Inhibition of adaptive immune responses leads to a fatal clinical outcome in SIV-infected pigtailed macaques but not vervet African green monkeys.

African green monkeys (AGM) and other natural hosts for simian immunodeficiency virus (SIV) do not develop an AIDS-like disease following SIV infection. To evaluate differences in the role of SIV-specific adaptive immune responses between natural and nonnatural hosts, we used SIV(agmVer90) to infect vervet AGM and pigtailed macaques (PTM). This infection results in robust viral replication in both vervet AGM and pigtailed macaques (PTM) but only induces AIDS in the latter species. We delayed the development of adaptive immune responses through combined administration of anti-CD8 and anti-CD20 lymphocyte-depleting antibodies during primary infection of PTM (n = 4) and AGM (n = 4), and compared these animals to historical controls infected with the same virus. Lymphocyte depletion resulted in a 1-log increase in primary viremia and a 4-log increase in post-acute viremia in PTM. Three of the four PTM had to be euthanized within 6 weeks of inoculation due to massive CMV reactivation and disease. In contrast, all four lymphocyte-depleted AGM remained healthy. The lymphocyte-depleted AGM showed only a trend toward a prolongation in peak viremia but the groups were indistinguishable during chronic infection. These data show that adaptive immune responses are critical for controlling disease progression in pathogenic SIV infection in PTM. However, the maintenance of a disease-free course of SIV infection in AGM likely depends on a number of mechanisms including non-adaptive immune mechanisms.

Magnetic Resonance Imaging Biomarkers of Renal Structure and Function

The kidney's major role in filtration depends on its high blood flow, concentrating mechanisms, and biochemical activation. The kidney's greatest strengths also lead to vulnerability for drug-induced nephrotoxicity and other renal injuries. The current standard to diagnose renal injuries is with a percutaneous renal biopsy, which can be biased and insufficient. In one particular case, biopsy of a kidney with renal cell carcinoma can actually initiate metastasis. Tools that are sensitive and specific to detect renal disease early are essential, especially noninvasive diagnostic imaging. While other imaging modalities (ultrasound and x-ray/CT) have their unique advantages and disadvantages, MRI has superb soft tissue contrast without ionizing radiation. More importantly, there is a richness of contrast mechanisms in MRI that has yet to be explored and applied to study renal disease.

The focus of this work is to advance preclinical imaging tools to study the structure and function of the renal system. Studies were conducted in normal and disease models to understand general renal physiology as well as pathophysiology. This dissertation is separated into two parts--the first is the identification of renal architecture with ex vivo MRI; the second is the characterization of renal dynamics and function with in vivo MRI. High resolution ex vivo imaging provided several opportunities including: 1) identification of fine renal structures, 2) implementation of different contrast mechanisms with several pulse sequences and reconstruction methods, 3) development of image-processing tools to extract regions and structures, and 4) understanding of the nephron structures that create MR contrast and that are important for renal physiology. The ex vivo studies allowed for understanding and translation to in vivo studies. While the structure of this dissertation is organized by individual projects, the goal is singular: to develop magnetic resonance imaging biomarkers for renal system.

The work presented here includes three ex vivo studies and two in vivo studies:

1) Magnetic resonance histology of age-related nephropathy in sprague dawley.

2) Quantitative susceptibility mapping of kidney inflammation and fibrosis in type 1 angiotensin receptor-deficient mice.

3) Susceptibility tensor imaging of the kidney and its microstructural underpinnings.

4) 4D MRI of renal function in the developing mouse.

5) 4D MRI of polycystic kidneys in rapamycin treated Glis3-deficient mice.

Increasing Motorcycle Taxi Driver Conspicuity in Tanzania

Motorcycle crash related injuries and deaths are increasing rapidly in many African nations. Utilizing conspicuity measures, such as wearing reflective, fluorescent safety vests, are effective as crash prevention strategies. Furthermore, use of some conspicuity measures is mandated by law among motorcycle-taxi drivers in Tanzania. Nonetheless, uptake remains low. Locally appropriate strategies to improve crash preventative behaviors are needed.

To explore whether use of conspicuity measures could be improved through eliminating cost-barriers, we tested a distribution strategy involving the provision of free motorcycle safety vests among a population of motorcycle-taxi drivers in Moshi, Tanzania. We conducted a cluster randomized controlled trial among 180 motorcycle-taxi drivers in which half of the participants (90) were randomized to the intervention arm and received a free reflective vest. The other half of the participants (90) were randomized to the control arm and did not receive free vests. Whether motorcycle taxi drivers used the reflective vest was then unobtrusively observed on city streets over a period of three months.

Mixed-effects logistic regression was used to estimate differential uptake of the vests between trial arms. At baseline, 3.3% of individuals in both arms used a reflective vest. In three months of follow-up, 79 drivers in the intervention arm and 82 drivers in the control arm were able to be observed. In the intervention arm the average proportion of observations during which drivers were observed to be using a reflective vest was 9.5%, compared to 2.0% in the control arm (odds ratio: 5.5, 95% confidence interval: 1.1-26.9, p-value: 0.04). Distribution of free reflective vests did lead to an increase in vest usage, however, the increase was minimal. Removing economic barriers alone appears insufficient to adequately improve adherence to conspicuity measures.