Time of treatment influences the appearance of drug-resistant parasites in Plasmodium falciparum infections

A deterministic mathematical model which predicts the probability of developing a new drug-resistant parasite population within the human host is reported, The model incorporates the host's specific antibody response to PfEMP1, and also investigates the influence of chemotherapy on the probability of developing a viable drug-resistant parasite population within the host. Results indicate that early, treatment, and a high antibody threshold coupled with a long lag time between antibody stimulation and activity, are risk factors which increase the likelihood of developing a viable drug-resistant parasite population. High parasite mutation rates and fast PfEMP1 var gene switching are also identified as risk factors. The model output allows the relative importance of the various risk factors as well as the relationships between them to be established, thereby increasing the understanding of the conditions which favour the development of a new drug-resistant parasite population.

Brief opportunistic intervention: The role of psychologists in initiating self-change amongst problem drinkers

Excessive consumption of alcohol is a serious public health problem. While intensive treatments are suitable for those who are physically dependent on alcohol, they are not cost-effective options for the vast majority of problem drinkers who are not dependent. There is good evidence that brief interventions are effective in reducing overall alcohol consumption, alcohol-related problems, and health-care utilisation among nondependent problem drinkers. Psychologists are in an ideal position to opportunistically detect people who drink excessively and to offer them brief advice to reduce their drinking. In this paper we outline the process involved in providing brief opportunistic screening and intervention for problem drinkers. We also discuss methods that psychologists can employ if a client is not ready to reduce drinking, or is ambivalent about change. Depending on the client's level of motivation to change, psychologists can engage in either an education-clarification approach, a commitment-enhancement approach, or a skills-training approach. Routine engagement in opportunistic intervention is an important public-health approach to reducing alcohol-related harm in the community.

Effect of leucaena supplementation level, and provision of urea, on utilisation by sheep of Rhodes grass hay

Tarramba leucaena (Leucaena leucocephala cv. Tarramba) foliage had per kilogram dry matter, 169 g protein and 29.8 g condensed tannins. Its value as a supplement, given either with or without urea, to sheep given a low-quality Callide Rhodes grass (Chloris gayana cv. Callide) hay was studied. Six rumen fistulated sheep (mean +/- s.d. liveweight, 34 +/- 1.4 kg) were used to compare 6 dietary treatments in an incomplete latin square design. Rhodes grass hay was given ad libitum either alone, or with urea 7 g/day (U), or with leucaena 150 g/day (L150), or leucaena with urea (L150U), or leucaena 300 g/day (L300), or leucaena with urea (L300U). Digestible organic matter intake was increased significantly by leucaena supplementation although digestibility of the whole diet did not alter. Rumen fluid ammonia-N was not altered by leucaena supplementation, but was increased by urea. This suggests that Tarramba foliage protein has some resistance to ruminal degradation. Liquid and solids passage rates were not affected by the treatments. Microbial nitrogen supply to the intestine (g/day), and the efficiency of microbial nitrogen synthesis (g/kg organic matter apparently digested in the rumen), were increased by leucaena supplementation (P

Towards a definition of "difference" in osteoarthritis

To assess existing information regarding detectable differences in osteoarthritis (OA), a systematic literature search was conducted up to December 1999. Thirty-three articles were considered methodologically relevant to the definition and categorization of detectable differences in OA. It was determined that the musculoskeletal literature contains a wealth of information that relates to observed changes, much of which is derived from the clinical trials literature, but there have been relatively few methodological studies that have systematically evaluated the nature, categorization, and relevance of the change. Furthermore, most of those that have been published take the perspective of an individual or groups of experts other than that of the patient. This summary of the current literature reveals that the diverse sources of information go part way towards developing an understanding of detectable differences and their importance in the area of OA research and clinical practice. Stakeholders' interests as well as factors that modulate perceptions of importance need to be taken under consideration. In particular, the patient's perspective of the importance of change at an individual level requires further evaluation. This area of clinical research is relatively underdeveloped, but there is considerable opportunity for progress.

Quantifying stresses and support requirements in the undercut and production level drifts of block and panel caving mines

A numerical modelling strategy has been developed in order to quantify the magnitude of induced stresses at the boundaries of production level and undercut level drifts for various in situ stress environments and undercut scenarios. The results of the stress modelling were in line with qualitative experiential guidelines and a limited number of induced stress measurements documented from caving sites. A number of stress charts were developed which quantify the maximum boundary stresses in drift roofs for varying in situ stress regimes, depths and undercut scenarios. This enabled many of the experiential guidelines to be quantified and bounded. A limited number of case histories of support and support performance in cave mine drifts were compared to support recommendations using the NGI classification system, The stress charts were used to estimate the Stress Reduction Factor for this system. The back-analyses suggested that the NGI classification system might be able to give preliminary estimates of support requirements in caving mines with modifications relating to rock bolt length and the support of production level intersections. (C) 2002 Elsevier Science Ltd. All rights reserved.

Estimating Two-Stage Models for Genetic Influences on Alcohol, Tobacco or Drug Use Initiation and Dependence Vulnerability in Twin and Family Data

Genetic research on risk of alcohol, tobacco or drug dependence must make allowance for the partial overlap of risk-factors for initiation of use, and risk-factors for dependence or other outcomes in users. Except in the extreme cases where genetic and environmental risk-factors for initiation and dependence overlap completely or are uncorrelated, there is no consensus about how best to estimate the magnitude of genetic or environmental correlations between Initiation and Dependence in twin and family data. We explore by computer simulation the biases to estimates of genetic and environmental parameters caused by model misspecification when Initiation can only be defined as a binary variable. For plausible simulated parameter values, the two-stage genetic models that we consider yield estimates of genetic and environmental variances for Dependence that, although biased, are not very discrepant from the true values. However, estimates of genetic (or environmental) correlations between Initiation and Dependence may be seriously biased, and may differ markedly under different two-stage models. Such estimates may have little credibility unless external data favor selection of one particular model. These problems can be avoided if Initiation can be assessed as a multiple-category variable (e.g. never versus early-onset versus later onset user), with at least two categories measurable in users at risk for dependence. Under these conditions, under certain distributional assumptions., recovery of simulated genetic and environmental correlations becomes possible, Illustrative application of the model to Australian twin data on smoking confirmed substantial heritability of smoking persistence (42%) with minimal overlap with genetic influences on initiation.

Development of a mungbean (Vigna radiata) RFLP linkage map and its comparison with lablab (Lablab purpureus) revelas a high level of colinearity between the two genomes

A genetic linkage map of mungbean (Vigna radiata, 2n = 2x = 22) consisting of 255 RFLP loci was developed using a recombinant inbred population of 80 individuals. The population was derived from an intersubspecific cross between the cultivated mungbean variety 'Berken' and a wild mungbean genotype 'ACC 41' (V radiata subsp. sublobata). The total length of the map, which comprised 13 linkage groups, spanned 737.9 cM with an average distance between markers of 3.0 cM and a maximum distance between linked markers of 15.4 cM. The mungbean map was compared to a previously published map of lablab (Lablab purpureus, 2n = 2x = 24) using a common set of 65 RFLP probes. In contrast to some other comparative mapping studies among members of the Fabaceae, where a high level of chromosomal rearrangement has been observed, marker order between mungbean and lablab was found to be highly conserved. However, the two genomes have apparently accumulated a large number of duplications/deletions after they diverged.

Bayesian feedback versus Markovian feedback in a two-level atom

We compare two different approaches to the control of the dynamics of a continuously monitored open quantum system. The first is Markovian feedback, as introduced in quantum optics by Wiseman and Milburn [Phys. Rev. Lett. 70, 548 (1993)]. The second is feedback based on an estimate of the system state, developed recently by Doherty and Jacobs [Phys. Rev. A 60, 2700 (1999)]. Here we choose to call it, for brevity, Bayesian feedback. For systems with nonlinear dynamics, we expect these two methods of feedback control to give markedly different results. The simplest possible nonlinear system is a driven and damped two-level atom, so we choose this as our model system. The monitoring is taken to be homodyne detection of the atomic fluorescence, and the control is by modulating the driving. The aim of the feedback in both cases is to stabilize the internal state of the atom as close as possible to an arbitrarily chosen pure state, in the presence of inefficient detection and other forms of decoherence. Our results (obtained without recourse to stochastic simulations) prove that Bayesian feedback is never inferior, and is usually superior, to Markovian feedback. However, it would be far more difficult to implement than Markovian feedback and it loses its superiority when obvious simplifying approximations are made. It is thus not clear which form of feedback would be better in the face of inevitable experimental imperfections.

Optical barcoding of colloidal suspensions: applications in genomics, proteomics and drug discovery

The enormous amount of information generated through sequencing of the human genome has increased demands for more economical and flexible alternatives in genomics, proteomics and drug discovery. Many companies and institutions have recognised the potential of increasing the size and complexity of chemical libraries by producing large chemical libraries on colloidal support beads. Since colloid-based compounds in a suspension are randomly located, an encoding system such as optical barcoding is required to permit rapid elucidation of the compound structures. We describe in this article innovative methods for optical barcoding of colloids for use as support beads in both combinatorial and non-combinatorial libraries. We focus in particular on the difficult problem of barcoding extremely large libraries, which if solved, will transform the manner in which genomics, proteomics and drug discovery research is currently performed.

Urine D-arabinitol/L-arabinitol ratio in diagnosing Candida infection in patients with haematological malignancy and HIV infection

Adult patients with hematologic malignancies along with HIV infected patients were prospectively studied to determine the performance of urine D-arabinitol/L-arabinitol (DA/LA) ratio in diagnosing invasive candidiasis. Ten evaluable febrile neutropenic patients had proven invasive candidiasis and elevated DA/LA ratios were found in 5. Invasive candidiasis with normal DA/LA ratios was most frequently due to Candida krusei infection. This Candida species is a non-producer of arabinitol. Only 4 of 81 febrile neutropenic patients given either antifungal prophylaxis or empiric antifungal treatment had elevated DA/LA ratios. Only 1 of 15 HIV positive patients with either oropharyngeal or esophageal candidiasis had elevated DA/LA ratios. Widespread use of fluconazole prophylaxis in bone marrow transplantation patients at the study hospital has led to an increased prevalence of C. krusei infection. This is the likely reason for the low sensitivity of the test in proven and suspected invasive Candida infections reported here. (C) 2002 Elsevier Science Inc. All rights reserved.

Genetic linkage analysis of the lesser grain borer Rhyzopertha dominica identifies two loci that confer high-level resistance to the fumigant phosphine

High levels of inheritable resistance to phosphine in Rhyzopertha dominica have recently, been detected in Australia and hi art effort to isolate the genes responsible For resistance we have used random amplified DNA fingerprinting (RAF) to produce a genetic linkage map of R. dominica. The map consists of 94 dominant DNA markers with art average distance between markers of 4.6 cM and defines nine linkage groups with a total recombination distance of 390.1 cM. We have identified two loci that are responsible for high-level resistance. One provides similar to50x resistance to phosphine while the other provides 12.5x resistance and in combination, the two genes act synergistically to provide a resistance level 250 x greater than that of fully susceptible beetles. The haploid genome size has been determined to be 4.76 x 10(8) bp, resulting in an average physical distance of 1.2 Mbp per map unit. No recombination has been observed between either of the two resistance loci and their adjacent DNA markers in a population of 44 fully resistant F-5 individuals, which indicates that the genes are likely to reside within 0.91 cM (1.1 Mbp) of the DNA markers.

Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity, and nature of drug

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl4)induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha(1)- acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P-app) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl4-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P-app or pK(a)) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

Absorption and dispersion by a multiple driven two-level atom

We investigate the absorption and dispersion properties of a two-level atom driven by a polychromatic field. The driving field is composed of a strong resonant (carrier) frequency component and a large number of symmetrically detuned sideband fields (modulators). A rapid increase in the absorption at the central frequency and the collapse of the response of the system from multiple frequencies to a single frequency are predicted to occur when the Rabi frequency of the modulating fields is equal to the Rabi frequency of the carrier field. These are manifestations of the undressing or a disentanglement of the atomic and driving field states, that leads to a collapse of the atom to its ground state. Our calculation permits consideration of the question of the undressing of the driven atom by a multiple-modulated field and the predicted spectra offer a method of observing undressing. Moreover, we find that the absorption and dispersion spectra split into multiplets whose structures depend on the Rabi frequency of the modulating fields. The spectral features can jump between different resonance frequencies by changing the Rabi frequency of the modulating fields or their initial phases, which can have potential applications as a quantum frequency filter.

The cyclotides: Novel macrocyclic peptides as scaffolds in drug design

Cyclotides are a novel class of circular, disulfide-rich peptides (similar to 30 amino acids) that display a broad range of bioactivities and have exceptionally high stability. Their physical properties, which include resistance to thermal and enzymatic degradation, can be attributed to their unique cyclic backbone and knotted arrangement of disulfide bonds. The applicability of linear peptides as drugs is potentially limited by their susceptibility to proteolytic cleavage and poor bioavailability. Such limitations may be overcome by using the cyclotide framework as a scaffold onto which new activities may be engineered. The potential use of cyclotides for drug design is evaluated here, with reference to rapidly increasing knowledge of natural cyclotides and the emergence of new techniques in peptide engineering.