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PubMed2003

Predicting the impact of antiretrovirals in resource-poor settings: preventing HIV infections whilst controlling drug resistance.

There is currently an opportunity to carefully plan the implementation of antiretroviral (ARV) therapy in the developing world. Here, we use mathematical models to predict the potential impact that low to moderate usage rates of ARVs might have in developing countries. We use our models to predict the relationship between the specific usage rate of ARVs (in terms of the percentage of those infected with HIV who receive such treatment) and: (i) the prevalence of drug-resistant HIV that will arise, (ii) the future transmission rate of drug-resistant strains of HIV, and (iii) the cumulative number of HIV infections that will be prevented through more widespread use of ARVs. We also review the current state of HIV/AIDS treatment programs in resource-poor settings and identify the essential elements of a successful treatment project, noting that one key element is integration with a strong prevention program. We apply both program experience from Haiti and Brazil and the insights gleaned from our modeling to address the emerging debate regarding the increased availability of ARVs in developing countries. Finally, we show how mathematical models can be used as tools for designing robust health policies for implementing ARVs in developing countries. Our results demonstrate that designing optimal ARV-based strategies to control HIV epidemics is extremely complex, as increasing ARV usage has both beneficial and detrimental epidemic-level effects. Control strategies should be based upon the overall impact on the epidemic and not simply upon the impact ARVs will have on the transmission and/or prevalence of ARV-resistant strains.

Anti-Retroviral Agents↗

PubMed1998

Is it possible to predict any properties of oxidative phosphorylation in a theoretical way?

Two theoretical approaches applied to oxidative phosphorylation, namely Metabolic Control Analysis (MCA) [ 1-7] and Non-Equilibrium Thermodynamics (NET) [8-11], turned out to be very useful tools for quantitative description and understanding of control and regulation of this process. However, they were not able to predict any new properties of the considered system. On the other hand, the previously developed dynamic model of oxidative phosphorylation [12-17], representing a kinetic approach, allowed to formulate several interesting predictions which can be tested experimentally. The most important of these predictions are: (1) Different steps of ATP-production must be directly activated to a similar extent as ATP-consumption during stimulation of ATP turnover by calcium-acting hormones as well as by neural signals during muscle contraction; (2) A universal activator/regulatory mechanism responsible for such a precise balance of activation should be identified; (3) The flux-force relationship for cytochrome oxidase can be inverse during the transition towards hypoxia and anoxia, when oxygen concentration falls below 30 microM; (4) The flux-force relationship can depend on the way in which the thermodynamic force is changed; (5) The pattern of metabolic control is completely different in normoxic and hypoxic conditions; in the latter case cytochrome oxidase has the flux control coefficient close to unity. Thus, the kinetic model of oxidative phosphorylation seems to be a useful scientific tool, offering some novel theoretical predictions, which then can be tested in the experimental way.

Adenosine Triphosphate↗

PubMed1991

Multiple drug regimens: medication compliance among veterans 65 years and older.

In this study we attempted to develop a profile that could be used prospectively to identify veterans over 64 years of age who might be at risk for medication noncompliance. Male veterans (N = 249) having from one to seven oral daily prescribed medications were studied. Instruments administered to determine their relationship to compliance were the Paired-Associate Test, the Mini Mental State, the Multidimensional Health Locus of Control, and the Standard Depression Scale. Compliance was determined by a pill count made at two home visits. Seventy-three percent of the subjects were noncompliant. Variables significantly related to noncompliance by bi-variate analysis were included in the stepwise logistic regression to develop a predictive model of noncompliance. Ethnicity and number of daily prescribed pills were the only significant variables in the final model. The model correctly classified the subjects as compliant/noncompliant in 77% of the cases. Discussions during home interviews revealed a number of common problems.

Age Factors↗

PubMed2005

Effect of background electrolytes and pH on the adsorption of Cu(II)/EDTA onto TiO2.

Cu(II)/EDTA adsorption onto TiO2 has been studied with a variation of pH, ionic strength, and type of background electrolytes. Cu(II) adsorption onto TiO2 increased as ionic strength increased when NaClO4 was used as a background electrolyte. This can be explained by the increase of exp(-FPsi/RT) as a part of the electrostatic correction within a surface complexation model. Model predictions described experimental adsorption trends. Types of background anions (ClO4, Cl, NO2, NO3, SO3, and PO4) did not affect adsorption trends and adsorption amounts of Cu(II) onto TiO2. However, different trends were observed with various types of background ions used as ionic strength in EDTA and Cu(II)-EDTA adsorption. EDTA adsorption was decreased by using Na2SO3 and Na3PO4 as background ions, while NaClO4, NaCl, NaNO2, and NaNO3 showed negligible interference on the EDTA adsorption, which matched well with model predictions. The presence Na2SO3 and Na3PO4 also interfered with Cu(II)-EDTA adsorption, to a somewhat greater extent compared to EDTA adsorption, especially at lower pH. This interference was also noted in Cu(II)-EDTA adsorption with a variation of Cu(II)-EDTA concentration at constant ionic strength (3 x 10(-3) M) by using Na2SO3 and Na3PO4, especially at lower ratios of Cu(II)-EDTA to Na2SO3 and Na3PO4. These results suggest that the ratio of Cu(II)-EDTA to Na2SO3 and Na3PO4 is an important factor for the controlling of competition between these background ions and Cu(II)-EDTA onto TiO2. Model prediction generally matched well with experimental adsorption using NaClO4, NaCl, NaNO2, and NaNO3 as backgrounds ions, while a severe deviation was observed in the presence of Na2SO3 and Na3PO4. These results suggest that the mobility of copper ions as Cu(II)-EDTA can be increased from polluted area in the presence of multivalent background ions, especially as the ratio of adsorbates/background ions decreased.

Journal Article↗

PubMedDate not supplied

Spatial and temporal modeling of microbial contaminants on grazing farmlands.

This paper introduces an integrated spatial and temporal modeling system developed mathematically for assessing microbial contaminants on animal-grazed farmlands. The model uses fecal coliform, specifically Escherichia coli, as an indicator of fecal contamination and describes the sources, sinks, transport processes, and fate of E. coli contaminants in catchments and associated streams. Spatial features include grazing location, land topography, distance to a nearby stream, and distance through the stream network to the outlet. Temporal features are population dynamics on the land surface, in flow, and on streambeds. The model applies the principles of conservation of mass balance on two different types of pools: grid cells on land surfaces and networked stream segments. The model aims to improve the prediction of the effects of different land management strategies on the fecal contamination of waterways. This is achieved by characterizing the movement of fecal contaminants from land to streams and in-stream mobilization. Processes of attenuation, diffusion, and transport govern the movement. Our study site is a hill land catchment with an area of 140 ha and is used exclusively for animal grazing. The model was calibrated with previous research results, and then tested using the data collected at the outlet of the catchment. The sensitivity of the model predictions was analyzed for different scenarios: effect of stock rate, attenuation rate, and flow volumes. The similar pattern between monitored and predicted E. coli concentration proved that the model captures the key features that control the population dynamics of fecal contaminants. Further experiments are required to expand the model's functionality for covering more mitigation options.

Animal Husbandry↗

PubMed2000

Hispanic adults' beliefs, attitudes, and intentions regarding the female condom.

The present study used the theory of planned behavior (TPB) (Ajzen, 1985) augmented by AIDS knowledge to investigate factors influencing intentions of Hispanic adults to use the female condom. A total of 146 persons (75 women and 71 men; mean age, 27 years) recruited from community-based organizations completed an anonymous survey regarding intentions to use the female condom with their main sex partner. The TPB model had greater predictive utility for women's, than for men's, female condom use intentions. For men, attitudes and norms did not predict female condom use intentions, but greater AIDS knowledge was related to lower intentions to use the female condom, above and beyond the TPB constructs. Perceived behavioral control, operationalized as self-efficacy, significantly increased the predictive utility of the TPB model for women's female condom use intentions but not for men's. Behavior change strategies to increase female condom use are discussed in light of these findings.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Normal and pathological NCAT image and phantom data based on physiologically realistic left ventricle finite-element models.

The four-dimensional (4-D) NURBS-based cardiac-torso (NCAT) phantom, which provides a realistic model of the normal human anatomy and cardiac and respiratory motions, is used in medical imaging research to evaluate and improve imaging devices and techniques, especially dynamic cardiac applications. One limitation of the phantom is that it lacks the ability to accurately simulate altered functions of the heart that result from cardiac pathologies such as coronary artery disease (CAD). The goal of this work was to enhance the 4-D NCAT phantom by incorporating a physiologically based, finite-element (FE) mechanical model of the left ventricle (LV) to simulate both normal and abnormal cardiac motions. The geometry of the FE mechanical model was based on gated high-resolution X-ray multislice computed tomography (MSCT) data of a healthy male subject. The myocardial wall was represented as a transversely isotropic hyperelastic material, with the fiber angle varying from -90 degrees at the epicardial surface, through 0 degrees at the midwall, to 90 degrees at the endocardial surface. A time-varying elastance model was used to simulate fiber contraction, and physiological intraventricular systolic pressure-time curves were applied to simulate the cardiac motion over the entire cardiac cycle. To demonstrate the ability of the FE mechanical model to accurately simulate the normal cardiac motion as well as the abnormal motions indicative of CAD, a normal case and two pathologic cases were simulated and analyzed. In the first pathologic model, a subendocardial anterior ischemic region was defined. A second model was created with a transmural ischemic region defined in the same location. The FE-based deformations were incorporated into the 4-D NCAT cardiac model through the control points that define the cardiac structures in the phantom which were set to move according to the predictions of the mechanical model. A simulation study was performed using the FE-NCAT combination to investigate how the differences in contractile function between the subendocardial and transmural infarcts manifest themselves in myocardial Single photon emission computed tomography (SPECT) images. The normal FE model produced strain distributions that were consistent with those reported in the literature and a motion consistent with that defined in the normal 4-D NCAT beating heart model based on tagged magnetic resonance imaging (MRI) data. The addition of a subendocardial ischemic region changed the average transmural circumferential strain from a contractile value of -0.09 to a tensile value of 0.02. The addition of a transmural ischemic region changed average circumferential strain to a value of 0.13, which is consistent with data reported in the literature. Model results demonstrated differences in contractile function between subendocardial and transmural infarcts and how these differences in function are documented in simulated myocardial SPECT images produced using the 4-D NCAT phantom. Compared with the original NCAT beating heart model, the FE mechanical model produced a more accurate simulation for the cardiac motion abnormalities. Such a model, when incorporated into the 4-D NCAT phantom, has great potential for use in cardiac imaging research. With its enhanced physiologically based cardiac model, the 4-D NCAT phantom can be used to simulate realistic, predictive imaging data of a patient population with varying whole-body anatomy and with varying healthy and diseased states of the heart that will provide a known truth from which to evaluate and improve existing and emerging 4-D imaging techniques used in the diagnosis of cardiac disease.

Algorithms↗

PubMed2005

The administrative control system of substance abuse managed care.

OBJECTIVE: This article searches for the dimensions of the administrative structures in outpatient substance abuse managed care that control the behavior of agency providers. It also ascertains how these dimensions, and several financial mechanisms, affect key aspects of the providers services: the average number of sessions of care that are delivered, the rate of completion of care, and the (estimated) rate at which clients control their substance use. DATA SOURCES: The data were collected in 1999 for this investigation. STUDY DESIGN: These data come from a nationally representative, cross-sectional sample of individual contracts between outpatient drug treatment providers and the Behavioral Health Managed Care Organizations (BHMCOs) that are empowered to regulate the delivery of services. Provider responses are analyzed here. DATA COLLECTION METHODS: Factor analyses at a contract level examine the structural dimensions of the control system. Multivariate analyses at the same level rely on generalized linear models to predict the dependent variables by the structural dimensions and financial mechanisms. FINDINGS: The factor analyses suggest that there are six multiple variable structural dimensions. The multivariate analyses suggest that the dimension that mandates follow-up of discharged clients tends to relate to more sessions of care and perhaps a higher rate of service completion. Most other dimensions are found to relate to fewer sessions of care, lower rates of service completion, or lower rates of control of substance abuse. No structural dimension relates to all dependent variables. Financial mechanisms evince varying relations to the sessions of care. They rarely relate to the other dependent variables. CONCLUSION: The results generally suggest that providers, payers, or policymakers might affect service provision by selecting BHMCOs that stress particular structural dimensions and financial mechanisms. However, managed care contracts most heavily rely on structural dimensions that restrict treatment sessions and fail to predict superior client outcomes.

Ambulatory Care↗

PubMed2005

Eye movement instabilities and nystagmus can be predicted by a nonlinear dynamics model of the saccadic system.

The study of eye movements and oculomotor disorders has, for four decades, greatly benefitted from the application of control theoretic concepts. This paper is an example of a complementary approach based on the theory of nonlinear dynamical systems. Recently, a nonlinear dynamics model of the saccadic system was developed, comprising a symmetric piecewise-smooth system of six first-order autonomous ordinary differential equations. A preliminary numerical investigation of the model revealed that in addition to generating normal saccades, it could also simulate inaccurate saccades, and the oscillatory instability known as congenital nystagmus (CN). By varying the parameters of the model, several types of CN oscillations were produced, including jerk, bidirectional jerk and pendular nystagmus. The aim of this study was to investigate the bifurcations and attractors of the model, in order to obtain a classification of the simulated oculomotor behaviours. The application of standard stability analysis techniques, together with numerical work, revealed that the equations have a rich bifurcation structure. In addition to Hopf, homoclinic and saddlenode bifurcations organised by a Takens-Bogdanov point, the equations can undergo nonsmooth pitchfork bifurcations and nonsmooth gluing bifurcations. Evidence was also found for the existence of Hopf-initiated canards. The simulated jerk CN waveforms were found to correspond to a pair of post-canard symmetry-related limit cycles, which exist in regions of parameter space where the equations are a slow-fast system. The slow and fast phases of the simulated oscillations were attributed to the geometry of the corresponding slow manifold. The simulated bidirectional jerk and pendular waveforms were attributed to a symmetry invariant limit cycle produced by the gluing of the asymmetric cycles. In contrast to control models of the oculomotor system, the bifurcation analysis places clear restrictions on which kinds of behaviour are likely to be associated with each other in parameter space, enabling predictions to be made regarding the possible changes in the oscillation type that may be observed upon changing the model parameters. The analysis suggests that CN is one of a range of oculomotor disorders associated with a pathological saccadic braking signal, and that jerk and pendular nystagmus are the most probable oscillatory instabilities. Additionally, the transition from jerk CN to bidirectional jerk and pendular nystagmus observed experimentally when the gaze angle or attention level is changed is attributed to a gluing bifurcation. This suggests the possibility of manipulating the waveforms of subjects with jerk CN experimentally to produce waveforms with an extended foveation period, thereby improving visual resolution.

Humans↗

PubMed1993

Cardiovascular applications of the ALOPEX optimization technique.

ALOPEX is a general optimization process incorporating a cost function containing a large number of parameters which may be simultaneously adjusted until the cost function reaches an optimum (maximum or minimum); local extremes are avoided by introducing random noise into the procedure. In this paper, ALOPEX is incorporated into a simple haemodynamic study in which an electric analogue model of the left ventricle is used to develop equations of myocardial stroke work. Pilot experiments were undertaken in rabbits (n = 5) to gauge the effectiveness of this optimizing technique. In the control state, calculated stroke work for the rabbit was determined to be 50 +/- 7 mmHg ml, while ALOPEX predicted a stroke work of 51 +/- 7 mmHg ml. ALOPEX is capable of following changing cardiovascular states when pharmacological agents are introduced. For example, after nitroprusside treatment, stroke work was reduced by 38 +/- 6% (P < 0.05) while ALOPEX predicted a 42 +/- 4% reduction from baseline (P < 0.05). Methoxamine treatment increased stroke work by 74 +/- 34%, while ALOPEX predicted a 73 +/- 43% increase above control values. There were no statistical differences between calculated and ALOPEX predicted values. Individual model parameters such as maximum left ventricular elastance (Emax) and left ventricular end diastolic volume (EDV) were also predicted correctly by ALOPEX. We have found that the ALOPEX optimization technique is useful in predicting components of multi-parametric functions. In particular, we have shown it to be adaptable to a simple haemodynamic model.

Algorithms↗

PubMed1992

Vocal intensity in speakers and singers.

Vocal intensity is studied as a function of fundamental frequency and lung pressure. A combination of analytical and empirical models is used to predict sound pressure levels from glottal waveforms of five professional tenors and twenty five normal control subjects. The glottal waveforms were obtained by inverse filtering the mouth flow. Empirical models describe features of the glottal flow waveform (peak flow, peak flow derivative, open quotient, and speed quotient) in terms of lung pressure and phonation threshold pressure, a key variable that incorporates the Fo dependence of many of the features of the glottal flow. The analytical model describes the contributions to sound pressure levels SPL by the vocal tract. Results show that SPL increases with Fo at a rate of 8-9 dB/octave provided that lung pressure is raised proportional to phonation threshold pressure. The SPL also increases at a rate of 8-9 dB per doubling of excess pressure over threshold, a new quantity that assumes considerable importance in vocal intensity calculations. For the same excess pressure over threshold, the professional tenors produced 10-12 dB greater intensity than the male nonsingers, primarily because their peak airflow was much higher for the same pressure. A simple set of rules is devised for predicting SPL from source waveforms.

Glottis↗

PubMed2004

The burden of treatment failure in type 2 diabetes.

OBJECTIVE: In type 2 diabetes, therapies to maintain blood glucose control usually fail after several years. We estimated the glycemic burden that accumulates from treatment failure and describe the time course and predictors of failure. RESEARCH DESIGN AND METHODS: A prospective, population-based study using retrospective observational data. We identified all 7208 complete courses of treatment with nondrug therapy, sulfonylurea monotherapy, metformin monotherapy, and combination oral antihyperglycemic therapy between 1994 and 2002, inclusive, among members of the Kaiser Permanente Northwest Region. We calculated mean cumulative glycemic burden, defined as HbA(1c)-months >8.0 or 7.0% for each treatment. We then measured the likelihood that the next HbA(1c) would exceed 8.0 and 7.0% after HbA(1c) exceeded each of ten hypothetical treatment thresholds. Finally, we estimated multivariate logistic regression models to predict when HbA(1c) would continue to deteriorate. RESULTS: In this well-controlled population, the average patient accumulated nearly 5 HbA(1c)-years of excess glycemic burden >8.0% from diagnosis until starting insulin and about 10 HbA(1c)-years of burden >7.0%. Whenever patients crossed the American Diabetes Association-recommended treatment threshold of 8.0%, their next HbA(1c) result was as likely to be <8.0 as >8.0%. Multivariate prediction models had highly statistically significant coefficients, but predicted <10% of the variation in future HbA(1c) results. CONCLUSIONS: Clinicians should change glucose-lowering treatments in type 2 diabetes much sooner or use treatments that are less likely to fail. An action point at 7.0% or lower is more likely to prevent additional deterioration than the traditional action point of 8.0%.

Blood Glucose↗

PubMed2006

Detection of hypopharyngeal squamous cell carcinoma using serum proteomics.

CONCLUSIONS: The combination of surface-enhanced laser desorption/ionization (SELDI) with bioinformatics tools could help find serum proteome biomarkers and establish a predictive model for early detection of hypopharyngeal squamous cell carcinoma (HSCC). OBJECTIVES: Proteomic profiling of serum using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is an emerging technique to identify new biomarkers in biological fluids and to establish clinically useful diagnostic computational models. We used it to find new potential biomarkers and to establish a predictive model for early detection of HSCC. MATERIALS AND METHODS: One hundred serum samples including 48 from HSCC patients and 52 from normal controls which were divided into a training set and a blind testing set were treated on WCX2 and IMAC3 protein chip, and serum protein or peptide patterns were detected by SELDI-TOF-MS. The data of spectra were analyzed by Biomarker Wizard software to screen serum proteome biomarkers of HSCC. A decision tree classification algorithm and blind validation were determined by Biomarker Pattern Software (BPS). RESULTS: Ranging from 2 to 30 kDa, 45 potential biomarkers could differentiate HSCC patients from normal controls (p < 0.05). Among them four candidate protein peaks with m/z values of 7796, 4216, 5927, and 5361Da were selected to establish a predictive model by BPS with sensitivity of 94% and specificity of 89%. A sensitivity of 92% and specificity of 82% were validated in the blind testing set.

Adult↗

PubMed1997

A limited sampling approach in bioequivalence studies.

A limited sampling model (LSM) has been developed for an antidepressant immediate-release product (Drug A) and an antiepileptic controlled release product (Drug B) to predict the area under the curve (AUC) and the maximum plasma concentration (Cmax) and to compare the bioequivalence of two formulations of each drug using predicted versus observed AUC and Cmax after a single oral dose. The LSM for drug A was developed using data from 10 healthy people. The correlation between plasma concentration (independent variable) at selected time points with the AUC or Cmax (dependent variable) was evaluated by simple regression analysis. The linear regression that gave the best correlation coefficient (r) for a single sampling time versus AUC or Cmax was chosen as the LSM. The model provided good estimates of AUC and Cmax for drug A. The 90% confidence interval on log transformed observed and predicted AUC and Cmax were as follows: AUC observed = 100% to 118%, AUC predicted = 101% to 117%, Cmax observed = 99% to 125%, and Cmax predicted = 100% to 131%. The LSM for drug B was developed using a similar approach to drug A. The 90% confidence interval on log transformed observed and predicted AUC and Cmax were: AUC observed = 99% to 110%, AUC predicted = 99% to 118%, Cmax observed = 107% to 120%, and Cmax predicted = 99% to 111%. Although the predicted Cmax did not meet the 90% confidence interval for drug A, the method described here may be used to estimate AUC and Cmax for a drug in bioequivalence studies without detailed blood sampling. More research is needed in this direction.

Anticonvulsants↗

PubMed2003

Risk factors for cesarean delivery at presentation of nulliparous patients in labor.

OBJECTIVE: To identify risk factors that place a term nulliparous patient in labor at risk for cesarean delivery. METHODS: This was a case-control, chart review study of 325 nulliparous patients presenting in labor at term with singleton vertex fetuses with either cesarean (patients) or vaginal (controls) delivery. Dichotomous variables were analyzed by chi(2) or Fisher exact tests; continuous variables were assessed by the Wilcoxon two-sample test. Multiple logistic regression was used to identify independent risk factors for cesarean delivery, and a model for predicting risk was built and evaluated. RESULTS: In univariate analysis, 22 variables were significantly different between patients and controls. Of 11 that were known within 2 hours of admission, five (change in cervical dilatation, maternal weight, gestational age, fetal station at 2 hours, and preeclampsia) remained independently significant in a multiple logistic regression model for cesarean delivery. The multiple regression model could divide our study population into quintiles in which the lowest risk group had a 5% incidence and the highest risk group had an 88% incidence of cesarean delivery. CONCLUSION: It may be possible to offer early cesarean delivery to patients at highest risk, reducing the potential morbidity of long labor or failed operative vaginal delivery followed by a later cesarean delivery.

Adult↗

PubMed2004

TNF-alpha neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome.

OBJECTIVES: Neutralization of TNF-alpha with either monoclonal antibodies or soluble receptors, although not curative, has significant clinical benefit in patients with rheumatoid arthritis (RA). In contrast, blockade of TNF-alpha has little clinical benefit in the majority of patients with systemic inflammatory response syndrome (SIRS) in spite of the identification of TNF-alpha as a key factor in its pathology. It is not clear why there is such a significant difference in the responses to TNF-alpha neutralization in these two conditions. Here we use mathematical modelling to investigate this discrepancy. METHODS: Using the known pharmacokinetic and pharmacodynamic properties of TNF-alpha-blocking biological agents, we constructed a mathematical model of the biological actions of soluble(s) TNFR2, Etanercept and Infliximab. RESULTS: Our model predicts that all three inhibitors, but especially Etanercept, are effective at controlling TNF-alpha levels in RA, which we propose is a condition in which TNF-alpha production and inhibition are in equilibrium. However, when free TNF-alpha drops to a low level, as can occur in SIRS, which we propose is a non-equilibrium condition, the sequestered TNF-alpha can act as a slow-release reservoir, thereby sabotaging its effectiveness. CONCLUSIONS: These results may explain the effectiveness of TNF-alpha blockade in the equilibrium condition RA and the ineffectiveness in the non-equilibrium condition SIRS.

Antibodies, Monoclonal↗

PubMedDate not supplied

A mechanical model of tumor encapsulation and transcapsular spread.

In this paper, a mathematical modeling framework is presented which describes the growth, encapsulation, and transcapsular spread of solid tumors. The model is based on the physical forces and cellular interactions involved in tumorigenesis and is used to test and compare the active (foreign body hypothesis) and passive (expansive growth hypothesis) hypotheses of capsule formation, such investigations being ideally suited to our mechanical model. The model simulations lead us to predict that, although an active response can successfully control tumor growth via the deposition of large amounts of collagen, this alone is insufficient for capsule formation. In contrast, a solely passive responsive is capable of producing an encapsulated tumor with minimal accumulation of connective tissue within the tumor. When both responses are active, a denser capsule forms and there is a significant increase in connective tissue within the tumor. Using a modified version of the model, in which tumor cells are assumed to produce degradative proteases at a rate which depends on the pressure they experience, it is also possible to show that transcapsular spread or invasion of the tumor may be due to the production by the tumor cells of proteases and their subsequent action.

Biomechanical Phenomena↗

PubMed2004

Hormonal exposures and breast cancer in a sample of women with systemic lupus erythematosus.

OBJECTIVES: To determine if breast cancer risk in women with SLE is modified by a history of exposure to hormone replacement therapy (HRT) or oral contraceptives (OC), after adjusting for other risk factors. METHODS: Data were pooled from SLE cohorts at three centres. For each female cohort member (n = 871), the probability of developing breast cancer was estimated from factors (age, parity, age at first live birth, age of menarche, personal history of benign breast disease, family history) in the Gail model, an established tool for predicting breast cancer risk. From these probabilities, the expected number of breast cancers for the cohort was estimated. Actual occurrence of cases was determined by linkage with regional cancer registries. Standardized incidence ratios (SIRs; ratio of cancers observed to expected) were calculated, with subgroup analyses according to HRT and OC exposure. RESULTS: In the cohort, 15 breast cancers occurred vs 7.2 predicted [SIR 2.1, 95% confidence interval (CI) 1.1, 3.5]. When controlling for Gail model risk factors, estimates were similar for women never exposed to HRT vs those exposed to HRT. Adjusted SIR estimates appeared similar also for women exposed or not exposed to OC. CONCLUSIONS: Although not definitive, the data suggest that the breast cancer experience in this sample is not completely explained by factors such as reproductive and family history, or by exogenous hormonal exposures. Other determinants, including medication exposures or genetic factors (possibly related to oestrogen receptors or metabolism) may be important. Variations in these factors might explain why an elevated risk of breast cancer has not been apparent in all SLE populations.

Adult↗