. The new pharmaceutical discovery technologies of mass screening, cloned drug targets, and combinatorial chemistry will assist in the efficient discovery of novel drug candidates. Incidentally, these techniques also will minimize the use of large numbers of living laboratory animals for anticonvulsant drug screening.

Voltage-dependent Na+ channels have long been recognized targets for anti-arrhythmic and local anesthetic drugs. Since the mid-1980s, Na+ channels have become widely accepted as the primary target of anticonvulsants with pharmacological profiles similar to phenytoin, carbamazepine, and lamotrigine. Results from animal models and a few preliminary clinical trials suggest that this class of drugs may also offer significant potential for reducing the neuronal damage caused by ischemic stroke, head trauma, and perhaps certain neurodegenerative diseases. Studies using site-directed mutations of Na+ channels with electrophysiology have provided extensive insight into both the physiology and the interaction of drug molecules with ion channels. This review includes an introduction to Na+ channel structure, molecular biology, and physiology as they relate to pharmacology. A review of several in vitro actions of Na+ channel blockers is provided. Neuroprotective actions with a variety of Na+ channel blockers in models of central nervous system disease in animals and in vitro models are reviewed. Although many voltage-dependent Na+ channel blockers have additional pharmacological targets, the hypothesis that anticonvulsant and neuroprotective actions results from the blockade of Na+ channels is explored.

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.

Significant advances have been made in understanding the molecular and cellular mechanisms underlying seizure disorders and the actions of antiepileptic drugs. Agents with new mechanisms of action or enhanced activity via known mechanisms might provide improved seizure control or more selective therapy for specific epilepsies. Gabapentin is a new antiepileptic drug that is structurally similar to the neurotransmitter GABA and the endogenous amino acid L-leucine. The mechanism of action of gabapentin is not fully understood, but its distinct profile of anticonvulsant activity in animal seizure models and its lack of activity at many drug binding sites associated with other antiepileptic drugs indicate that its mechanism of action is novel.

A number of biological factors have been identified which correlate with prognosis in neuroblastoma. Among these are genetic aberrations, including ploidy, deletions of chromosome 1p and N-myc amplification. Conventional methods of detecting these changes, such as tissue culture for karyotyping and Southern blotting, are time-consuming and yield interpretable results in only a small proportion of cases. We have developed interphase fluorescence in situ hybridisation for use on tumour imprints and bone marrow smears, allowing rapid visualisation of the relevant genetic changes. Valuable prognostic information is therefore available in a few days: the results in our cases were later confirmed by conventional methods. In the foreseeable future it will be possible to define distinct prognostic categories on the basis both of this genetic information and other parameters, and separate therapeutic strategies may then be employed for the different patient groups. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11

Recent in vitro and in vivo experiments have suggested that excitatory amino acid antagonists, particularly those active at the N-methyl-D-aspartate receptor subtype, are effective in ameliorating ischemic injury due to their antiexcitotoxic activity. However, these drugs are also potent and effective in vivo anticonvulsants. The present experiments compared the noncompetitive N-methyl-D-aspartate antagonists phencyclidine and MK-801 with the anticonvulsant phenytoin in a model of focal brain ischemia. Fisher F-344 rats were subjected to tandem occlusion of the middle cerebral and ipsilateral common carotid arteries under halothane anesthesia. Compounds were administered intravenously 30 minutes and 24 hours after arterial occlusion; infarct size was assessed at 48 hours after occlusion. Phencyclidine had no effect on infarct volume at 1 mg/kg, significantly reduced (by 36%) infarct volume at 3 mg/kg, and produced a nonsignificant 26% decrease at 10 mg/kg. The more potent and selective noncompetitive antagonist MK-801 reduced (by 32%) infarct volume significantly at 0.1 mg/kg, produced a nonsignificant 23% decrease at 0.3 mg/kg, and had no effect at 0.5 mg/kg. Phenytoin, which is not a glutamate antagonist, reduced the infarct volume by 45% at 28 mg/kg. A single dose of phenytoin (28 mg/kg) administered 30 minutes after occlusion was neuroprotective, but delaying drug administration for more than 2 hours was ineffective. These data suggest that blockade of the N-methyl-D-aspartate receptor is effective in reducing the infarct size after focal cerebral ischemia. The neuroprotective activity of phenytoin suggests that this may be related to the common anticonvulsant action.

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Four general mechanisms can hypothetically contribute to or mediate localized synchronization of neuronal activity: (a) recurrent excitatory chemical synapses, (b) electrotonic coupling via gap junctions, (c) electrical field effects (ephaptic interactions), and (d) changes in the concentration of extracellular ions (e.g., K+). It has generally been believed that synchronization of epileptiform bursts derives primarily, if not exclusively, from recurrent excitatory chemical synapses. Dual intracellular recordings from the CA3 area of the hippocampus have been used to demonstrate the existence of recurrent synaptic excitation, and computer simulations have provided a theoretical framework for the idea that relatively sparse interactions through recurrent excitatory chemical synapses can generate synchronized bursting after inhibitory pathways are blocked with convulsant agents. Additional experimental studies have supported the hypothesis that a model for seizure discharge, the penicillin-induced paroxysmal depolarization shift (PDS), is associated with a large increase in excitatory synaptic conductance. However, recent studies have suggested that electrical interactions are also likely to play an important role in spike synchronization during epileptic discharges. Several research groups have used in vitro preparations to show that afterdischarges and spontaneous bursts of population spikes (which represent synchronized action potentials) can occur after chemical synaptic transmission has been blocked in solutions containing low [Ca2+]. Although this result was first observed in the CA1 area, it has recently been confirmed in other regions of the hippocampus. These experiments indicate that mechanisms other than chemical synaptic transmission are capable of synchronizing action potentials in the hippocampus. In this chapter, two forms of electrical interaction that could mediate synchronization will be considered: (a) electrotonic coupling through gap junctions and (b) electrical field effects through extracellular space. Changes in the concentration of extracellular ions are another mechanism not involving chemical synapses. However, it seems unlikely that ionic changes act on the rapid time scale of electrical interactions, and their contribution is discussed elsewhere in this volume. We review evidence for the existence of electrotonic coupling and electrical field effects in the hippocampus and neocortex, and discuss their possible involvement in the synchronization of epileptiform events.(ABSTRACT TRUNCATED AT 400 WORDS)

The anticonvulsant effect of a series of 6-alkoxy-N,N-disubstituted-2-pyridinamines is described. An investigation was carried out to optimize the activity/side-effect ratio in this series of compounds. The most desirable profile was seen with 1-[6-(2-methylpropoxy)-2-pyridinyl]piperazine, 6, and this compound was selected for a more complete pharmacological evaluation. Overall, 6 has a pharmacological profile that is very similar to that of diphenylhydantoin (phenytoin). While nearly equipotent to phenytoin, animal studies suggest a fairly short duration of action. In addition, 6 exhibited some troublesome side effects including central nervous system depression and hypothermia.

Just as Arden and D’Arcy identify and realise the potential of setting political plays in non-contemporary historical periods, other dramatists have fruitfully exploited conventional reactions to foreign political regimes, sometimes to make an oblique comment on matters ‘closer to home’, or alternatively to throw into relief a general inadequacy of political response to anything other than the immediate.

This paper reports the mortality experience of a cohort of 7680 men who had first been employed before 1965 in one of six factories in the British chemical or plastics industry where formaldehyde had been manufactured or used. All the jobs undertaken by each man were classified, on the basis of subjective information, into four categories in terms of exposure to formaldehyde. More than 98% of the workforce were traced to the end of 1981. No deaths from nasal cancer were reported (1.07 expected), and no excess mortality was found for cancers at any of the sites previously reported to be possibly associated with formaldehyde. In one factory a significantly high mortality from lung cancer was found (standardised mortality ratio 124; 95% confidence limits 104, 148) when the mortality rates of England and Wales were used as a standard, but not when an adjustment was made based on the local area mortality. Within the factory the increased mortality was limited to men who had been exposed to "high" levels of formaldehyde. There were no trends of increasing mortality with duration of work or interval since first exposure. This result may be a chance finding or reflect the influence of smoking or some other factor. Although a carcinogenic action of formaldehyde seems less likely as an explanation it cannot be excluded. The statistical power of the study to detect various risks of nasal cancer is described.

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From Sandow's excitation-contraction coupling hypothesis and reasonable assumptions I obtain the kinetics of the active state, (AS), and thence, via empirical equations for series elastic and contractile components for frog sartorius around 20 degrees C, the tension, P, and dP/dt vs. time. Assumptions: (a) Rate of Ca(+2) injection is proportional to the Ca gradient, and a permeability, which increases from zero to a limit as the membrane potential rises above a threshold. (b) Released Ca(+2) is bound by the "muscle machinery," M, and removed by a carrier pump. (c) The AS is proportional to the concentration of Ca-M. The kinetic pattern depends mainly upon the mechanism; the time scale was fixed by the amount of Ca(+2) injected. Depending upon the time course and repetition pattern chosen for the action potential, I obtain P and dP/dt, that agree well with experiment, for normal, potentiated, and summed twitches, tetani, and tension redevelopment after a quick release. Upon excitation the AS rises rapidly to 88%, declines thereafter in twitches, but rises slowly in unfused fashion toward 100% in tetani. The knee in dP/dt marks the first maximum in the AS. Potentiators should raise it in tetani as well as in twitches. Velocity and dP/dt show a much higher fusion frequency than P. The model integrates diverse observations. It may be tested by measuring tension and intramyofibrillar Ca(+2) under controlled depolarization.

Death rates for an extensive list of different cancers have been calculated for each of the 1366 Local Authority areas [in England and Wales] as constituted in 1971 as well as aggregated areas such as Counties. Maps of the geographical distribution of these cancers are shown in this volume....Following the map sections of the atlas there is a one-page summary of some features of the deaths from each cancer. These include the numbers of deaths and the death rates per million population by age groups for each sex in tabular and in graphical form for England and Wales as a whole. Data are for the period 1968-1978 and are from the Office of Population Censuses and Surveys. (EXCERPT)