Modelling monsoons: understanding and predicting current and future behaviour

The global monsoon system is so varied and complex that understanding and predicting its diverse behaviour remains a challenge that will occupy modellers for many years to come. Despite the difficult task ahead, an improved monsoon modelling capability has been realized through the inclusion of more detailed physics of the climate system and higher resolution in our numerical models. Perhaps the most crucial improvement to date has been the development of coupled ocean-atmosphere models. From subseasonal to interdecadal time scales, only through the inclusion of air-sea interaction can the proper phasing and teleconnections of convection be attained with respect to sea surface temperature variations. Even then, the response to slow variations in remote forcings (e.g., El Niño—Southern Oscillation) does not result in a robust solution, as there are a host of competing modes of variability that must be represented, including those that appear to be chaotic. Understanding the links between monsoons and land surface processes is not as mature as that explored regarding air-sea interactions. A land surface forcing signal appears to dominate the onset of wet season rainfall over the North American monsoon region, though the relative role of ocean versus land forcing remains a topic of investigation in all the monsoon systems. Also, improved forecasts have been made during periods in which additional sounding observations are available for data assimilation. Thus, there is untapped predictability that can only be attained through the development of a more comprehensive observing system for all monsoon regions. Additionally, improved parameterizations - for example, of convection, cloud, radiation, and boundary layer schemes as well as land surface processes - are essential to realize the full potential of monsoon predictability. A more comprehensive assessment is needed of the impact of black carbon aerosols, which may modulate that of other anthropogenic greenhouse gases. Dynamical considerations require ever increased horizontal resolution (probably to 0.5 degree or higher) in order to resolve many monsoon features including, but not limited to, the Mei-Yu/Baiu sudden onset and withdrawal, low-level jet orientation and variability, and orographic forced rainfall. Under anthropogenic climate change many competing factors complicate making robust projections of monsoon changes. Absent aerosol effects, increased land-sea temperature contrast suggests strengthened monsoon circulation due to climate change. However, increased aerosol emissions will reflect more solar radiation back to space, which may temper or even reduce the strength of monsoon circulations compared to the present day. Precipitation may behave independently from the circulation under warming conditions in which an increased atmospheric moisture loading, based purely on thermodynamic considerations, could result in increased monsoon rainfall under climate change. The challenge to improve model parameterizations and include more complex processes and feedbacks pushes computing resources to their limit, thus requiring continuous upgrades of computational infrastructure to ensure progress in understanding and predicting current and future behaviour of monsoons.

Scope and Limitations of The Co-Drug Approach to Topical Drug Delivery

Many currently available drugs show unfavourable physicochemical properties for delivery into or across the skin and temporary chemical modulation of the penetrant is one option to achieve improved delivery properties. Pro-drugs are chemical derivatives of an active drug which is covalently bonded to an inactive pro-moiety in order to overcome pharmaceutical and pharmacokinetic barriers. A pro-drug relies upon conversion within the body to release the parent active drug (and pro-moiety) to elicit its pharmacological effect. The main drawback of this approach is that the pro-moiety is essentially an unwanted ballast which, when released, can lead to adverse effects. The term ‘co-drug’ refers to two or more therapeutic compounds active against the same disease bonded via a covalent chemical linkage and it is this approach which is reviewed for the first time in the current article. For topically applied co-drugs, each moiety is liberated in situ, either chemically or enzymatically, once the stratum corneum barrier has been overcome by the co-drug. Advantages include synergistic modulation of the disease process, enhancement of drug delivery and pharmacokinetic properties and the potential to enhance stability by masking of labile functional groups. The amount of published work on co-drugs is limited but the available data suggest the co-drug concept could provide a significant therapeutic improvement in dermatological diseases. However, the applicability of the co-drug approach is subject to strict limitations pertaining mainly to the availability of compatible moieties and physicochemical properties of the overall molecule.

Topical delivery of a naproxen-dithranol co-drug: in vitro skin penetration, permeation, and staining

Purpose This work probed the topical delivery and skin-staining properties of a novel co-drug, naproxyl-dithranol (Nap-DTH), which comprises anti-inflammatory (naproxen) and anti-proliferative (dithranol) moieties. Method Freshly excised, full-thickness porcine ear skin was dosed with saturated solutions of the compounds. After 24 h, the skin was recovered and used to prepare comparative depth profiles by the tape-stripping technique and to examine the extent of skin staining. Results Depth profiles showed that Nap-DTH led to a 5-fold increase in drug retention in the skin compared to dithranol. The application of Nap-DTH also demonstrated improved stability, resulting in lower levels of dithranol degradation products in the skin. Furthermore, significantly less naproxen from hydrolysed Nap-DTH permeated into the receptor phase compared to naproxen when applied alone (0.08 ± 0.03 nmol cm-² and 180 ± 60 nmol cm-², respectively). Moreover, the reduced staining of the skin was very apparent for Nap-DTH compared to dithranol. Conclusions Topical delivery of Nap-DTH not only improves the delivery of naproxen and dithranol, but also reduces unwanted effects of the parent moieties, in particular the skin staining, which is a major issue concerning the use of dithranol.

Comparison of sample size formulae for 2x2 cross-over designs applied to bioequivalence studies

We consider the comparison of two formulations in terms of average bioequivalence using the 2 × 2 cross-over design. In a bioequivalence study, the primary outcome is a pharmacokinetic measure, such as the area under the plasma concentration by time curve, which is usually assumed to have a lognormal distribution. The criterion typically used for claiming bioequivalence is that the 90% confidence interval for the ratio of the means should lie within the interval (0.80, 1.25), or equivalently the 90% confidence interval for the differences in the means on the natural log scale should be within the interval (-0.2231, 0.2231). We compare the gold standard method for calculation of the sample size based on the non-central t distribution with those based on the central t and normal distributions. In practice, the differences between the various approaches are likely to be small. Further approximations to the power function are sometimes used to simplify the calculations. These approximations should be used with caution, because the sample size required for a desirable level of power might be under- or overestimated compared to the gold standard method. However, in some situations the approximate methods produce very similar sample sizes to the gold standard method. Copyright © 2005 John Wiley & Sons, Ltd.

Active-control trials with binary data: a comparison of methods for testing superiority or non-inferiority using the odds ratio

This paper considers methods for testing for superiority or non-inferiority in active-control trials with binary data, when the relative treatment effect is expressed as an odds ratio. Three asymptotic tests for the log-odds ratio based on the unconditional binary likelihood are presented, namely the likelihood ratio, Wald and score tests. All three tests can be implemented straightforwardly in standard statistical software packages, as can the corresponding confidence intervals. Simulations indicate that the three alternatives are similar in terms of the Type I error, with values close to the nominal level. However, when the non-inferiority margin becomes large, the score test slightly exceeds the nominal level. In general, the highest power is obtained from the score test, although all three tests are similar and the observed differences in power are not of practical importance. Copyright (C) 2007 John Wiley & Sons, Ltd.

Control of framework stoichiometry in MeGaPO laumontites using 1-methylimidazole as structure-directing agent

A series of heterometal substituted gallium phosphates, (N2C4H7)(0.5+x)[Me0.5+xGa2.5-x(PO4)(3)] (Me = Mn, Fe, Co and Zn, x approximate to 0.25), has been synthesised under solvothermal conditions at 433 K in ethylene glycol using I-methylimidazole as a templating agent and their structures determined at 150 K using single-crystal X-ray diffraction. The compounds are isostructural, crystallising in the monoclinic space group C 2/c, with lattice parameters ca. 15 x 13 x 15 angstrom and beta = 112 degrees, and adopt the laumontite framework type (LAU). The incorporation of 1-methylimidazole cations into the one-dimensional pore systems of these materials is about three quarters the uptake value obtained previously for the less-bulky amine cations of imidazole and pyridine in other MeGaPO laumontites, which have the formula (TH)[MeGa2(PO4)(3)] (Me = Mn, Fe, Co and Zn; T = C5H5N and C3N2H4). The size, shape and charge of the amine clearly influence both the metal-phosphate framework stoichiometry (i.e. Me2+:Ga3+ ratio) and the framework charge. (C) 2007 Elsevier Inc. All rights reserved.

Example uses of a learning object

A self study course for learning to program using the C programming language has been developed. A Learning Object approach was used in the design of the course. One of the benefits of the Learning Object approach is that the learning material can be reused for different purposes. 'Me course developed is designed so that learners can choose the pedagogical approach most suited to their personal learning requirements. For all learning approaches a set of common Assessment Learning Objects (ALOs or tests) have been created. The design of formative assessments with ALOs can be carried out by the Instructional Designer grouping ALOs to correspond to a specific assessment intention. The course is non-credit earning, so there is no summative assessment, all assessment is formative. In this paper examples of ALOs and their uses is presented together with their uses as decided by the Instructional Designer and learner. Personalisation of the formative assessment of skills can be decided by the Instructional Designer or the learner using a repository of pre-designed ALOs. The process of combining ALOs can be carried out manually or in a semi-automated way using metadata that describes the ALO and the skill it is designed to assess.

Therapeutic and cytotoxic effects of the novel antipsoriasis codrug, naproxyl-dithranol, on HaCaT cells

A novel topical codrug, naproxyl–dithranol (Nap-DTH), in which dithranol and naproxen are linked via an ester in a 1:1 ratio to form a single chemical entity, was synthesized. The antiproliferative, anti-inflammatory and toxic effects of Nap-DTH were assessed, at the cellular level, using various in vitro methods. Cultured HaCaT keratinocytes were treated with Nap-DTH, and the cellular effects were compared with those of the parent compounds, individually and as a 1:1 mixture of naproxen:dithranol to mimic 1:1 in situ liberation from Nap-DTH. The results demonstrate that Nap-DTH did not modify proliferation and only exhibited slight toxic effects after 24 h at concentrations >21 μM. At a lower concentration (3.4 μM), Nap-DTH did not alter cell proliferation or inflammation, which suggests that the codrug is therapeutically inert. Relating to this, the 1:1 mixture of naproxen:dithranol exhibited the lowest toxic effect and the highest antiproliferative effect on HaCaT keratinocytes compared to dithranol at the same concentration. Moreover, the 1:1 mixture exhibited a reduced inflammatory effect compared to dithranol alone, as reflected by the upregulation of cyclooxygenase-2 by 45% and 136%, respectively. In spite of the 1:1 mixture showing a greater downregulation of Ki-67 and a 2-fold reduction of proliferating cell nuclear antigen (both cellular markers of proliferation) than dithranol, dithranol showed a much greater induction of cleaved caspase-3 protein expression (upregulated by 287%, compared to 85% for the 1:1 mixture). This suggests that when dithranol was administered with naproxen, inhibition of cell growth plays a more important role in the antiproliferation effects than the induction of apoptotic cell death. These results confirm that the codrug would lead to a better therapeutic profile and fewer adverse effects compared to its parent compounds.

Parenting by anxious mothers: effects of disorder subtype, context and child characteristics

Background:  There has been increasing research interest in parenting by anxious adults; however, little is known about anxiety-subtype effects, or effects of the context in which parenting is assessed. Methods:  Two groups of anxious mothers, social phobia (N = 50), generalised anxiety disorder (N = 38), and nonanxious controls (N = 62) were assessed with their 4.9-year-old children in three tasks: two presented threat specifically relevant to each maternal disorder, namely, a social threat task where the child had to give a speech, and a nonsocial threat task where the child had to explore potentially scary objects; the third was a nonthreat task (playing with play dough). Seven parenting dimensions were scored. Effects on parenting of maternal anxiety subgroup and task, and their interactions, were examined, as were effects of earlier child behavioural inhibition and currently manifest anxiety. Results:  There were no parenting differences between maternal groups in the nonthreat play-dough task; parenting difficulties in the two anxious groups were principally evident in the disorder-specific challenge. Parenting differences between nonanxious and anxious mothers occurred independently of child characteristics. There was little evidence for particular forms of parenting difficulty being unique to maternal disorder. Conclusions:  Anxious mothers’ parenting difficulties emerge when occurring under challenge, especially when this is disorder-specific. These effects should be considered in research and clinical practice.

Distribution of esterase activity in porcine ear skin, and the effects of freezing and heat separation

Porcine ear skin is widely used to study skin permeation and absorption of ester compounds, whose permeation and absorption profiles may be directly influenced by in situ skin esterase activity. Importantly, esterase distribution and activity in porcine ear skin following common protocols of skin handling and storage have not been characterised. Thus, we have compared the distribution and hydrolytic activity of esterases in freshly excised, frozen, heated and explanted porcine ear skin. Using an esterase staining kit, esterase activity was found to be localised in the stratum corneum and viable epidermis. Under frozen storage and a common heating protocol of epidermal sheet separation, esterase staining in the skin visibly diminished. This was confirmed by a quantitative assay using HPLC to monitor the hydrolysis of aspirin, in freshly excised, frozen or heated porcine ear skin. Compared to vehicle-only control, the rate of aspirin hydrolysis was approximately three-fold higher in the presence of freshly excised skin, but no different in the presence of frozen or heated skin. Therefore, frozen and heat-separated porcine ear skin should not be used to study the permeation of ester-containing permeants, in particular co-drugs and pro-drugs, whose hydrolysis or degradation can be modulated by skin esterases.

Effects of urban ventilation patterns on the carbon monoxide concentration in a high-rise mega city

Carbon monoxide (CO) concentration data from 1999–2006, monitored at 5 different pollution stations in a high-rise mega city (Hong Kong), were collected and investigated. The spatio-temporal characteristics of urban CO concentration profiles were obtained. A new approach was put forward to examine the relationship between urban CO concentration and different wind flow patterns. Rather than relying on the meteorological data from a single weather station, usually adopted in previous studies, four weather stations on the boundary of Hong Kong territory were used in the present study so as to identify 16 different wind flow patterns, among which a typical urban heat island circulation (UHIC) can be distinguished. Higher concentrations were observed to be associated with the flow pattern of an inflow from Lau Fau Shan (LFS) station which is located in the northwest of Hong Kong. This suggests that the ability of dilution for north-to-west wind is relatively weak due to the pollutants carried from outside Hong Kong. The effectiveness of wind speed on the alleviation of urban concentration is dependent on the initial concentration of the approaching wind. The increase of wind speed of north-to-west wind from 0 m/s to 6 m/s has little effect on the reduction of urban CO concentration, especially on the non-roadside stations. By contrast, for the southerly marine wind, pollution concentration decreases sharply with an increase in the wind speed. It was also found that urban heat island circulation (UHIC) is conducive of the accumulation of pollutants, especially at night. There exists a positive correlation between CO concentration and UHI intensity. This correlation is much stronger at night compared to during the day. Keywords: urban pollution monitoring, urban ventilation pattern, urban heat island circulation, mega city