A two-dimensional mathematical model of percutaneous drug absorption

Background When a drug is applied on the skin surface, the concentration of the drug accumulated in the skin and the amount of the drug eliminated into the blood vessel depend on the value of a parameter, r. The values of r depend on the amount of diffusion and the normalized skin-capillary clearence. It is defined as the ratio of the steady-state drug concentration at the skin-capillary boundary to that at the skin-surface in one-dimensional models. The present paper studies the effect of the parameter values, when the region of contact of the skin with the drug, is a line segment on the skin surface. Methods Though a simple one-dimensional model is often useful to describe percutaneous drug absorption, it may be better represented by multi-dimensional models. A two-dimensional mathematical model is developed for percutaneous absorption of a drug, which may be used when the diffusion of the drug in the direction parallel to the skin surface must be examined, as well as in the direction into the skin, examined in one-dimensional models. This model consists of a linear second-order parabolic equation with appropriate initial conditions and boundary conditions. These boundary conditions are of Dirichlet type, Neumann type or Robin type. A finite-difference method which maintains second-order accuracy in space along the boundary, is developed to solve the parabolic equation. Extrapolation in time is applied to improve the accuracy in time. Solution of the parabolic equation gives the concentration of the drug in the skin at a given time. Results Simulation of the numerical methods described is carried out with various values of the parameter r. The illustrations are given in the form of figures. Conclusion Based on the values of r, conclusions are drawn about (1) the flow rate of the drug, (2) the flux and the cumulative amount of drug eliminated into the receptor cell, (3) the steady-state value of the flux, (4) the time to reach the steady-state value of the flux and (5) the optimal value of r, which gives the maximum absorption of the drug. The paper gives valuable information which can be obtained by this two-dimensional model, that cannot be obtained with one-dimensional models. Thus this model improves upon the much simpler one-dimensional models. Some future directions of the work based on this model and the one-dimensional non-linear models that exist in the literature, are also discussed

Melioidosis in South Asia (India, Nepal, Pakistan, Bhutan and Afghanistan).

Despite the fact that South Asia is predicted to have the highest number of cases worldwide, melioidosis is a little-known entity in South Asian countries. It has never been heard of by the majority of doctors and has as yet failed to gain the attention of national Ministries of Health and country offices of the World Health Organization (WHO). Although a few centers are diagnosing increasing numbers of cases, and the mortality documented from these institutions is relatively high (nearly 20%), the true burden of the disease remains unknown. In India, most cases have been reported from southwestern coastal Karnataka and northeastern Tamil Nadu, although this probably simply reflects the presence of centers of excellence and researchers with an interest in the disease. As elsewhere, the majority of cases have type 2 diabetes mellitus and occupational exposure to the environment. Most present with community-acquired pneumonia and/or bacteremia, especially during heavy rainfall. The high seropositivity rate (29%) in Karnataka and isolation of B. pseudomallei from the environment in Tamil Nadu and Kerala confirm India as melioidosis-endemic, although the full extent of the distribution of the organism across the country is unknown. There are limited molecular epidemiological data, but, thus far, the majority of Indian isolates have appeared distinct from those from South East Asia and Australia. Among other South Asian countries, Sri Lanka and Bangladesh are known to be melioidosis-endemic, but there are no cases that have conclusively proved to have been acquired in Nepal, Bhutan, Afghanistan or Pakistan. There are no surveillance systems in place for melioidosis in South Asian countries. However, over the past two years, researchers at the Center for Emerging and Tropical Diseases of Kasturba Medical College, University of Manipal, have established the Indian Melioidosis Research Forum (IMRF), held the first South Asian Melioidosis Congress, and have been working to connect researchers, microbiologists and physicians in India and elsewhere in South Asia to raise awareness through training initiatives, the media, workshops, and conferences, with the hope that more patients with melioidosis will be diagnosed and treated appropriately. However, much more work needs to be done before we will know the true burden and distribution of melioidosis across South Asia

Engineering Cowpea Mosaic Virus RNA-2 into a Vector to Express Heterologous Proteins in Plants

AbstractA series of new cowpea mosaic virus (CPMV) RNA-2-based expression vectors were designed. The jellyfish green fluorescent protein (GFP) was introduced between the movement protein (MP) and the large (L) coat protein or downstream of the small (S) coat protein. Release of the GFP inserted between the MP and L proteins was achieved by creating artificial processing sites each side of the insert, either by duplicating the MP-L cleavage site or by introducing a sequence encoding the foot-and-mouth disease virus (FMDV) 2A catalytic peptide. Eight amino acids derived from the C-terminus of the MP and 14–19 amino acids from the N-terminus of the L coat protein were necessary for efficient processing of the artificial Gln/Met sites. Insertion of the FMDV 2A sequence at the C-terminus of the GFP resulted in a genetically stable construct, which produced particles containing about 10 GFP-2A-L fusion proteins. Immunocapture experiments indicated that some of the GFP is present on the virion surface. Direct fusion of GFP to the C-terminus of the S coat protein resulted in a virus which was barely viable. However, when the sequence of GFP was linked to the C-terminus by an active FMDV 2A sequence, a highly infectious construct was obtained

The NMR side-chain assignments and solution structure of enzyme IIBcellobiose of the phosphoenolpyruvate-dependent phosphotransferase system of Escherichia coli

The assignment of the side-chain Nh IR resonances and the determination of the three-dimensional solution structure of the C10S mutant of enzyme IIBcellobiose (IIBcel) of the phosphoenolpyruvate-dependent phosphotransferase system of Escherichia coli are presented. The side-chain resonances were assigned nearly completely using a variety of mostly heteronuclear NMR experiments, including HCCH-TOCSY, HCCH-COSY, and COCCH-TOCSY experiments as well as CBCACOHA, CBCA(CO)NH, and HBHA(CBCA)(CO)NH experiments.In order to obtain the three-dimensional structure, NOE data were collected from N-15-NOESY-HSQC, C-13-HSQC-NOESY, and 2D NOE experiments. The distance restraints derived from these NOE data were used in distance geometry calculations followed by molecular dynamics and simulated annealing protocols. In an iterative procedure, additional NOE assignments were derived from the calculated structures and new structures were calculated. The final set of structures, calculated with approximately 2000 unambiguous and ambiguous distance restraints, has an rms deviation of 1.1 Angstrom, on C alpha atoms. IIBcel consists of a four stranded parallel beta-sheet, in the order 2134. The sheet is flanked with two and three alpha-helices on either side. Residue 10, a cysteine in the wild-type enzyme, which is phosphorylated during the catalytic cycle, is located at the end of the first beta-strand. A loop that is proposed to be involved in the binding of the phosphoryl-group follows the cysteine. The loop appears to be disordered in the unphosphorylated state.</p

Effect of genotyping error in model-free linkage analysis using microsatellite or single-nucleotide polymorphism marker maps

Errors while genotyping are inevitable and can reduce the power to detect linkage. However, does genotyping error have the same impact on linkage results for single-nucleotide polymorphism (SNP) and microsatellite (MS) marker maps? To evaluate this question we detected genotyping errors that are consistent with Mendelian inheritance using large changes in multipoint identity-by-descent sharing in neighboring markers. Only a small fraction of Mendelian consistent errors were detectable (e.g., 18% of MS and 2.4% of SNP genotyping errors). More SNP genotyping errors are Mendelian consistent compared to MS genotyping errors, so genotyping error may have a greater impact on linkage results using SNP marker maps. We also evaluated the effect of genotyping error on the power and type I error rate using simulated nuclear families with missing parents under 0, 0.14, and 2.8% genotyping error rates. In the presence of genotyping error, we found that the power to detect a true linkage signal was greater for SNP (75%) than MS (67%) marker maps, although there were also slightly more false-positive signals using SNP marker maps (5 compared with 3 for MS). Finally, we evaluated the usefulness of accounting for genotyping error in the SNP data using a likelihood-based approach, which restores some of the power that is lost when genotyping error is introduced

Closing the sea surface mixed layer temperature budget from in situ observations alone: Operation Advection during BoBBLE

Sea surface temperature (SST) is a fundamental driver of tropical weather systems such as monsoon rainfall and tropical cyclones. However, understanding of the factors that control SST variability is lacking, especially during the monsoons when in situ observations are sparse. Here we use a ground-breaking observational approach to determine the controls on the SST variability in the southern Bay of Bengal. We achieve this through the first full closure of the ocean mixed layer energy budget derived entirely from in situ observations during the Bay of Bengal Boundary Layer Experiment (BoBBLE). Locally measured horizontal advection and entrainment contribute more significantly than expected to SST evolution and thus oceanic variability during the observation period. These processes are poorly resolved by state-of-the-art climate models, which may contribute to poor representation of monsoon rainfall variability. The novel techniques presented here provide a blueprint for future observational experiments to quantify the mixed layer heat budget on longer time scales and to evaluate these processes in models