Practical Review of the Current Management of Fournier's Gangrene.

Background: Fournier's gangrene is a fulminant disease. If diagnosed and treated early, mortality can be minimized, but morbidity can still be important with extensive soft tissue defects affecting form and function. We aimed to perform a comprehensive review and provide the current evidenced-based management to treat this condition. Methods: A review was conducted to identify relevant published articles involving Fournier's gangrene in PubMed on September 8, 2021. Search keywords included "{[(Fournier's gangrene) AND (reconstruction)] OR [Fournier's gangrene]} AND [(repair) OR (management)]." Results: A total of 108 articles met the inclusion criteria. The comorbidities most frequently associated included diabetes, hypertension, and obesity. Pillars of treatment involve urgent debridement, fluid resuscitation, IV antibiotics, and reconstruction. Several variables must be considered, including time to debridement, duration of antibiotics, debridement, and an individualized approach to choose a reconstructive option. Skin grafts and multiple types of flaps are commonly used for reconstruction. Conclusions: Treatment of Fournier's gangrene should be initiated as early as possible. Surgeons' expertise, patient preference, and resources available are essential factors that should direct the election of reconstruction.

Use of the Scan-and-Plan Workflow in Next-Generation Robot-Assisted Pedicle Screw Insertion: Retrospective Cohort Study and Literature Review.

OBJECTIVE: To report our experience using the scan-and-plan workflow and review current literature on surgical efficiency, safety, and accuracy of next-generation robot-assisted (RA) spine surgery. METHODS: The records of patients who underwent RA pedicle screw fixation were reviewed. The accuracy of pedicle screw placement was determined based on the Ravi classification system. To evaluate workflow efficiency, 3 demographically matched cohorts were created to analyze differences in time per screw placement (defined as operating room [OR] time divided by number of screws placed). Group A had <4 screws placed, Group B had 4 screws placed, and Group C had >4 screws placed. Intraoperative errors and postoperative complications were collected to elucidate safety. RESULTS: Eighty-four RA cases (306 pedicle screws) were included for analysis. The mean number of screws placed was 2.1 ± 0.3 in Group A and 6.4 ± 1.2 in Group C; 4 screws were placed in Group B patients. The accuracy rate (Ravi grade I) was 98.4%. Screw placement time was significantly longer in Group A (101 ± 37.7 minutes) than Group B (50.5 ± 25.4 minutes) or C (43.6 ± 14.7 minutes). There were no intraoperative complications, robot failures, or in-hospital complications requiring a return to the OR. CONCLUSIONS: The scan-and-plan workflow allowed for a high degree of accuracy. It was a safe method that provided a smooth and efficient OR workflow without registration errors or robotic failures. After the placement of 4 pedicle screws, the per-screw time remained constant. Further studies regarding efficiency and utility in multilevel procedures are necessary.

Amyloid-Beta Modulates Low-Threshold Activated Voltage-Gated L-Type Calcium Channels of Arcuate Neuropeptide Y Neurons Leading to Calcium Dysregulation and Hypothalamic Dysfunction.

Weight loss is an early manifestation of Alzheimer's disease that can precede the cognitive decline, raising the possibility that amyloid-ß (Aß) disrupts hypothalamic neurons critical for the regulation of body weight. We previously reported that, in young transgenic mice overexpressing mutated amyloid precursor protein (Tg2576), Aß causes dysfunction in neuropeptide Y (NPY)-expressing hypothalamic arcuate neurons before plaque formation. In this study, we examined whether Aß causes arcuate NPY neuronal dysfunction by disrupting intracellular Ca2+ homeostasis. Here, we found that the L-type Ca2+ channel blocker nimodipine could hyperpolarize the membrane potential, decrease the spontaneous activity, and reduce the intracellular Ca2+ levels in arcuate NPY neurons from Tg2576 brain slices. In these neurons, there was a shift from high to low voltage-threshold activated L-type Ca2+ currents, resulting in increased Ca2+ influx closer to the resting membrane potential, an effect recapitulated by Aß1-42 and reversed by nimodipine. These low voltage-threshold activated L-type Ca2+ currents were dependent in part on calcium/calmodulin-dependent protein kinase II and IP3 pathways. Furthermore, the effects on intracellular Ca2+ signaling by both a positive (ghrelin) and negative (leptin) modulator were blunted in these neurons. Nimodipine pretreatment restored the response to ghrelin-mediated feeding in young (3-5 months), but not older (10 months), female Tg2576 mice, suggesting that intracellular Ca2+ dysregulation is only reversible early in Aß pathology. Collectively, these findings provide evidence for a key role for low-threshold activated voltage gated L-type Ca2+ channels in Aß-mediated neuronal dysfunction and in the regulation of body weight.SIGNIFICANCE STATEMENT Weight loss is one of the earliest manifestations of Alzheimer's disease (AD), but the underlying cellular mechanisms remain unknown. Disruption of intracellular Ca2+ homeostasis by amyloid-ß is hypothesized to be critical for the early neuronal dysfunction driving AD pathogenesis. Here, we demonstrate that amyloid-ß causes a shift from high to low voltage-threshold activated L-type Ca2+ currents in arcuate neuropeptide Y neurons. This leads to increased Ca2+ influx closer to the resting membrane potential, resulting in intracellular Ca2+ dyshomeostasis and neuronal dysfunction, an effect reversible by the L-type Ca2+ channel blocker nimodipine early in amyloid-ß pathology. These findings highlight a novel mechanism of amyloid-ß-mediated neuronal dysfunction through L-type Ca2+ channels and the importance of these channels in the regulation of body weight.

Use of a Wireless Video-EEG System to Monitor Epileptiform Discharges Following Lateral Fluid-Percussion Induced Traumatic Brain Injury.

The lateral fluid percussion injury (FPI) model is well established and has been used to study TBI and post-traumatic epilepsy (PTE). However, considerable variability has been reported for the specific parameters used in different studies that have employed this model, making it difficult to harmonize and interpret the results between laboratories. For example, variability has been reported regarding the size and location of the craniectomy, how the Luer lock hub is placed relative to the craniectomy, the atmospheric pressure applied to the dura and the duration of the pressure pulse. Each of these parameters can impact injury severity, which directly correlates with the incidence of PTE. This has been manifested as a wide range of mortality rates, righting reflex times and incidence of convulsive seizures reported. Here we provide a detailed protocol for the method we have used to help facilitate harmonization between studies. We used FPI in combination with a wireless EEG telemetry system to continuously monitor for electrographic changes and detect seizure activity.  FPI is induced by creating a 5 mm craniectomy over the left hemisphere, between the Bregma and Lambda and adjacent to the lateral ridge. A Luer lock hub is secured onto the skull over the craniectomy. This hub is connected to the FPI device, and a 20-millisecond pressure pulse is delivered directly to the intact dura through pressure tubing connected to the hub via a twist lock connector. Following recovery, rats are re-anesthetized to remove the hub. Five 0.5 mm, stainless steel EEG electrode screws are placed in contact with the dura through the skull and serve as four recording electrodes and one reference electrode. The electrode wires are collected into a pedestal connector which is secured into place with bone cement. Continuous video/EEG recordings are collected for up to 4 weeks post TBI.

Leptin Dysfunction and Alzheimer's Disease: Evidence from Cellular, Animal, and Human Studies.

There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer's disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.

A physical sciences network characterization of circulating tumor cell aggregate transport.

Circulating tumor cells (CTC) have been implicated in the hematogenous spread of cancer. To investigate the fluid phase of cancer from a physical sciences perspective, the multi-institutional Physical Sciences-Oncology Center (PS-OC) Network performed multidisciplinary biophysical studies of single CTC and CTC aggregates from a patient with breast cancer. CTCs, ranging from single cells to aggregates comprised of 2-5 cells, were isolated using the high-definition CTC assay and biophysically profiled using quantitative phase microscopy. Single CTCs and aggregates were then modeled in an in vitro system comprised of multiple breast cancer cell lines and microfluidic devices used to model E-selectin mediated rolling in the vasculature. Using a numerical model coupling elastic collisions between red blood cells and CTCs, the dependence of CTC vascular margination on single CTCs and CTC aggregate morphology and stiffness was interrogated. These results provide a multifaceted characterization of single CTC and CTC aggregate dynamics in the vasculature and illustrate a framework to integrate clinical, biophysical, and mathematical approaches to enhance our understanding of the fluid phase of cancer.

Sweeping lymph node micrometastases off their feet: an engineered model to evaluate natural killer cell mediated therapeutic intervention of circulating tumor cells that disseminate to the lymph nodes.

Approximately 90% of cancer related deaths are due to metastasis. Cells from the primary tumor can metastasize through either the vascular or lymphatic circulation. Cancer cells in circulation are called circulating tumor cells (CTCs) and it has been shown that bone marrow is a niche for homing of blood borne CTCs from several epithelial tumors. Cancer cells found in bone marrow are termed disseminated tumor cells (DTCs). Likewise, CTCs in the lymphatic circulation are more often seeded in the sentinel lymph nodes (SLN) that drain the tumor. Micrometastases (<2 mm) occur after the arrest and implantation of DTCs in lymph nodes over time. This paper presents a cell culture platform termed microbubbles formed in polydimethylsiloxane (PDMS) from a microfabricated silicon wafer for mimicking lymph node micrometastases. We cultured lymph node seeking cancer cells in microbubbles to evaluate the efficacy of natural killer (NK) mediated therapy for targeting lymph node micrometastasis. The microbubble platform consists of an array of microcavities that provides a unique microenvironment for mimicking the deep cortical unit of the lymph nodes. We show that cancer cells cultured in microbubbles with therapeutic NK cells undergo apoptosis after 24 h in culture. Since lymph node metastases are prevalent across several types of cancer, this platform may be useful for developing improved cancer therapies for targeting lymph node micrometastases.