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At least 1,801 records · Page 100Linked to original sources
PubMed2005

A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer.

PURPOSE: To determine the anti-tumor activity DX-8951f when administered as a 30-minute infusion daily for 5 days every 3 weeks to patients with previously untreated metastatic gastric cancer, and to evaluate toxicities and pharmacokinetics (PK) of DX-8951f in this patient population. PATIENTS AND METHODS: Forty-one patients were enrolled. All had previously untreated metastatic gastric cancer. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every 2 courses using RECIST criteria. RESULTS: Thirty-nine patients were evaluable. Two patients achieved a partial response (PR) and 18 achieved stable disease (SD), including five patients with unconfirmed PR. A total of 141 courses of therapy were delivered (median 3, range 1-10). The most common drug-related toxicity was neutropenia. Non-hematologic toxicities were mostly mild to moderate; the most common were nausea, vomiting and anorexia. Plasma concentrations of DX-8951 (the anhydrous form of DX-8951f) were well described using a linear 2-compartment PK model. All concentrations and dose events were simultaneously modeled and explained by the population PK model. There was no evidence of non-linearity in the elimination PK, auto-inhibition or induction of DX-8951 clearance over the five days of administration. CONCLUSIONS: DX-8951f had modest activity against metastatic gastric cancer and its PK was dose-proportional. The toxicity profile was predictable and manageable. Further development of this agent is warranted.

Adenocarcinoma↗
PubMedDate not supplied

Functional and modelling studies of the binding of human monoclonal anti-DNA antibodies to DNA.

The relationships between the antigen-binding specificities of four human monoclonal anti-DNA antibodies and the structural aspects of the combining sites of two of these were examined. Competition ELISAs were used to examine the reactivities of two IgM MAbs (WRI-176 and RT-79) and two IgG mAbs (D5 and B3) to a wide range of polynucleotides. The mAbs WRI-176 and RT-79 were found to bind predominantly ssDNA, with a preference for poly (dT), whilst D5 and B3 bound components of both ss- and dsDNA, and Z-DNA. The mAb B3 also exhibited a preference for A(T) rich nucleotides. Computer models were generated for the Fv regions of WRI-176 and B3. Models for RT-79 and D5 were not generated as the structure of the long CDR-H3 loops in these mAbs could not be predicted. The B3 combining site contains a groove flanked by three arginines at positions CDR-L1-27A, CDR-L2-54 and CDR-H2-53. Using interactive molecular graphics, B-DNA was docked into the B3 antigen combining site along the plane of the VH/VL interface, whilst Z-DNA was best-fitted at approximately 90 degrees to this direction. The models provide a hypothesis to explain the ability of a single autoantibody to bind two different antigens. In addition, aspects of the base specificity of B3 may be explained. The model of the WRI-176 Fv region revealed a relatively flat surface, on which a large number of hydrophobic and aromatic residues were present. Trp-H52, in particular, is prominent on the surface. This may participate in ssDNA binding through base stacking interactions. The models allow identification of potential targets for site-directed mutagenesis.

Amino Acid Sequence↗
PubMed2005

The role of spatial mixing in the spread of foot-and-mouth disease.

A model of epidemic dispersal (based on the assumption that susceptible cattle were homogeneously mixed over space, or non-spatial model) was compared to a partially spatially explicit and discrete model (the spatial model), which was composed of differential equations and used geo-coded data (Euclidean distances between county centroids). While the spatial model accounted for intra- and inter-county epidemic spread, the non-spatial model did not assess regional differences. A geo-coded dataset that resembled conditions favouring homogeneous mixing assumptions (based on the 2001 Uruguayan foot-and-mouth disease epidemic), was used for testing. Significant differences between models were observed in the average transmission rate between farms, both before and after a control policy (animal movement ban) was imposed. They also differed in terms of daily number of infected farms: the non-spatial model revealed a single epidemic peak (at, approximately, 25 epidemic days); while the spatial model revealed two epidemic peaks (at, approximately, 12 and 28 days, respectively). While the spatial model fitted well with the observed cumulative number of infected farms, the non-spatial model did not (P<0.01). In addition, the spatial model: (a) indicated an early intra-county reproductive number R of approximately 87 (falling to <1 within 25 days), and an inter-county R<1; (b) predicted that, if animal movement restrictions had begun 3 days before/after the estimated initiation of such policy, cases would have decreased/increased by 23 or 26%, respectively. Spatial factors (such as inter-farm distance and coverage of vaccination campaigns, absent in non-spatial models) may explain why partially explicit spatial models describe epidemic spread more accurately than non-spatial models even at early epidemic phases. Integration of geo-coded data into mathematical models is recommended.

Animals↗
PubMed2001

Absence of population genetic differentiation in the New Zealand greenshell mussel Perna canaliculus (Gmelin 1791) as assessed by allozyme variation.

Genetic variation in the endemic New Zealand greenshell mussel, Perna canaliculus (Gmelin 1791), was examined using starch-gel electrophoresis at seven protein-coding loci (Idh; Acon-1; Acon-2; Gpd; Pgi; Pgm; Pgd) in 35 populations (N=1038 mussels). For all loci and all populations, Fisher's exact tests indicated highly significant departures from Hardy-Weinberg equilibrium (HWE), but this overall result was caused by significant heterozygote deficiencies at only two loci (Pgm and Pgd), and in only three northern populations (Kuaotunu, Te Haumi and Days Bay). Allelic and genotypic differentiation between population pairs at individual loci and across all loci were nonsignificant, and genotypic disequilibrium at each locus pair was also nonsignificant for all populations. Genetic variation in all populations was high (mean heterozygosity, 0.210+/-0.113), while Nei's D among populations was very low (0.002+/-0.002). Low population subdivision (&theta;=-0.001+/-0.002) and high levels of gene flow (Nm(p)=10.18; Nm(&theta;)=infinity) also indicated that the single panmictic unit model best explains population genetic homogeneity in P. canaliculus over a north-south distance >2000 km. Lack of genetic subdivision in this species is discussed in light of two previous allozyme studies, with differing results: one suggested that a north-south division exists between greenshell mussel stocks, and the other suggested that population structure in this species can be explained through isolation by distance model modified by local hydrology.

Journal Article↗
PubMed2004

Obsessive-compulsive disorder as a disturbance of security motivation.

The authors hypothesize that the symptoms of obsessive-compulsive disorder (OCD), despite their apparent nonrationality, have what might be termed an epistemic origin--that is, they stem from an inability to generate the normal "feeling of knowing" that would otherwise signal task completion and terminate the expression of a security motivational system. The authors compare their satiety-signal construct, which they term yedasentience, to various other senses of the feeling of knowing and indicate why OCD-like symptoms would stem from the abnormal absence of such a terminator emotion. In addition, they advance a tentative neuropsychological model to explain its underpinnings. The proposed model integrates many previous disparate observations and concepts about OCD and embeds it within the broader understanding of normal motivation.

Affect↗
PubMed1999

Complex systems model of dietary choice with implications for improving diets and promoting vegetarianism.

An important step toward improving nutrition and promoting vegetarianism in the general population is to understand how consumers make dietary choices. Researchers from many clinical and social sciences are interested in dietary choice but have not combined their research into a comprehensive model to explain consumer actions. No one model has offered a good explanation for the fact that, although many people successfully change their diet significantly (often toward health-improving, plant-based diets) and are happy with the change, the public and health professionals often perceive dietary change as being difficult and unlikely to succeed. I have termed these observations "the paradox of dietary change." The present computer model uses the emerging science of complex systems analysis, which offers an intuitive method for studying evidence about dietary choice from many fields, including public health, clinical science, economics, sociology, marketing, and genetics, and for combining individual choice with social interaction. The results suggest an explanation for the paradox and methods for helping society shift toward healthier and more plant-based diets. In particular, they suggest how and why major changes might be easier to make than incremental ones, and why this makes dietary change seem more difficult to consumers than it actually is.

Choice Behavior↗
PubMed1987

1987 Volvo award in clinical sciences. A new clinical model for the treatment of low-back pain.

Because there is increasing concern about low-back disability and its current medical management, this analysis attempts to construct a new theoretic framework for treatment. Observations of natural history and epidemiology suggest that low-back pain should be a benign, self-limiting condition, that low back-disability as opposed to pain is a relatively recent Western epidemic, and that the role of medicine in that epidemic must be critically examined. The traditional medical model of disease is contrasted with a biopsychosocial model of illness to analyze success and failure in low-back disorders. Studies of the mathematical relationship between the elements of illness in chronic low-back pain suggest that the biopsychosocial concept can be used as an operational model that explains many clinical observations. This model is used to compare rest and active rehabilitation for low-back pain. Rest is the commonest treatment prescribed after analgesics but is based on a doubtful rationale, and there is little evidence of any lasting benefit. There is, however, little doubt about the harmful effects--especially of prolonged bed rest. Conversely, there is no evidence that activity is harmful and, contrary to common belief, it does not necessarily make the pain worse. Experimental studies clearly show that controlled exercises not only restore function, reduce distress and illness behavior, and promote return to work, but actually reduce pain. Clinical studies confirm the value of active rehabilitation in practice. To achieve the goal of treating patients rather than spines, we must approach low-back disability as an illness rather than low-back pain as a purely physical disease. We must distinguish pain as a purely the symptoms and signs of distress and illness behavior from those of physical disease, and nominal from substantive diagnoses. Management must change from a negative philosophy of rest for pain to more active restoration of function. Only a new model and understanding of illness by physicians and patients alike makes real change possible.

Back Pain↗
PubMed2000

Constraints on models for the flagellar rotary motor.

Most bacteria that swim are propelled by flagellar filaments, each driven at its base by a rotary motor embedded in the cell wall and cytoplasmic membrane. A motor is about 45 nm in diameter and made up of about 20 different kinds of parts. It is assembled from the inside out. It is powered by a proton (or in some species, a sodium-ion) flux. It steps at least 400 times per revolution. At low speeds and high torques, about 1000 protons are required per revolution, speed is proportional to protonmotive force, and torque varies little with temperature or hydrogen isotope. At high speeds and low torques, torque increases with temperature and is sensitive to hydrogen isotope. At room temperature, torque varies remarkably little with speed from about -100 Hz (the present limit of measurement) to about 200 Hz, and then it declines rapidly reaching zero at about 300 Hz. These are facts that motor models should explain. None of the existing models for the flagellar rotary motor completely do so.

Bacterial Physiological Phenomena↗
PubMed2005

Superfluidity of dense 4He in vycor.

We calculate properties of a model of 4He in Vycor using the path integral Monte Carlo method. We find that 4He forms a distinct layered structure with a highly localized first layer, a disordered second layer with some atoms delocalized and able to give rise to the observed superfluid response, and higher layers of nearly perfect crystals. The addition of a single 3He atom was enough to bring down the total superfluidity by blocking the exchange in the second layer. Our results are consistent with the persistent liquid-layer model to explain the observations. Such a model may be relevant to the experiments on bulk solid 4He, if there is a fine network of grain boundaries in those systems.

Journal Article↗
PubMed1996

On the relation between comodulation masking release and temporal modulation transfer functions.

Explanations for the phenomenon known as comodulation masking release (CMR) generally assume that temporal envelope information from different peripheral filters is compared, thus entailing multiple envelope representations. Here it is shown that a leaky-integrator model, yielding a single envelop representation extracted from a broad frequency range, provides an alternative account of CMR. One prediction obtained from model simulations is that adding a single tone to the stimulus will disrupt the CMR effect, leading to an increase in thresholds. Supporting evidence from several experiments shows that the magnitude of CMR is reduced following the addition of a single tone, even when separated from comodulated masking and flanking bands by more than an octave. Whereas these findings are consistent with the leaky-integrator model, they cannot be easily explained by models which assume multiple envelope representations.

Adult↗
PubMed1997

Amplitude modulation depth discrimination of a sinusoidal carrier: effect of stimulus duration.

Discrimination of the change in depth of sinusoidal amplitude modulation (AM) was investigated as a function of stimulus duration. The carrier frequency was 4000 Hz, the standard modulation depth (m) was either 0.1, 0.18, or 0.3, and the modulation rate was either 10, 20, 40, or 80 Hz. For all standard depths and modulation rates, threshold (delta m) decreased by more than a factor o two as stimulus duration doubled from the shortest duration used up to a certain duration (critical duration), beyond which the threshold decreased only slightly or remained constant. The critical duration corresponded to about four cycles of modulation. Psychometric functions were measured for different stimulus durations to examine the extent to which a multiple-looks model could explain the present data. This model provided a reasonable prediction of the change in AM depth discrimination threshold as a function of stimulus duration.

Adult↗
PubMed2002

General and relationship-specific models of social cognition: explaining the overlap and discrepancies.

BACKGROUND: This study examined the degree of overlap and sources of discrepancies between two alternative models of social cognition in early adolescence, a general model based on 'theory of mind' and a relationship-specific model rooted in attachment theory. METHODS: We administered newly developed, age-appropriate measures of advanced theory of mind or 'mentalising' and child-parent attachment, indexed by the coherence of children's narratives about attachment relationships, to a sample of 70 early adolescents (mean age 12.6 years). RESULTS: The central findings were that, as expected, there was significant overlap between the mentalising and attachment indices of social cognition (r(70) = .35, p < .01). The overlap was not significantly mediated by verbal ability or general measures of parenting. There were also substantial discrepancies in children's performance on these measures that were conceptually interesting and statistically reliable. Specifically, adolescent reports of parenting discriminated between measures of mentalising and attachment coherence. In addition, those children who exhibited a less coherent model of attachment than was predicted from performance on a mentalising task were more likely to be rated as exhibiting a 'Dismissing/Avoidant' style in the attachment interview. CONCLUSIONS: Findings support a connection between mentalising and attachment in early adolescence, and further suggest that social cognitive processes may be context and relationship-specific.

Adolescent↗
PubMed1995

The effect of fluticasone propionate aqueous nasal spray on nasal mucosal inflammation in perennial allergic rhinitis.

Mast cell degranulation, and the subsequent recruitment of infiltrating inflammatory cells, such as eosinophils, into the nasal mucosa has long been considered the most important model to explain allergic rhinitis. Several studies show a decrease in the number of eosinophils and possibly also mast cells during local corticosteroid treatment. Over the last decade, a new model to explain allergic inflammation has evolved. In this model, Langerhans' cells and T-cells play an important role. Langerhans' cells possess a high affinity receptor for IgE. In patients with allergic rhinitis, allergen provocation results in stimulation of T-cells by the IgE-positive Langerhans' cells. The T-cells produce a number of cytokines which stimulate IgE production as well as the inflammatory reaction. The number of T-cells is not usually influenced by corticosteroid treatment; however, the function of the T-cells, shown by the spectrum of cytokines produced, is clearly influenced. The cells that are most dramatically affected by local corticosteroid treatment are the Langerhans' cells, which completely disappear during treatment. This decrease suggests that there is a reduction in antigen presentation. The subsequent decrease in T-cell stimulation may result in a reduction of the reactions that are dependent on T-cell-derived mediators.

Administration, Topical↗
PubMed2003

Attitudes to terminal patients' unorthodox therapy: Finnish doctors' responses to a case scenario.

We carried out a postal survey of a sample of Finnish doctors ( n=1182) concerning their attitudes and ethical decisions in end-of-life care. A scenario was presented in which a patient with terminal cancer wished to obtain unorthodox treatment. Factors possibly influencing decision making such as general attitudes, life values and demographics were investigated. The response rate was 62%. The patient's plan to use unorthodox treatment was accepted by 54% of doctors. Gender or speciality did not influence the decision, but doctor's age was a significant factor ( P=0.0005). Doctors aged 35-49 years were more accepting; younger and older ones less accepting. Doctors who had clinical experience in terminal care were more compliant to the patient's plan ( P=0.034). A stepwise logistic regression analysis was used to create a model for explaining not accepting versus accepting the treatment with the background variables. Altogether eight independent significant variables were included in the final model of explaining a doctor's choice in the presented scenario. According to the model the patient's wish was more frequently accepted if the doctor was middle-aged, had clinical experience in terminal care, valued a high standard of living, considered terminal care satisfying, was less critical of health economics, considered advance directives helpful, had a high fear-of-death index score, and valued professional status less.

Adult↗
PubMed1989

A model for the ability of drugs to induce enhanced DNase I cleavage.

A common property of sequence-selective DNA-binding drugs lies in their ability to induce an enhanced DNase I cleavage in regions surrounding their binding sites. A hypothetical model to explain the enhancements induced by drug binding to the minor-groove of DNA is presented. It involves the participation of three different single models: a mass action effect produced by the enzyme redistribution after drug binding; changes in the minor groove width size; and interactions between the enzyme and the drug, so increasing the cleavage in places located close to the binding site. The model is tested by using statistical data analysis. The hypothetical model might explain the experimental results better than any of the single models alone, but these models also appear to render significant results.

Base Sequence↗
PubMed2000

Analysis of the French liver transplant waiting list, 1992-1996.

BACKGROUND: In organ transplantation, each country has specific rules of allocation. We have retrospectively evaluated the French liver transplant waiting list for the period 1992-1996, during which time the rules for allocation remained stable. Mortality while on the waiting list and waiting times were the two principal endpoints. METHODS: Using the Etablissement Français des Greffes (EFG) registry, the study was conducted in three steps: (1) description of the waiting list population; (2) analysis of the outcome of patients, with the use of a logistic model to explain death while on the waiting list; (3) estimation of waiting times and use of a Cox model to explain waiting times. RESULTS: The distribution of patients with regard to degree of urgency, age, blood type, and liver disease was variable according to the the EFG region. The outcome of patients was variable according to blood type and to EFG region. Patients classed as "extremely urgent" did not have a different outcome compared to elective patients. The logistic model indicated that two factors influenced the death: blood group and EFG region. Waiting times were variable according to EFG region; age and blood group had an influence on waiting times for a graft. The Cox model indicated the independent influence of EFG region on waiting times. CONCLUSION: We found geographical disparities between patients with respect to time on the waiting list. However, the database must be improved by including the risk profile of each patient, leading to changes in rules for a better allocation of transplants.

ABO Blood-Group System↗
PubMed2002

Models of skeletal muscle to explain the increase in passive stiffness in desmin knockout muscle.

Absence of desmin in skeletal muscle was found to induce an increase in passive stiffness. The present study aimed at developing rheological models of passive muscle to explain this stiffening. Models were elaborated by using experimental data depicting muscle viscoelastic behaviour. The experimental protocol included stepwise extension tests applied on control and desmin knockout soleus muscles from mice. Linear and non-linear models were composed of elastic and viscous elements. They were constructed with the aim at taking the presence or absence of desmin into account by simulating desmin as an elastic element. Furthermore, associated adaptation of connective tissues in absence of desmin was modelled as an additional elastic element. Differences in passive behaviour induced by absence of desmin were predicted by using a linear model and a non-linear one. The non-linear model was selected because: (1) it is able to predict experimental viscoelastic kinetics accounting for the increase in passive stiffness in muscles lacking desmin, (2) its design is consistent with morphological data, and (3) stiffness characteristics of its elements are in accordance with the literature. Finally, this modelling approach demonstrates that both absence of desmin and adaptation of connective tissue are required to explain the increase in passive stiffness in desmin knockout muscles.

Animals↗

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