Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease.

Clarkson disease, or monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

A ligand-independent Tie2-activating antibody reduces vascular leakage in models of Clarkson disease.

Vascular dysfunction resulting from endothelial hyperpermeability is a common and important feature of critical illness due to sepsis, trauma, and other conditions associated with acute systemic inflammation. Clarkson disease [monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS)] is a rare, orphan disorder marked by spontaneous and recurrent episodes of hypotensive shock and peripheral edema due to widespread vascular leakage in peripheral tissues. Mortality from acute flares approaches 30% due to lack of effective therapies. We evaluated a monoclonal antibody (4E2) specific for the endothelial receptor tyrosine kinase Tie2 in ISCLS models. 4E2 activated Tie2 in ISCLS patient-derived endothelial cells and reduced baseline and proinflammatory mediator-induced barrier dysfunction. 4E2 also reduced mortality and/or vascular leakage associated with systemic histamine challenge or influenza infection in the SJL/J mouse model of ISCLS. These findings support a critical role for Tie2 dysregulation in ISCLS and highlight a viable therapeutic approach to this catastrophic disorder.

Pressure Ulcer Trends in the United States: A Cross-Sectional Assessment from 2008-2019.

INTRODUCTION: Decubitus ulcers are a morbid and costly problem faced by healthcare systems and patients across the country. We aim to examine current patterns and characteristics of patients admitted to the hospital with a pressure ulcer. MATERIALS AND METHODS: From a nationally representative sample of hospital discharge records, the Nationwide Inpatient Sample (NIS), patients with a diagnosis of pressure ulcer 2008-2019 were identified. Patient volume, demographic and clinical data were analyzed for change over time. RESULTS: The volume of pressure ulcer patients as a proportion of all hospital patients remained constant from 2008 to 2019 (P = .479). During the study period, the proportion of ulcer patients that underwent an ulcer-related procedure significantly decreased (P < .001) while the proportion of ulcers considered severe significantly increased (P < .001). CONCLUSIONS: Our analysis suggests the prevalence of decubitus ulcers remained stable during the time period, with increased severity but reduced frequency of operative intervention.

Complications of Aesthetic Surgical Tourism Treated in the USA: A Systematic Review.

BACKGROUND: Medical tourism has grown increasingly popular in the past few decades. Cosmetic surgery centers have developed in vacation locales, offering procedures at lower prices. However, surgeons and patients alike are often unprepared for management of complications after patients return to the USA. The aim of this study is to provide an overview of US cosmetic surgery tourism patients and the complications faced by US healthcare providers. METHODS: A systematic review was performed using the Web of Science, Cochrane, Embase, Scopus, and PubMed databases up to February 2022; included articles were full-text, English language, and reported complications of patients receiving postoperative care in the USA after cosmetic surgery abroad. Two independent reviewers performed screening for article eligibility with a 3rd for conflict resolution. Patient demographics, procedure characteristics, and outcomes were extracted and aggregated. RESULTS: Twenty studies were included, describing 214 patients. Most patients were female (98.1%, n = 210), middle-aged, and Hispanic. The most common destination country was the Dominican Republic (82.7%, n = 177) and the most common surgical procedure was abdominoplasty (35.7%, n = 114). Complications were mainly infectious (50.9%, n = 112) and required prolonged treatment periods often greater than two months, with high rates of hospitalization (36.8%) and surgical management (51.8%). CONCLUSIONS: Cosmetic surgery tourism is a growing industry with adverse implications for the US healthcare system and patients themselves. This review aims to serve as a reference to prepare plastic surgeons for the scope of complications associated with cosmetic tourism and improve counseling to better prepare patients for the financial and health risks. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Understanding public perception of bra size.

BACKGROUND: Breast cup size is often used in conversations between patients and their surgeons to communicate about goals and expectations for postoperative results. Cup size, however, is a poorly defined concept. The goal of this study was to assess whether the perception of breast cup size is consistent in a general population of survey respondents. METHODS: A survey consisting of a demographic questionnaire, personal bra use questionnaire, and 27 de-identified preoperative images of patient's breasts was administered to 500 respondents using the Amazon MTurk platform. Survey respondents were asked to guess the cup size for each of 27 patients. RESULTS: On average, respondents correctly identified the patient's reported cup size 43.32% of the time. Male and female respondents chose the same cup size for most breast images. Survey respondents who had professional fittings were significantly less likely to accurately identify cup size (38.75% vs. 42.67%, p = 0.02). Those who had a personal history of breast surgery were also less likely to choose correctly (36.92% vs. 43.86%, p < 0.01). CONCLUSION: The results of this study suggest that the perception of cup size is broadly similar across a general population sample. However, subgroups who would be expected to have more knowledge about and experience with breast sizing-including women who have had professional bra fittings and women who have had breast surgery-differ significantly in their perception of cup size. This suggests that cup size language should be used with caution in preoperative discussions between patients and their surgeons.

Shifting the Goalpost in Ventral Hernia Care: 5-year Outcomes after Ventral Hernia Repair with Poly-4-hydroxybutyrate Mesh.

PURPOSE: Ventral hernia repair (VHR) can be augmented with biosynthetic poly-4-hydroxybutryate mesh (P4HB). Long-term outcomes, including quality of life outcomes, after VHR with P4HB mesh are not well established. Our study sought to assess these outcomes 5 years after repair. METHODS: Patients who received VHR using P4HB by the senior author between 01/2015 and 09/2017 were retrospectively identified. Patients were prospectively interviewed for quality of life assessment using the Hernia-Related Quality-of-Life Survey (HerQLes) and Abdominal Hernia-Q (AHQ) and screened for recurrence. Those who screened positive were asked to follow up in clinic to confirm recurrence. Both 5-year quality of life and recurrence were univariately assessed with patient and operative factors. RESULTS: 51 patients met inclusion criteria. 43 patients completed 5-year quality of life assessment (84.3% response rate). Quality of life scores at all postoperative time periods were greater than preoperative scores. Further, quality of life at 5 years is greater than that assessed 0-2 years following VHR. Most patients achieve their best quality of life in the 5-year time period. Thirty-five patients had clinical follow-up in the 5-year time period, 7 experienced recurrences (20% recurrence rate). There was no difference in 5-year quality of life assessment between those who had a recurrence and those who did not. CONCLUSION: Patient quality of life following VHR with P4HB improves immediately and continues to improve 5 years following repair. There are no differences in quality of life with onset of recurrence. Quality of life should be the primary outcome of success in VHR.

Preoperative Computed Tomography Morphological Features Indicative of Incisional Hernia Formation After Abdominal Surgery.

OBJECTIVE: To investigate key morphometric features identifiable on routine preoperative computed tomography (CT) imaging indicative of incisional hernia (IH) formation following abdominal surgery. BACKGROUND: IH is a pervasive surgical disease that impacts all surgical disciplines operating in the abdominopelvic region and affecting 13% of patients undergoing abdominal surgery. Despite the significant costs and disability associated with IH, there is an incomplete understanding of the pathophysiology of hernia. METHODS: A cohort of patients (n=21,501) that underwent colorectal surgery was identified, and clinical data and demographics were extracted, with a primary outcome of IH. Two datasets of case-control matched pairs were created for feature measurement, classification, and testing. Morphometric linear and volumetric measurements were extracted as features from anonymized preoperative abdominopelvic CT scans. Multivariate Pearson testing was performed to assess correlations among features. Each feature's ability to discriminate between classes was evaluated using 2-sided paired t testing. A support vector machine was implemented to determine the predictive accuracy of the features individually and in combination. RESULTS: Two hundred and twelve patients were analyzed (106 matched pairs). Of 117 features measured, 21 features were capable of discriminating between IH and non-IH patients. These features are categorized into three key pathophysiologic domains: 1) structural widening of the rectus complex, 2) increased visceral volume, 3) atrophy of abdominopelvic skeletal muscle. Individual prediction accuracy ranged from 0.69 to 0.78 for the top 3 features among 117. CONCLUSIONS: Three morphometric domains identifiable on routine preoperative CT imaging were associated with hernia: widening of the rectus complex, increased visceral volume, and body wall skeletal muscle atrophy. This work highlights an innovative pathophysiologic mechanism for IH formation hallmarked by increased intra-abdominal pressure and compromise of the rectus complex and abdominopelvic skeletal musculature.

Use of Cosmetic Facial Injectables After Facial Aesthetic Surgery.

BACKGROUND: Over the last 2 decades, both invasive and minimally invasive aesthetic procedures have proliferated. Aesthetic surgeons often recommend injectable treatments after cosmetic facial surgery for multiple reasons. However, literature is lacking on how cosmetic surgery affects postoperative facial injectable use. OBJECTIVES: The aim of this study was to identify predictors of facial injectable use after cosmetic facial surgery. METHODS: All adult patients operated on by a single surgeon between 2013 and 2021 were retrospectively reviewed. Patients who had any of the following cosmetic facial surgeries were included: rhytidectomy, blepharoplasty, rhinoplasty, or genioplasty. Patient demographics, clinical history, intraoperative factors, and use of cosmetic facial injectables (neurotoxin, facial fillers, deoxycholic acid, poly-l-lactic acid) were recorded. RESULTS: A total of 227 patients who underwent facial cosmetic surgery were reviewed, of whom 158 were included. Of these, 89 patients had rhytidectomy (56.3%), 112 had blepharoplasty (70.9%), 28 had rhinoplasty (17.7%), and 7 had genioplasty (4.4%). Injectables were administered to 44.3% of patients after their surgery (n = 73), compared with only 17.7% before surgery (n = 28) (P < 0.001). The most common postoperative injectables were neurotoxins (48.5%) and facial fillers (46.0%), followed by deoxycholic acid (2.7%) and poly-l-lactic acid (2.7%). Multivariate regression revealed factors positively correlated with future injectable use were index blepharoplasty or rhinoplasty, and history of preoperative neurotoxin injection (P < 0.05). CONCLUSIONS: Cosmetic facial injectables are an important consideration in achieving and maintaining optimal facial aesthetics. Their use, especially neurotoxins and facial fillers, has increased among patients postoperatively. These results highlight the contribution of injectable procedures in the context of multidimensional care for augmenting facial aesthetics.

Higher n-3 Polyunsaturated Fatty Acid Diet Improves Long-Term Neuropathological and Functional Outcome after Repeated Mild Traumatic Brain Injury.

Repeated mild traumatic brain injury (TBI) can cause persistent neuropathological effects and is a major risk factor for chronic traumatic encephalopathy. PUFAs (n-3 polyunsaturated fatty acids) were shown to improve acute TBI outcomes in single-injury models in most cases. In this study, we demonstrate positive effects of dietary n-3 PUFA on long-term neuropathological and functional outcome in a clinically relevant model of repeated mild TBI using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Adult mice, reared on n-3 PUFA adequate (higher n-3 PUFA) or deficient (lower n-3 PUFA) diets, were given a mild CHIMERA daily for 3 consecutive days. At 2 months after injury, visual function and spatial memory were evaluated. Glia cell activation was assessed by immunostaining using antibodies of ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein, and axonal damage was examined using silver staining. Repeated CHIMERA (rCHIMERA)-induced gliosis was significantly suppressed in the optic tract, corpus callosum, and hippocampus of mice fed the n-3 PUFA adequate diet compared to the deficient diet group. Considerable axonal damage was detected in the optic tract after rCHIMERA, but the adequate diet group displayed less axonal damage compared to the deficient diet group. rCHIMERA induced a drastic reduction in N1 amplitude of the visual evoked potential in both diet groups and the a-wave amplitude of the electroretinogram in the deficient diet group. However, reduction of N1 and a-wave amplitude were less severe in the adequate diet group. The Morris water maze probe test indicated a significant decrease in the number of platform crossings in the deficient diet group compared to the adequate group. In summary, dietary n-3 PUFA can attenuate persistent glial cell activation and axonal damage and improve deficits in visual function and spatial memory after repeated mild TBI. These data support the neuroprotective potential of a higher n-3 PUFA diet in ameliorating the adverse outcome of repeated mild TBI.

Need for Vitreous Surgeries in Proliferative Diabetic Retinopathy in 10-Year Follow-Up: India Retinal Disease Study Group Report No. 2.

INTRODUCTION: To report the 10-year rate of vitrectomies and the associated factors in people with proliferative diabetic retinopathy (PDR) from a multicentric cohort of people with diabetes mellitus. METHODS: Ten centres in India with established vitreoretinal (VR) services for over 10 years were invited to provide long-term data on PDR. People with Type 1 or 2 diabetes with a clinical diagnosis of active PDR in 1 or both eyes were included. Baseline data collected included age, sex, duration of diabetes, source of referral and best-corrected visual acuity, and diabetic retinopathy status in both eyes. Available follow-up data included the numbers of panretinal photocoagulation (PRP) sessions, cataract surgery, treatment of diabetic macular oedema, use of anti-vascular endothelial growth factor (VEGF) therapy, vitrectomy with or without retinal surgeries over 10 years. RESULTS: Over 10 years, 89% needed supplemental PRP after initial complete PRP. One-third required retinal surgery, 16% needed intravitreal injection. Men (74.5%) had significant higher risk for vitreous (VR) surgery. Of the group with low-risk PDR, 56.8% did not require VR surgery, p < 0.001. Of the patients who underwent cataract surgery and had intravitreal anti-VEGF injections, 78.5 and 28.2% needed subsequent vitreous (VR) surgery, p = 0.006 and <0.0001, respectively. Independent predictors of need for vitreoretinal surgery included those who underwent cataract surgery and those with poor baseline visual acuity (logMAR). Eyes at lower risk for VR surgery included the eyes previously treated with PRP and low-risk PDR at baseline. CONCLUSION: Despite initial "complete" PRP, one-third of our study cohort needed vitrectomies over 10 years, highlighting that these patients require regular follow-up for a long period of time.

Investigation of the effect of dietary intake of omega-3 polyunsaturated fatty acids on trauma-induced white matter injury with quantitative diffusion MRI in mice.

Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.

Prevalence and incidence of visual impairment in patients with proliferative diabetic retinopathy in India.

To provide the real-world outcomes of people with proliferative diabetic retinopathy (PDR) in India and highlight opportunities for improvement of their disease status and to evaluate their visual acuity (VA) status. A multicenter retrospective study in which ten centers in India with established vitreoretinal services for over 10 years were invited to provide long-term data on PDR. This study population were of Indian nationality. Patients with a diagnosis of type 1 or 2 diabetes with a clinical diagnosis of active PDR in any or both eyes, who had long term follow-up for up to 10 years were included. Baseline data collected included age, sex, duration of diabetes, source of referral and best-corrected visual acuity, diabetic retinopathy status in both eyes. Available follow-up data on VA were collected at 6 months post baseline, 5 years and 10 years within a ± 3 months window. Evaluating the presenting VA of people with PDR, short-term outcomes at 6 months and the incidence of visual impairment (VI) at 5 and 10 years are the main outcome of the study. Data was available for 516, 424 and 455 patients at baseline, 5 years and 10 years respectively. Gender and duration of diabetes did not have statistically significant effect on VI outcomes. Eyes receiving treatment early in the disease course (i.e. baseline VA ≥ 6/12) had significantly better VA outcomes at 10 years versus eyes treated at a later stage (i.e. baseline VA < 6/12) (p = <0.0001). On comparing eyes with stable treated PDR and persistent PDR at end of 10 year follow up, a significantly higher percentage of eyes in the stable treated group maintained VA of ≥ 6/12 (55.1% vs. 24.2%) (p = < 0.0001), indicating persistent disease activity due to inadequate treatment results in worse VA outcomes. We found no trend in VI or blindness with increasing levels of age at both 5- and 10-year time points (p > 0.05). The age standardized incidence for VI was 11.10% (95% CI 8.1, 14.2) and for blindness was found to be 7.7% (95% CI 5.2, 10.3). Our results suggest that despite robust recent clinical trial results showing that pan retinal photocoagulation is an excellent treatment for PDR, people with diabetes in India need to be made aware of annual screening and treatment of their eyes to avoid vision impairment and blindness.

Multiple Mild Traumatic Brain Injuries Lead to Visual Dysfunction in a Mouse Model.

Visual dysfunction is a common occurrence after traumatic brain injury (TBI). We investigated in this study effects of single or multiple mild TBI on visual function in mice using a closed head injury model that permits unconstrained head movement after impact. Adult mice were briefly anesthetized with isoflurane and given one or three mild TBI with the closed head injury by mechanically engineered rotational acceleration (CHIMERA) device with an interinjury interval of 24 h. Mice were then tested in the Morris water maze, visual cliff, and open field tests from day 19 to day 32 and for visual evoked potential at 5 weeks after the last injury and euthanized. Mice with multiple TBI showed impaired performance in the visible platform water maze test and had increased errors in the visual cliff test. Further, there was a graded difference in visual evoked potential, with the single injury mice showing modest reduction in N1 amplitude whereas the multiple injuries produced significant reduction compared to sham and single injury groups. The optic tract of the injured mice showed increases in glial cell immunostaining. The increase in glial fibrillary acid protein immunostaining reached statistical significance for both injured groups whereas the ionized calcium binding adaptor molecule 1 immunostaining was only significantly increased in the optic tract of repeatedly injured mice. These results indicate that multiple injuries using CHIMERA may result in visual deficits, which can affect certain behavioral performances. The change in vision may be a useful marker when monitoring repeated TBI outcome and screening for protective agents from TBI.

Impact of venting incision on graft detachment in Descemet stripping automated endothelial keratoplasty.

PURPOSE: To evaluate the impact of venting incision on graft detachment in Descemet stripping automated endothelial keratoplasty (DSAEK). MATERIALS AND METHODS: Retrospective comparative study on DSAEK procedure performed with (n = 13) and without (n = 39) venting incision. Patients were treated with DSAEK for various causes of endothelial decompensation between February 2014 and April 2016. The rate of postoperative graft detachments documented on anterior segment optical coherence tomography was compared in both groups. RESULTS: Paracentral venting incision decreases the rate of graft displacement. Non-venting group (nvg) had 28.2% graft displacement compared to venting group (vg) which had 7.6% graft displacement. CONCLUSION: Venting incision is a simple and safe manoeuvre to facilitate graft adherence in DSAEK, especially in caseswith presence of high-risk factors for graft detachment.

Using double pulsed-field gradient MRI to study tissue microstructure in traumatic brain injury (TBI).

Double pulsed-field gradient (dPFG) MRI is proposed as a new sensitive tool to detect and characterize tissue microstructure following diffuse axonal injury. In this study dPFG MRI was used to estimate apparent mean axon diameter in a diffuse axonal injury animal model and in healthy fixed mouse brain. Histological analysis was used to verify the presence of the injury detected by MRI.

Perinatal Brain Docosahexaenoic Acid Concentration Has a Lasting Impact on Cognition in Mice.

Background: Premature infants are deprived of prenatal accumulation of brain docosahexaenoic acid [DHA (22:6n-3)], an omega-3 fatty acid [ω-3 FA (n-3 FA)] important for proper development of cognitive function. The resulting brain DHA deficit can be reversed by ω-3 FA supplementation.Objective: The objective was to test whether there is a critical period for providing ω-3 FA to correct cognitive deficits caused by developmental ω-3 FA deprivation in mice.Methods: Twelve timed-pregnant mice [embryonic day 14 (E14), C57/BL6NCr] were fed an ω-3 FA-deficient diet containing 0.04% α-linolenic acid [ALA (18:3n-3)], and their offspring were fed the same deficient diet (Def group) or changed to an ω-3 FA-adequate diet containing 3.1% ALA at 3 wk, 2 mo, or 4 mo of age. In parallel, 3 E14 pregnant mice were fed the adequate diet and their offspring were fed the same diet (Adeq group) throughout the experiment. Brain FA composition, learning and memory, and hippocampal synaptic protein expression were evaluated at 6 mo by gas chromatography, the Morris water maze test, and western blot analysis, respectively.Results: Maternal dietary ω-3 FA deprivation decreased DHA by >50% in the brain of their offspring at 3 wk of age. The Def group showed significantly worse learning and memory at 6 mo than those groups fed the adequate diet. These pups also had decreased hippocampal expression of postsynaptic density protein 95 (43% of Adeq group), Homer protein homolog 1 (21% of Adeq group), and synaptosome-associated protein of 25 kDa (64% of Adeq group). Changing mice to the adequate diet at 3 wk, 2 mo, or 4 mo of age restored brain DHA to the age-matched adequate concentration. However, deficits in hippocampal synaptic protein expression and spatial learning and memory were normalized only when the diet was changed at 3 wk.Conclusion: Developmental deprivation of brain DHA by dietary ω-3 FA depletion in mice may have a lasting impact on cognitive function if not corrected at an early age.

Repetitive Closed-Head Impact Model of Engineered Rotational Acceleration Induces Long-Term Cognitive Impairments with Persistent Astrogliosis and Microgliosis in Mice.

Repeated mild traumatic brain injury (rmTBI) has been identified by epidemiology as a high-risk factor for dementia at a later stage in life. Animal models to replicate complex features of human rmTBI and/or to evaluate long-term effects on brain function have not been established. In this study, we used a novel closed-head impact model of engineered rotational acceleration (CHIMERA) to investigate the long-term neuropathological and cognitive functional consequences of rmTBI. Adult C57BL/6 male mice were subjected to CHIMERA for 3 consecutive days 24 h apart. Functional outcomes were assessed by the beam walk and Morris water maze tests. Neuropathology was evaluated by immunostaining of glial fibrillary acidic protein (GFAP), amyloid precursor protein (APP), and ionizing calcium-binding adaptor molecule-1 (Iba-1), and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blotting of GFAP, Iba-1, and tumor necrosis factor (TNF)-α. Repeated CHIMERA (rCHIMERA) resulted in motor deficits at 3 days, and in learning and memory impairments that were sustained up to 6 months post injury. GFAP and TNF-α gene expression was increased within a week, whereas astrogliosis and microgliosis were induced starting from day 1 up to 6.5 months after rCHIMERA with upregulated GFAP and Iba-1 protein levels. rCHIMERA also induced APP deposition from day 1 to day 7, but this diminished by 1 month. In conclusion, rCHIMERA produces long-lasting cognitive impairments with astrogliosis and microgliosis in mice, suggesting that rCHIMERA can be a useful animal model to study the long-term complications, as well as the cellular and molecular mechanisms, of human rmTBI.

Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function.

Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development. N-docosahexaenoylethanolamine (synaptamide), an endogenous metabolite of DHA, potently promotes neurogenesis, neuritogenesis and synaptogenesis; however, the underlying molecular mechanism is not known. Here, we demonstrate orphan G-protein coupled receptor 110 (GPR110, ADGRF1) as the synaptamide receptor, mediating synaptamide-induced bioactivity in a cAMP-dependent manner. Mass spectrometry-based proteomic characterization and cellular fluorescence tracing with chemical analogues of synaptamide reveal specific binding of GPR110 to synaptamide, which triggers cAMP production with low nM potency. Disruption of this binding or GPR110 gene knockout abolishes while GPR110 overexpression enhances synaptamide-induced bioactivity. GPR110 is highly expressed in fetal brains but rapidly decreases after birth. GPR110 knockout mice show significant deficits in object recognition and spatial memory. GPR110 deorphanized as a functional synaptamide receptor provides a novel target for neurodevelopmental control and new insight into mechanisms by which DHA promotes brain development and function.