Targeted microbubbles: a novel application for the treatment of kidney stones

Kidney stone disease is endemic. Extracorporeal shockwave lithotripsy was the first major technological breakthrough where focused shockwaves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: (i) bisphosphonates attach to hydroxyapatite crystals with high affinity; and (ii) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randall's plaques, which also contain hydroxyapatite crystals, can also be targeted to pre-emptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by virtue of being used as an adjunct to traditional imaging methods, especially useful in high-risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine

Urinary Tract Stones and Osteoporosis: Findings From the Women's Health Initiative

Kidney and bladder stones (urinary tract stones) and osteoporosis are prevalent, serious conditions for postmenopausal women. Men with kidney stones are at increased risk of osteoporosis; however, the relationship of urinary tract stones to osteoporosis in postmenopausal women has not been established. The purpose of this study was to determine whether urinary tract stones are an independent risk factor for changes in bone mineral density (BMD) and incident fractures in women in the Women's Health Initiative (WHI). Data were obtained from 150,689 women in the Observational Study and Clinical Trials of the WHI with information on urinary tract stones status: 9856 of these women reported urinary tract stones at baseline and/or incident urinary tract stones during follow‐up. Cox regression models were used to determine the association of urinary tract stones with incident fractures and linear mixed models were used to investigate the relationship of urinary tract stones with changes in BMD that occurred during WHI. Follow‐up was over an average of 8 years. Models were adjusted for demographic and clinical factors, medication use, and dietary histories. In unadjusted models there was a significant association of urinary tract stones with incident total fractures (HR 1.10; 95% CI, 1.04 to 1.17). However, in covariate adjusted analyses, urinary tract stones were not significantly related to changes in BMD at any skeletal site or to incident fractures. In conclusion, urinary tract stones in postmenopausal women are not an independent risk factor for osteoporosis. © 2015 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115895/1/jbmr2553.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115895/2/jbmr2553_am.pd

Quantification of Renal Stone Contrast with Ultrasound in Human Subjects

Purpose: Greater visual contrast between calculi and tissue would improve ultrasound (US) imaging of urolithiasis and potentially expand clinical use. The color Doppler twinkling artifact has been suggested to provide enhanced contrast of stones compared with brightness mode (B-mode) imaging, but results are variable. This work provides the first quantitative measure of stone contrast in humans for B-mode and color Doppler mode, forming the basis to improve US for the detection of stones. Materials and Methods: Using a research ultrasound system, B-mode imaging was tuned for detecting stones by applying a single transmit angle and reduced signal compression. Stone twinkling with color Doppler was tuned by using low-frequency transmit pulses, longer pulse durations, and a high-pulse repetition frequency. Data were captured from 32 subjects, with 297 B-mode and Doppler images analyzed from 21 subjects exhibiting twinkling signals. The signal to clutter ratio (i.e., stone to background tissue) (SCR) was used to compare the contrast of a stone on B-mode with color Doppler, and the contrast between stone twinkling and blood-flow signals within the kidney. Results: The stone was the brightest object in only 54% of B-mode images and 100% of Doppler images containing stone twinkling. On average, stones were isoechoic with the tissue clutter on B-mode (SCR = 0 dB). Stone twinkling averaged 37 times greater contrast than B-mode (16 dB, p < 0.0001) and 3.5 times greater contrast than blood-flow signals (5.5 dB, p = 0.088). Conclusions: This study provides the first quantitative measure of US stone to tissue contrast in humans. Stone twinkling contrast is significantly greater than the contrast of a stone on B-mode. There was also a trend of stone twinkling signals having greater contrast than blood-flow signals in the kidney. Dedicated optimization of B-mode and color Doppler stone imaging could improve US detection of stones

First-in-human clinical trial of ultrasonic propulsion of kidney stones

PURPOSE: Ultrasonic propulsion is a new technology using focused ultrasound energy applied transcutaneously to reposition kidney stones. We report what are to our knowledge the findings from the first human investigational trial of ultrasonic propulsion toward the applications of expelling small stones and dislodging large obstructing stones. MATERIALS AND METHODS: Subjects underwent ultrasonic propulsion while awake without sedation in clinic, or during ureteroscopy while anesthetized. Ultrasound and a pain questionnaire were completed before, during and after propulsion. The primary outcome was to reposition stones in the collecting system. Secondary outcomes included safety, controllable movement of stones and movement of stones less than 5 mm and 5 mm or greater. Adverse events were assessed weekly for 3 weeks. RESULTS: Kidney stones were repositioned in 14 of 15 subjects. Of the 43 targets 28 (65%) showed some level of movement while 13 (30%) were displaced greater than 3 mm to a new location. Discomfort during the procedure was rare, mild, brief and self-limited. Stones were moved in a controlled direction with more than 30 fragments passed by 4 of the 6 subjects who had previously undergone a lithotripsy procedure. The largest stone moved was 10 mm. One patient experienced pain relief during treatment of a large stone at the ureteropelvic junction. In 4 subjects a seemingly large stone was determined to be a cluster of small passable stones after they were moved. CONCLUSIONS: Ultrasonic propulsion was able to successfully reposition stones and facilitate the passage of fragments in humans. No adverse events were associated with the investigational procedure

Comparison of Tissue Injury from Focused Ultrasonic Propulsion of Kidney Stones Versus Extracorporeal Shock Wave Lithotripsy

Purpose Focused ultrasonic propulsion is a new non-invasive technique designed to move kidney stones and stone fragments out of the urinary collecting system. However, the extent of tissue injury associated with this technique is not known. As such, we quantitated the amount of tissue injury produced by focused ultrasonic propulsion under simulated clinical treatment conditions, and under conditions of higher power or continuous duty cycles, and compared those results to SWL injury. Materials and Methods A human calcium oxalate monohydrate stone and/or nickel beads were implanted (with ureteroscopy) into 3 kidneys of live pigs (45–55 kg) and repositioned using focused ultrasonic propulsion. Additional pig kidneys were exposed to SWL level pulse intensities or continuous ultrasound exposure of 10 minutes duration (ultrasound probe either transcutaneous or on the kidney). These kidneys were compared to 6 kidneys treated with an unmodified Dornier HM3 Lithotripter (2400 shocks, 120 SWs/min and 24 kV). Histological analysis was performed to assess the volume of hemorrhagic tissue injury created by each technique (% functional renal volume, FRV). Results SWL produced a lesion of 1.56±0.45% FRV. Ultrasonic propulsion produced no detectable lesion with the simulated clinical treatment. A lesion of 0.46±0.37% FRV or 1.15±0.49% FRV could be produced if excessive treatment parameters were used while the ultrasound probe was placed on the kidney. Conclusions Focused ultrasonic propulsion produced no detectable morphological injury to the renal parenchyma when using clinical treatment parameters and produced injury comparable in size to SWL when using excessive treatment parameters

Update on clinical trials of kidney stone repositioning and preclinical results of stone breaking with one system

Our goal is an office-based, handheld ultrasound system to target, detach, break, and/or expel stones and stone fragments from the urinary collecting system to facilitate natural clearance. Repositioning of stones in humans (maximum 2.5 MPa, and 3-second bursts) and breaking of stones in a porcine model (maximum 50 cycles, 20 Hz repetition, 30 minutes, and 7 MPa peak negative pressure) have been demonstrated using the same 350-kHz probe. Repositioning in humans was conducted during surgery with a ureteroscope in the kidney to film stone movement. Independent video review confirmed stone movements (≥ 3 mm) in 15 of 16 kidneys (94%). No serious or unanticipated adverse events were reported. Experiments of burst wave lithotripsy (BWL) effectiveness on breaking human stones implanted in the porcine bladder and kidney demonstrated fragmentation of 8 of 8 stones on post mortem dissection. A 1-week survival study with the BWL exposures and 10 specific-pathogen-free pigs, showed all findings were within normal limits on clinical pathology, hematology, and urinalysis. These results demonstrate that repositioning of stones with ultrasonic propulsion and breaking of stones with BWL are safe and effective

Improving burst wave lithotripsy effectiveness for small stones and fragments by increasing frequency: theoretical modeling and ex vivo study

Introduction and Objective: In clinical trial NCT03873259, a 2.6-mm lower pole stone was treated transcutaneously and ex vivo with 390-kHz burst wave lithotripsy (BWL) for 40 minutes and failed to break. The stone was subsequently fragmented with 650-kHz BWL after a 4-minute exposure. This study investigated how to fragment small stones and why varying BWL frequency may more effectively fragment stones to dust. Methods: A linear elastic model was used to calculate the stress created inside stones from shock wave lithotripsy (SWL) and different BWL frequencies mimicking the stone’s size, shape, lamellar structure, and composition. To test model predictions about the impact of BWL frequency, matched pairs of stones (1-5 mm) were treated at 1) 390 kHz, 2) 830 kHz, and 3) 390 kHz followed by 830 kHz. The mass of fragments greater than 1 and 2 mm was measured over 10 minutes of exposure. Results: The linear elastic model predicts that the maximum principal stress inside a stone increases to more than 5.5 times the pressure applied by the ultrasound wave as frequency is increased, regardless of composition tested. The threshold frequency for stress amplification is proportionate to the wave speed divided by the stone diameter. Thus, smaller stones may be likely to fragment at higher frequency, but not lower frequency below a limit. Unlike with SWL, this amplification in BWL occurs consistently with spherical and irregularly shaped stones. In water tank experiments, stones smaller than the threshold size broke fastest at high frequency (p=0.0003), whereas larger stones broke equally well to sub-millimeter dust at high, low, or mixed frequency. Conclusions: For small stones and fragments, increasing frequency of BWL may produce amplified stress in the stone causing the stone to break. Using the strategies outlined here, stones of all sizes may be turned to dust efficiently with BWL

Flexible modelling of spatial variation in agricultural field trials with the R package INLA

The objective of this paper was to fit different established spatial models for analysing agricultural field trials using the open-source R package INLA. Spatial variation is common in field trials, and accounting for it increases the accuracy of estimated genetic effects. However, this is still hindered by the lack of available software implementations. We compare some established spatial models and show possibilities for flexible modelling with respect to field trial design and joint modelling over multiple years and locations. We use a Bayesian framework and for statistical inference the integrated nested Laplace approximations (INLA) implemented in the R package INLA. The spatial models we use are the well-known independent row and column effects, separable first-order autoregressive ( AR1⊗AR1 ) models and a Gaussian random field (Matérn) model that is approximated via the stochastic partial differential equation approach. The Matérn model can accommodate flexible field trial designs and yields interpretable parameters. We test the models in a simulation study imitating a wheat breeding programme with different levels of spatial variation, with and without genome-wide markers and with combining data over two locations, modelling spatial and genetic effects jointly. The results show comparable predictive performance for both the AR1⊗AR1 and the Matérn models. We also present an example of fitting the models to a real wheat breeding data and simulated tree breeding data with the Nelder wheel design to show the flexibility of the Matérn model and the R package INLA

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

DNA methylation profiles delineate epigenetic heterogeneity in seminoma and non-seminoma

Background: It remains important to understand the biology and identify biomarkers for less studied cancers like testicular cancer. The purpose of this study was to determine the methylation frequency of several cancer-related genes in different histological types of testicular cancer and normal testis tissues (NT). Methods: DNA was isolated from 43 seminomas (SEs), 14 non-SEs (NSEs) and 23 NT, and was assayed for promoter methylation status of 15 genes by quantitative methylation-specific PCR. The methylation status was evaluated for an association with cancer, and between SEs and NSEs. Results: We found differential methylation pattern in SEs and NSEs. MGMT, VGF, ER-Β and FKBP4 were predominately methylated in NSEs compared with SEs. APC and hMLH1 are shown to be significantly more methylated in both subtypes in comparison with NT. When combining APC, hMLH1, ER-Β and FKBP4, it is possible to identify 86% of the NSEs, whereas only 7% of the SEs. Conclusions: Our results indicate that the methylation profile of cancer-associated genes in testicular cancer correlates with histological types and show cancer-specific pattern for certain genes. Further methylation analysis, in a larger cohort is needed to elucidate their role in testicular cancer development and potential for therapy, early detection and disease monitoring