Channels underlying neuronal calcium-activated potassium currents

In many cell types rises in cytosolic calcium, either due to influx from the extracellular space, or by release from an intracellular store activates calcium dependent potassium currents on the plasmalemma. In neurons, these currents are largely activated following calcium influx via voltage gated calcium channels active during the action potentials. Three types of these currents are known: I-c. I-AHP and I-sAHP. These currents can be distinguished by clear differences in their pharmacology and kinetics. Activation of these potassium currents modulates action potential time course and the repetitive firing properties of neurons. Single channel studies have identified two types of calcium-activated potassium channel which can also be separated on biophysical and pharmacological grounds and have been named BK and SK channels. It is now clear that BK channels underlie Ic whereas SK channels underlie I-AHP. The identity of the channels underlying I-sAHP are not known. In this review, we discuss the properties of the different types of calcium-activated potassium channels and the relationship between these channels and the macroscopic currents present in neurons. (C) 2002 Elsevier Science Ltd. All rights reserved.

Thermal stability of mixed-cation alpha-sialon ceramics

A series of alpha-sialon (alpha') compositions containing mixed stabilising cations were prepared, by introducing additional CaO to a basic Sm alpha-sialon compositions. The thermal stability of these Sm-Ca-containing alpha-sialon phases was investigated using XRD, SEM and EDXS techniques. It was found that the addition of calcium into the Sm alpha-sialon systems greatly improved the stability of the alpha-sialon phases. Calcium was found to be incorporated into the alpha-sialon structure, coexistent with the samarium, and partitioning of the calcium and samarium was observed between the alpha' phase and grain boundary phases. This indicates a technique which may be used to improve the thermal stability of the alpha' phase while maintaining good refractory phases at the gialon grain boundaries. (C) 2003 Elsevier Science B.V. All rights reserved.

Excitatory synaptic transmission in the lateral and central amygdala

The amygdala plays a major role in the acquisition and expression of fear conditioning. NMDA receptor-dependent synaptic plasticity within the basolateral amygdala has been proposed to underlie the acquisition and possible storage of fear memories. Here the properties of fast glutamatergic transmission in the lateral and central nuclei of the amygdala are presented. In the lateral amygdala, two types of neurons, interneurons and projection neurons, could be distinguished by their different firing properties. Glutamatergic inputs to interneurons activated AMPA receptors with inwardly rectifying current-voltage relations (I-Vs), whereas inputs to projection neurons activated receptors that had linear I-Vs, indicating that receptors on interneurons lack GluR2 subunits. Inputs to projection neurons formed dual component synapses with both AMPA and NMDA components, whereas at inputs to interneurons, the contribution of NMDA receptors was very small. Neurons in the central amygdala received dual component glutamatergic inputs that activated AMPA receptors with linear I-Vs. NMDA receptor-mediated EPSCs had slow decay time constants in the central nucleus. Application of NR2B selective blockers ifenprodil or CP-101,606 blocked NMDA EPSCs by 70% in the central nucleus, but only by 30% in the lateral nucleus. These data show that the distribution of glutamatergic receptors on amygdalar neurons is not uniform. In the lateral amygdala, interneurons and pyramidal neurons express AMPA receptors with different subunit compositions. Synapses in the central nucleus activate NMDA receptors that contain NR1 and NR2B subunits, whereas synapses in the lateral nucleus contain receptors with both NR2A and NR2B subunits.

Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise.

Predicting energy requirements in the clinical setting: Are current methods evidence based?

Estimating energy requirements is necessary in clinical practice when indirect calorimetry is impractical. This paper systematically reviews current methods for estimating energy requirements. Conclusions include: there is discrepancy between the characteristics of populations upon which predictive equations are based and current populations; tools are not well understood, and patient care can be compromised by inappropriate application of the tools. Data comparing tools and methods are presented and issues for practitioners are discussed. (C) 2003 International Life Sciences Institute.

Cyclopropyl fatty acids implicate a radical but not a cation as an intermediate in P450(BM3)-catalysed hydroxylations

Novel cyclopropyl containing fatty acids are good substrates for P450(BM3) catalysed hydroxylation and analysis of their oxidation products indicates the presence of a radical intermediate (maximum rebound rate 2.6x10(10) s(-1)) and the absence of any cationic intermediate.

Current smoking and the risk of non-fatal myocardial infarction in the WHO MONICA Project populations

Background: Cohort studies have shown that smoking has a substantial influence on coronary heart disease mortality in young people. Population based data on non-fatal events have been sparse, however. Objective: To study the impact of smoking on the risk of non-fatal acute myocardial infarction (MI) in young middle age people. Methods: From 1985 to 1994 all non-fatal MI events in the age group 35 - 64 were registered in men and women in the WHO MONICA ( multinational monitoring of trends and determinants in cardiovascular disease) project populations ( 18 762 events in men and 4047 in women from 32 populations from 21 countries). In the same populations and age groups 65 741 men and 66 717 women participated in the surveys of risk factors ( overall response rate 72%). The relative risk of non-fatal MI for current smokers was compared with non-smokers, by sex and five year age group. Results: The prevalence of smoking in people aged 35 - 39 years who experienced non-fatal MI events was 81% in men and 77% in women. It declined with increasing age to 45% in men aged 60 - 64 years and 36% in women, respectively. In the 35 - 39 years age group the relative risk of non-fatal MI for smokers was 4.9 (95% confidence interval (CI) 3.9 to 6.1) in men and 5.3 ( 95% CI 3.2 to 8.7) in women, and the population attributable fractions were 65% and 55%, respectively. Conclusions: During the study period more than half of the non-fatal MIs occurring in young middle age people can be attributed to smoking.

Implications of current ecological thinking for biodiversity conservation: A review of the salient issues

Given escalating concern worldwide about the loss of biodiversity, and given biodiversity's centrality to quality of life, it is imperative that current ecological knowledge fully informs societal decision making. Over the past two decades, ecological science has undergone many significant shifts in emphasis and perspective, which have important implications for how we manage ecosystems and species. In particular, a shift has occurred from the equilibrium paradigm to one that recognizes the dynamic, non-equilibrium nature of ecosystems. Revised thinking about the spatial and temporal dynamics of ecological systems has important implications for management. Thus, it is of growing concern to ecologists and others that these recent developments have not been translated into information useful to managers and policy makers. Many conservation policies and plans are still based on equilibrium assumptions. A fundamental difficulty with integrating current ecological thinking into biodiversity policy and management planning is that field observations have yet to provide compelling evidence for many of the relationships suggested by non-equilibrium ecology. Yet despite this scientific uncertainty, management and policy decisions must still be made. This paper was motivated by the need for considered scientific debate on the significance of current ideas in theoretical ecology for biodiversity conservation. This paper aims to provide a platform for such discussion by presenting a critical synthesis of recent ecological literature that (1) identifies core issues in ecological theory, and (2) explores the implications of current ecological thinking for biodiversity conservation.

Odorant-induced currents in intact patches from rat olfactory receptor neurons: Theory and experiment

Odorant-induced currents in mammalian olfactory receptor neurons have proved difficult to obtain reliably using conventional whole-cell recording. By using a mathematical model of the electrical circuit of the patch and rest-of-cell, we demonstrate how cell-attached patch measurements can be used to quantitatively analyze responses to odorants or a high (100 mM) K+ solution. High K+ induced an immediate current flux from cell to pipette, which was modeled as a depolarization of similar to 52 mV, close to that expected from the Nernst equation (56 mV), and no change in the patch conductance. By contrast, a cocktail of cAMP-stimulating odorants induced a current flux from pipette into cell following a significant (4-10 s) delay. This was modeled as an average patch conductance increase of 36 pS and a depolarization of 13 mV, Odorant-induced single channels had a conductance of 16 pS. In cells bathed with no Mg2+ and 0.25 mM Ca2+, odorants induced a current flow from cell to pipette, which was modeled as a patch conductance increase of similar to 115 pS and depolarization of similar to 32 mV, All these results are consistent with cAMP-gated cation channels dominating the odorant response, This approach, which provides useful estimates of odorant-induced voltage and conductance changes, is applicable to similar measurements in any small cells.