A Lipid-Structured Model of Atherosclerosis with Macrophage Proliferation.

Atherosclerotic plaques are fatty deposits that form in the walls of major arteries and are one of the major causes of heart attacks and strokes. Macrophages are the main immune cells in plaques and macrophage dynamics influence whether plaques grow or regress. Macrophage proliferation is a key process in atherosclerosis, particularly in the development of mid-stage plaques, but very few mathematical models include proliferation. In this paper we reframe the lipid-structured model of Ford et al. (J Theor Biol 479:48-63, 2019. https://doi.org/10.1016/j.jtbi.2019.07.003 ) to account for macrophage proliferation. Proliferation is modelled as a non-local decrease in the lipid structural variable. Steady state analysis indicates that proliferation assists in reducing eventual necrotic core lipid content and spreads the lipid load of the macrophage population amongst the cells. The contribution of plaque macrophages from proliferation relative to recruitment from the bloodstream is also examined. The model suggests that a more proliferative plaque differs from an equivalent (defined as having the same lipid content and cell numbers) recruitment-dominant plaque in the way lipid is distributed amongst the macrophages. The macrophage lipid distribution of an equivalent proliferation-dominant plaque is less skewed and exhibits a local maximum near the endogenous lipid content.

A Lipid-Structured Model of Atherosclerotic Plaque Macrophages with Lipid-Dependent Kinetics.

Atherosclerotic plaques are fatty growths in artery walls that cause heart attacks and strokes. Plaque formation is driven by macrophages that are recruited to the artery wall. These cells consume and remove blood-derived lipids, such as modified low-density lipoprotein. Ineffective lipid removal, due to macrophage death and other factors, leads to the accumulation of lipid-loaded macrophages and formation of a necrotic lipid core. Experimental observations suggest that macrophage functionality varies with the extent of lipid loading. However, little is known about the influence of macrophage lipid loads on plaque fate. Extending work by Ford et al. (J Theor Biol 479:48-63, 2019) and Chambers et al. (A lipid-structured model of atherosclerosis with macrophage proliferation, 2022), we develop a plaque model where macrophages are structured by their ingested lipid load and behave in a lipid-dependent manner. The model considers several macrophage behaviours, including recruitment to and emigration from the artery wall; proliferation and apotosis; ingestion of plaque lipids; and secondary necrosis of apoptotic cells. We consider apoptosis, emigration and proliferation to be lipid-dependent and we model these effects using experimentally informed functions of the internalised lipid load. Our results demonstrate that lipid-dependent macrophage behaviour can substantially alter plaque fate by changing both the total quantity of lipid in the plaque and the distribution of lipid between the live cells, dead cells and necrotic core. The consequences of macrophage lipid-dependence are often unpredictable because lipid-dependent effects introduce subtle, nonlinear interactions between the modelled cell behaviours. These observations highlight the importance of mathematical modelling in unravelling the complexities of macrophage lipid accumulation during atherosclerotic plaque formation.

A new lipid-structured model to investigate the opposing effects of LDL and HDL on atherosclerotic plaque macrophages.

Atherosclerotic plaques form in artery walls due to a chronic inflammatory response driven by lipid accumulation. A key component of the inflammatory response is the interaction between monocyte-derived macrophages and extracellular lipid. Although concentrations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles in the blood are known to affect plaque progression, their impact on the lipid load of plaque macrophages remains unexplored. In this paper, we develop a lipid-structured mathematical model to investigate the impact of blood LDL/HDL levels on plaque composition, and lipid distribution in plaque macrophages. A reduced subsystem, derived by summing the equations of the full model, describes the dynamics of biophysical quantities relating to plaque composition (e.g. total number of macrophages, total amount of intracellular lipid). We also derive a continuum approximation of the model to facilitate analysis of the macrophage lipid distribution. The results, which include time-dependent numerical solutions and asymptotic analysis of the unique steady state solution, indicate that plaque lipid content is sensitive to the influx of LDL relative to HDL capacity. The macrophage lipid distribution evolves in a wave-like manner towards an equilibrium profile which may be monotone decreasing, quasi-uniform or unimodal, attaining its maximum value at a non-zero lipid level. Our model also reveals that macrophage uptake may be severely impaired by lipid accumulation. We conclude that lipid accumulation in plaque macrophages may serve as a partial explanation for the defective uptake of apoptotic cells (efferocytosis) often reported in atherosclerotic plaques.

Intake of selenium in the prevention of prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Recent studies have suggested that selenium intake may prevent the risk of developing prostate cancer. Results from some of these studies have given conflicting results. Because of these discrepant results we sought to explore the association between selenium intake and prostate cancer by conducting a systematic review and meta-analysis of the literature. METHODS: We systematically searched MEDLINE, EMBASE and Cochrane Library between 1966 and May 2005 for articles that examined the association between intake of selenium and the risk of prostate cancer. We abstracted the data from relevant studies. A random effects model was used to estimate pooled relative risks for both cohort and case-control studies. Heterogeneity was assessed graphically using a Funnel Plot. RESULTS: Sixteen studies (eleven cohort studies and five case-control studies) were included in the final analysis. The pooled relative risk of prostate cancer for any intake of selenium was 0.72 (0.61-0.84) for cohort studies and 0.74 (0.61-1.39) for case-control studies. The pooled relative risk of moderate intake was 0.74 (0.61-0.90) for cohort studies and 0.74 (0.39-1.39) for case-control studies. A dose-response trend was observed when we stratified the studies by disease severity. CONCLUSION: The results of our systematic review suggest that selenium intake may reduce the risk of prostate cancer. The results confirm the need for large randomized controlled trials, which are ongoing, to answer this question.

Clinical impact of point-of-care vs laboratory measurement of anticoagulation.

Patients using anticoagulation point-of-care (POC) monitors are advised to periodically test these systems against laboratory methods to monitor performance. The international normalized ratio (INR), however, can vary between test systems owing to different instrument-reagent combinations. In a randomized study evaluating warfarin self-management, we compared INR measured by patients on a POC monitor (ProTime, International Technidyne Corporation, Edison, NJ) with those obtained at a hospital laboratory within 1 hour Ninety-one paired INR determinations from 55 patients met inclusion criteria. Clinical agreement in which POC and laboratory INR were within or outside the target INR range occurred in 56 (62%) of 91 cases (kappa = 0.35). The mean (SD) difference between POC and laboratory INR was 0.44 (0.61). Six pairs differed by 1 or more INR units, 3 at study initiation resulting in POC monitor replacement. The accuracy of INR self-testing with ProTime was acceptable. The small failure rate of INR agreement might be clinically important, suggesting the need for external quality control systems.

A randomized trial of patient self-managed versus physician-managed oral anticoagulation.

BACKGROUND: Self-management (SM) of warfarin by patients is an attractive strategy, particularly if it improves anticoagulation control and can be done safely under minimal physician supervision. OBJECTIVE: To compare the effect of SM with physician-management (PM) on the maintenance of therapeutic anticoagulation. METHODS: A randomized, open-label eight-month trial was performed. Patients 18 years of age and older were eligible if they were receiving warfarin for at least one month before enrolment and required anticoagulation for at least one year to a target international normalized ratio (INR) of 2.0 to 3.0 or 2.5 to 3.5. Exclusion criteria were a known hypercoaguable disorder, mental incompetence, a language barrier or an inability to attend training sessions. Patients randomly assigned to SM tested their INR using a point-of-care device (Pro Time Microcogulation System, International Technidyne Corporation, USA) and adjusted their warfarin doses using a nomogram. Patients randomly assigned to PM received usual care from their general practitioner. The primary outcome was to demonstrate 20% improvement in anticoagulation control by SM. RESULTS: One hundred forty patients were randomly assigned (70 per group). Thirteen patients dropped out of SM early due to an inability to self-manage. Based on intention-to-treat analysis, there was no difference in the proportion of INR in range (SM 64.8% versus PM 58.7%, P=0.23) or time in target range (SM 71.8% versus PM 63.2%, P=0.14). Patients managing their own therapy spent less time below the therapeutic range (15.0% versus 27.3%, P=0.04). There were three major complications of thrombosis or bleeding, all occurring in the PM arm. All patients who completed SM preferred to continue with that strategy. CONCLUSIONS: SM was not significantly better than PM in maintaining therapeutic anticoagulation. SM was feasible and appeared safe in the present study population.

Evaluation of captopril for the management of hypertension in autonomic dysreflexia: a pilot study.

OBJECTIVE: To evaluate the efficacy of captopril for management of hypertensive urgencies in autonomic dysreflexia. DESIGN: A 1-year, prospective, open-label pilot study. SETTING: Rehabilitation hospital. PATIENTS: Twenty-six consecutive patients older than 15 years with spinal cord injury above T6. INTERVENTIONS: During an autonomic dysreflexia episode, captopril 25mg was administered sublingually if systolic blood pressure (SBP) was at or above 150mmHg despite the use of nondrug measures. If SBP remained elevated 30 minutes after captopril administration, 1 dose of immediate-release nifedipine 5mg was given as rescue by the bite and swallow method and repeated, if necessary, in 15 minutes. MAIN OUTCOME MEASURE: SBP 30 minutes after captopril administration at initial autonomic dysreflexia episode. RESULTS: A total of 33 autonomic dysreflexia episodes were documented, of which 18 episodes in 5 patients were treated with drug therapy. Captopril alone was effective in 4 of 5 initial episodes (80%). Mean SBPs at baseline and 30 minutes after captopril were 178+/-18mmHg and 133+/-28mmHg, respectively. There were no cases of reactive hypotension. The addition of nifedipine successfully reduced SBP in the remaining patient. Of the combined 18 initial and repeat autonomic dysreflexia episodes, 94% were successfully treated with our protocol. CONCLUSION: Captopril appears to be safe and effective for autonomic dysreflexia management.

Assessment of vision-related function in patients with age-related macular degeneration.

OBJECTIVE: To investigate the validity of the visual function index (VF-14) in assessing visual function in patients with age-related macular degeneration (AMD). DESIGN: Prospective noncomparative observational case series. PARTICIPANTS: One hundred fifty-nine consecutive patients attending a sole practitioner's academic retina-only clinic from May 1998 through August 1998 and from May 1999 through August 1999. MAIN OUTCOME MEASURES: Correlations were calculated between the VF-14 scores and the medical outcomes study 36-item short form (SF-36), weighted comorbidity scale, visual acuity and clinical AMD severity (stage), and vision self-assessment scales. Documentation of the severity of macular degeneration was performed by a sole examiner. RESULTS: There was a moderately strong correlation between visual acuity and trouble with vision (r = 0.51), satisfaction with vision (r = -0.50), and overall quality of vision (r = -0.56). A strong correlation was noted between VF-14 score and patients' self-rating of amount of trouble with vision (r = -0.67), satisfaction with vision (r = 0.62), and overall quality of vision (r = 0.67). In comparison, correlations between SF-36 score and patients' self-rating of amount of trouble with vision, satisfaction with vision, and overall quality of vision ranged from r = 0.37 to r = -0.40. Linear regression analysis for the overall study population indicated that AMD severity was not an independently significant predictor of VF-14 score after adjusting for visual acuity. However, among patients with 20/20 vision in the better eye, AMD severity was an independently significant predictor of VF-14 score after adjusting for visual acuity in the worse eye. CONCLUSIONS: The VF-14 exhibits a considerable degree of validity as a measure of functional impairment in patients with AMD. Age-related macular degeneration severity was an independently significant predictor of VF-14 score in the group of patients with 20/20 vision in the better eye, but this did not hold true for the overall study population. Age-related macular degeneration is associated with substantial impairment in reported visual function.