HPV clearance and the neglected role of stochasticity.

Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response. To date, little attention has been paid to the potential role of stochastic cell dynamics in the time it takes to clear an HPV infection. In this study, we combine mechanistic mathematical models at the cellular level with epidemiological data at the population level to disentangle the respective roles of immune capacity and cell dynamics in the clearing mechanism. Our results suggest that chance-in form of the stochastic dynamics of basal stem cells-plays a critical role in the elimination of HPV-infected cell clones. In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance-the rest is taken care of by the stochastic proliferation dynamics in the basal layer. In HIV-negative individuals, the contribution of the immune response may be negligible.

Specialist and primary care physicians' views on barriers to adequate preparation of patients for renal replacement therapy: a qualitative study.

BACKGROUND: Early preparation for renal replacement therapy (RRT) is recommended for patients with advanced chronic kidney disease (CKD), yet many patients initiate RRT urgently and/or are inadequately prepared. METHODS: We conducted audio-recorded, qualitative, directed telephone interviews of nephrology health care providers (n = 10, nephrologists, physician assistants, and nurses) and primary care physicians (PCPs, n = 4) to identify modifiable challenges to optimal RRT preparation to inform future interventions. We recruited providers from public safety-net hospital-based and community-based nephrology and primary care practices. We asked providers open-ended questions to assess their perceived challenges and their views on the role of PCPs and nephrologist-PCP collaboration in patients' RRT preparation. Two independent and trained abstractors coded transcribed audio-recorded interviews and identified major themes. RESULTS: Nephrology providers identified several factors contributing to patients' suboptimal RRT preparation, including health system resources (e.g., limited time for preparation, referral process delays, and poorly integrated nephrology and primary care), provider skills (e.g., their difficulty explaining CKD to patients), and patient attitudes and cultural differences (e.g., their poor understanding and acceptance of their CKD and its treatment options, their low perceived urgency for RRT preparation; their negative perceptions about RRT, lack of trust, or language differences). PCPs desired more involvement in preparation to ensure RRT transitions could be as "smooth as possible", including providing patients with emotional support, helping patients weigh RRT options, and affirming nephrologist recommendations. Both nephrology providers and PCPs desired improved collaboration, including better information exchange and delineation of roles during the RRT preparation process. CONCLUSIONS: Nephrology and primary care providers identified health system resources, provider skills, and patient attitudes and cultural differences as challenges to patients' optimal RRT preparation. Interventions to improve these factors may improve patients' preparation and initiation of optimal RRTs.

Apparent treatment-resistant hypertension and chronic kidney disease: another cardiovascular-renal syndrome?

To identify patients at increased risk of cardiovascular (CV) outcomes, apparent treatment-resistant hypertension (aTRH) is defined as having a blood pressure above goal despite the use of 3 or more antihypertensive therapies of different classes at maximally tolerated doses, ideally including a diuretic. Recent epidemiologic studies in selected populations estimated the prevalence of aTRH as 10% to 15% among patients with hypertension and that aTRH is associated with elevated risk of CV and renal outcomes. Additionally, aTRH and CKD are associated. Although the pathogenesis of aTRH is multifactorial, the kidney is believed to play a significant role. Increased volume expansion, aldosterone concentration, mineralocorticoid receptor activity, arterial stiffness, and sympathetic nervous system activity are central to the pathogenesis of aTRH and are targets of therapies. Although diuretics form the basis of therapy in aTRH, pathophysiologic and clinical data suggest an important role for aldosterone antagonism. Interventional techniques, such as renal denervation and carotid baroreceptor activation, modulate the sympathetic nervous system and are currently in phase III trials for the treatment of aTRH. These technologies are as yet unproven and have not been investigated in relationship to CV outcomes or in patients with CKD.

The Effect of Diet-Induced Obesity and Subsequent Weight Loss on Body Composition, Glucose Clearance, Metabolite Profile and Liver Amp-Activated Protein Kinase in Mice

Obesity, currently an epidemic, is a difficult disease to combat because it is marked by both a change in body weight and an underlying dysregulation in metabolism, making consistent weight loss challenging. We sought to elucidate this metabolic dysregulation resulting from diet-induced obesity (DIO) that persists through subsequent weight loss. We hypothesized that weight gain imparts a change in “metabolic set point” persisting through subsequent weight loss and that this modification may involve a persistent change in hepatic AMP-activated protein kinase (AMPK), a key energy-sensing enzyme in the body. To test these hypotheses, we tracked metabolic perturbations through this period, measuring changes in hepatic AMPK. To further understand the role of AMPK we used AICAR, an AMPK activator, following DIO. Our findings established a more dynamic metabolic model of DIO and subsequent weight loss. We observed hepatic AMPK elevation following weight loss, but AICAR administration without similar dieting was unsuccessful in improving metabolic dysregulation. Our findings provide an approach to modeling DIO and subsequent dieting that can be built upon in future studies and hopefully contribute to more effective long-term treatments of obesity.

In vivo small animal micro-CT using nanoparticle contrast agents.

Computed tomography (CT) is one of the most valuable modalities for in vivo imaging because it is fast, high-resolution, cost-effective, and non-invasive. Moreover, CT is heavily used not only in the clinic (for both diagnostics and treatment planning) but also in preclinical research as micro-CT. Although CT is inherently effective for lung and bone imaging, soft tissue imaging requires the use of contrast agents. For small animal micro-CT, nanoparticle contrast agents are used in order to avoid rapid renal clearance. A variety of nanoparticles have been used for micro-CT imaging, but the majority of research has focused on the use of iodine-containing nanoparticles and gold nanoparticles. Both nanoparticle types can act as highly effective blood pool contrast agents or can be targeted using a wide variety of targeting mechanisms. CT imaging can be further enhanced by adding spectral capabilities to separate multiple co-injected nanoparticles in vivo. Spectral CT, using both energy-integrating and energy-resolving detectors, has been used with multiple contrast agents to enable functional and molecular imaging. This review focuses on new developments for in vivo small animal micro-CT using novel nanoparticle probes applied in preclinical research.