Redefinition of the kilogram, ampere, kelvin and mole: a proposed approach to implementing CIPM recommendation 1 (CI-2005)

The International System of Units (SI) is founded on seven base units, the metre, kilogram, second, ampere, kelvin, mole and candela corresponding to the seven base quantities of length, mass, time, electric current, thermodynamic temperature, amount of substance and luminous intensity. At its 94th meeting in October 2005, the International Committee for Weights and Measures (CIPM) adopted a recommendation on preparative steps towards redefining the kilogram, ampere, kelvin and mole so that these units are linked to exactly known values of fundamental constants. We propose here that these four base units should be given new definitions linking them to exactly defined values of the Planck constant h, elementary charge e, Boltzmann constant k and Avogadro constant NA, respectively. This would mean that six of the seven base units of the SI would be defined in terms of true invariants of nature. In addition, not only would these four fundamental constants have exactly defined values but also the uncertainties of many of the other fundamental constants of physics would be either eliminated or appreciably reduced. In this paper we present the background and discuss the merits of these proposed changes, and we also present possible wordings for the four new definitions. We also suggest a novel way to define the entire SI explicitly using such definitions without making any distinction between base units and derived units. We list a number of key points that should be addressed when the new definitions are adopted by the General Conference on Weights and Measures (CGPM), possibly by the 24th CGPM in 2011, and we discuss the implications of these changes for other aspects of metrology.

Redefinition of the kilogram: a decision whose time has come

The kilogram, the base unit of mass in the International System of Units (SI), is defined as the mass m(K) of the international prototype of the kilogram. Clearly, this definition has the effect of fixing the value of m(K) to be one kilogram exactly. In this paper, we review the benefits that would accrue if the kilogram were redefined so as to fix the value of either the Planck constant h or the Avogadro constant NA instead of m(K), without waiting for the experiments to determine h or NA currently underway to reach their desired relative standard uncertainty of about 10−8. A significant reduction in the uncertainties of the SI values of many other fundamental constants would result from either of these new definitions, at the expense of making the mass m(K) of the international prototype a quantity whose value would have to be determined by experiment. However, by assigning a conventional value to m(K), the present highly precise worldwide uniformity of mass standards could still be retained. The advantages of redefining the kilogram immediately outweigh any apparent disadvantages, and we review the alternative forms that a new definition might take.

Regulation of glycogen synthase kinase 3 in human platelets: a possible role in platelet function?

In this study we show that both glycogen synthase kinase 3 (GSK3) isoforms, GSK3alpha and GSK3beta, are present in human platelets and are phosphorylated on Ser(21) and Ser(9), respectively, in platelets stimulated with collagen, convulxin and thrombin. Phosphorylation of GSK3alpha/beta was dependent on phosphoinositide 3-kinase (PI3K) activity and independent of platelet aggregation, and correlated with a decrease in GSK3 activity that was preserved by pre-incubating platelets with PI3K inhibitor LY294002. Three structurally distinct GSK3 inhibitors, lithium, SB415286 and TDZD-8, were found to inhibit platelet aggregation. This implicates GSK3 as a potential regulator of platelet function. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Molecular interactions between the penetration enhancer 1,8-cineole and human skin

Penetration enhancers are chemicals that temporarily and reversibly diminish the barrier function of the outermost layer of skin, the stratum corneum, to facilitate drug delivery to and through the tissue. In the current study, the complex mechanisms by which 1,8-cineole, a potent terpene penetration enhancer, disrupts the stratum corneum barrier is investigated using post-mortem skin samples. In order to validate the use of excised tissue for these and related studies, a fibre optical probe coupled to an FT-Raman spectrometer compared spectroscopic information for human skin recorded from in vivo and in vitro sampling arrangements. Spectra from full-thickness (epidermis and dermis) post-mortem skin samples presented to the spectrometer with minimal sample preparation (cold acetone rinse) were compared with the in vivo system (the forearms of human volunteers). No significant differences in the Raman spectra between the in vivo and in vitro samples were observed, endorsing the use of post-mortem or surgical samples for this investigational work. Treating post-mortem samples with the penetration enhancer revealed some unexpected findings: while evidence for enhancer-induced disruption of the barrier lipid packing in the stratum corneum was detected in some samples, spectra from other samples revealed an increase in lipid order on treatment with the permeation promoter. These findings are consistent with phase-separation of the enhancer within the barrier lipid domains as opposed to homogeneous disruption of the lipid lamellae. Copyright (C) 2006 John Wiley & Sons, Ltd.

Liposomes and skin: From drug delivery to model membranes

The early eighties saw the introduction of liposomes as skin drug delivery systems, initially promoted primarily for localised effects with minimal systemic delivery. Subsequently, a novel ultradeformable vesicular system (termed "Transfersomes" by the inventors) was reported for transdermal delivery with an efficiency similar to subcutaneous injection. Further research illustrated that the mechanisms of liposome action depended on the application regime and the vesicle composition and morphology. Ethical, health and supply problems with human skin have encouraged researchers to use skin models. 'IYaditional models involved polymer membranes and animal tissue, but whilst of value for release studies, such models are not always good mimics for the complex human skin barrier, particularly with respect to the stratum corneal intercellular lipid domains. These lipids have a multiply bilayered organization, a composition and organization somewhat similar to liposomes, Consequently researchers have used vesicles as skin model membranes. Early work first employed phospholipid liposomes and tested their interactions with skin penetration enhancers, typically using thermal analysis and spectroscopic analyses. Another approach probed how incorporation of compounds into liposomes led to the loss of entrapped markers, analogous to "fluidization" of stratum corneum lipids on treatment with a penetration enhancer. Subsequently scientists employed liposomes formulated with skin lipids in these types of studies. Following a brief description of the nature of the skin barrier to transdermal drug delivery and the use of liposomes in drug delivery through skin, this article critically reviews the relevance of using different types of vesicles as a model for human skin in permeation enhancement studies, concentrating primarily on liposomes after briefly surveying older models. The validity of different types of liposome is considered and traditional skin models are compared to vesicular model membranes for their precision and accuracy as skin membrane mimics. (c) 2008 Elsevier B.V. All rights reserved.

Can drug-bearing liposomes penetrate intact skin?

Using liposomes to deliver drugs to and through human skin is controversial, as their function varies with type and composition. Thus they may act as drug carriers controlling release of the medicinal agent. Alternatively, they may provide a localized depot in the skin so minimizing systemic effects or can be used for targeting delivery to skin appendages (hair follicles and sweat glands). Liposomes may also enhance transdermal drug delivery, increasing systemic drug concentrations. With such a multiplicity of functions, it is not surprising that mechanisms of liposomal delivery of therapeutic agents to and through the skin are unclear. Accordingly, this article provides an overview of the modes and mechanisms of action of different vesicles as drug delivery vectors in human skin. Our conclusion is that vesicles, depending on the composition and method of preparation, can vary with respect to size, lamellarity, charge, membrane fluidity or elasticity and drug entrapment. This variability allows for multiple functions ranging from local to transdermal effects. Application to dissimilar skins (animal or human) via diverse protocols may reveal different mechanisms of action with possible vesicle skin penetration reaching different depths, from surface assimilation to (rarely) the viable tissue and subsequent systemic absorption.

Drug interaction and location in liposomes: correlation with polar surface areas

An important step in liposome characterization is to determine the location of a drug within the liposome. This work thus investigated the interaction of dipalmitoylphosphatidylcholine liposomes with drugs of varied water solubility, polar surface area (PSA) and partition coefficient using high sensitivity differential scanning calorimetry. Lipophilic estradiol (ES) interacted strongest with the acyl chains of the lipid membrane, followed by the somewhat polar 5-fluorouracil (5-FU). Strongly hydrophilic mannitol (MAN) showed no evidence of interaction but water soluble polymers inulin (IN) and an antisense oligonucleotide (OLG), which have very high PSAs, interacted with the lipid head groups. Accordingly, the drugs could be classified as: hydrophilic ones situated in the aqueous core and which may interact with the head groups; those located at the water-bilayer interface with some degree of penetration into the lipid bilayer; those lipophilic drugs constrained within the bilayer. (c) 2004 Elsevier B.V. All rights reserved.

Neural response to emotional prosody in schizophrenia and in bipolar affective disorder

Background Evidence suggests a reversal of the normal left-lateralised response to speech in schizophrenia. Aims To test the brain's response to emotional prosody in schizophrenia and bipolar disorder. Method BOLD contrast functional magnetic resonance imaging of subjects while they passively listened or attended to sentences that differed in emotional prosody Results Patients with schizophrenia exhibited normal right-lateralisation of the passive response to 'pure' emotional prosody and relative left-lateralisation of the response to unfiltered emotional prosody When attending to emotional prosody, patients with schizophrenia activated the left insula more than healthy controls. When listening passively, patients with bipolar disorder demonstrated less activation of the bilateral superior temporal gyri in response to pure emotional prosody, and greater activation of the left superior temporal gyrus in response to unfiltered emotional prosody In both passive experiments, the patient groups activated different lateral temporal lobe regions. Conclusions Patients with schizophrenia and bipolar disorder may display some left-lateralisation of the normal right-lateralised temporal lobe response to emotional prosody. Declaration of interest R.M. received a studentship from Neuraxis,, and funding from the Neuroscience and Psychiatry Unit, University of Manchester.

The neural response to emotional prosody, as revealed by functional magnetic resonance imaging

Prosody is an important feature of language, comprising intonation, loudness, and tempo. Emotional prosodic processing forms an integral part of our social interactions. The main aim of this study was to use bold contrast fMRI to clarify the normal functional neuroanatomy of emotional prosody, in passive and active contexts. Subjects performed six separate scanning studies, within which two different conditions were contrasted: (1) "pure" emotional prosody versus rest; (2) congruent emotional prosody versus 'neutral' sentences; (3) congruent emotional prosody versus rest; (4) incongruent emotional prosody versus rest; (5) congruent versus incongruent emotional prosody; and (6) an active experiment in which subjects were instructed to either attend to the emotion conveyed by semantic content or that conveyed by tone of voice. Data resulting from these contrasts were analysed using SPM99. Passive listening to emotional prosody consistently activated the lateral temporal lobe (superior and/or middle temporal gyri). This temporal lobe response was relatively right-lateralised with or without semantic information. Both the separate and direct comparisons of congruent and incongruent emotional prosody revealed that subjects used fewer brain regions to process incongruent emotional prosody than congruent. The neural response to attention to semantics, was left lateralised, and recruited an extensive network not activated by attention to emotional prosody. Attention to emotional prosody modulated the response to speech, and induced right-lateralised activity, including the middle temporal gyrus. In confirming the results of lesion and neuropsychological studies, the current study emphasises the importance of the right hemisphere in the processing of emotional prosody, specifically the lateral temporal lobes. (C) 2003 Elsevier Science Ltd. All rights reserved.

Design and development of a haptic dental training system - hapTEL

This paper presents a novel design of a virtual dental training system (hapTEL) using haptic technology. The system allows dental students to learn and practice procedures such as dental drilling, caries removal and cavity preparation for tooth restoration. This paper focuses on the hardware design, development and evaluation aspects in relation to the dental training and educational requirements. Detailed discussions on how the system offers dental students a natural operational position are documented. An innovative design of measuring and connecting the dental tools to the haptic device is also shown. Evaluation of the impact on teaching and learning is discussed.

Effect of headgroup size, charge, and solvent structure on polymer−micelle interactions, studied by molecular dynamics simulations

We performed atomistic molecular dynamics simulations of anionic and cationic micelles in the presence of poly(ethylene oxide) (PEO) to understand why nonionic water-soluble polymers such as PEO interact strongly with anionic micelles but only weakly with cationic micelles. Our micelles include sodium n-dodecyl sulfate (SDS), n-dodecyl trimethylammonium chloride (DTAC), n-dodecyl ammonium chloride (DAC), and micelles in which we artificially reverse the sign of partial charges in SDS and DTAC. We observe that the polymer interacts hydrophobically with anionic SDS but only weakly with cationic DTAC and DAC, in agreement with experiment. However, the polymer also interacts with the artificial anionic DTAC but fails to interact hydrophobically with the artificial cationic SDS, illustrating that large headgroup size does not explain the weak polymer interaction with cationic micelles. In addition, we observe through simulation that this preference for interaction with anionic micelles still exists in a dipolar "dumbbell" solvent, indicating that water structure and hydrogen bonding alone cannot explain this preferential interaction. Our simulations suggest that direct electrostatic interactions between the micelle and polymer explain the preference for interaction with anionic micelles, even though the polymer overall carries no net charge. This is possible given the asymmetric distribution of negative charges on smaller atoms and positive charges oil larger units in the polymer chain.

Molecular dynamics simulation of interactions between a sodium dodecyl sulfate micelle and a poly(ethylene oxide) polymer

We have performed atomistic molecular dynamics simulations of an anionic sodium dodecyl sulfate (SDS) micelle and a nonionic poly(ethylene oxide) (PEO) polymer in aqueous solution. The micelle consisted of 60 surfactant molecules, and the polymer chain lengths varied from 20 to 40 monomers. The force field parameters for PEO were adjusted by using 1,2-dimethoxymethane (DME) as a model compound and matching its hydration enthalpy and conformational behavior to experiment. Excellent agreement with previous experimental and simulation work was obtained through these modifications. The simulated scaling behavior of the PEO radius of gyration was also in close agreement with experimental results. The SDS-PEO simulations show that the polymer resides on the micelle surface and at the hydrocarbon-water interface, leading to a selective reduction in the hydrophobic contribution to the solvent-accessible surface area of the micelle. The association is mainly driven by hydrophobic interactions between the polymer and surfactant tails, while the interaction between the polymer and sulfate headgroups on the micelle surface is weak. The 40-monomer chain is mostly wrapped around the micelle, and nearly 90% of the monomers are adsorbed at low PEO concentration. Simulations were also performed with multiple 20-monomer chains, and gradual addition of polymer indicates that about 120 monomers are required to saturate the micelle surface. The stoichiometry of the resulting complex is in close agreement with experimental results, and the commonly accepted "beaded necklace" structure of the SDS-PEO complex is recovered by our simulations.