Late-onset Cholestasis with Paucity of Portal Area Secondary to HNF1ß Deficiency in Adulthood: A Case Report.

Hepatocyte nuclear factor 1ß (HNF1ß) is essential for biliary development, while its genetic defect triggers the dysplasia of interlobular bile ducts, leading to life-threatening hepatitis and cholestasis. To date, this disorder has mainly been documented in neonates. Here, we report a case of cholestasis in an adult patient caused by a de novo HNF1ß mutation. A liver biopsy revealed remarkable shrinkage of the portal area accompanied by a decrease or absence of interlobular bile ducts, veins, and arteries in the portal area. Our case showed that an HNF1ß defect could induce late-onset cholestasis with paucity of the portal area in adulthood.

Real-Time Passive Acoustic Mapping Using Sparse Matrix Multiplication.

Passive acoustic mapping enables the spatiotemporal monitoring of cavitation with circulating microbubbles during focused ultrasound (FUS)-mediated blood-brain barrier opening. However, the computational load for processing large data sets of cavitation maps or more complex algorithms limit the visualization in real-time for treatment monitoring and adjustment. In this study, we implemented a graphical processing unit (GPU)-accelerated sparse matrix-based beamforming and time exposure acoustics in a neuronavigation-guided ultrasound system for real-time spatiotemporal monitoring of cavitation. The system performance was tested in silico through benchmarking, in vitro using nonhuman primate (NHP) and human skull specimens, and demonstrated in vivo in NHPs. We demonstrated the stability of the cavitation map for integration times longer than 62.5 [Formula: see text]. A compromise between real-time displaying and cavitation map quality obtained from beamformed RF data sets with a size of 2000 ×128 ×30 (axial [Formula: see text]) was achieved for an integration time of [Formula: see text], which required a computational time of 0.27 s (frame rate of 3.7 Hz) and could be displayed in real-time between pulses at PRF = 2 Hz. Our benchmarking tests show that the GPU sparse-matrix algorithm processed the RF data set at a computational rate of [Formula: see text]/pixel/sample, which enables adjusting the frame rate and the integration time as needed. The neuronavigation system with real-time implementation of cavitation mapping facilitated the localization of the cavitation activity and helped to identify distortions due to FUS phase aberration. The in vivo test of the method demonstrated the feasibility of GPU-accelerated sparse matrix computing in a close to a clinical condition, where focus distortions exemplify problems during treatment. These experimental conditions show the need for spatiotemporal monitoring of cavitation with real-time capability that enables the operator to correct or halt the sonication in case substantial aberrations are observed.

Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery.

Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet's sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using » dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping.

Brain diseases including neurological disorders and tumors remain under treated due to the challenge to access the brain, and blood-brain barrier (BBB) restricting drug delivery which, also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with microbubbles is the sole method to open the BBB noninvasively, locally, and transiently and facilitate drug delivery, while translation to the clinic is challenging due to long procedure, targeting limitations, or invasiveness of current systems. In order to provide rapid, flexible yet precise applications, we have designed a noninvasive FUS and monitoring system with the protocol tested in monkeys (from in silico preplanning and simulation, real-time targeting and acoustic mapping, to post-treatment assessment). With a short procedure (30 min) similar to current clinical imaging duration or radiation therapy, the achieved targeting (both cerebral cortex and subcortical structures) and monitoring accuracy was close to the predicted 2-mm lower limit. This system would enable rapid clinical transcranial FUS applications outside of the MRI system without a stereotactic frame, thereby benefiting patients especially in the elderly population.