UTX condensation underlies its tumour-suppressive activity.

UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

Is the Use of Dexmedetomidine Upon Emergence From Anesthesia Associated With Neck Hematoma Formation Following Head and Neck Microvascular Reconstruction?

BACKGROUND: Dexmedetomidine (DEX) is a highly selective alpha-2-receptor agonist, and its use has not been well studied in major microvascular reconstructive surgery of the head and neck. PURPOSE: The purpose is to measure the association between DEX and neck hematoma formation in subjects undergoing head and neck microvascular reconstructive surgery. STUDY DESIGN, SETTING, SAMPLE: The investigators implemented a retrospective cohort study on subjects undergoing microvascular head and neck reconstruction for benign and malignant pathology at the University of Alabama at Birmingham from 2014 to 2021. Patients with unresectable tumors were excluded. PREDICTOR VARIABLE: The predictor variable was the intraoperative use of DEX upon emergence from general anesthesia. Subjects received standard anesthetic drugs and DEX, while control subjects received only standard anesthetic drugs. MAIN OUTCOME VARIABLE(S): The primary outcome was postoperative neck hematoma formation necessitating a return to the operating theater. The secondary outcome was the length of stay (LOS). COVARIATES: The covariates were demographic, operative, and oral morphine equivalents of anesthesia drugs. ANALYSES: Bivariate analyses were performed using the Student's t-test and the χ2 test for continuous and categorical variables. Multivariate regression analyses were conducted to assess for associations between DEX and the outcomes adjusted for confounding variables when present. P values of < .05 were regarded as statistically significant. RESULTS: A total of 297 subjects (mean age, 59.6 years, and standard deviation [SD], 14.9) with 61.6% male received DEX, and 304 subjects (mean age, 58.9 years, and SD, 14.6) with 60.2% male served as controls (P > .5). A total of 11 postoperative neck hematoma occurred in the control group when compared to 2 in the DEX (relative risk = 5.4, 95% confidence interval [CI], 1.2 to 24, P = .02). The mean LOS was 7.7 (SD, 4.3) and 9.4 (SD, 8.1) for the DEX and control groups (95% CI, 0.7 to 2.8, P < .01). After adjusting for tobacco history, tracheostomy, and neck dissection, DEX (Beta coefficient (B) = -1.7, 95% CI -2.7 to -0.7, P < .01) and neck dissection (B = 2.2, 95% CI 1.0 to 3.4, P < .01) were statistically associated with LOS. CONCLUSION AND RELEVANCE: The use of intraoperative DEX upon emergence from general anesthesia was associated with lower postoperative neck hematoma formation and a shorter length of stay following microvascular head and neck reconstruction.

Pharmacologic Manipulation of Late SV40 Factor Suppresses Wnt Signaling and Inhibits Growth of Allogeneic and Syngeneic Colon Cancer Xenografts.

Aberrant hyperactivation of Wnt signaling, driven by nuclear ß-catenin in the colonic epithelium, represents the seminal event in the initiation and progression of colorectal cancer (CRC). Despite its established role in CRC tumorigenesis, clinical translation of Wnt inhibitors remains unsuccessful. Late SV40 factor (LSF; encoded by TFCP2) is a transcription factor and a potent oncogene. The current study identified a chemotype, named factor quinolinone inhibitors (FQIs), that specifically inhibits LSF DNA-binding, partner protein-binding, and transactivation activities. The role of LSF and FQIs in CRC tumor growth was examined. Herein, the study showed that LSF and ß-catenin interacted in several CRC cell lines irrespective of their mutational profile, which was disrupted by FQI2-34. FQI2-34 suppressed Wnt activity in CRC cells in a dose-dependent manner. Leveraging both allogeneic and syngeneic xenograft models showed that FQI2-34 suppressed CRC tumor growth, significantly reduced nuclear ß-catenin, and down-regulated Wnt targets such as axis inhibition protein 2 (AXIN-2) and SRY-box transcription factor 9, in the xenograft cells. FQI2-34 suppressed the proliferation of xenograft cells. Adenocarcinomas from a series of stage IV CRC patients revealed a positive correlation between LSF expression and Wnt targets (AXIN-2 and SRY-box transcription factor 9) within the CRC cells. Collectively, this study uncovers the Wnt inhibitory and CRC growth-suppressive effects of these LSF inhibitors in CRC cells, revealing a novel target in CRC therapeutics.

A Role for Insulin-like Growth Factor 1 in the Generation of Epileptic Spasms in a murine model.

OBJECTIVE: Infantile spasms are associated with a wide variety of clinical conditions, including perinatal brain injuries. We have created a model in which prolonged infusion of tetrodotoxin (TTX) into the neocortex, beginning in infancy, produces a localized lesion and reproduces the behavioral spasms, electroencephalogram (EEG) abnormalities, and drug responsiveness seen clinically. Here, we undertook experiments to explore the possibility that the growth factor IGF-1 plays a role in generating epileptic spasms. METHODS: We combined long-term video EEG recordings with quantitative immunohistochemical and biochemical analyses to unravel IGF-1's role in spasm generation. Immunohistochemistry was undertaken in surgically resected tissue from infantile spasms patients. We used viral injections in neonatal conditional IGF-1R knock-out mice to show that an IGF-1-derived tripeptide (1-3)IGF-1, acts through the IGF-1 receptor to abolish spasms. RESULTS: Immunohistochemical methods revealed widespread loss of IGF-1 from cortical neurons, but an increase in IGF-1 in the reactive astrocytes in the TTX-induced lesion. Very similar changes were observed in the neocortex from patients with spasms. In animals, we observed reduced signaling through the IGF-1 growth pathways in areas remote from the lesion. To show the reduction in IGF-1 expression plays a role in spasm generation, epileptic rats were treated with (1-3)IGF-1. We provide 3 lines of evidence that (1-3)IGF-1 activates the IGF-1 signaling pathway by acting through the receptor for IGF-1. Treatment with (1-3)IGF-1 abolished spasms and hypsarrhythmia-like activity in the majority of animals. INTERPRETATION: Results implicate IGF-1 in the pathogenesis of infantile spasms and IGF-1 analogues as potential novel therapies for this neurodevelopmental disorder. ANN NEUROL 2022;92:45-60.

Host Defense against Klebsiella pneumoniae Pneumonia Is Augmented by Lung-Derived Mesenchymal Stem Cells.

Klebsiella pneumoniae is a common cause of Gram-negative pneumonia. The spread of antibiotic-resistant and hypervirulent strains has made treatment more challenging. This study sought to determine the immunomodulatory, antibacterial, and therapeutic potential of purified murine stem cell Ag-1+ (Sca-1+) lung mesenchymal stem cells (LMSCs) using in vitro cell culture and an in vivo mouse model of pneumonia caused by K pneumoniae. Sca-1+ LMSCs are plastic adherent, possess colony-forming capacity, express mesenchymal stem cell markers, differentiate into osteogenic and adipogenic lineages in vitro, and exhibit a high proliferative capacity. Further, these Sca-1+ LMSCs are morphologically similar to fibroblasts but differ ultrastructurally. Moreover, Sca-1+ LMSCs have the capacity to inhibit LPS-induced secretion of inflammatory cytokines by bone marrow-derived macrophages and neutrophils in vitro. Sca-1+ LMSCs inhibit the growth of K pneumoniae more potently than do neutrophils. Sca-1+ LMSCs also possess the intrinsic ability to phagocytize and kill K. pneumoniae intracellularly. Whereas the induction of autophagy promotes bacterial replication, inhibition of autophagy enhances the intracellular clearance of K. pneumoniae in Sca-1+ LMSCs during the early time of infection. Adoptive transfer of Sca-1+ LMSCs in K. pneumoniae-infected mice improved survival, reduced inflammatory cells in bronchoalveolar lavage fluid, reduced inflammatory cytokine levels and pathological lesions in the lung, and enhanced bacterial clearance in the lung and in extrapulmonary organs. To our knowledge, these results together illustrate for the first time the protective role of LMSCs in bacterial pneumonia.

Supplemental Regional Block Anesthesia Reduces Opioid Utilization Following Free Flap Reconstruction of the Oral Cavity: A Prospective, Randomized Clinical Trial.

PURPOSE: Regional anesthesia has been shown to effectively manage acute pain and reduce opioid utilization in the early postoperative period following colorectal, orthopedic, and thoracic surgeries. The same effect, however, has not been demonstrated in major head and neck surgery. The purpose of this study is to determine whether supplemental regional anesthesia reduces opioid utilization following microvascular free flap reconstruction of the oral cavity. METHODS: A prospective, randomized clinical trial was conducted for patients undergoing oral cavity reconstruction using microvascular free tissue transfer between January 2020 and March 2022. The predictor variable was a regional anesthetic nerve block, delivered preoperatively, at the flap donor site. The primary and secondary outcomes were opioid utilization, measured in oral morphine equivalent (OME), from postoperative day 1 to 5, and hospital length of stay (LOS), respectively. Covariates included age, sex, tobacco and alcohol history, prior radiation therapy, pathology, oral site, flap type, tracheostomy, and neck dissection. Student's t test, χ2 test, and linear regression models were computed using correlations with 95% confidence intervals (CIs). For all statistical tests, P values of <.05 were regarded as statistically significant. RESULTS: Ninety-eight participants completed the study. The mean age was 56 years with 55% male. Forty-eight patients received a presurgical regional anesthesia block, and 50 patients served as control subjects. Bivariate analysis demonstrated an even distribution of all study variables. Total OME utilization was significantly less in the treatment group compared to the control group, (166.32 vs 118.43 OME; 95% CI, 1.32 to 94.45; P = .04). The LOS was comparable (6.60 vs 6.48 days; 95% CI, -0.53 to 0.77; P = .71). Tobacco use had a positive effect (B = 0.28; 95% CI, 21.63 to 115.31; P = .005) while the block had a negative effect with total OME, (B = -0.19; 95% CI, -90.39 to -0.59; P = .047). The extent of the neck dissection (B = 0.207; 95% CI, 0.026 to 1.403; P = .042) was a positive predictor for LOS. Overall, there were no adverse events associated with the regional block throughout the study period. CONCLUSIONS: Supplemental regional anesthesia is safe and associated with reduced opioid utilization in patients undergoing vascularized free flap reconstruction of composite oral cavity defects and does not prolong the length of hospitalization.

Neocortical Slow Oscillations Implicated in the Generation of Epileptic Spasms.

OBJECTIVE: Epileptic spasms are a hallmark of severe seizure disorders. The neurophysiological mechanisms and the neuronal circuit(s) that generate these seizures are unresolved and are the focus of studies reported here. METHODS: In the tetrodotoxin model, we used 16-channel microarrays and microwires to record electrophysiological activity in neocortex and thalamus during spasms. Chemogenetic activation was used to examine the role of neocortical pyramidal cells in generating spasms. Comparisons were made to recordings from infantile spasm patients. RESULTS: Current source density and simultaneous multiunit activity analyses indicate that the ictal events of spasms are initiated in infragranular cortical layers. A dramatic pause of neuronal activity was recorded immediately prior to the onset of spasms. This preictal pause is shown to share many features with the down states of slow wave sleep. In addition, the ensuing interictal up states of slow wave rhythms are more intense in epileptic than control animals and occasionally appear sufficient to initiate spasms. Chemogenetic activation of neocortical pyramidal cells supported these observations, as it increased slow oscillations and spasm numbers and clustering. Recordings also revealed a ramp-up in the number of neocortical slow oscillations preceding spasms, which was also observed in infantile spasm patients. INTERPRETATION: Our findings provide evidence that epileptic spasms can arise from the neocortex and reveal a previously unappreciated interplay between brain state physiology and spasm generation. The identification of neocortical up states as a mechanism capable of initiating epileptic spasms will likely provide new targets for interventional therapies. ANN NEUROL 2021;89:226-241.

Neurobehavioral deficits and a progressive ictogenesis in the tetrodotoxin model of epileptic spasms.

OBJECTIVE: Our goal was to determine whether animals with a history of epileptic spasms have learning and memory deficits. We also used continuous (24/7) long-term electroencephalographic (EEG) recordings to evaluate the evolution of epileptiform activity in the same animals over time. METHODS: Object recognition memory and object location memory tests were undertaken, as well as a matching to place water maze test that evaluated working memory. A retrospective analysis was undertaken of long-term video/EEG recordings from rats with epileptic spasms. The frequency and duration of the ictal events of spasms were quantified. RESULTS: Rats with a history of epileptic spasms showed impairment on the three behavioral tests, and their scores on the object recognition memory and matching to place water maze tests indicated neocortical involvement in the observed impaired cognition. Analysis of EEG recordings unexpectedly showed that the ictal events of spasms and their accompanying behaviors progressively increased in duration over a 2-week period soon after onset, after which spasm duration plateaued. At the same time, spasm frequency remained unchanged. Soon after spasm onset, ictal events were variable in wave form but became more stereotyped as the syndrome evolved. SIGNIFICANCE: Our EEG findings are the first to demonstrate progressive ictogenesis for epileptic spasms. Furthermore, in demonstrating cognitive deficits in the tetrodotoxin model, we have met a criterion for an animal model of West syndrome. Animal models will allow in-depth studies of spasm progression's potential role in cognitive regression and may elucidate why early treatment is considered essential for improved neurodevelopmental outcomes in children.

Does Early Oral Intake After Microvascular Free Flap Reconstruction of the Oral Cavity Lead to Increased Postoperative Complications?

PURPOSE: Data on timing of oral intake (PO) after free flap reconstruction of the oral cavity have been limited. Recent studies have shown that early PO after free flap reconstruction does not lead to increased morbidity and has resulted in decreased hospital stay. The objective of this study is to assess postoperative complications associated with timing of PO after free flap reconstruction of the oral cavity and to define clinical predictors of postoperative complications. METHODS: This was a retrospective comparative cohort study and comprised of patients who underwent free flap reconstruction of the oral cavity between January 2014 and December 2019 in the Department of Oral and Maxillofacial Surgery at the University of Alabama at Birmingham. The predictor variable was timing of PO grouped into early (<5 days) and late (>5 days), postoperatively. The primary and secondary outcomes were postoperative complications and hospital length of stay (LOS), respectively. Covariates included age, gender, pathology, reconstruction site, flap type, tracheostomy, neck dissection, defect volume (cm3), skin paddle size (cm2), and gastrostomy tube (g-tube). Student's t-test, Chi-squared test, and binary logistic regression models were computed using odds ratios (ORs) with 95% confidence intervals (CIs). For all statistical tests, P values of < .05 were regarded as statistically significant. RESULTS: The sample consisted of 415 patients (253 males and 162 females), with a mean age of 58.8 years (range, 14.4-88.2 years). The majority had malignant pathology (68.9%) with defects involving the mandible (52.3%) and reconstructed with a radial forearm (43.6%), followed by fibula (39%), and osteocutaneous radial forearm (13%). Seventy one "early PO" and 344 "late PO" patients were analyzed. Early PO was associated with lower postoperative complications compared with the late PO group (RR = 0.847, 95% CI 0.747-0.960, P = .031) and shorter hospital LOS (6 vs 9 days, 95% CI 2.2459-3.720, P < .001). A regression model showed a 2% increase for postoperative complications with each unit (cm3) increase of defect volume (OR = 1.002, 95% CI 1.000-1.004, P = .035) and 2.286 times higher odds for postoperative complication in patients with a g-tube (95% CI 1.271-4.110, P = .006). CONCLUSIONS: Early PO after free flap reconstruction of the oral cavity was not associated with increased postoperative outcomes or delayed hospital course. Variables such as defect location, defect volume, and tracheostomy may increase the risk for postoperative complications and can help guide surgeons in deciding the optimal timing for PO postoperatively.

Complications in oncologic mandible reconstruction: A comparative study between the osteocutaneous radial forearm and fibula free flap.

BACKGROUND: The osteocutaneous radial forearm free flap (OC-RFFF) has been proposed as a safe and reliable free flap for head and neck reconstruction with low donor site morbidity. The purpose of this study is to compare the late complications (>30 days) associated with using the OC-RFFF versus the free fibula flap (FFF) for mandibular reconstruction following oncologic segmental resection. METHODS: We conducted a single-institution, retrospective study composed of patients who underwent oncologic microvascular composite mandibular reconstruction with either the OC-RFFF or FFF. The primary predictor variable was the type of free flap used. The outcome variable was late complication postoperatively (>30 days). RESULTS: A total of 93 patients (28, OC-RFFF and 65, FFF) were analyzed. The majority of patients were male (62%) and with AJCC stage T4a disease (72%). Mean hospital length of stay was comparable between the two flap groups (p = .50). OC-RFFF was associated with more late complications (p = .03) compared to FFF. Nonunion occurred in 10.7% of OC-RFFF and 0% of FFF. Partial or complete flap failure was seen in 7.1% and 0% in the OC-RFFF and FFF, respectively. Two-year disease-free survival was comparable in both groups (p > .05). CONCLUSIONS: The results of this study suggest that the rate of nonunion and odds of having a late complication were significantly greater in the OC-RFFF compared to the FFF following oncologic mandibular reconstruction. However, flap success, early complications (<30 days), and length of hospital stay were comparable between the two flaps.

Combined Nasal Endoscopic and Subfrontal Craniotomy for Resection Tumors of Anterior Skull Base.

OBJECTIVE: Sinonasal tumors invading anterior skull base is difficult to treat in Otorhinolaryngology and Neurosurgery. Treatment requires the collaboration of ear, nose and throat (ENT) and neurosurgeon to remove the tumor completely. This study was to evaluate the outcome of combined technique nasal endoscopic and subfrontal approach in case of sinonasal tumors involving anterior skull base. METHODS: Retrospective cross-sectional study. RESULTS: The study was a cross-sectional study that had taken place at Otorhinolaryngology and Neurosurgery Department of Cho Ray Hospital, Vietnam. All 45 patients were enrolled and underwent the surgery. 71.1% of these cases were malignant tumors. The ratio of sinonasal malignant tumor is squamous cell carcinoma and esthesioneuroblastoma were 24.4% and 11.1%, respectively. All the cases were diagnosed as sinonasal tumor invading anterior skull base and successfully removed by combining nasal endoscopic approach with subfrontal craniotomy. CONCLUSIONS: The combined nasal endoscopic with subfrontal craniotomy for resection nasoethmoid tumor invading the brain show a good result. This technique is an important adjunct that contribute to the treatment of anterior skull base tumor involving the brain.

CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3.

Neutrophil migration to the site of bacterial infection is a critical step in host defense. Exclusively produced in the bone marrow, neutrophil release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx during bacterial infections, its role in regulating neutrophil recruitment, granulopoiesis, and neutrophil mobilization in response to lung infection-induced sepsis is unclear. Here, we used a murine model of intrapulmonary Streptococcus pneumoniae infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx to control bacterial growth in the lungs, as well as bacterial dissemination, resulting in improved host survival. This was shown in Cxcl1 -/- mice, which exhibited defective amplification of early neutrophil precursors in granulocytic compartments, and CD62L- and CD49d-dependent neutrophil release from the marrow. Administration of recombinant CXCL2 and CXCL5 after infection rescues the impairments in neutrophil-dependent host defense in Cxcl1 -/- mice. Taken together, these findings identify CXCL1 as a central player in host defense, granulopoiesis, and mobilization of neutrophils during Gram-positive bacterial pneumonia-induced sepsis.

Brain state-dependent high-frequency activity as a biomarker for abnormal neocortical networks in an epileptic spasms animal model.

OBJECTIVE: Epileptic spasms are a hallmark of a severe epileptic state. A previous study showed neocortical up and down states defined by unit activity play a role in the generation of spasms. However, recording unit activity is challenging in clinical settings, and more accessible neurophysiological signals are needed for the analysis of these brain states. METHODS: In the tetrodotoxin model, we used 16-channel microarrays to record electrophysiological activity in the neocortex during interictal periods and spasms. High-frequency activity (HFA) in the frequency range of fast ripples (200-500 Hz) was analyzed, as were slow wave oscillations (1-8 Hz), and correlated with the neocortical up and down states defined by multiunit activity (MUA). RESULTS: HFA and MUA had high temporal correlation during interictal and ictal periods. Both increased strikingly during interictal up states and ictal events but were silenced during interictal down states and preictal pauses, and their distributions were clustered at the peak of slow oscillations in local field potential recordings. In addition, both HFA power and MUA firing rates were increased to a greater extent during spasms than interictal up states. During non-rapid eye movement sleep, the HFA rhythmicity faithfully followed the MUA up and down states, but during rapid eye movement sleep when MUA up and down states disappeared the HFA rhythmicity was largely absent. We also observed an increase in the number of HFA down state minutes prior to ictal onset, consistent with the results from analyses of MUA down states. SIGNIFICANCE: This study provides evidence that HFA may serve as a biomarker for the pathological up states of epileptic spasms. The availability of HFA recordings makes this a clinically practical technique. These findings will likely provide a novel approach for localizing and studying epileptogenic neocortical networks not only in spasms patients but also in other types of epilepsy.

Acthar® Gel (repository corticotropin injection) dose-response relationships in an animal model of epileptic spasms.

Studies were undertaken to evaluate the effectiveness of Acthar® Gel (repository corticotropin injection [RCI]) in the tetrodotoxin (TTX) model of early-life-induced epileptic spasms. Repository corticotropin injection (RCI) is widely used in the United States to treat infantile spasms. A major component of RCI is N25 deamidated ACTH. Additionally, we hoped to provide some insight into the possible role circulating corticosteroids play in spasm cessation by comparing the RCI dose-response relationships for spasm suppression to RCI-induced corticosterone release from the adrenal gland. Spasms were induced by chronic TTX infusion into the neocortex beginning on postnatal day 11. Repository corticotropin injection (RCI) dosages were between 8 and 32 IU/kg/day. Drug titration protocols were used, and comparisons were made to injections of a vehicle gel. Video/EEG recordings (24/7) monitored the drug's effects continuously for up to 2 months. Tetrodotoxin (TTX)-infused control rats were monitored for the same period of time. In separate experiments, the same dosages of RCI were given to rats and 1 h later plasma was collected and assayed for corticosterone. A parallel study compared the effects of 1-day and 10-day RCI treatments on circulating corticosterone. Results showed that RCI was ineffective at dosages of 8, 12, and 16 IU/kg/day but eliminated spasms in 66% of animals treated with 24 or 32 IU/kg/day. Treating animals with 32 IU/kg/day alone produced the same degree of spasms suppression as observed during the titration protocols. In rats that had hypsarrhythmia-like activity, RCI eliminated this abnormal interictal EEG pattern in all rats that became seizure-free. In terms of plasma corticosterone, 1- and 10-day treatments with RCI produced similar increases in this hormone and the levels increased linearly with increasing dosages of RCI. This stood in sharp contrast to the sigmoid-like dose-response curve for decreases in spasm counts. Our results further validate the TTX model as relevant for the study of infantile spasms. The model should be useful for investigating how RCI acts to eliminate seizures and hypsarrhythmia. Dose-response results suggest that either very high concentrations of circulating corticosteroids are required to abolish spasms or RCI acts through a different mechanism.

Does Supplemental Regional Anesthesia Decrease Length of Stay and Opioid Use for Patients Undergoing Head and Neck Microvascular Reconstruction?

PURPOSE: The purpose of this study was to compare length of hospital stay and opioid usage among head and neck surgery (HNS) patients treated with and without regional anesthesia for microvascular free-flap donor sites. METHODS: The authors performed a retrospective cohort study for HNS patients undergoing microvascular free-flap reconstruction. The control group received no regional anesthesia. The experimental group had a regional anesthesia nerve block performed immediately before surgery. The primary outcome variable was length of stay, and the secondary outcome variable was total morphine milliequivalents. The data were analyzed using Student t tests, analysis of variance, Mann-Whitney U test, Kruskal-Wallis test, χ2 test, and multiple linear regression. RESULTS: The study sample was composed of 148 patients with a mean age of 58.1 years. The mean length of stay for the control group was 6.74 ± 1.57 days, compared with the experimental group at 5.84 ± 1.01 days (P < .0001). The mean morphine milliequivalent was 256.5 ± 164.6 mg for the control group and 208.9 ± 164.8 mg for the experimental group (P = .56). Importantly, the demographics, pathology spectrum, flap selection, duration of procedure, and complication rate were similar in both groups. CONCLUSIONS: This study demonstrates that for HNS patients undergoing microvascular reconstruction, regional nerve block at the donor site is associated with significantly shorter hospital stays. Although there was a trend toward decreased opioid usage in the regional anesthesia group, these results did not reach statistical significance. Consideration should be given to incorporate regional anesthesia techniques into early recovery after surgery protocols for centers performing high-volume head and neck microvascular reconstruction.

Adipose Grafting for Volume and Scar Release.

ABSTRACT: Adipose fat grafting (AFG) is a popular technique used to add volume in the face, breasts, and other tissue deficient areas of the body. In terms of scar release, not only has fat provided additional soft tissue coverage but also the relief of pain in scars in those patients suffering from disease processes, such as complex regional pain syndrome with steroid-induced atrophy, burn scars, morphea, and lupus. The purpose of this article is to demonstrate the senior author's technique and outcomes of using AFG in the face and body for treating volume deficiency, atrophic scarring, and deformities.A retrospective chart review of 127 AFG procedures of the face and body from September 2006 to September 2019 was performed. Of these, 14 patients had scar releases performed with fat grafting of areas of scar contracture. Fat was harvested from the abdomen, thighs, and flanks using Toomey syringes or an enclosed power-assisted system with 3.7- or 3.0-mm cannulas. Grafting in small areas, such as the face, was performed with the 0.9-mm blunt cannula.The majority of AFG was completed in the face (45%), followed by breasts (22%), and scar contracture (16%). The mean volume of fat grafted in procedures involving the breasts, buttocks, and face was 102, 182, and 21 mL, respectively. For scar contracture, the mean volume was 38 mL and for deformations, 27 mL. Sixteen percent of the cohort required at least 1 additional AFG procedure to achieve satisfactory results. There were no major complications, such as skin loss, vascular injury, embolization, or blindness. Minor complications, such as erythema, edema, and hematoma at the fat harvest or graft site, did occur and were managed with local measures.Autologous fat grafting has consistently resulted in volume correction. In addition, in patients with autoimmune disorders, burn scars, and retracted scars, not only has there been volume correction but also decreased pain in the area of treatment. In our series of patients, we described our technique of AFG for the face, body, and scar contracture. Our results demonstrate that AFG remains an inexpensive, safe, and effective treatment option to achieve volume.

Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms.

Abnormal high frequency oscillations (HFOs) in EEG recordings are thought to be reflections of mechanisms responsible for focal seizure generation in the temporal lobe and neocortex. HFOs have also been recorded in patients and animal models of infantile spasms. If HFOs are important contributors to infantile spasms then anticonvulsant drugs that suppress these seizures should decrease the occurrence of HFOs. In experiments reported here, we used long-term video/EEG recordings with digital sampling rates capable of capturing HFOs. We tested the effectiveness of vigabatrin (VGB) in the TTX animal model of infantile spasms. VGB was found to be quite effective in suppressing spasms. In 3 of 5 animals, spasms ceased after a daily two week treatment. In the other 2 rats, spasm frequency dramatically decreased but gradually increased following treatment cessation. In all animals, hypsarrhythmia was abolished by the last treatment day. As VGB suppressed the frequency of spasms, there was a decrease in the intensity of the behavioral spasms and the duration of the ictal EEG event. Analysis showed that there was a burst of high frequency activity at ictal onset, followed by a later burst of HFOs. VGB was found to selectively suppress the late HFOs of ictal complexes. VGB also suppressed abnormal HFOs recorded during the interictal periods. Thus VGB was found to be effective in suppressing both the generation of spasms and hypsarrhythmia in the TTX model. Vigabatrin also appears to preferentially suppress the generation of abnormal HFOs, thus implicating neocortical HFOs in the infantile spasms disease state.