Monitoring dynamic calcium homeostasis alterations by T₁-weighted and T₁-mapping cardiac manganese enhanced MRI (MEMRI) in a murine myocardial infarction model

Manganese has been used as a T₁-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn²) enter viable myocardial cells via voltage gated calcium channels, manganese-enhanced MRI (MEMRI) is sensitive to the viability and the inotropic state of the heart. In spite of the established importance of calcium regulation in the heart both prior to, and following, myocardial injury, monitoring strategies to assess calcium homeostasis in affected cardiac tissues are limited. This study implements a T₁-mapping method to obtain quantitative information both dynamically and over a range of MnCl₂ infusion doses. In order to optimize the current manganese infusion protocols, both dose dependent and temporal washout studies were performed. A non-linear relationship between infused MnCl₂ solution dose and increase in left ventricular free wall relaxation rate (∆R₁) was observed. Control mice also exhibited significant manganese clearance over time, with approximately 50% decrease of ∆R₁ occurring in just 2.5 hours. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. Using the measured relationship between infused MnCl₂ and ∆R₁, absolute Mn concentration ICP-MS data analysis provided a means to estimate the absolute heart Mn concentration in vivo. We have shown that this technique has the sensitivity to observe or monitor potential Ca²+ handling alterations in vivo due to the physiological remodeling following myocardial infarction. Left ventricular free wall ∆R₁ values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than healthy left ventricular free wall tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future therapeutic treatment or evaluation of disease progression.M.S.Committee Chair: Hu, Tom; Committee Co-Chair: Rahnema, Farzad; Committee Member: Wang, Chris; Committee Member: Yanasak, Natha

A margin-based analysis of the dosimetric impact of motion on step-and-shoot IMRT lung plans

PURPOSE: Intrafraction motion during step-and-shoot (SNS) IMRT is known to affect the target dosimetry by a combination of dose blurring and interplay effects. These effects are typically managed by adding a margin around the target. A quantitative analysis was performed, assessing the relationship between target motion, margin size, and target dosimetry with the goal of introducing new margin recipes. METHODS: A computational algorithm was used to calculate 1,174 motion-encoded dose distributions and DVHs within the patient’s CT dataset. Sinusoidal motion tracks were used simulating intrafraction motion for nine lung tumor patients, each with multiple margin sizes. RESULTS: D(95%) decreased by less than 3% when the maximum target displacement beyond the margin experienced motion less than 5 mm in the superior-inferior direction and 15 mm in the anterior-posterior direction. For target displacements greater than this, D(95%) decreased rapidly. CONCLUSIONS: Targets moving in excess of 5 mm outside the margin can cause significant changes to the target. D(95%) decreased by up to 20% with target motion 10 mm outside the margin, with underdosing primarily limited to the target periphery. Multi-fractionated treatments were found to exacerbate target under-coverage. Margins several millimeters smaller than the maximum target displacement provided acceptable motion protection, while also allowing for reduced normal tissue morbidity

Assessing alterations in myocardial MN²⁺ fluxes following myocardial infarction in a murine model using T₁₋-mapping manganese-enhanced MRI

During cardiac ischemia, intracellular calcium (Ca²⁺) overload occurs which can result in cell death. MRI T₁ shortening contrast agent manganese (Mn²⁺) acts as a surrogate marker for Ca²⁺. Cardiac T₁-mapping manganese-enhanced MRI (MEMRI) techniques were applied to study the efflux of Mn²⁺ from both healthy mice and mice post-myocardial infarction (MI) surgery. Temporal changes in the myocardial relaxation rate, ∆R₁, post-MnCl₂ infusion were shown to be linearly correlated to the absolute Mn content. The relative importance of individual efflux mechanisms in healthy mice was investigated by inhibiting the sodium-calcium exchanger (NCX) with SEA0400, following infusion of MnCl₂, with SEA0400 reducing the rate of Mn²⁺ efflux. Regional alterations in Mn²⁺ uptake and efflux were also studied post-myocardial infarction, allowing for the identification of potentially salvageable myocardium in the peri-infarcted zone surrounding the necrosed tissue. Application of pharmacokinetic models to in vivo and elemental analysis data from both the healthy and MI mice groups suggested that the NCX was more active in Mn²⁺ efflux than for Ca²⁺ and that there was an increase in Mn²⁺ uptake due to the disease condition, consistent with Ca²⁺ overloading. Studying Mn²⁺ efflux using these protocols could provide a pre-clinical model for examining alterations in relative Ca²⁺ fluxes and to potentially monitor disease progression.Ph.D.Committee Co-Chair: Hu, Tom; Committee Co-Chair: Rahnema, Farzad; Committee Member: Cho, Sang; Committee Member: Schumacher, Autumn; Committee Member: Wang, Chris; Committee Member: Yanasak, Natha

A comparative analysis of disability in individuals with bipolar affective disorder and schizophrenia in a sub-Saharan African mental health hospital: towards evidence-guided rehabilitation intervention

PURPOSE: Bipolar affective disorder (BAD) and schizophrenia are two severe psychotic conditions that are associated with disability. The present study was designed to compare the pattern of disability between clinically stable individuals with BAD and schizophrenia in a sub-Saharan mental health facility. METHODS: A total of 200 consecutive participants (made up of 100 each among clinically stable individuals with BAD and schizophrenia) were recruited. All participants had their diagnoses confirmed using Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID), after which the designed questionnaire and the 36-item World Health Organisation Disability Assessment Schedule interview (WHODAS II) were administered to them. RESULTS: In this study, the level of disability among participants with BAD was better compared to those with schizophrenia as determined by mean WHODAS score of 24.93 and 27.02, respectively. Similarly, there was a significant difference between participants with BAD and schizophrenia with respect to four domains of the WHODAS-II, viz, self-care (p < 0.001), getting along with others (p < 0.001), life activities (p < 0.001) and participation in the society (p < 0.001). The factors that were significantly associated with disability in the two groups (BAD and schizophrenia) were: unemployment status (p < 0.001) and remittance source of income (p < 0.001), while those that spent not more than ₦2,000 (13 dollars) per month on treatment (p = 0.004) were observed to be less disabled. CONCLUSIONS: Overall, participants with BAD fared better in the level of disability and most of the measured domains of disability in comparison with those with schizophrenia. Both socio-demographic and treatment-related factors seem to define the pattern disability among participants. Thus, evidence-guided preventive and rehabilitative treatment strategies directed against functional impairment using prioritized model among individuals with BAD and schizophrenia are advocated.Dapo Adebowale Adegbaju, Andrew Toyin Olagunju, Richard Uwakw