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PubMed1993

Crossbridges in the complete unit cell of rigor insect flight muscle imaged by three-dimensional reconstruction from oblique sections.

We have computed two types of 3-D reconstructions from single images of oblique transverse sections through rigor insect flight muscle (IFM) that permit simultaneous examination of all myosin crossbridges within the unit cell. One type, crystallographic serial section reconstruction (CSSR), utilizes primarily real space image manipulations of the periodic crossbridge lattice to obtain a 3-D reconstruction from a single image. The CSSRs, which do not average successive unit cells along the filament axis, reveal variations in the rigor double chevrons within the 116 nm long axial repeat and in particular show that specific crossbridges are absent. CSSRs establish that in rigor, the 116 nm period contains nine 12.9 nm repeats of attached crossbridges rather than the eight 14.5 nm repeats of myosin head origins observed in the relaxed state. This indicates that dominance of the actin repeat on myosin head form enforces axial and azimuthal changes on the crossbridge origins on the thick filament. The second type, superlattice reconstruction (SLR), is carried out entirely in Fourier space and produces an averaged reconstruction with the symmetry of the unit cell enforced. SLRs measure the 3-D transform of the complete unit cell, permitting direct comparison with X-ray diagrams from native muscle. Averaging several SLRs together has produced the highest resolution reconstruction of IFM to date. Oblique section reconstructions made by both methods confirm in greater detail the presence of two-headed lead crossbridges and single-headed rear crossbridges implying heads with differing angles and conformation. Reduced twist in the thin filament coincident with the lead crossbridge is also apparent. We have modeled several interpretations of this reduced twist in terms of structural changes in both myosin and actin at the lead bridge. In addition, these 3-D images resolve a feature just Z-ward of the rear crossbridge where antibody labeling has identified part of the large troponin complex of IFM.

Actins↗

PubMed1994

Estimation of total coronary artery flow using measurements of flow in the ascending aorta.

This paper describes a technique for estimation of total (right+left) coronary artery flow using MRI flow measurements in the ascending aorta. The technique is based on the principle that the flow in a vessel branch is equal to the difference of the net flow measured above and below the branch ostia. Aortic net flow is measured at four or more axial oblique slices from below the aortic valve to above the highest location of the coronary vessel ostia in late diastole. A flow model properly interprets the flow measurements in slices that contain the coronary ostia. Results in five normal subjects show that total coronary artery flow can be measured with a standard error of about 90 cc/min, 30% of total coronary artery flow. Potential clinical uses include noninvasive measurement of coronary flow reserve. Pulse sequence improvements are necessary to reduce examination time and improve accuracy and precision.

Algorithms↗

PubMed1990

Replacement of the Escherichia coli trp operon attenuation control codons alters operon expression.

To test features of the current model of transcription attenuation in amino acid biosynthetic operons, alterations were introduced into the trp operon leader region and expression of the mutated operons was examined in miaA and miaA+ Escherichia coli strains that lacked the trp repressor. The miaA mutation prevents modification of the adenosine residue immediately 3' of the anticodon of tRNAs that interact with codons beginning with uridine. The undermodified tRNA(Trp) in miaA strains is thought to increase readthrough at the trp attenuator by slowing ribosome movement over two tandem Trp codons in the 14-codon leader peptide coding region. The rate of translation of these two "control codons" is thought to be the key step in determining the extent of transcription attenuation in the trp leader region. Sequential deletion of trpL DNA specifying the leader peptide initiation region, RNA segment 1, RNA segment 2 and RNA segment 3 alternately decreased and increased trp operon expression, a result consistent with previous findings in another bacterium and the generally accepted model for transcription attenuation. Replacement of the tandem Trp control codons by AGG-UGC (Arg-Cys) codons eliminated the miaA-dependent increase in transcription readthrough. Replacement of the Trp control codons by AGG-UGA (Arg-stop) codons caused complete readthrough at the trp attenuator as well as abolishing the miaA effect. Presumably, the ribosome terminating translation at the new UGA codon mimics the effect of a stalled ribosome at the Trp control codons. This finding suggests that ribosome dissociation at some stop codons is slow relative to the time required for transcription of the trp leader region. Thus, most ribosomes translating the trp leader peptide coding region may remain attached to the natural UGA stop codon until after the attenuation decision is made. The interpretation supports models for trp operon attenuation in which the elevated basal level readthrough is determined by occasional ribosome release prior to synthesis of the 3:4 terminator hairpin.

Amino Acid Sequence↗

PubMed2004

Kinetics of Zn release in soils and prediction of Zn concentration in plants using diffusive gradients in thin films.

Effective concentrations (CE) of Zn measured by the technique of DGT (diffusive gradients in thin films) were compared, along with total concentrations of Zn and the concentrations of Zn in soil solutions, to Zn concentrations in plants. Soils variously contaminated with Zn were collected in the vicinity of two galvanized electrical transmission towers (pylons) and two motorway crash barriers. Lepidium sativum was grown in each soil and in corresponding control soils amended with ZnCl2 to similar total Zn concentrations. CE, concentrations in soil solution, and total Zn were measured in all soils, and total Zn was measured in the plant shoots. The CE values, soil solution Zn, and shoot Zn concentrations were all larger in ZnCl2 amended soils than in field contaminated soils at corresponding total Zn. Correlations between the concentration of Zn in the plants and the measured soil parameter followed the order CE > soil solution > total Zn. The low scatter in the plot of log plant concentration versus log CE revealed a relationship with two distinct features. Plant Zn was between 100 and 300 mg/kg up to an effective Zn concentration of about 2 mg/L, above which plant Zn increased steadily with increasing CE. Use of a dynamic model to interpret the DGT measurement suggests that the intrinsic rate of release of Zn from solid phase to solution, expressed as a rate constant, is much higher for soils that receive fresh supplies of Zn. This finding provides a mechanistic basis for reconciling laboratory experiments, where metal is freshly amended, to data obtained in the field. The potential of DGT as a surrogate for metal availability to plants is further confirmed by this work.

Belgium↗

PubMed2001

Using features of Arden Syntax with object-oriented medical data models for guideline modeling.

Computer-interpretable guidelines (CIGs) can deliver patient-specific decision support at the point of care. CIGs base their recommendations on eligibility and decision criteria that relate medical concepts to patient data. CIG models use expression languages for specifying these criteria, and define models for medical data to which the expressions can refer. In developing version 3 of the GuideLine Interchange Format (GLIF3), we used existing standards as the medical data model and expression language. We investigated the object-oriented HL7 Reference Information Model (RIM) as a default data model. We developed an expression language, called GEL, based on Arden Syntax's logic grammar. Together with other GLIF constructs, GEL reconciles incompatibilities between the data models of Arden Syntax and the HL7 RIM. These incompatibilities include Arden's lack of support for complex data types and time intervals, and the mismatch between Arden's single primary time and multiple time attributes of the HL7 RIM.

Decision Making, Computer-Assisted↗

PubMed2006

Effect of a posterior dynamic implant adjacent to a rigid spinal fixator.

BACKGROUND: A slightly degenerated disc adjacent to a segment that has to be fused is sometimes instrumented with a dynamic fixator. The dynamic implant is assumed to reduce disc loads at that level and to preserve disc function, thus inhibiting the progression of degeneration. METHODS: A three-dimensional finite element model of the lumbar spine was used to study the effect of a dynamic implant on the mechanical behavior at the corresponding level. After studying a healthy lumbar spine for comparison, a rigid fixator and a bone graft were inserted at L2/L3. Healthy and degenerated discs were assumed at the adjacent level, i.e. L3/L4. An additional paired dynamic posterior fixator was then implemented at level L3/L4. Finally, the segment with the dynamic fixator was distracted to the height of a healthy disc. The loading cases of walking, extension, flexion and axial rotation were simulated. FINDINGS: A dynamic implant reduces intersegmental rotation for walking, extension and flexion as well as facet joint forces for axial rotation at its insertion level. Intradiscal pressure is not markedly reduced by a dynamic implant. Moreover, there are no substantial differences between the mechanical behavior of rigid and dynamic fixators. INTERPRETATION: Our model does not predict major differences in the mechanical effects between rigid and dynamic fixators despite the extreme assumption that a dynamic implant does not transfer moments. The results do not support the assumption that disc loads are significantly reduced by a dynamic implant. For axial rotation, however, dynamic fixation devices do reduce the force in the facet joint.

Back↗

PubMed1992

Symmetry conditions for binding processes.

Symmetry conditions are derived for global and local binding processes in biological macromolecules. It is shown that the conditions applying in the case of the macromolecule as a whole are decoupled from those referring to individual sites. In the case of two sites, the global binding curve is always symmetric, and the individual-site binding curves are always asymmetric, unless the two sites are identical or independent. In the case of three sites or more, individual-site binding curves can show symmetric or asymmetric behavior. The conditions derived for symmetry in the local description of binding processes also apply to the case of linkage among different ligands and to steady-state kinetics. Application to the analysis of oxygen binding to human hemoglobin under physiological conditions provides a model-independent interpretation of the asymmetric nature of the binding curve. Asymmetry of the global binding curve can coexist with symmetric or asymmetric binding to the individual alpha and beta chains. If the binding curves of the two chains are symmetric, then subunit heterogeneity and asymmetric interactions must exist in the hemoglobin tetramer. On the other hand, if the binding curves of the two chains are asymmetric, then subunit heterogeneity and asymmetric interactions are not necessary for global asymmetric binding.

Allosteric Regulation↗

PubMed2001

The pursuit of excellence is not optional in the voluntary sector, it is essential.

This paper outlines the continuous improvement journey of a voluntary organisation. The significant level of organisational growth and improving quality of services described is clearly linked to the organisation's commitment to improvement. One of the approaches used in adopting a total quality culture was the EFQM model, specifically interpreted for the voluntary sector. Until recently such an approach would have been considered alien to the sector, not least because of its origins in the business community. This article contradicts this assumption. Issues addressed include how the improvement process is driven, the use of performance measurement, external verification and the difficulties in accessing sector appropriate benchmark data. It is suggested that the pursuit of excellence is no longer optional for the voluntary sector, it is essential.

Activities of Daily Living↗

PubMed2006

Evaluating therapeutic targets for reperfusion-related brain hemorrhage.

OBJECTIVE: Early reperfusion after an ischemic stroke can cause blood-brain barrier injury with subsequent cerebral edema and devastating brain hemorrhage. These complications of early reperfusion, which result from excess production of reactive oxygen species, significantly limit the benefits of stroke therapies. In this article, we use a novel animal model that facilitates identification of specific components of the reperfusion injury process, including vascular injury and secondary brain damage, and allows assessment of therapeutic interventions. METHODS: Knock-out (KO) mice containing 50% manganese-superoxide dismutase activity (SOD2-KO) and transgenic mice overexpressing SOD2 undergo transient focal ischemia and reperfusion followed by assessment of infarct, edema, hemorrhage rates, metalloproteinase activation, and microvascular injury. RESULTS: SOD2-KO mice demonstrate delayed (>24h) blood-brain barrier breakdown associated with activation of matrix metalloproteinases, inflammation, and high brain hemorrhage rates. These adverse consequences are absent in wild-type littermates and minocycline-treated SOD2-KO animals. Increased hemorrhage rates also are absent in SOD2 overexpressors, which have reduced vascular endothelial cell death. Finally, we show that the tight junction membrane protein, occludin, is an early and specific target in oxidative stress-induced microvascular injury. INTERPRETATION: This model is ideal for studying ischemia/reperfusion-induced vascular injury and secondary brain hemorrhage and offers a unique opportunity to evaluate antioxidant-based neurovascular protective strategies as potential adjunct treatments to currently approved stroke therapies such as thrombolysis and endovascular clot retrieval.

Animals↗

PubMed2005

Edges and bars: where do people see features in 1-D images?

There have been two main approaches to feature detection in human and computer vision--based either on the luminance distribution and its spatial derivatives, or on the spatial distribution of local contrast energy. Thus, bars and edges might arise from peaks of luminance and luminance gradient respectively, or bars and edges might be found at peaks of local energy, where local phases are aligned across spatial frequency. This basic issue of definition is important because it guides more detailed models and interpretations of early vision. Which approach better describes the perceived positions of features in images? We used the class of 1-D images defined by Morrone and Burr in which the amplitude spectrum is that of a (partially blurred) square-wave and all Fourier components have a common phase. Observers used a cursor to mark where bars and edges were seen for different test phases (Experiment 1) or judged the spatial alignment of contours that had different phases (e.g. 0 degrees and 45 degrees ; Experiment 2). The feature positions defined by both tasks shifted systematically to the left or right according to the sign of the phase offset, increasing with the degree of blur. These shifts were well predicted by the location of luminance peaks (bars) and gradient peaks (edges), but not by energy peaks which (by design) predicted no shift at all. These results encourage models based on a Gaussian-derivative framework, but do not support the idea that human vision uses points of phase alignment to find local, first-order features. Nevertheless, we argue that both approaches are presently incomplete and a better understanding of early vision may combine insights from both.

Contrast Sensitivity↗

PubMed2001

Effect of temperature on the adsorption of adenine.

Equilibrium adsorption isotherms for the purine base adenine on the surface of graphite crystals have been obtained at 30, 40, 50, and 60 degrees C by frontal analysis using water as a mobile phase. These data were fitted to the Langmuir isotherm model and interpreted in terms of the well-characterized adsorbate monolayer structure. A van't Hoff plot was used to estimate the adsorption enthalpy, -delta H degree which we determined to be 20 kJ mol-1. The susceptibility of nucleic acid bases to aqueous-phase hydrolysis may have been a limiting feature for their inclusion in the primordial genetic architecture; our results suggest that the effects of temperature and the presence of inorganic solids must also be included when assessing the prebiotic availability of adenine.

Adenine↗

PubMed2005

Biodegradable mucoadhesive particulates for nasal and pulmonary antigen and DNA delivery.

Biodegradable polymer and particulate carriers have been shown to be of considerable potential for the delivery of peptides, proteins and DNA in animal models. In the context of vaccine delivery to the upper and lower respiratory tracts, the use of mucoadhesive agents offers a strategy for the facilitation of increased residence time and increased vaccine efficacy. Additional concerns addressed here include the potential of uptake of vaccine formulations by the primary olfactory nerves in the nasal cavity, effective delivery to the lung, strategies to maximise the immunopotentiation of candidate vaccine formulations, as well as the evaluation of animal models and interpretation of engendered immune responses in terms of antigen-specific antibody production. Experimental data are presented that demonstrate the potential of muco- and bioadhesive agents in combination with liposomes for intranasal (i.n.) delivery of tetanus toxoid in mice. A delivery system utilising chitosan for the formulation of microspheres by the spray-drying method is described and assessed for intranasal vaccine delivery, and porous particles with potential for pulmonary administration are also outlined.

Administration, Intranasal↗

PubMed2004

Novel stress echocardiographic model incorporating the extent and severity of wall motion abnormality for risk stratification and prognosis.

The prognostic value of stress echocardiography to predict future cardiac events using the extent and severity of wall motion abnormalities is not well defined. The objective of this study was to develop and validate a prognostic model for interpretation of stress echocardiographic studies by using the extent and severity of wall motion abnormalities. We evaluated 1,500 patients (59 +/- 13 years old; 51% men) who underwent stress echocardiography (34% on the treadmill exercise and 66% on dobutamine). Left ventricular regional wall motion was assessed by consensus of 2 experienced echocardiographers. Follow-up periods (mean 2.7 +/- 1.0 years) for confirmed myocardial infarction (n = 31) and cardiac death (n = 44) were identified. Multivariate regression analysis identified 2 independent predictors of cardiac events: the number of left ventricular wall segments with new wall motion abnormalities (an index of the extent of ischemia) and the maximal magnitude of new wall motion abnormalities (an index of the severity of ischemia). The ischemic extent (chi-square 48.7, p <0.0001) and maximal severity (chi-square 52.0, p <0.0001) were exponentially correlated with an increase in event rate. On the basis of these data, a prognostic model was defined that uses ischemic extent and maximal severity as stress-dependent orthogonal variables. With this 3-dimensional model, the predicted event rate ranged over sevenfold, from a low of 0.9%/year in patients without any wall motion abnormalities to a high of 6.7%/year in patients with extensive and severe wall motion abnormalities. The extent and severity of wall motion abnormalities by stress echocardiography are independent and cumulative predictors of prognosis in patients who have suspected or known ischemic heart disease.

Aged↗

PubMed2004

Modeling trends in HIV incidence among homosexual men in Australia 1995-2006.

BACKGROUND: Previous mathematical models have indicated that any decrease in HIV incidence in homosexual men due to decreased infectiousness from antiretroviral treatment (ARV) may be offset by modest increases in unsafe sex. The aims of this study were to assess the effects of ARV use and increasing unprotected anal intercourse with casual partners (UAIC) in homosexual men on HIV incidence during 1995-2001 and to project HIV incidence depending on trends in ARV use and UAIC. METHODS: A mathematical model of HIV transmission among homosexual men in Australia was developed. HIV incidence during 1995-2001 was estimated assuming that 70% of men in whom HIV was diagnosed received ARVs and assuming a 10% annual increase in UAIC. For 2001-2006, scenarios included ARV levels remaining at 70% or declining to 50% by 2006, combined with UAIC levels remaining at the 2001 level or continuing to increase annually by 10%. FINDINGS: The number of incident HIV cases per year was predicted to have declined during 1996-1998 due to the introduction of effective ARVs, with a slow increase during 1998-2001 due to increased levels of UAIC when use of therapies was fairly stable. From 2001, a continued increase in UAIC was predicted to lead to a rise in HIV incidence. A rise in UAIC combined with a moderate decline in ARV use could lead to a 50% increase in HIV incidence by 2006. INTERPRETATION: These models suggest that widespread ARV use has had some effect in reducing HIV incidence among homosexual men in Australia. However, if current trends in UAIC and ARV use continue, a resurgent HIV epidemic is predicted.

Anti-Retroviral Agents↗

PubMed2004

Crystal structures of HbA2 and HbE and modeling of hemoglobin delta 4: interpretation of the thermal stability and the antisickling effect of HbA2 and identification of the ferrocyanide binding site in Hb.

Hemoglobin A(2) (alpha(2)delta(2)) is an important hemoglobin variant which is a minor component (2-3%) in the circulating red blood cells, and its elevated concentration in beta-thalassemia is a useful clinical diagnostic. In beta-thalassemia major, where there is beta-chain production failure, HbA(2) acts as the predominant oxygen deliverer. HbA(2) has two more important features. (1) It is more resistant to thermal denaturation than HbA, and (2) it inhibits the polymerization of deoxy sickle hemoglobin (HbS). Hemoglobin E (E26K(beta)), formed as a result of the splice site mutation on exon 1 of the beta-globin gene, is another important hemoglobin variant which is known to be unstable at high temperatures. Both heterozygous HbE (HbAE) and homozygous HbE (HbEE) are benign disorders, but when HbE combines with beta-thalassemia, it causes E/beta-thalassemia which has severe clinical consequences. In this paper, we present the crystal structures of HbA(2) and HbE at 2.20 and 1.74 A resolution, respectively, in their R2 states, which have been used here to provide the probable explanations of the thermal stability and instability of HbA(2) and HbE. Using the coordinates of R2 state HbA(2), we modeled the structure of T state HbA(2) which allowed us to address the structural basis of the antisickling property of HbA(2). Using the coordinates of the delta-chain of HbA(2) (R2 state), we also modeled the structure of hemoglobin homotetramer delta(4) that occurs in the case of rare HbH disease. From the differences in intersubunit contacts among beta(4), gamma(4), and delta(4), we formed a hypothesis regarding the possible tetramerization pathway of delta(4). The crystal structure of a ferrocyanide-bound HbA(2) at 1.88 A resolution is also presented here, which throws light on the location and the mode of binding of ferrocyanide anion with hemoglobin, predominantly using the residues involved in DPG binding. The pH dependence of ferrocyanide binding with hemoglobin has also been investigated.

Alternative Splicing↗

PubMed1992

Personality and psychopathology: an application of the five-factor model.

Our review is concerned with the relationship of the five-factor model of personality to psychopathology, focusing in particular on Axis II personality disorders and depression. The five factors provide a particularly compelling model for interpreting the Axis II personality disorders as maladaptive variants of normal personality traits. However, we also discuss methodological and conceptual limitations of this application. There has been little research on the relationship of Openness, Agreeableness, and Conscientiousness to Axis I mental disorders, but considerable attention has been given to Neuroticism and Extraversion. We focus in particular on the difficulty in distinguishing between the various ways in which personality can relate to depression, either as a predisposition to, a complication of, a pathoplastic effect upon, or a spectrum variant of the mental disorder. We conclude with recommendations for future research.

Diagnosis, Differential↗

PubMed2002

The hot IVGTT two-compartment minimal model: an improved version.

The two-compartment minimal model (2CMM) interpretation of a labeled intravenous glucose tolerance test (IVGTT) is a powerful tool to assess glucose metabolism in a single individual. It has been reported that a derived 2CMM parameter describing the proportional effect of glucose on insulin-independent glucose disposal can take physiologically unplausible negative values. In addition, precision of 2CMM parameter estimates is sometimes not satisfactory. Here we resolve the above issues by presenting an improved version of 2CMM that relies on a new assumption on the constant component R(d0) of insulin-independent glucose disposal. Here R(d0) is not fixed to 1 mg x kg(-1) x min(-1) but instead is expressed as a fraction of steady-state glucose disposal. The new 2CMM is identified on the same stable labeled IVGTT data base on which the original 2CMM was formulated. A more reliable insulin-independent glucose disposal portrait is obtained while that of insulin action remains unchanged. The new 2CMM also improves the precision with which model parameters and metabolic indexes are estimated.

Diabetes Mellitus↗

PubMed2006

Cost-effectiveness of self-managed versus physician-managed oral anticoagulation therapy.

BACKGROUND: Patient self-management of long-term oral anticoagulation therapy is an effective strategy in a number of clinical situations, but it is currently not a funded option in the Canadian health care system. We sought to compare the incremental cost and health benefits of self-management with those of physician management from the perspective of the Canadian health care payer over a 5-year period. METHODS: We developed a Bayesian Markov model comparing the costs and quality-adjusted life years (QALYs) accrued to patients receiving oral anticoagulation therapy through self-management or physician management for atrial fibrillation or for a mechanical heart valve. Five health states were defined: no events, minor hemorrhagic events, major hemorrhagic events, thrombotic events and death. Data from published literature were used for transition probabilities. Canadian 2003 costs were used, and utility estimates were obtained from various published sources. RESULTS: Self-management resulted in 3.50 fewer thrombotic events, 0.78 fewer major hemorrhagic events and 0.12 fewer deaths per 100 patients than physician management. The average discounted incremental cost of self-management over physician management was found to be 989 dollars (95% confidence interval [CI] 310 dollars-1655 dollars) per patient and the incremental QALYs gained was 0.07 (95% CI 0.06-0.08). The cost-effectiveness of self-management was 14,129 dollars per QALY gained. There was a 95% chance that self-management would be cost-effective at a willingness to pay of 23,800 dollars per QALY. Results were robust in probabilistic and deterministic sensitivity analyses. INTERPRETATION: This model suggests that self-management is a cost-effective strategy for those receiving long-term oral anticoagulation therapy for atrial fibrillation or for a mechanical heart valve.

Administration, Oral↗