A very complicated UTI: malakoplakia following E. coli urinary tract infection.

Malakoplakia is a rare inflammatory disorder believed to result from a defect in macrophage phagocytic function triggering a granulomatous reaction. It can present with genitourinary, gastrointestinal, or cutaneous manifestations in immunocompromised or, less commonly, immunocompetent hosts. We describe a case of renal malakoplakia in a young, otherwise healthy patient presenting with nephromegaly and sepsis following an E. coli urinary tract infection. We discuss diagnosis and management, including antibiotic selection and the decision to pursue nephrectomy. This case highlights the potential for kidney recovery with prolonged antibiotic therapy in conjunction with adjunct immunomodulatory therapies and source control.

Coherent olfactory bulb gamma oscillations arise from coupling independent columnar oscillators.

Spike timing-based representations of sensory information depend on embedded dynamical frameworks within neuronal networks that establish the rules of local computation and interareal communication. Here, we investigated the dynamical properties of olfactory bulb circuitry in mice of both sexes using microelectrode array recordings from slice and in vivo preparations. Neurochemical activation or optogenetic stimulation of sensory afferents evoked persistent gamma oscillations in the local field potential. These oscillations arose from slower, GABA(A) receptor-independent intracolumnar oscillators coupled by GABA(A)-ergic synapses into a faster, broadly coherent network oscillation. Consistent with the theoretical properties of coupled-oscillator networks, the spatial extent of zero-phase coherence was bounded in slices by the reduced density of lateral interactions. The intact in vivo network, however, exhibited long-range lateral interactions that suffice in simulation to enable zero-phase gamma coherence across the olfactory bulb. The timing of action potentials in a subset of principal neurons was phase-constrained with respect to evoked gamma oscillations. Coupled-oscillator dynamics in olfactory bulb thereby enable a common clock, robust to biological heterogeneities, that is capable of supporting gamma-band spike synchronization and phase coding across the ensemble of activated principal neurons.NEW & NOTEWORTHY Odor stimulation evokes rhythmic gamma oscillations in the field potential of the olfactory bulb, but the dynamical mechanisms governing these oscillations have remained unclear. Establishing these mechanisms is important as they determine the biophysical capacities of the bulbar circuit to, for example, maintain zero-phase coherence across a spatially extended network, or coordinate the timing of action potentials in principal neurons. These properties in turn constrain and suggest hypotheses of sensory coding.

Fully Customizable, Low-Cost, Multi-Contact Nerve Cuffs for Spatially Selective Neuromodulation.

Selective neuromodulation of peripheral nerves is an emerging treatment for neurological diseases that are resistant to traditional drug therapy. While nerve cuffs with multichannel stimulation can be made by many varied methods, they usually require specialized microfabrication or additive manufacturing equipment. A truly low-cost and effective method of creating a custom cuff has not been accessible to researchers to prototype new methodologies and therapies in acute studies. Here, we present an inexpensive, highly repeatable method to create multi-contact nerve cuffs that require a simple postproduction PEDOT:PSS coating to improve the tissue/electrode interface. We demonstrate spatially selective neuromodulation with the proposed cuff design on the rat sciatic by preferentially activating the tibialis anterior (TA) and the lateral gastrocnemius (LG) in longitudinal and transverse stimulation patterns. This demonstrates that the proposed cuff fabrication method was not only effective for selective neuromodulation, but it is also significantly lower in cost, fully-customizable, and easily manufactured for future selective neuromodulation studies.

Wireless Galvanic Impulse Communication for High-Throughput, Low-Power, Miniaturized Neuromodulation Implants.

Deeply implanted bioelectronic devices that selectively record and stimulate peripheral nerves have the potential to revolutionize healthcare by delivering on-demand, personalized therapy. A key barrier to this goal is the lack of a miniaturized, robust, and energy-efficient wireless link capable of transmitting data from multiple sensing channels. To address this issue, we present a wireless galvanic impulse link that uses two 500µm diameter planar electrodes on the outside of a nerve cuff to transmit data to a wearable receiver on the skin's surface at rates greater than 1Mbps. To achieve an energy-efficient, high data rate link, our protocol encodes information in the timing of narrow biphasic pulses that is reconstructed by the wearable receiver. We use a combination of modeling and in vivo and in vitro experimentation to demonstrate the viability of the link. We demonstrate losses lower than 60dB even with significant, 50mm lateral misalignment, ensuring a sufficient signal-to-noise ratio for robust operation. Using a custom, flexible nerve cuff, we demonstrate data transmission in a 14mm-thick rodent animal model and in a 42mm-thick heterogeneous human tissue phantom.

Soluble ECM promotes organotypic formation in lung alveolar model.

Micropatterned suspension culture creates consistently sized and shaped cell aggregates but has not produced organotypic structures from stable cells, thus restricting its use in accurate disease modeling. Here, we show that organotypic structure is achieved in hybrid suspension culture via supplementation of soluble extracellular matrix (ECM). We created a viable lung organoid from epithelial, endothelial, and fibroblast human stable cell lines in suspension culture. We demonstrate the importance of soluble ECM in organotypic patterning with the emergence of lumen-like structures with airspace showing feasible gas exchange units, formation of branching, perfusable vasculature, and long-term 70-day maintenance of lumen structure. Our results show a dependent relationship between enhanced fibronectin fibril assembly and the incorporation of ECM in the organoid. We successfully applied this technology in modeling lung fibrosis via bleomycin induction and test a potential antifibrotic drug in vitro while maintaining fundamental cell-cell interactions in lung tissue. Our human fluorescent lung organoid (hFLO) model represents features of pulmonary fibrosis which were ameliorated by fasudil treatment. We also demonstrate a 3D culture method with potential of creating organoids from mature cells, thus opening avenues for disease modeling and regenerative medicine, enhancing understanding of lung cell biology in health and lung disease.

A Low-Cost, Wireless, Multi-Channel Deep Brain Stimulation System for Rodents.

We present a small (43mm x 24mm x 15mm), off-the-shelf wireless neurostimulator for rodent deep brain stimulation research. Our device enables researchers to wirelessly configure stimulator settings, such as amplitude, pulse width, channel selection, and frequency, via a phone app. The system uses impedance-independent current-mode stimulation and steers current to a selected channel. In addition to monophasic and biphasic stimulation, the system also supports arbitrary waveform stimulation using pre-stored lookup tables. The system uses a configurable grounding phase to clear residual charge and a stimulation compliance monitor to ensure safe operation. The compliance monitor wirelessly reports the current during stimulation, the amount of passive recharge current, and the DC voltage of the electrode interface. The 400mAh battery is easy to replace and can go over 40 hours between charges. The system can be built for less than $50 using easy-to-source components to support inexpensive, highly-parallel research applications.

The ECM: To Scaffold, or Not to Scaffold, That Is the Question.

The extracellular matrix (ECM) has pleiotropic effects, ranging from cell adhesion to cell survival. In tissue engineering, the use of ECM and ECM-like scaffolds has separated the field into two distinct areas-scaffold-based and scaffold-free. Scaffold-free techniques are used in creating reproducible cell aggregates which have massive potential for high-throughput, reproducible drug screening and disease modeling. Though, the lack of ECM prevents certain cells from surviving and proliferating. Thus, tissue engineers use scaffolds to mimic the native ECM and produce organotypic models which show more reliability in disease modeling. However, scaffold-based techniques come at a trade-off of reproducibility and throughput. To bridge the tissue engineering dichotomy, we posit that finding novel ways to incorporate the ECM in scaffold-free cultures can synergize these two disparate techniques.

An Improved Scalable Hydrogel Dish for Spheroid Culture.

Research in fields studying cellular response to surface tension and mechanical forces necessitate cell culture tools with tunability of substrate stiffness. We created a scalable hydrogel dish design to facilitate scaffold-free formation of multiple spheroids in a single dish. Our novel design features inner and outer walls, allowing efficient media changes and downstream experiments. The design is easily scalable, accommodating varying numbers of microwells per plate. We report that non-adherent hydrogel stiffness affects spheroid morphology and compaction. We found that spheroid morphology and viability in our hydrogel dishes were comparable to commercially available Aggrewell™800 plates, with improved tunability of surface stiffness and imaging area. Device function was demonstrated with a migration assay using two investigational inhibitors against EMT. We successfully maintained primary-derived spheroids from murine and porcine lungs in the hydrogel dish. These features increase the ability to produce highly consistent cell aggregates for biological research.

A wireless millimetre-scale implantable neural stimulator with ultrasonically powered bidirectional communication.

Clinically approved neural stimulators are limited by battery requirements, as well as by their large size compared with the stimulation targets. Here, we describe a wireless, leadless and battery-free implantable neural stimulator that is 1.7 mm3 and that incorporates a piezoceramic transducer, an energy-storage capacitor and an integrated circuit. An ultrasonic link and a hand-held external transceiver provide the stimulator with power and bidirectional communication. The stimulation protocols were wirelessly encoded on the fly, reducing power consumption and on-chip memory, and enabling protocol complexity with a high temporal resolution and low-latency feedback. Uplink data indicating whether stimulation occurs are encoded by the stimulator through backscatter modulation and are demodulated at the external transceiver. When embedded in ex vivo porcine tissue, the integrated circuit efficiently harvested ultrasonic power, decoded downlink data for the stimulation parameters and generated current-controlled stimulation pulses. When cuff-mounted and acutely implanted onto the sciatic nerve of anaesthetized rats, the device conferred repeatable stimulation across a range of physiological responses. The miniaturized neural stimulator may facilitate closed-loop neurostimulation for therapeutic interventions.

A wireless and artefact-free 128-channel neuromodulation device for closed-loop stimulation and recording in non-human primates.

Closed-loop neuromodulation systems aim to treat a variety of neurological conditions by delivering and adjusting therapeutic electrical stimulation in response to a patient's neural state, recorded in real time. Existing systems are limited by low channel counts, lack of algorithmic flexibility, and the distortion of recorded signals by large and persistent stimulation artefacts. Here, we describe an artefact-free wireless neuromodulation device that enables research applications requiring high-throughput data streaming, low-latency biosignal processing, and simultaneous sensing and stimulation. The device is a miniaturized neural interface capable of closed-loop recording and stimulation on 128 channels, with on-board processing to fully cancel stimulation artefacts. In addition, it can detect neural biomarkers and automatically adjust stimulation parameters in closed-loop mode. In a behaving non-human primate, the device enabled long-term recordings of local field potentials and the real-time cancellation of stimulation artefacts, as well as closed-loop stimulation to disrupt movement preparatory activity during a delayed-reach task. The neuromodulation device may help advance neuroscientific discovery and preclinical investigations of stimulation-based therapeutic interventions.

Toward true closed-loop neuromodulation: artifact-free recording during stimulation.

Closed-loop and responsive neuromodulation systems improve open-loop neurostimulation by responding directly to measured neural activity and providing adaptive, on-demand therapy. To be effective, these systems must be able to simultaneously record and stimulate neural activity, a task made difficult by persistent stimulation artifacts that distort and obscure underlying biomarkers. To enable simultaneous stimulation and recording, several techniques have been proposed. These techniques involve artifact-preventing system configurations, resilient recording front-ends, and back-end signal processing for removing recorded artifacts. Co-designing and integrating these artifact cancellation techniques will be key to enabling neuromodulation systems to stimulate and record at the same time. Here, we review the state-of-the-art for these techniques and their role in achieving artifact-free neuromodulation.

Powering and communication for OMNI: A distributed and modular closed-loop neuromodulation device.

A distributed, modular, intelligent, and efficient neuromodulation device, called OMNI, is presented. It supports closed-loop recording and stimulation on 256 channels from up to 4 physically distinct neuromodulation modules placed in any configuration around the brain, hence offering the capability of addressing neural disorders that are presented at the network level. The specific focus of this paper is the communication and power distribution network that enables the modular and distributed nature of the device.

Cost-effective workup for tonsillitis. Testing, treatment, and potential complications.

Despite increased strictness in surgical criteria, tonsillectomy continues to be one of the most common outpatient surgical procedures performed in the United States. The primary care physician is integrally involved in the diagnosis and treatment of tonsillitis, the chief reason for tonsillectomy. This article gives guidelines for diagnosis and management of tonsillitis and provides an overview of its potential complications.