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PubMed1997

Salary inequality and primary care integration in South Africa.

Separation of curative and preventive health programmes often impairs the coordination of primary care in developing countries. Salary differentials between organisations may aggravate non-cooperation. Implementation of a unitary national health service by South Africa's first democratically elected government has been hampered by salary differences, but no organisation possessed information on their magnitude. This paper reports on a study which estimated the distribution and conditions of service of all 224,000 public health sector personnel in South Africa, modelled options for equalising salaries between health authorities, and considered the financial and political feasibility of the options. The most important salary differential was between provincial and local authority nurses. The option to increase salaries selectively for personnel in rural and primary care would be most feasible and most in keeping with government plans. Health service unions face conflicts of interest, and professional organisations may oppose changes in nurses' roles. In a rapidly changing health system with fragmented managerial information, a combination of administrative survey, quantitative modelling and policy analysis helped clarify a key obstacle to reform. The South African case is a warning to other countries that decentralised pay bargaining may result in uncoordinated care which may be costly and difficult to overcome.

Adult↗
PubMed2005

Theory of electrostatically regulated binding of T4 gene 32 protein to single- and double-stranded DNA.

Bacteriophage T4 gene 32 protein (gp32) is a single-stranded DNA binding protein, which is essential for DNA replication, recombination, and repair. In a recent article, we described a new method using single DNA molecule stretching measurements to determine the noncooperative association constants K(ds) to double-stranded DNA for gp32 and *I, a truncated form of gp32. In addition, we developed a single molecule method for measuring K(ss), the association constant of these proteins to single-stranded DNA. We found that in low salt both K(ds) and K(ss) have a very weak salt dependence for gp32, whereas for *I the salt dependence remains strong. In this article we propose a model that explains the salt dependence of gp32 and *I binding to single-stranded nucleic acids. The main feature of this model is the strongly salt-dependent removal of the C-terminal domain of gp32 from its nucleic acid binding site that is in pre-equilibrium to protein binding to both double-stranded and single-stranded nucleic acid. We hypothesize that unbinding of the C-terminal domain is associated with counterion condensation of sodium ions onto this part of gp32, which compensates for sodium ion release from the nucleic acid upon its binding to the protein. This results in the salt-independence of gp32 binding to DNA in low salt. The predictions of our model quantitatively describe the large body of thermodynamic and kinetic data from bulk and single molecule experiments on gp32 and *I binding to single-stranded nucleic acids.

Amino Acid Sequence↗
PubMed2000

Episomal and stable expression of the luciferase reporter gene for quantifying Leishmania spp. infections in macrophages and in animal models.

We have expressed the reporter firefly luciferase gene (LUC) in Leishmania donovani and Leishmania major either as part of episomal vectors or integrated into the parasite genome under the control of their respective ribosomal promoter regions. An excellent linear correlation between parasite number and luciferase activity was observed with all the transfectants. LUC-expressing recombinant parasites were useful to monitor Leishmania spp. infections in macrophages or in animal models. For prolonged growth in absence of drug selection, such as within animal models, quantitation of parasites is more reliable when the reporter gene LUC is stably integrated in the parasite genome. These recombinant strains should be useful tools to monitor Leishmania growth under a number of conditions.

Animals↗
PubMed2002

Hydrazones of 1,2-benzisothiazole hydrazides: synthesis, antimicrobial activity and QSAR investigations.

A series of hydrazones of 1,2-benzisothiazole hydrazides 1a-m, 2a-m, 3a-m, 4a-m, 5a-m as well as their cyclic (1 and 4) and acyclic (2, 3 and 5) 1,2-benzisothiazole parent hydrazides, were synthesised and evaluated as antibacterial and antifungal agents. All of the 2-amino-1,2-benzisothiazol-3(2H)-one derivatives, belonging to series I and IV, showed a good antibacterial activity against Gram positive bacteria. Most of them were active against yeasts too. Compounds 1 and 4, together with 1l, proved to be the most effective compounds. Quantitative structure-activity relationship (QSAR) investigation with a 2D-QSAR analysis was applied to find a correlation between different experimental or calculated physicochemical parameters of the compounds studied. A 3D-QSAR study was performed, applying Comparative Molecular Similarity Indices Analysis (CoMSIA) method, to derive quantitative models relating the structural features of 1,2-benzisothiazole derivatives 1, 1a-m and 4, 4a-m and their antimicrobial activity against Bacillus subtilis, resulted the most sensitive micro-organism.

Anti-Bacterial Agents↗
PubMed2002

Is global outcome predictable in the rehabilitation of patients with musculoskeletal disorders? A pilot study.

Definition of prognostic factors for outcome quality is of increasing interest in rehabilitation medicine. The main question of this pilot study in 552 patients was whether global outcome could be predicted by a team-based chief physician specialized in physical medicine and rehabilitation (PMR), and whether other predictive factors would exist (ICIDH-2 levels, pain, working incapacity). Little data is available about the possibility of global prediction of prognosis in the rehabilitation of patients with musculoskeletal disorders. All 552 patients met each member of the rehabilitation team and key data from each patient was discussed at the rehabilitation conference within the first 2 days. On entry to the study, a chief physician specialized in PMR assessed the patient's key data, which was structured according to ICIDH-2 (ICF) and assessed quantitatively on a scale from zero to ten. Second, the PMR physician rated the expected global prognosis on the basis of ICIDH-2 and other key data, and in respect to the defined rehabilitation goals (see Table 2). At the same time, the patient and an assistant doctor (AD) assessed pain scores (VAS 0-10) and the actual working incapacity (%). These assessments were completed within the first 3 days and were repeated before discharge. Assessment of outcome was rated by both, separately, according to the above-mentioned scale. Different regression models were calculated, searching for significant differences between the numerous variables. In the regression models, the best predictor for outcome was the PMR physician assessment. Complete and good correspondence between prediction and outcome was obtained in 71.4% (42.1% and 29.3%, respectively) in the descriptive model. Quantitatively assessed ICIDH-2 levels, pain at entrance and working incapacity at entrance were not predictive factors for global outcome. The global outcome was rated as very good/good in 79.0% of cases by patient and in 75.1% cases by the AD, as moderate in 13.9% of cases by the patient and 18.4% of cases by the AD, and as poor/worsening in 7.1% of cases by the patient and in 6.5% of cases by the AD. Rating of outcome by the patient and the AD gave complete and good correspondence in 87.6% and no correspondence in only 2.6% of cases. Pain could be reduced highly significantly (P<0.001). There was a highly significant degree of correlation between quality of outcome and pain relief (outcome 'very good' and 'good', P<0.001; 'moderate', P=0.003; 'poor/worsening', not significant). Partial or complete reduction of working incapacity could be reached in 30% of the patients. This had no statistical influence on global outcome; neither did persistent working incapacity. Prediction of global outcome by a team-based PMR assessment seems to be a useful semiquantitative method with high predictive value. The method, including the critical point of validation, is currently being extensively discussed. Prediction is an integral process based on the high information grade of a multiprofessional rehabilitation team, the ICIDH-2 structures, the definition of rehabilitation goals, the knowledge and experience in bio-psycho-social medicine and the application of common sense. Rating of global outcome by the patient/AD is an integrative process as well. Pain relief is an important and very strong factor, with a high degree of influence on global outcome in musculoskeletal rehabilitation, probably by improving quality of life. Working incapacity is no reason for refusing patients rehabilitation and both improvement of working capacity and persistence of working incapacity, has no statistical influence on global outcome. Finally, the extent of the four ICIDH-2 levels, especially negative contextual factors, were not predictive, that is, they had no significant influence on global outcome in this study. In conclusion, prediction of global outcome by a team-based chief physician specialized in PMR is of high predictive value, practicable and useful for rehabilitation processes, quality assurance, insurance companies and health policies. To our knowledge, this is the first published study on this topic.

Adolescent↗
PubMed2000

Force production by single kinesin motors.

Motor proteins such as kinesin, myosin and polymerase convert chemical energy into work through a cycle that involves nucleotide hydrolysis. Kinetic rates in the cycle that depend upon load identify transitions at which structural changes, such as power strokes or diffusive motions, are likely to occur. Here we show, by modelling data obtained with a molecular force clamp, that kinesin mechanochemistry can be characterized by a mechanism in which a load-dependent isomerization follows ATP binding. This model quantitatively accounts for velocity data over a wide range of loads and ATP levels, and indicates that movement may be accomplished through two sequential 4-nm substeps. Similar considerations account for kinesin processivity, which is found to obey a load-dependent Michaelis-Menten relationship.

Adenosine Triphosphate↗
PubMed2003

Osmotic water transport through carbon nanotube membranes.

We use molecular dynamics simulations to study osmotically driven transport of water molecules through hexagonally packed carbon nanotube membranes. Our simulation setup comprises two such semipermeable membranes separating compartments of pure water and salt solution. The osmotic force drives water flow from the pure-water to the salt-solution compartment. Monitoring the flow at molecular resolution reveals several distinct features of nanoscale flows. In particular, thermal fluctuations become significant at the nanoscopic length scales, and as a result, the flow is stochastic in nature. Further, the flow appears frictionless and is limited primarily by the barriers at the entry and exit of the nanotube pore. The observed flow rates are high (5.8 water molecules per nanosecond and nanotube), comparable to those through the transmembrane protein aquaporin-1, and are practically independent of the length of the nanotube, in contrast to predictions of macroscopic hydrodynamics. All of these distinct characteristics of nanoscopic water flow can be modeled quantitatively by a 1D continuous-time random walk. At long times, the pure-water compartment is drained, and the net flow of water is interrupted by the formation of structured solvation layers of water sandwiched between two nanotube membranes. Structural and thermodynamic aspects of confined water monolayers are studied.

Membranes, Artificial↗
PubMed2006

QSAR study of 1,4-dihydropyridine calcium channel antagonists based on gene expression programming.

The gene expression programming, a novel machine learning algorithm, is used to develop quantitative model as a potential screening mechanism for a series of 1,4-dihydropyridine calcium channel antagonists for the first time. The heuristic method was used to search the descriptor space and select the descriptors responsible for activity. A nonlinear, six-descriptor model based on gene expression programming with mean-square errors 0.19 was set up with a predicted correlation coefficient (R2) 0.92. This paper provides a new and effective method for drug design and screening.

Algorithms↗
PubMed2004

Esters, amides and substituted derivatives of cinnamic acid: synthesis, antimicrobial activity and QSAR investigations.

A series of esters (I(a-k)), substituted derivatives (II(a-d)) and amides (III(a-q)) of cinnamic acid were synthesized and evaluated as antibacterial and antifungal agents. All the derivatives belonging to the series I, II and III showed antimicrobial activity comparable to the standard. Compounds I(f) and II(c) proved to be the most effective compounds. Quantitative structure-activity relationship (QSAR) investigation with multiple linear regression analysis was applied to find a correlation between different calculated physicochemical parameters of the compounds and biological activity. The quantitative models relating the structural features of cinnamic acid derivatives I(a-k), II(a-d) and III(a-q) and their antimicrobial activity showed that Gram negative Escherichia coli and Candida albicans (fungus) were the most sensitive microorganisms.

Amides↗
PubMed2001

Genetic determinism in the relationship between human CD4+ and CD8+ T lymphocyte populations?

The adaptive immune system in mammals acts in a coordinated manner to eliminate environmentally derived pathogens. Humans, mice and rats show within species variation in the levels and ratios of their peripheral CD4+ and CD8+ T cells and to a significant degree this variation is under the control of polymorphic genes. Whether genes act separately to specify CD4+ and CD8+ subpopulation levels or whether CD8+ variation is controlled through gene and environmental action on CD4+ cells or vice versa, is not known. We use a quantitative modelling approach in identical and non-identical female human twins to delineate the lines of control which act upon and between CD4+ and CD8+ subsets. The major findings of the study are: (1) genetic variation controls CD8+ T cell levels through two major routes-the first is via an effect on CD4+ T cells which accounts for the observed co-variation between CD4+ and CD8+ T cells, the second is through direct action on CD8+ T cell levels. (2) No evidence of a gene effect from CD8+ T cells on CD4+ cells is observed. Our findings have implications for the evolution of the complex defence system of which CD4+ and CD8+ T cells are a crucial part and encourage further work towards locating common pleiotropic quantitative trait loci responsible for variation in numbers of T cells.

CD4-Positive T-Lymphocytes↗
PubMed1988

Maternal transmission of retroviral disease: transgenic mice as a rapid test system for evaluating perinatal and transplacental antiretroviral therapy.

Transgenic mouse strains carrying Moloney murine leukemia virus (Mo-MuLV) in the germ line were found to serve as rapid and quantitative models of in utero and perinatal retroviral infection for evaluating strategies of antiretroviral therapy. In these strains virus activation leads to virus expression, viral spread associated with the development of viremia, and subsequent T-cell leukemia/lymphoma. To test these transgenic strains for their usefulness in evaluating antiretroviral agents, the effect of the drug 3'-azido-3'-deoxythymidine (AZT) on the development of viremia and subsequent disease was examined. The assessment of mice for viremia at 1 month of age appeared to be the most useful assay because it was rapid and quantitative. AZT was most effective in preventing viremia in transgenic strains that activate Mo-MuLV after birth and had more variable effects in strains that activate prior to birth. However, in six of seven of the strains examined, AZT led to a marked improvement in survival and reduced the onset of T-cell leukemia/lymphoma. These results provide evidence for effective antiretroviral therapy during gestation and in the perinatal period and are of potential significance for the management of the maternal transmission of human retroviruses.

Animals↗
PubMed1975

Dominance and reproduction in Baboons (Papio cynocephalus).

This monograph reports on a 14 month study of yellow baboons (Papio cynocephalus) in the Masai-Amboseli Game Reserve, Kenya. The study was an attempt to determine the relationship between agonistic dominance and reproductive success in male baboons and centered around testing a priority-of-access model of mating behavior. Explicit criteria for determining dominance in baboons are presented and the consistency of dominance relationships through time is analyzed for all classes of individuals. Related data on reproductive cycle length, perineal and behavioral indications of the optimal day for mating, changes in female behavior during estrus, and effects of the presence of estrous females on group organization are also included. This work constitutes the first comprehensive field study of baboon mating systems and social organization and emphasizes the use of systematic behavior sampling techniques in the field and quantitative models in the study of primate social behavior.

Aggression↗
PubMed2004

A graph theory analysis of renal glomerular microvascular networks.

A graph theory model and its invariants are used to compare previously published renal glomerular networks of six adult rats, one adult uremic rat, and one newborn rat. Invariants calculated include order, size, cycle rank, eccentricity, root distance, planarity, and vertex degree distribution. These invariants enabled the differentiation of six normal adult glomerular microvascular networks from that of the uremic glomerulus and from that of the normal newborn glomerulus. These invariants might then be used to differentiate between normal and pathological vascular networks. Also proposed are graph theory invariants that might be used to develop a quantitative model for angiogenesis.

Animals↗
PubMed2002

Mucosal folding in biologic vessels.

A two-layer model is used to simulate the mechanical behavior of an airway or other biological vessel under external compressive stress or smooth muscle constriction sufficient to cause longitudinal mucosal buckling. Analytic andfinite element numerical methods are used to examine the onset of buckling. Post-buckling solutions are obtained by finite element analysis, then verified with large-scale physical model experiments. The two-layer model provides insight into how the stiffness of a vessel wall changes due to changes in the geometry and intrinsic material stiffnesses of the wall components. Specifically, it predicts that the number of mucosal folds in the buckled state is diminished most by increased thickness of the inner collagen-rich layer, and relatively little by increased thickness of the outer submucosal layer. An increase in the ratio of the inner to outer material stiffnesses causes an intermediate reduction in the number of folds. Results are cast in a simple form that can easily be used to predict buckling in a variety of vessels. The model quantitatively confirms that an increase in the thickness of the inner layer leads to a reduction in the number of mucosal folds, and further, that this can lead to increased vessel collapse at high levels of smooth muscle constriction.

Bronchi↗
PubMed1982

[Effectiveness of selection for thorax length in model Drosophila populations in chemical mutagen exposure].

Artificial selection for increasing and decreasing Drosophila thorax length was carried out over 20 generations. Chemical mutagen, dimethylsulfate (DMS) was regularly applied to enhance genetic variation in selected lines. It was determined that under the influence of mutagen the efficiency of selection for decreasing thorax length was much higher, while selection course for increasing thorax length was not affected significantly. Regression coefficient of responses to selection, general for males and females, was equal to b = -0.035 +/- 0.004 for lines of negative direction of selection when the mutagen was applied and -b = -0.023 +/- 0.004 without mutagenesis; for lines of positive direction b = 0.026 +/- 0.005 and b = 0.024 +/- 0.005. Fitness component variation by artificial selection was studied. A complex correlation was detected between direction of selection, the shift value of model quantitative character and fitness component variation by selection. The main factor stimulating a sharp drop of average fitness of lines appeared to be the influence of directional artificial selection. The regular treatment by a moderate dose of the mutagen did not affect markedly the average fitness variation of selected lines.

Animals↗
PubMed1991

A stochastic branching model with formation of subunits applied to the growth of intestinal crypts.

The intestinal epithelium is one of the most rapidly regenerating tissues in mammals. Cell production takes place in the intestinal crypts which contain about 250 cells. Only a minority of 1-60 proliferating cells are able to maintain a crypt over a long period of time. However, so far attempts to identify these stem cells were unsuccessful. Therefore, little is known about their cellular growth and selfmaintenance properties. On the other hand, the crypts appear to exhibit a life cycle which starts by fission of existing crypts and ends by fission or extinction. Data on these processes have recently become available. Here, we demonstrate how these data on the life cycle of the macroscopic crypt structure can be used to derive a quantitative model of the microscopic process of stem cell growth. The model assumptions are: (1) stem cells undergo a time independent supracritical Markovian branching process (Galton-Watson process); (2) a crypt divides if the number of stem cells exceeds a given threshold and the stem cells are distributed to both daughter crypts according to binomial statistics; (3) the size of the crypt is proportional to the stem cell number. This model combining two different stochastic branching processes describes a new class of processes whose stationary stability and asymptotic behavior are examined. This model should be applicable to various growth processes with formation of subunits (e.g. population growth with formation of colonies in biology, ecology and sociology). Comparison with crypt data shows that intestinal stem cells have a probability of over 0.8 of dividing asymmetrically and that the threshold number should be 8 or larger.

Animals↗
PubMed2000

Tec family kinases modulate thresholds for thymocyte development and selection.

Tec family kinases are implicated in T cell receptor (TCR) signaling, and combined mutation of inducible T cell kinase (Itk) and resting lymphocyte kinase (Rlk)/Txk in mice dramatically impairs mature T cell function. Nonetheless, mutation of these kinases still permits T cell development. While itk(-)(/)- mice exhibit mild reductions in T cells with decreased CD4/CD8 cell ratios, rlk(-)(/)-itk(-)(/)- mice have improved total T cell numbers yet maintain decreased CD4/CD8 ratios. Using TCR transgenics and an in vitro thymocyte deletion model, we demonstrate that mutation of Tec kinases causes graded defects in thymocyte selection, leading to a switch from negative to positive selection in rlk(-)(/)-itk(-)(/)- animals. The reduction in both positive and negative selection and decreased CD4/CD8 ratios correlates with decreased biochemical parameters of TCR signaling, specifically defects in capacitive Ca(2+) influx and activation of the mitogen-activated kinases extracellular signal-regulated kinase 1 and 2. Thus, Tec kinases influence cell fate determination by modulating TCR signaling, leading to altered thresholds for thymocyte selection. These results provide support for a quantitative model for thymic development and provide evidence that defects in negative selection can substantially alter thymic cellularity.

Animals↗
PubMed2005

Observation volumes and {gamma}-factors in two-photon fluorescence fluctuation spectroscopy.

Fluorescence fluctuation spectroscopy has become an important measurement tool for investigating molecular dynamics, molecular interactions, and chemical kinetics in biological systems. Although the basic theory of fluctuation spectroscopy is well established, it is not widely recognized that saturation of the fluorescence excitation can dramatically alter the size and profile of the fluorescence observation volume from which fluorescence fluctuations are measured, even at relatively modest excitation levels. A precise model for these changes is needed for accurate analysis and interpretation of fluctuation spectroscopy data. We here introduce a combined analytical and computational approach to characterize the observation volume under saturating conditions and demonstrate how the variation in the volume is important in two-photon fluorescence correlation spectroscopy. We introduce a simple approach for analysis of fluorescence correlation spectroscopy data that can fully account for the effects of saturation, and demonstrate its success for characterizing the observed changes in both the amplitude and relaxation timescale of measured correlation curves. We also discuss how a quantitative model for the observed phenomena may be of broader importance in fluorescence fluctuation spectroscopy.

Biophysics↗