This is actually a wonderful article1 on a method that will not take off in the United States for a few reasons. Although the cost noted to produce the final product in country (Korea) is low, it would cost much more here in the United States, and that is problematic when most surgeons want an easier route to success. Aside from the unnecessary long course of antibiotic, and my own fixation with drain usage, the method has great merit albeit from an intraoral access; it fine tunes on operation long viewed here (in the United States) as secondary to a rhinoplasty. This method also increases patient input relative to the final result. In addition, the comment that this procedure is 3 hours without this planning vs 1 hour with, is unrealistic as this procedure can easily be done in experienced hands by any route in 60 to 80 minutes or less.
Τετάρτη 29 Νοεμβρίου 2017
Aesthetic Refinements in C-V Flap: Raising a Perfect Cylinder
Nipple reconstruction is the keystone procedure to complete an aesthetically satisfying postmastectomy breast reconstruction. Positioning the nipple at the edge of the breast cone and achieving symmetry with the contralateral side (native or reconstructed nipple) are critical in completing a pleasing result. Furthermore, patient expectations are always higher; aesthetics becomes of paramount concern after having gone through the feelings connected with the disease.
Modified Levator Muscle Resection Using Putterman Muller's Muscle-Conjunctival Resection-Ptosis Clamp
Abstract
Background
The traditional technique for levator muscle resection includes a time-consuming dissection procedure that causes tissue trauma and swelling. The Putterman ptosis clamp has been popularly used in recent years for conjunctival müllerectomy. In this paper, we describe a modified surgical technique for ptosis treatment using the Putterman ptosis clamp. The modified technique improves the surgical results of levator muscle resection. Objectives
We performed a retrospective case-series study to determine the outcomes and complications associated with the use of the Putterman ptosis clamp in levator muscle resection. Methods
Adults aged ≥18 years with moderate-to-severe ptosis underwent the modified technique for levator muscle resection. We first performed dissection to expose the aponeurosis and tarsus. Then, we placed the Putterman ptosis clamp to measure redundant aponeurotic and septal tissues and to perform the resection. Following the adjustment of the eyelid fissure, we refixed the levator muscle to the tarsus with 4-0 vicryl stitches. Results
Seventeen patients (34 eyes) were included in the study. Of the 34 eyes, 31 (91.2%) experienced the complete resolution of ptosis after the surgery. One patient (2 eyes, 5.9%) had mild bilateral dermatochalasis and received revision surgery 6 months postoperative. One patient (1 eye, 2.9%) lost the crease of the left eye and received revision surgeries 2 and 6 months after the first surgery. No residual ptosis or severe adverse events were noted in the patients. Conclusions
Modified levator muscle resection using the Putterman ptosis clamp is an effective procedure for ptosis treatment. Level of Evidence: 4
Commentary on: Cannula vs Sharp Needle for Placement of Soft Tissue Fillers: An Observational Cadaver Study
Over the last ten years, the use of synthetic cosmetic tissue fillers has become transformative with regards to what outcomes may be accomplished. While there are many choices in fillers, most injectors utilize hyaluronic acid (HA) class fillers as their first choice for wrinkle filling or volume enhancement. Throughout this time, innovators have discovered additional tissue planes and off-label techniques for correction of areas such as the tear trough.1,2 Reported adverse events relating to filler use can occur with virtually any location, from mild, such as the Tyndall effect, to extremely serious, like intra-arterial injections that produce local tissue slough, blindness, or stroke.3,4 Conversely, minor-level filler-related adverse events seem to occur for unknown reasons. The good news, however, is that HA tissue fillers produce good clinical outcomes time and time again for patients. The bad news is that there are myths and wrong assumptions regarding precision of where the filler goes once it leaves the needle. When we think that we are acting in a safe, precise fashion, a new study like this one is a cause to reassess how one injects tissue fillers. Going forward, we simply cannot be attempting advanced tissue filler techniques with techniques of yesteryear and wrong techniques.
Commentary on: Modified Levator Muscle Resection Using Putterman Müller’s Muscle-Conjunctival Resection-Ptosis Clamp
The author provides an update on his previously reported technique to advance the levator aponeurosis in the correction of upper eyelid ptosis, now with a larger volume of cases.1 I compliment the author on his successful and good results.
Breast Erythema in a Patient With Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report Discussing Cutaneous Manifestations
Abstract
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare clinical entity. This is a case report of a 71-year-old female with a history of bilateral breast augmentation 16 years prior who presented to an outside facility with swelling and erythema of her right breast. She was found to have a mass on imaging. Biopsy was consistent with BIA-ALCL. She was initiated on chemotherapy and eventually was referred to our hospital where she underwent breast implant explantation with total capsulectomy, including removal of the mass. This patient's erythema could represent another manifestation or treatment effect of BIA-ALCL. Level of Evidence: 5
Patient-specific puzzle implant preformed with 3d-printed rapid prototype model for combined orbital floor and medial wall fracture
Publication date: Available online 29 November 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Young Chul Kim, Kyung Hyun Min, Jong Woo Choi, Kyung S. Koh, Tae Suk Oh, Woo Shik Jeong
BackgroundThe management of combined orbital floor and medial wall fractures involving the inferomedial strut is challenging due to absence of stable cornerstone. In this article, we proposed surgical strategies using customized 3D puzzle implant preformed with Rapid Prototype (RP) skull model.MethodsRetrospective review was done in 28 patients diagnosed with combined orbital floor and medial wall fracture. Using preoperative CT scans, original and mirror imaged RP skull models for each patient were prepared and sterilized. In all patients, porous polyethylene-coated titanium mesh was premolded onto RP skull model in two ways; Customized 3D jigsaw puzzle technique was used in 15 patients with comminuted inferomedial strut, whereas individual 3D implant technique was used in each fracture for 13 patients with intact inferomedial strut. Outcomes including enophthalmos, visual acuity, presence of diplopia were assessed and orbital volume was measured using OsiriX software preoperatively and postoperatively.ResultsSatisfactory results were achieved in both groups in terms of clinical improvements. Of 10 patients with preoperative diplopia, 9 improved in 6 months, except one with persistent symptom who underwent extraocular muscle rupture. 18 patient who had moderate to severe enophthalmos preoperatively improved, and one remained with mild degree. Orbital volume ratio, defined as volumetric ratio between affected and control orbit, decreased from 127.6% to 99.79% (p<0.05) in comminuted group, and that in intact group decreased from 117.03% to 101.3% (p<0.05).ConclusionOur surgical strategies using the jigsaw puzzle and individual reconstruction technique provide accurate restoration of combined orbital floor and medial wall fractures.
Option grids in melanoma - an underused tool
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Joseph Ward, Umar Butt, Barry Powell
Effect of carpal tunnel release on median nerve epineurial flux
Publication date: Available online 29 November 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Zofia Bochen, Magdalena Murawska, Bartlomiej H. Noszczyk
Medikamentöse Therapie neuroendokriner Neoplasien des Gastrointestinaltrakts
Zusammenfassung
Hintergrund
Neuroendokrine Neoplasien (NEN) des Verdauungstrakts stellen eine seltene und heterogene Gruppe von Tumorerkrankungen dar. Dies erschwert die Vorgabe einheitlicher Therapieschemata.
Ziel
Die aktuelle Datenlage zur medikamentösen Therapie gastrointestinaler NEN soll dargestellt werden.
Methoden
Diskussion publizierter Studien und Expertenempfehlungen zur medikamentösen Therapie von gastroenteropankreatischen neuroendokrinen Neoplasien (GEP-NEN)
Ergebnisse
Wichtigstes therapeutisches Prinzip ist die komplette chirurgische Tumorentfernung. Ist diese nicht möglich, erfolgt die Therapie in der Regel multimodal und multidisziplinär und orientiert sich an der Tumorentität, dem individuellen Spontanverlauf sowie der Beschwerdesymptomatik. Bei Vorliegen eines spezifischen klinischen Hormonsyndroms sind langwirksame Somatostatinanaloga (SSA) die Therapie der Wahl. Sie stellen auch die Grundlage der antiproliferativen Therapie gut differenzierter gastroenteropankreatischer neuroendokriner Tumoren (GEP-NET) dar. Bei ausreichender Somatostatinrezeptor-Expression des Tumors steht als systemische Therapieoption die Peptidradiorezeptortherapie (PRRT) zur Verfügung. Bei gering differenzierten neuroendokrinen Karzinomen und NET des Pankreas stellen Platin- bzw. Streptozotocin-basierte Chemotherapien eine wichtige Therapieoption dar. Der Multityrosinkinaseinhibitor Sunitinib und der mTOR-Inhibitor Everolimus sind für die Behandlung pankreatischer NET zugelassen, Everolimus zudem auch für gastrointestinale NEN.
Schlussfolgerungen
Zur Behandlung von GEP-NEN stehen eine Reihe effektiver therapeutischer Optionen zur Verfügung. Die Entscheidung für ein Therapiekonzept sollte individuell im Rahmen eines in der Behandlung dieser Tumoren erfahrenen interdisziplinären Tumorboards festgelegt werden.
Paraneoplastic Pemphigus. A Life-Threatening Autoimmune Blistering Disease
Publication date: December 2017
Source:Actas Dermo-Sifiliográficas (English Edition), Volume 108, Issue 10
Author(s): A. Tirado-Sánchez, A. Bonifaz
Paraneoplastic pemphigus (PNP), a subset of pemphigus, is a unique autoimmune blistering condition that can affect multiple organs other than the skin. It is a life-threatening disease associated with an underlying malignancy, most commonly of lymphoproliferative origin. The clinical picture may resemble pemphigus, pemphigoid, erythema multiforme, graft-versus-host disease, or lichen planus. The earliest and most consistent finding is a painful, severe, chronic and often recalcitrant stomatitis. Treatment of PNP is difficult. Immunosuppressive agents are required to decrease blistering, and treating the underlying tumor may control autoantibody production. In this review, we included essential diagnostic aspects of PNP and the most useful treatment options in the dermatologist practice.
Graphical abstract
Impact on Quality of Life in Dermatology Patients Attending an Emergency Department
Publication date: December 2017
Source:Actas Dermo-Sifiliográficas (English Edition), Volume 108, Issue 10
Author(s): A. Alegre-Sánchez, D. de Perosanz-Lobo, A. Pascual-Sánchez, C. Pindado-Ortega, P. Fonda-Pascual, Ó.M. Moreno-Arrones, P. Jaén-Olasolo
IntroductionDermatological complaints have been estimated to represent up to 5–10% of all the visits to emergency departments. The main objective of our study was to determine how affected is the Health related Quality of Life (HRQL) in a series of patients attending an emergency department due to skin symptoms.Patients and methodsA prospective study during one month (July 2016) was conducted in a hospital with full-time on-call dermatologists. The Short-Form SF-12v2 Health Survey and the Dermatology Life Quality Index (DLQI) were offered to all the patients over 18 years old attending the emergency department with cutaneous complaints. Clinical and epidemiological characteristics were also collected.ResultsIn total 108 patients completed the study. Mean age found was 45.1±16.1 years. Mean DLQI score found was 10.56±6.12. Fifty-three patients (49%) had a score of 11 or higher in the DLQI questionnaire. Most affected subscales were "Symptoms and Feelings" in DLQI scale and "Overall Health" and "Vitality" for the SF-12. A very significant difference (p<0.0001) was found between women's (12.4±5.7) and men's (7.5±5.6) DLQI mean score (mean difference of 4.9; 95% confidence interval of the difference: 2.7–7.1).ConclusionsPatients visiting emergency units with cutaneous complaints seem to feel a moderate-large impact on their quality of life which is mainly related to the symptoms and feelings that they are experiencing. This impact is significantly higher among women.
Graphical abstract
Randomized Split-face, Controlled Comparison of Treatment with 1565 nm Non-ablative Fractional Laser for Enlarged Facial Pores
Abstract
Enlarged pores are common cosmetic concerns1. Though non-ablative fractional lasers (NAFLs) have been used reducing enlarged facial pores, a prospective, split-face, controlled study with objective assessment is still in blank. 1,565 nm NAFL (M22 ™ ResurFX™, Lumenis® Ltd, Yokneam, Israel), proved effective on skin elasticity and stretch marks2, was further aimed to assess for its safety and efficacy on enlarged facial pores.
This article is protected by copyright. All rights reserved.
Chemical characterization of PM 2.5 collected from a rural coastal island of the Bay of Bengal (Bhola, Bangladesh)
Abstract
This work focuses on the chemical characterization of fine aerosol particles (PM2.5) collected from a rural remote island of the Bay of Bengal (Bhola, Bangladesh) from April to August, 2013. PM2.5 particle-loaded filters were analyzed for organic carbon (OC), elemental carbon (EC), water-soluble ions, and selected saccharides (levoglucosan, mannosan, galactosan, arabitol, and mannitol). The average PM2.5 mass was 15.0 ± 6.9 μg m−3. Organic carbon and elemental carbon comprised roughly half of the analyzed components. Organic carbon was the predominant contributor to total carbon (TC) and accounting for about 28% of PM2.5 mass. Secondary organic carbon (SOC) was inferred to be ~ 26% of OC. The sum of ions comprised ~ 27% of PM2.5 mass. The contribution of sea salt aerosol was smaller than expected for a sea-near site (17%), and very high chloride depletion was observed (78%). NssSO42− was a dominant ionic component with an average concentration of 2.0 μg m−3 followed by Na+, NH4+, and nssCa2+. The average concentration of arabitol and mannitol was 0.11 and 0.14 μg m−3, respectively, while levoglucosan and its stereoisomers (mannosan and galactosan) were bellow detection limit. NH4+/SO42− equivalent ratio was 0.30 ± 0.13 indicating that secondary inorganic aerosol is not the main source of SO42−. Enrichment factor (EF) analysis showed that SO42− and NO3− were enriched in atmospheric particles compared to sea aerosol and soil indicating their anthropogenic origin. Higher OC/EC ratio (3.70 ± 0.88) was a good indicator of the secondary organic compounds formation. Other ratios (OC/EC, K+/EC, nssSO42−/EC) and correlation analysis suggested mixed sources for carbonaceous components. Arabitol and mannitol both showed strong correlation with EC having R 2 value 0.89 and 0.95, respectively. Air mass trajectories analysis showed that concentrations of soil and anthropogenic species were lower for air masses originating from the sea (May–August) and were higher when air came from land (April).
Option grids in melanoma - an underused tool
It is not uncommon for patients faced with a new diagnosis of malignant melanoma to experience significant upset and confusion. During this distressing period, NICE guidance (NG14) recommends that patients with AJCC Stage IB-IIC disease should consider whether they wish to undergo sentinel lymph node biopsy (SLNB)1. The decision to undergo SLNB can be difficult and should ideally be reached following informed and considered discussion with patients guided as to the relative merits of SLNB by their plastic surgeon.
Effect of carpal tunnel release on median nerve epineurial flux
It is believed that increased pressure that develops in the carpal tunnel syndrome (CTS) leads to nerve compression and a gradual decrease in neurovascular blood flow. Animal experiments showed that early nerve release restores neurovascular flow; however, late decompression has no effect.1 This finding raises the questions of whether carpal tunnel release increases blood flow in the median nerve and whether nerve ischemia may be associated with carpal tunnel etiology. The objective of this study was to evaluate the immediate effects of tunnel release and determine its influence on median nerve flux.
Patient-specific puzzle implant preformed with 3d-printed rapid prototype model for combined orbital floor and medial wall fracture
The management of combined orbital floor and medial wall fractures involving the inferomedial strut is challenging due to absence of stable cornerstone. In this article, we proposed surgical strategies using customized 3D puzzle implant preformed with Rapid Prototype (RP) skull model.
Fatal toxoplasmosis in a southern muriqui (Brachyteles arachnoides) from São Paulo state, Brazil: Pathological, immunohistochemical, and molecular characterization
Abstract
We report the pathological, immunohistochemical, and molecular features of fatal acute systemic toxoplasmosis in an adult, female, free-living southern muriqui (Brachyteles arachnoides) from São Paulo state, Brazil. PCR-RFLP genotyping analysis identified the #21 genotype of Toxoplasma gondii. This represents the first report of acute toxoplasmosis involving this genotype in humans and animals.
How language couldn’t have evolved: a critical examination of Berwick and Chomsky’s theory of language evolution
Abstract
This article examines some recent work by Berwick and Chomsky as presented in their book Why Only Us? Language and Evolution (2015). As I understand them, Berwick and Chomsky's overarching purpose is to explain how human language could have arisen in so short an evolutionary period. After articulating their strategy, I argue that they fall far short of reaching this goal. A co-evolutionary scenario linking the mechanisms that realize the language system, both with one other and with cognitive mechanisms capable of exploiting linguistic expressions, is surely unavoidable. And yet this is precisely what Berwick and Chomsky in effect rule out.
Dermatologist Density and Volume and Costs of Dermatology Procedures
This cross-sectional study uses the 2013 Medicare Provider Utilization and Payment Database to characterize the effect of geographic variations in dermatologist density on the provision of dermatology procedures within Medicare.
Topical Tacalcitol for a Family With Follicular Keratosis of the Chin
This case report describes the use of topical tacalcitol to treat follicular keratosis of the chin in 2 brothers.
Laboratory Monitoring During Systemic Terbinafine Therapy for Pediatric Onychomycosis
This retrospective medical record review examines the prevalence of laboratory monitoring and laboratory abnormalities during systemic terbinafine therapy in pediatric onychomycosis.
Allergen Concerns and Popular Skin Care Products
To the Editor We read with great interest the article by Xu et al published in a recent issue of JAMA Dermatology highlighting the high prevalence of contact allergens in common moisturizers. Their data mirror similar results in our recent study investigating contact allergens in pediatric personal care products marketed as hypoallergenic, dermatologist recommended and/or tested, fragrance free, or paraben free. Similar to the study by Xu et al, which found that 88% of common moisturizers contained at least 1 common contact allergen, we found that 167 of 187 of our selection of pediatric products (89%) contained at least 1 allergen.
Allergen Concerns and Popular Skin Care Products
To the Editor We read with great interest the Original Investigation by Xu et al titled "Consumer Preferences, Product Characteristics, and Potentially Allergenic Ingredients in Best-Selling Moisturizers" and published in a recent issue of JAMA Dermatology. In discussions with dermatology colleagues regarding this article, we noticed another disturbing marketing trend: the labeling of skin care products marketed for babies.
Allergen Concerns and Popular Skin Care Products—Reply
In Reply We thank Hamann and Thyssen, as well as Harview and Hsiao, for their interest in our work and thoughtful commentaries. We agree that the safety and affordability of cosmetics and personal care products explicitly marketed toward the pediatric population is important to public health. In a recent publication of all adverse events (AE) submitted to the US Food and Drug Administration surrounding cosmetics and personal care products from 2004 to 2016, baby products were associated with the highest percentage of self-reported serious AEs (eg, death, serious injury, or hospitalization).
Preference-Based QOL Measures for Economic Evaluations in Early Melanoma
This study uses randomized clinical trial data to compare utility scores from the AQoL-8D and the FACT-M and evaluate the sensitivity of both instruments in identifying the influence of fear of cancer recurrence on health-related quality of life in patients with early-stage melanoma.
Heterozygosity for the Mood Disorder-Associated Variant Gln460Arg Alters P2X7 Receptor Function and Sleep Quality
A single nucleotide polymorphism substitution from glutamine (Gln, Q) to arginine (Arg, R) at codon 460 of the purinergic P2X7 receptor (P2X7R) has repeatedly been associated with mood disorders. The P2X7R-Gln460Arg variant per se is not compromised in its function. However, heterologous expression of P2X7R-Gln460Arg together with wild-type P2X7R has recently been demonstrated to impair receptor function. Here we show that this also applies to humanized mice coexpressing both human P2X7R variants. Primary hippocampal cells derived from heterozygous mice showed an attenuated calcium uptake upon agonist stimulation. While humanized mice were unaffected in their behavioral repertoire under basal housing conditions, mice that harbor both P2X7R variants showed alterations in their sleep quality resembling signs of a prodromal disease stage. Also healthy heterozygous human subjects showed mild changes in sleep parameters. These results indicate that heterozygosity for the wild-type P2X7R and its mood disorder-associated variant P2X7R-Gln460Arg represents a genetic risk factor, which is potentially able to convey susceptibility to mood disorders.
SIGNIFICANCE STATEMENT Depression and bipolar disorder are the most common mood disorders. The P2X7 receptor (P2X7R) regulates many cellular functions. Its polymorphic variant Gln460Arg has repeatedly been associated with mood disorders. Genetically engineered mice, with human P2X7R, revealed that heterozygous mice (i.e., they coexpress the disease-associated Gln460Arg variant together with its normal version) have impaired receptor function and showed sleep disturbances. Human participants with the heterozygote genotype also had subtle alterations in their sleep profile. Our findings suggest that altered P2X7R function in heterozygote individuals disturbs sleep and might increase the risk for developing mood disorders.
Phosphoinositol-4,5-Bisphosphate Regulates Auditory Hair-Cell Mechanotransduction-Channel Pore Properties and Fast Adaptation
Membrane proteins, such as ion channels, interact dynamically with their lipid environment. Phosphoinositol-4,5-bisphosphate (PIP2) can directly or indirectly modify ion-channel properties. In auditory sensory hair cells of rats (Sprague Dawley) of either sex, PIP2 localizes within stereocilia, near stereocilia tips. Modulating the amount of free PIP2 in inner hair-cell stereocilia resulted in the following: (1) the loss of a fast component of mechanoelectric-transduction current adaptation, (2) an increase in the number of channels open at the hair bundle's resting position, (3) a reduction of single-channel conductance, (4) a change in ion selectivity, and (5) a reduction in calcium pore blocking effects. These changes occur without altering hair-bundle compliance or the number of functional stereocilia within a given hair bundle. Although the specific molecular mechanism for PIP2 action remains to be uncovered, data support a hypothesis for PIP2 directly regulating channel conformation to alter calcium permeation and single-channel conductance.
SIGNIFICANCE STATEMENT How forces are relayed to the auditory mechanoelectrical transduction (MET) channel remains unknown. However, researchers have surmised that lipids might be involved. Previous work on bullfrog hair cells showed an effect of phosphoinositol-4,5-bisphosphate (PIP2) depletion on MET current amplitude and adaptation, leading to the postulation of the existence of an underlying myosin-based adaptation mechanism. We find similar results in rat cochlea hair cells but extend these data to include single-channel analysis, hair-bundle mechanics, and channel-permeation properties. These additional data attribute PIP2 effects to actions on MET-channel properties and not motor interactions. Further findings support PIP2's role in modulating a fast, myosin-independent, and Ca2+-independent adaptation process, validating fast adaptation's biological origin. Together this shows PIP2's pivotal role in auditory MET, likely as a direct channel modulator.
Neuromedin B Expression Defines the Mouse Retrotrapezoid Nucleus
The retrotrapezoid nucleus (RTN) consists, by definition, of Phox2b-expressing, glutamatergic, non-catecholaminergic, noncholinergic neurons located in the parafacial region of the medulla oblongata. An unknown proportion of RTN neurons are central respiratory chemoreceptors and there is mounting evidence for biochemical diversity among these cells. Here, we used multiplexed in situ hybridization and single-cell RNA-Seq in male and female mice to provide a more comprehensive view of the phenotypic diversity of RTN neurons. We now demonstrate that the RTN of mice can be identified with a single and specific marker, Neuromedin B mRNA (Nmb). Most (~75%) RTN neurons express low-to-moderate levels of Nmb and display chemoreceptor properties. Namely they are activated by hypercapnia, but not by hypoxia, and express proton sensors, TASK-2 and Gpr4. These Nmb-low RTN neurons also express varying levels of transcripts for Gal, Penk, and Adcyap1, and receptors for substance P, orexin, serotonin, and ATP. A subset of RTN neurons (~20–25%), typically larger than average, express very high levels of Nmb mRNA. These Nmb-high RTN neurons do not express Fos after hypercapnia and have low-to-undetectable levels of Kcnk5 or Gpr4 transcripts; they also express Adcyap1, but are essentially devoid of Penk and Gal transcripts. In male rats, Nmb is also a marker of the RTN but, unlike in mice, this gene is expressed by other types of nearby neurons located within the ventromedial medulla. In sum, Nmb is a selective marker of the RTN in rodents; Nmb-low neurons, the vast majority, are central respiratory chemoreceptors, whereas Nmb-high neurons likely have other functions.
SIGNIFICANCE STATEMENT Central respiratory chemoreceptors regulate arterial PCO2 by adjusting lung ventilation. Such cells have recently been identified within the retrotrapezoid nucleus (RTN), a brainstem nucleus defined by genetic lineage and a cumbersome combination of markers. Using single-cell RNA-Seq and multiplexed in situ hybridization, we show here that a single marker, Neuromedin B mRNA (Nmb), identifies RTN neurons in rodents. We also suggest that >75% of these Nmb neurons are chemoreceptors because they are strongly activated by hypercapnia and express high levels of proton sensors (Kcnk5 and Gpr4). The other RTN neurons express very high levels of Nmb, but low levels of Kcnk5/Gpr4/pre-pro-galanin/pre-pro-enkephalin, and do not respond to hypercapnia. Their function is unknown.
Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway
Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in high-density cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability.
SIGNIFICANCE STATEMENT Our study uncovered a novel mechanism that targets the Kv2.1 voltage-gated potassium channel to two distinct trafficking pathways and two distinct subcellular destinations: the somatodendritic plasma membrane and that of the axon initial segment. We also identified a distinct motif, including putative phosphorylation sites, that is important for the AIS localization. This raises the possibility that the destination of a channel protein can be dynamically regulated via changes in post-translational modification, which would impact the excitability of specific membrane compartments.
Optogenetic Activation of the fruitless-Labeled Circuitry in Drosophila subobscura Males Induces Mating Motor Acts
It remains an enigma how the nervous system of different animal species produces different behaviors. We studied the neural circuitry for mating behavior in Drosophila subobscura, a species that displays unique courtship actions not shared by other members of the genera including the genetic model D. melanogaster, in which the core courtship circuitry has been identified. We disrupted the D. subobscura fruitless (fru) gene, a master regulator for the courtship circuitry formation in D. melanogaster, resulting in complete loss of mating behavior. We also generated frusoChrimV, which expresses the optogenetic activator Chrimson fused with a fluorescent marker under the native fru promoter. The fru-labeled circuitry in D. subobscura visualized by frusoChrimV revealed differences between females and males, optogenetic activation of which in males induced mating behavior including attempted copulation. These findings provide a substrate for neurogenetic dissection and manipulation of behavior in non-model animals, and will help to elucidate the neural basis for behavioral diversification.
SIGNIFICANCE STATEMENT How did behavioral specificity arise during evolution? Here we attempted to address this question by comparing the parallel genetically definable neural circuits controlling the courtship behavior of Drosophila melanogaster, a genetic model, and its relative, D. subobscura, which exhibits a courtship behavioral pattern unique to it, including nuptial gift transfer. We found that the subobscura fruitless circuit, which is required for male courtship behavior, was slightly but clearly different from its melanogaster counterpart, and that optogenetic activation of this circuit induced subobscura-specific behavior, i.e., regurgitating crop contents, a key element of transfer of nuptial gift. Our study will pave the way for determining how and which distinctive cellular elements within the fruitless circuit determine the species-specific differences in courtship behavior.
Optogenetic Inhibition Reveals Distinct Roles for Basolateral Amygdala Activity at Discrete Time Points during Risky Decision Making
Decision making is a multifaceted process, consisting of several distinct phases that likely require different cognitive operations. Previous work showed that the basolateral amygdala (BLA) is a critical substrate for decision making involving risk of punishment; however, it is unclear how the BLA is recruited at different stages of the decision process. To this end, the current study used optogenetics to inhibit the BLA during specific task phases in a model of risky decision making (risky decision-making task) in which rats choose between a small, "safe" reward and a large reward accompanied by varying probabilities of footshock punishment. Male Long–Evans rats received intra-BLA microinjections of viral vectors carrying either halorhodopsin (eNpHR3.0-mCherry) or mCherry alone (control) followed by optic fiber implants and were trained in the risky decision-making task. Laser delivery during the task occurred during intertrial interval, deliberation, or reward outcome phases, the latter of which was further divided into the three possible outcomes (small, safe; large, unpunished; large, punished). Inhibition of the BLA selectively during the deliberation phase decreased choice of the large, risky outcome (decreased risky choice). In contrast, BLA inhibition selectively during delivery of the large, punished outcome increased risky choice. Inhibition had no effect during the other phases, nor did laser delivery affect performance in control rats. Collectively, these data indicate that the BLA can either inhibit or promote choice of risky options, depending on the phase of the decision process in which it is active.
SIGNIFICANCE STATEMENT To date, most behavioral neuroscience research on neural mechanisms of decision making has used techniques that preclude assessment of distinct phases of the decision process. Here we show that optogenetic inhibition of the BLA has opposite effects on choice behavior in a rat model of risky decision making, depending on the phase in which inhibition occurs. BLA inhibition during a period of deliberation between small, safe and large, risky outcomes decreased risky choice. In contrast, BLA inhibition during receipt of the large, punished outcome increased risky choice. These findings highlight the importance of temporally targeted approaches to understand neural substrates underlying complex cognitive processes. More importantly, they reveal novel information about dynamic BLA modulation of risky choice.
Frontal Eye Field Inactivation Diminishes Superior Colliculus Activity, But Delayed Saccadic Accumulation Governs Reaction Time Increases
Stochastic accumulator models provide a comprehensive framework for how neural activity could produce behavior. Neural activity within the frontal eye fields (FEFs) and intermediate layers of the superior colliculus (iSC) support such models for saccade initiation by relating variations in saccade reaction time (SRT) to variations in such parameters as baseline, rate of accumulation of activity, and threshold. Here, by recording iSC activity during reversible cryogenic inactivation of the FEF in four male nonhuman primates, we causally tested which parameter(s) best explains concomitant increases in SRT. While FEF inactivation decreased all aspects of ipsilesional iSC activity, decreases in accumulation rate and threshold poorly predicted accompanying increases in SRT. Instead, SRT increases best correlated with delays in the onset of saccade-related accumulation. We conclude that FEF signals govern the onset of saccade-related accumulation within the iSC, and that the onset of accumulation is a relevant parameter for stochastic accumulation models of saccade initiation.
SIGNIFICANCE STATEMENT The superior colliculus (SC) and frontal eye fields (FEFs) are two of the best-studied areas in the primate brain. Surprisingly, little is known about what happens in the SC when the FEF is temporarily inactivated. Here, we show that temporary FEF inactivation decreases all aspects of functionally related activity in the SC. This combination of techniques also enabled us to relate changes in SC activity to concomitant increases in saccadic reaction time (SRT). Although stochastic accumulator models relate SRT increases to reduced rates of accumulation or increases in threshold, such changes were not observed in the SC. Instead, FEF inactivation delayed the onset of saccade-related accumulation, emphasizing the importance of this parameter in biologically plausible models of saccade initiation.
Orientation Tuning of Correlated Activity in the Developing Lateral Geniculate Nucleus
Neural circuits and the cells that comprise them undergo developmental changes in the spatial organization of their connections and in their temporal response properties. Within the lateral geniculate nucleus (LGN) of the dorsal thalamus, these changes have pronounced effects on the spatiotemporal receptive fields (STRFs) of neurons. An open and unresolved question is how STRF maturation affects stimulus-evoked correlated activity between pairs of LGN neurons during development. This is an important question to answer because stimulus-evoked correlated activity likely plays a role in establishing the specificity of thalamocortical connectivity and the receptive fields (RFs) of postsynaptic cortical neurons. Using multielectrode recording methods and white noise stimuli, we recorded neural activity from ensembles of LGN neurons in cats across early development. As expected, there was a progressive maturation of the spatial and temporal properties of visual responses. Using drifting bar stimuli and cross-correlation analysis, we also determined the orientation-tuning bandwidth of correlated activity between pairs of LGN neurons at different stages of development (Sillito and Jones, 2002; Andolina et al., 2007; Stanley et al., 2012; Kelly et al., 2014). Despite the larger RFs and slower responses of immature LGN neurons compared with mature neurons, our results show that correlated activity in the LGN was as tightly tuned for orientation early in development as it was in the adult. Closer examination revealed this age-invariant orientation tuning of correlated activity likely involves cellular mechanisms related to spike fatigue in young animals and a progressive decrease in response latency with development.
SIGNIFICANCE STATEMENT Orientation tuning is a fundamental property of neurons in primary visual cortex. An important and unresolved question is how orientation tuning emerges during brain development. This study explores a potential mechanism for the establishment of orientation tuning based on correlated activity patterns among ensembles of maturing neurons in the lateral geniculate nucleus (LGN) of the thalamus. Results show that correlated activity between pairs of LGN neurons is more tightly tuned than predictions based simply on receptive field size, indicating that correlated activity has the properties needed to play an important role in the development of geniculocortical circuits and the emergence of cortical orientation tuning.
HuD and the Survival Motor Neuron Protein Interact in Motoneurons and Are Essential for Motoneuron Development, Function, and mRNA Regulation
Motoneurons establish a critical link between the CNS and muscles. If motoneurons do not develop correctly, they cannot form the required connections, resulting in movement defects or paralysis. Compromised development can also lead to degeneration because the motoneuron is not set up to function properly. Little is known, however, regarding the mechanisms that control vertebrate motoneuron development, particularly the later stages of axon branch and dendrite formation. The motoneuron disease spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein leading to defects in vertebrate motoneuron development and synapse formation. Here we show using zebrafish as a model system that SMN interacts with the RNA binding protein (RBP) HuD in motoneurons in vivo during formation of axonal branches and dendrites. To determine the function of HuD in motoneurons, we generated zebrafish HuD mutants and found that they exhibited decreased motor axon branches, dramatically fewer dendrites, and movement defects. These same phenotypes are present in animals expressing low levels of SMN, indicating that both proteins function in motoneuron development. HuD binds and transports mRNAs and one of its target mRNAs, Gap43, is involved in axonal outgrowth. We found that Gap43 was decreased in both HuD and SMN mutants. Importantly, transgenic expression of HuD in motoneurons of SMN mutants rescued the motoneuron defects, the movement defects, and Gap43 mRNA levels. These data support that the interaction between SMN and HuD is critical for motoneuron development and point to a role for RBPs in SMA.
SIGNIFICANCE STATEMENT In zebrafish models of the motoneuron disease spinal muscular atrophy (SMA), motor axons fail to form the normal extent of axonal branches and dendrites leading to decreased motor function. SMA is caused by low levels of the survival motor neuron (SMN) protein. We show in motoneurons in vivo that SMN interacts with the RNA binding protein, HuD. Novel mutants reveal that HuD is also necessary for motor axonal branch and dendrite formation. Data also revealed that both SMN and HuD affect levels of an mRNA involved in axonal growth. Moreover, expressing HuD in SMN-deficient motoneurons can rescue the motoneuron development and motor defects caused by low levels of SMN. These data support that SMN:HuD complexes are essential for normal motoneuron development and indicate that mRNA handling is a critical component of SMA.
Why Do Irrelevant Alternatives Matter? An fMRI-TMS Study of Context-Dependent Preferences
Both humans and animals are known to exhibit a violation of rationality known as "decoy effect": introducing an irrelevant option (a decoy) can influence choices among other (relevant) options. Exactly how and why decoys trigger this effect is not known. It may be an example of fast heuristic decision-making, which is adaptive in natural environments, but may lead to biased choices in certain markets or experiments. We used fMRI and transcranial magnetic stimulation to investigate the neural underpinning of the decoy effect of both sexes. The left ventral striatum was more active when the chosen option dominated the decoy. This is consistent with the hypothesis that the presence of a decoy option influences the valuation of other options, making valuation context-dependent even when choices appear fully rational. Consistent with the idea that control is recruited to prevent heuristics from producing biased choices, the right inferior frontal gyrus, often implicated in inhibiting prepotent responses, connected more strongly with the striatum when subjects successfully overrode the decoy effect and made unbiased choices. This is further supported by our transcranial magnetic stimulation experiment: subjects whose right inferior frontal gyrus was temporarily disrupted made biased choices more often than a control group. Our results suggest that the neural basis of the decoy effect could be the context-dependent activation of the valuation area. But the differential connectivity from the frontal area may indicate how deliberate control monitors and corrects errors and biases in decision-making.
SIGNIFICANCE STATEMENT Standard theories of rational decision-making assume context-independent valuations of available options. Motivated by the importance of this basic assumption, we used fMRI to study how the human brain assigns values to available options. We found activity in the valuation area to be consistent with the hypothesis that values depend on irrelevant aspects of the environment, even for subjects whose choices appear fully rational. Such context-dependent valuations may lead to biased decision-making. We further found differential connectivity from the frontal area to the valuation area depending on whether biases were successfully overcome. This suggests a mechanism for making rational choices despite the potential bias. Further support was obtained by a transcranial magnetic stimulation experiment, where subjects whose frontal control was temporarily disrupted made biased choices more often than a control group.
Recruitment of Foveal Retinotopic Cortex During Haptic Exploration of Shapes and Actions in the Dark
The role of the early visual cortex and higher-order occipitotemporal cortex has been studied extensively for visual recognition and to a lesser degree for haptic recognition and visually guided actions. Using a slow event-related fMRI experiment, we investigated whether tactile and visual exploration of objects recruit the same "visual" areas (and in the case of visual cortex, the same retinotopic zones) and if these areas show reactivation during delayed actions in the dark toward haptically explored objects (and if so, whether this reactivation might be due to imagery). We examined activation during visual or haptic exploration of objects and action execution (grasping or reaching) separated by an 18 s delay. Twenty-nine human volunteers (13 females) participated in this study. Participants had their eyes open and fixated on a point in the dark. The objects were placed below the fixation point and accordingly visual exploration activated the cuneus, which processes retinotopic locations in the lower visual field. Strikingly, the occipital pole (OP), representing foveal locations, showed higher activation for tactile than visual exploration, although the stimulus was unseen and location in the visual field was peripheral. Moreover, the lateral occipital tactile–visual area (LOtv) showed comparable activation for tactile and visual exploration. Psychophysiological interaction analysis indicated that the OP showed stronger functional connectivity with anterior intraparietal sulcus and LOtv during the haptic than visual exploration of shapes in the dark. After the delay, the cuneus, OP, and LOtv showed reactivation that was independent of the sensory modality used to explore the object. These results show that haptic actions not only activate "visual" areas during object touch, but also that this information appears to be used in guiding grasping actions toward targets after a delay.
SIGNIFICANCE STATEMENT Visual presentation of an object activates shape-processing areas and retinotopic locations in early visual areas. Moreover, if the object is grasped in the dark after a delay, these areas show "reactivation." Here, we show that these areas are also activated and reactivated for haptic object exploration and haptically guided grasping. Touch-related activity occurs not only in the retinotopic location of the visual stimulus, but also at the occipital pole (OP), corresponding to the foveal representation, even though the stimulus was unseen and located peripherally. That is, the same "visual" regions are implicated in both visual and haptic exploration; however, touch also recruits high-acuity central representation within early visual areas during both haptic exploration of objects and subsequent actions toward them. Functional connectivity analysis shows that the OP is more strongly connected with ventral and dorsal stream areas when participants explore an object in the dark than when they view it.
White Matter Structure in Older Adults Moderates the Benefit of Sleep Spindles on Motor Memory Consolidation
Sleep spindles promote the consolidation of motor skill memory in young adults. Older adults, however, exhibit impoverished sleep-dependent motor memory consolidation. The underlying pathophysiological mechanism(s) explaining why motor memory consolidation in older adults fails to benefit from sleep remains unclear. Here, we demonstrate that male and female older adults show impoverished overnight motor skill memory consolidation relative to young adults, with the extent of impairment being associated with the degree of reduced frontal fast sleep spindle density. The magnitude of the loss of frontal fast sleep spindles in older adults was predicted by the degree of reduced white matter integrity throughout multiple white matter tracts known to connect subcortical and cortical brain regions. We further demonstrate that the structural integrity of selective white matter fiber tracts, specifically within right posterior corona radiata, right tapetum, and bilateral corpus callosum, statistically moderates whether sleep spindles promoted overnight consolidation of motor skill memory. Therefore, white matter integrity within tracts known to connect cortical sensorimotor control regions dictates the functional influence of sleep spindles on motor skill memory consolidation in the elderly. The deterioration of white matter fiber tracts associated with human brain aging thus appears to be one pathophysiological mechanism influencing subcortical–cortical propagation of sleep spindles and their related memory benefits.
SIGNIFICANCE STATEMENT Numerous studies have shown that sleep spindle expression is reduced and sleep-dependent motor memory is impaired in older adults. However, the mechanisms underlying these alterations have remained unknown. The present study reveals that age-related degeneration of white matter within select fiber tracts is associated with reduced sleep spindles in older adults. We further demonstrate that, within these same fiber tracts, the degree of degeneration determines whether sleep spindles can promote motor memory consolidation. Therefore, white matter integrity in the human brain, more than age per se, determines the magnitude of decline in sleep spindles in later life and, with it, the success (or lack thereof) of sleep-dependent motor memory consolidation in older adults.
A Presynaptic Function of Shank Protein in Drosophila
Human genetic studies support that loss-of-function mutations in the SH3 domain and ankyrin repeat containing family proteins (SHANK1-3), the large synaptic scaffolding proteins enriched at the postsynaptic density of excitatory synapses, are causative for autism spectrum disorder and other neuropsychiatric disorders in humans. To better understand the in vivo functions of Shank and facilitate dissection of neuropathology associated with SHANK mutations in human, we generated multiple mutations in the Shank gene, the only member of the SHANK family in Drosophila melanogaster. Both male and female Shank null mutants were fully viable and fertile with no apparent morphological or developmental defects. Expression analysis revealed apparent enrichment of Shank in the neuropils of the CNS. Specifically, Shank coexpressed with another PSD scaffold protein, Homer, in the calyx of mushroom bodies in the brain. Consistent with high expression in mushroom body calyces, Shank mutants show an abnormal calyx structure and reduced olfactory acuity. These morphological and functional phenotypes were fully rescued by pan-neuronal reexpression of Shank, and only partially rescued by presynaptic but no rescue by postsynaptic reexpression of Shank. Our findings thus establish a previously unappreciated presynaptic function of Shank.
SIGNIFICANCE STATEMENT Mutations in SHANK family genes are causative for idiopathic autism spectrum disorder. To understand the neural function of Shank, a large scaffolding protein enriched at the postsynaptic densities, we examined the role of Drosophila Shank in synapse development at the peripheral neuromuscular junctions and the central mushroom body calyx. Our results demonstrate that, in addition to its conventional postsynaptic function, Shank also acts presynaptically in synapse development in the brain. This study offers novel insights into the synaptic role of Shank.
Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial {beta}-Endorphin Expression
The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial β-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced β-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-α, IL-1β, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-α, IL-1β, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and β-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated β-endorphin expression in cultured primary microglia, whereas treatment with β-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of β-endorphin in vitro and in vivo and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38β, but not siRNA/p38α, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-α mRNA using siRNA fully inhibited exenatide-induced spinal microglial β-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and β-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated β-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38β/CREB and subsequent IL-10 receptor/STAT3 signal pathways.
SIGNIFICANCE STATEMENT Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor β-endorphin from microglia. GLP-1 receptor agonism induces β-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and β-endorphin expression subsequently through the Gs-cAMP/PKA/p38β/CREB and IL-10/IL-10 receptor-α/STAT3 signal transduction pathways.
Stimulation of the Locus Ceruleus Modulates Signal-to-Noise Ratio in the Olfactory Bulb
Norepinephrine (NE) has been shown to influence sensory, and specifically olfactory processing at the behavioral and physiological levels, potentially by regulating signal-to-noise ratio (S/N). The present study is the first to look at NE modulation of olfactory bulb (OB) in regards to S/N in vivo. We show, in male rats, that locus ceruleus stimulation and pharmacological infusions of NE into the OB modulate both spontaneous and odor-evoked neural responses. NE in the OB generated a non-monotonic dose–response relationship, suppressing mitral cell activity at high and low, but not intermediate, NE levels. We propose that NE enhances odor responses not through direct potentiation of the afferent signal per se, but rather by reducing the intrinsic noise of the system. This has important implications for the ways in which an animal interacts with its olfactory environment, particularly as the animal shifts from a relaxed to an alert behavioral state.
SIGNIFICANCE STATEMENT Sensory perception can be modulated by behavioral states such as hunger, fear, stress, or a change in environmental context. Behavioral state often affects neural processing via the release of circulating neurochemicals such as hormones or neuromodulators. We here show that the neuromodulator norepinephrine modulates olfactory bulb spontaneous activity and odor responses so as to generate an increased signal-to-noise ratio at the output of the olfactory bulb. Our results help interpret and improve existing ideas for neural network mechanisms underlying behaviorally observed improvements in near-threshold odor detection and discrimination.
Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury
Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.
SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI.
Deficiency of the Thyroid Hormone Transporter Monocarboxylate Transporter 8 in Neural Progenitors Impairs Cellular Processes Crucial for Early Corticogenesis
Thyroid hormones (THs) are essential for establishing layered brain structures, a process called corticogenesis, by acting on transcriptional activity of numerous genes. In humans, deficiency of the monocarboxylate transporter 8 (MCT8), involved in cellular uptake of THs before their action, results in severe neurological abnormalities, known as the Allan–Herndon–Dudley syndrome. While the brain lesions predominantly originate prenatally, it remains unclear how and when exactly MCT8 dysfunction affects cellular processes crucial for corticogenesis. We investigated this by inducing in vivo RNAi vector-based knockdown of MCT8 in neural progenitors of the chicken optic tectum, a layered structure that shares many developmental features with the mammalian cerebral cortex. MCT8 knockdown resulted in cellular hypoplasia and a thinner optic tectum. This could be traced back to disrupted cell-cycle kinetics and a premature shift to asymmetric cell divisions impairing progenitor cell pool expansion. Birth-dating experiments confirmed diminished neurogenesis in the MCT8-deficient cell population as well as aberrant migration of both early-born and late-born neuroblasts, which could be linked to reduced reelin signaling and disorganized radial glial cell fibers. Impaired neurogenesis resulted in a reduced number of glutamatergic and GABAergic neurons, but the latter additionally showed decreased differentiation. Moreover, an accompanying reduction in untransfected GABAergic neurons suggests hampered intercellular communication. These results indicate that MCT8-dependent TH uptake in the neural progenitors is essential for early events in corticogenesis, and help to understand the origin of the problems in cortical development and function in Allan–Herndon–Dudley syndrome patients.
SIGNIFICANCE STATEMENT Thyroid hormones (THs) are essential to establish the stereotypical layered structure of the human forebrain during embryonic development. Before their action on gene expression, THs require cellular uptake, a process facilitated by the TH transporter monocarboxylate transporter 8 (MCT8). We investigated how and when dysfunctional MCT8 can induce brain lesions associated with the Allan–Herndon–Dudley syndrome, characterized by psychomotor retardation. We used the layered chicken optic tectum to model cortical development, and induced MCT8 deficiency in neural progenitors. Impaired cell proliferation, migration, and differentiation resulted in an underdeveloped optic tectum and a severe reduction in nerve cells. Our data underline the need for MCT8-dependent TH uptake in neural progenitors and stress the importance of local TH action in early development.
Transition: Message from the Editor-in-Chief
With this issue I will step down as Editor-In-Chief of Neuro-Oncology. My recent election as President of the Society for Neuro-Oncology precludes me from holding both positions at the same time. I will always be grateful for the tremendous privilege of serving as Editor-In-Chief for the past four years. With the support of the neuro-oncology community, the Society for Neuro-Oncology (SNO), the European Association of Neuro-Oncology (EANO), and the Japanese Society for Neuro-Oncology (JSNO) the journal has flourished. Neuro-Oncology has increasingly become a forum for important research in the field, with the impact factor rising to 7.786 and submissions on track to exceed 900 this year. This success would not be possible without the dedication and hard work of our Managing Editor, Elizabeth Martinson, the team at Oxford University Press led by Phil Bishop, and the support and invaluable guidance of our Executive Editors (Kenneth Aldape, Ryo Nishikawa, and Riccardo Soffietti), our Associate Editors (Terri Armstrong, Karla Ballman, E. Antonio Chiocca, Frank Furnari, Monika Hegi, Koichi Ichimura, Mark Kieran, Minesh Mehta, Whitney Pope, David Schiff, and Wolfgang Wick), and our Editorial Board. I will always be indebted to them.
IDH mutation testing in gliomas—where do we draw the line?
See the article by DeWitt et al on pages 1640–1650.
Corrigenda
Corrigendum to Zhang et al. HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro Oncol (doi: 10.1093/neuonc/not131) first published online November 7, 2013.
Putting “multiforme” back into glioblastoma: intratumoral transcriptome heterogeneity is a consequence of its complex morphology
genomicsglioblastomaheterogeneityhistologytranscriptome
Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study
Abstract
Background
Patients treated for medulloblastoma who experience posterior fossa syndrome (PFS) demonstrate increased risk for neurocognitive impairment at one year post diagnosis. The aim of the study was to examine longitudinal trajectories of neuropsychological outcomes in patients who experienced PFS compared with patients who did not. Methods
Participants were 36 patients (22 males) who experienced PFS and 36 comparison patients (21 males) who were matched on age at diagnosis and treatment exposure but did not experience PFS. All patients underwent serial evaluation of neurocognitive functioning spanning 1 to 5 years post diagnosis. Results
The PFS group demonstrated lower estimated mean scores at 1, 3, and 5 years post diagnosis on measures of general intellectual ability, processing speed, broad attention, working memory, and spatial relations compared with the non-PFS group. The PFS group exhibited estimated mean scores that were at least one standard deviation below the mean for intellectual ability, processing speed, and broad attention across all time points and for working memory by 5 years post diagnosis. Processing speed was stable over time. Attention and working memory declined over time. Despite some change over time, caregiver ratings of executive function and behavior problem symptoms remained within the average range. Conclusion
Compared with patients who do not experience PFS, patients who experience PFS exhibit greater neurocognitive impairment, show little recovery over time, and decline further in some domains. Findings highlight the particularly high risk for long-term neurocognitive problems in patients who experience PFS and the need for close follow-up and intervention.Corrigenda
Corrigendum to Raleigh et al. Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome. Neuro Oncol (2017) 19 (1): 78–88 first published online June 9, 2016.
A description of familial clustering of meningiomas in the Utah population
Abstract
Background
Meningiomas are common intracranial tumors in adults, yet the genetics and cause of sporadic meningiomas are not well understood. Few familial clusters have been reported. The aim of this study was to investigate the familiality of meningiomas within the Utah Population Database. Methods
Meningioma cases reported in the Utah Cancer Registry were identified. Relative risk of their relatives was calculated. All possible cases were assessed with the Genealogical Index of Familiality (GIF), which measures average pairwise relatedness of all possible pairs using the Malecot coefficient of kinship. Clusters of cases descending from a common ancestor were identified. Results
Eight hundred fifty-eight meningioma cases were reported. The relative risk of a first- or second-degree relative was 3.13 (95% CI: 1.67, 5.36) or 2.28 (1.30, 3.70), respectively. The GIF statistic demonstrated a clear excess of relationships for genetic distance <4 (closer than first cousins). We identified 920 pedigrees, including 2–21 meningioma cases. One hundred eighty-nine of these pedigrees, including 2–15 cases, had a significant excess (P < 0.05) of meningioma cases over what was expected. Conclusions
This Utah population–based analysis of meningiomas shows clear evidence of familial clustering and supports both a familial and a germline variant basis for meningioma. These clusters may allow identification of genes likely to contribute to tumorigenesis in high-risk pedigrees. These relative risk data provide the basis for further investigations of genetic contributions to meningioma. These data may contribute to developing a basis for determining screening criteria of higher-risk pedigrees for the presence of meningiomas.Outcome of patients with intracranial non-germinomatous germ cell tumors—lessons from the SIOP-CNS-GCT-96 trial
Abstract
Background
Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy. Methods
All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites. Results
Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort. Conclusion
In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease.Cost-effectiveness of radiation and chemotherapy for high-risk low-grade glioma
Abstract
Background
The addition of procarbazine, lomustine, vincristine (PCV) chemotherapy to radiotherapy (RT) for patients with high-risk (≥40 y old or subtotally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy. Methods
A decision tree with an integrated 3-state Markov model was created to follow patients with high-risk LGG after surgery treated with RT versus RT+PCV. Patients existed in one of 3 health states: stable, progressive, or dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the health care perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters. Results
Modeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs 5.17 for RT alone) at an incremental cost of $48635 ($188234 for RT+PCV vs $139598 for RT alone), resulting in an incremental cost-effectiveness ratio of $10186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100000 per QALY. Conclusion
The addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG.Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations
Abstract
Background
Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines. Methods
From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods. Results
In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients <55 years. Applying the independently confirmed age cutoff of 55 years to glioblastoma patients (64%) would result in $403200 saved (43%). By not performing sequencing in patients ≥55 years, the turn-around time to final integrated neuropathological diagnosis is reduced by 53%, allowing these patients to gain earlier benefits from personalized genomic medicine. Conclusion
The negligible prevalence of noncanonical IDH mutations in glioblastoma patients ≥55 years argues against universal IDH sequencing in this population. We predict that adoption of this age-based sequencing cutoff recommendation from the 2016 WHO guidelines will result in significant cost and time savings throughout the global health care system.Corrigenda
Corrigendum to Zhou et al. MRI features predict survival and molecular markers in diffuse lower-grade gliomas. Neuro Oncol (2017) 19 (6): 862–870 first published online January 24, 2017.
Corrigenda
Corrigendum to Arif et al. VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties. Neuro Oncol (doi:10.1093/neuonc/now297) first published online February 28, 2017.
Corrigenda
Corrigendum to Cicone et al. Comment to Hatzoglou et al: dynamic contrast-enhanced MRI perfusion versus 18FDG PET/CT in differentiating brain tumor progression from radiation injury. Neuro Oncol (doi:10.1093/neuonc/now283) first published online 10 February 2017.
PET imaging in patients with meningioma—report of the RANO/PET Group
Abstract
Meningiomas are the most frequent nonglial primary brain tumors and represent about 30% of brain tumors. Usually, diagnosis and treatment planning are based on neuroimaging using mainly MRI or, rarely, CT. Most common treatment options are neurosurgical resection and radiotherapy (eg, radiosurgery, external fractionated radiotherapy). For follow-up after treatment, a structural imaging technique such as MRI or CT is used. However, these structural imaging modalities have limitations, particularly in terms of tumor delineation as well as diagnosis of posttherapeutic reactive changes. Molecular imaging techniques such as PET can characterize specific metabolic and cellular features which may provide clinically relevant information beyond that obtained from structural MR or CT imaging alone. Currently, the use of PET in meningioma patients is steadily increasing. In the present article, we provide recommendations for the use of PET imaging in the clinical management of meningiomas based on evidence generated from studies being validated by histology or clinical course.Golgi phosphoprotein 3 promotes glioma progression via inhibiting Rab5-mediated endocytosis and degradation of epidermal growth factor receptor
Abstract
Background
Golgi phosphoprotein 3 (GOLPH3) is associated with worse prognosis of gliomas, but its role and mechanism in glioma progression remain largely unknown. This study aimed to explore the role and mechanism of GOLPH3 in glioma progression. Methods
The expression of GOLPH3 in glioma tissues was detected by quantitative PCR, immunoblotting, and immunohistochemistry. GOLPH3's effect on glioma progression was examined using cell growth assays and an intracranial glioma model. The effect of GOLPH3 on epidermal growth factor receptor (EGFR) stability, endocytosis, and degradation was examined by immunoblotting and immunofluorescence. The activity of Rab5 was checked by glutathione S-transferase pulldown assay. Results
GOLPH3 was upregulated in gliomas, and its downregulation inhibited glioma cell proliferation both in vitro and in vivo. Furthermore, GOLPH3 depletion dampened EGFR signaling by enhancing EGFR endocytosis, driving EGFR into late endosome and promoting lysosome-mediated degradation. Interestingly, GOLPH3 bound to Rab5 and GOLPH3 downregulation promoted the activation of Rab5. In addition, Rab5 depletion abolished the effect of GOLPH3 on EGFR endocytosis and degradation. Conclusion
Our results imply that GOLPH3 promotes glioma cell proliferation via inhibiting Rab5-mediated endocytosis and degradation of EGFR, thereby activating the phosphatidylinositol-3 kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) signaling pathway. We find a new mechanism by which GOLPH3 promotes tumor progression through regulating cell surface receptor trafficking. Extensive and intensive understanding of the role of GOLPH3 in glioma progression may provide an opportunity to develop a novel molecular therapeutic target for gliomas.Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis
Abstract
Background
Glioblastoma represents an archetypal example of a heterogeneous malignancy. To understand the diverse molecular consequences of this complex tumor ecology, we analyzed RNA-seq data generated from commonly identified intratumoral structures in glioblastoma enriched using laser capture microdissection. Methods
Raw gene-level values of fragments per kilobase of transcript per million reads mapped and the associated clinical data were acquired from the publicly available Ivy Glioblastoma Atlas Project database and analyzed using MetaboAnalyst (v3.0). The database includes gene expression data generated from multiple structural features commonly identified in glioblastoma enriched by laser capture microdissection. Results
We uncovered a relationship between subtype heterogeneity in glioblastoma and its unique tumor microenvironment, with infiltrating cells harboring a proneural signature while the mesenchymal subtype was enriched in perinecrotic regions. When evaluating the tumors' transcriptional profiles in the context of their derived structural regions, there was a relatively small amount of intertumoral heterogeneity in glioblastoma, with individual regions from different tumors clustering tightly together. Analyzing the transcriptional profiles in the context of evolutionary progression identified unique cellular programs associated with specific phases of gliomagenesis. Mediators of cell signaling and cell cycle progression appear to be critical events driving proliferation in the tumor core, while in addition to a multiplex strategy for promoting angiogenesis and/or an immune-tolerant environment, transformation to perinecrotic zones involved global metabolic alterations. Conclusion
These findings suggest that intratumoral heterogeneity in glioblastoma is a conserved, predictable consequence to its complex microenvironment, and combinatorial approaches designed to target these unequivocally present tumor biomes may lead to therapeutic gains.Diagnostic challenges in meningioma
Abstract
Advances in molecular profiling and the application of advanced imaging techniques are currently refreshing diagnostic considerations in meningioma patients. Not only technical refinements but also sophisticated histopathological and molecular studies have the potential to overcome some of the challenges during meningioma management. Exact tumor delineation, assessment of tumor growth, and pathophysiological parameters were recently addressed by "advanced" MRI and PET. In the field of neuropathology, high-throughput sequencing and DNA methylation analysis of meningioma tissue has greatly advanced the knowledge of molecular aberrations in meningioma patients. These techniques allow for more reliable prediction of the biological behavior and clinical course of meningiomas and subsequently have the potential to guide individualized meningioma therapy. However, higher costs and longer duration of full molecular work-up compared with histological assessment may delay the implementation into clinical routine.This review highlights the diagnostic challenges of meningiomas from both the neuroimaging as well as the neuropathological side and presents the latest scientific achievements and studies potentially helping in overcoming these challenges. It complements the recently proposed European Association of Neuro-Oncology guidelines on treatment and diagnosis of meningiomas by integrating data on nonstandard imaging and molecular assessments most likely impacting the future.Not your garden-variety bacteremia: Gardnerella in an immunocompromised man
Abstract
Gardnerella is a common colonizer of the genitourinary tract, but systemic Gardnerella infections are rare and are usually associated with surgical instrumentation of the genitourinary tract. Presented is a case of symptomatic and transient Gardnerella bacteremia in an adult male patient with AIDS following a traumatic urinary catheter insertion.Augmented marker tracking for peri-acetabular osteotomy surgery
Abstract
Objective
To develop a hybrid augmented marker-based navigation system for acetabular reorientation during peri-acetabular osteotomy (PAO).
Methods
The system consists of a tracking unit attached to the patient's pelvis, augmented marker attached to the acetabular fragment and a host computer to do all the computations and visualization. The augmented marker is comprised of an external planar Aruco marker facing toward the tracking unit and an internal inertial measurement unit (IMU) to measure its orientation. The orientation output from the IMU is sent to the host computer. The tracking unit streams a live video of the augmented marker to the host computer, where the planar marker is detected and its pose is estimated. A Kalman filter-based sensor fusion combines the output from marker tracking and the IMU. We validated the proposed system using a plastic bone study and a cadaver study. Every time, we compared the inclination and anteversion values measured by the proposed system to those from a previously developed optical tracking-based navigation system.
Results
Mean absolute differences for inclination and anteversion were 1.34 ( \(\pm \,1.50\) ) and 1.21 ( \(\pm \, 1.07\) ) \(^\circ \) , respectively, for the cadaver study. Mean absolute differences were 1.63 ( \(\pm \,1.48\) ) and 1.55 ( \(\pm \,1.49\) ) \(^\circ \) for inclination and anteversion for the plastic bone study. In both validation studies, very strong correlations were observed.
Conclusion
We successfully demonstrated the feasibility of our system to measure the acetabular orientation during PAO.
Case study: Scoliosis in a Bonobo (Pan paniscus)
Abstract
Differential diagnosis of observed morphological features on an adult male bonobo skeleton was consistent with idiopathic scoliosis. Directional asymmetry was an order of magnitude higher compared with asymptomatic skeletons. This possible case of idiopathic scoliosis contributes to data that suggest a weaker tie between bipedalism and scoliosis than previously hypothesized.
What the Jeweller’s Hand Tells the Jeweller’s Brain: Tool Use, Creativity and Embodied Cognition
Abstract
The notion that human activity can be characterised in terms of dynamic systems is a well-established alternative to motor schema approaches. Key to a dynamic systems approach is the idea that a system seeks to achieve stable states in the face of perturbation. While such an approach can apply to physical activity, it can be challenging to accept that dynamic systems also describe cognitive activity. In this paper, we argue that creativity, which could be construed as a 'cognitive' activity par excellence, arises from the dynamic systems involved in jewellery making. Knowing whether an action has been completed to a 'good' standard is a significant issue in considering acts in creative disciplines. When making a piece of jewellery, there a several criteria which can define 'good'. These are not only the aesthetics of the finished piece but also the impact of earlier actions on subsequent ones. This suggests that the manner in which an action is coordinated is influenced by the criteria by which the product is judged. We see these criteria as indicating states for the system, e.g. in terms of a space of 'good' outcomes and a complementary space of 'bad' outcomes. The skill of the craftworker is to navigate this space of available states in such a way as to minimise risk, effort and other costs and maximise benefit and quality of the outcome. In terms of postphenomonology, this paper explores Ihde's human-technology relations and relates these to the concepts developed here.
Long-term effect of the insoluble thread-lifting technique.
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Long-term effect of the insoluble thread-lifting technique.
Clin Cosmet Investig Dermatol. 2017;10:483-491
Authors: Fukaya M
Abstract
Background: Although the thread-lifting technique for sagging faces has become more common and popular, medical literature evaluating its effects is scarce. Studies on its long-term prognosis are particularly uncommon.
Patients and methods: One hundred individuals who had previously undergone insoluble thread-lifting were retrospectively investigated. Photos in frontal and oblique views from the first and last visits were evaluated by six female individuals by guessing the patients' ages. The mean guessed age was defined as the apparent age, and the difference between the real and apparent ages was defined as the youth value. The difference between the youth values before and after the thread-lift was defined as the rejuvenation effect and analyzed in relation to the time since the operation, the number of threads used and the number of thread-lift operations performed.
Results: The rejuvenation effect decreased over the first year after the operation, but showed an increasing trend thereafter. The rejuvenation effect increased with the number of threads used and the number of thread-lift operations performed.
Conclusion: The insoluble thread-lifting technique appears to be associated with both early and late effects. The rejuvenation effect appeared to decrease during the first year, but increased thereafter. A multicenter trial is necessary to confirm these findings.
PMID: 29180885 [PubMed]
Redefining face contour with a novel anti-aging cosmetic product: an open-label, prospective clinical study.
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Redefining face contour with a novel anti-aging cosmetic product: an open-label, prospective clinical study.
Clin Cosmet Investig Dermatol. 2017;10:473-482
Authors: Garre A, Martinez-Masana G, Piquero-Casals J, Granger C
Abstract
Background: Skin aging is accelerated by multiple extrinsic factors: ultraviolet radiation, smoking and pollution increase oxidative activity, damaging cellular and extracellular components such as DNA, proteins, and lipids. With age, collagen and hyaluronic acid levels decline, resulting in loss of elasticity and moisture of the skin. Over time this damage leads to characteristic signs that make the skin look older: altered facial contour, sagging skin, wrinkles, and an uneven complexion. This study evaluated the anti-aging effects of a new facial cream formulated with carnosine, Alteromonas ferment extract, crosspolymer hyaluronic acid, and a tripeptide.
Methods: An open-label intra-individual study to assess the anti-aging efficacy of the investigational product in 33 women aged 45 to 65 years. The product was applied twice daily for 56 days. Facial contour and skin deformation, elasticity, hydration, and complexion were measured with specialized equipment at baseline and days 28 and 56. Additionally, subjects completed questionnaires at days 28 and 56 on the perceived efficacy and cosmetic characteristics of the product.
Results: After 56 days of use of the investigational product, a redefining effect was observed, with a significant decrease in sagging jawline (7%). Skin was significantly more hydrated (12%), firmer (29%), and more elastic (20%) (P<0.001 for all). On complexion assessment, skin texture (a measure of skin smoothness) and spots (brown and red skin lesions) also improved significantly (12% and 6% decrease, respectively). In the subjective self-evaluation, the majority of subjects reported that the skin was visibly tightened and more elastic, flexible, and moisturized (91%, 88%, 91%, and 90%, respectively). The product was well tolerated with no adverse events reported during the study.
Conclusion: This new cosmetic product demonstrated anti-aging effects after 56 days of use, most notably a redefined facial contour and improved complexion. It is a safe and effective anti-aging product.
PMID: 29180884 [PubMed]
Revision Surgery for Zygoma Reduction: Causes, Indications, Solutions, and Results from a 5-Year Review of 341 Cases.
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Revision Surgery for Zygoma Reduction: Causes, Indications, Solutions, and Results from a 5-Year Review of 341 Cases.
Aesthetic Plast Surg. 2017 Feb;41(1):161-170
Authors: Lee SW, Jeong YW, Myung Y
Abstract
BACKGROUND: Many patients undergo a revision surgery after malar reduction, which is one of the most popular aesthetic surgeries in Asia. We reviewed the leading causes of revision for malar reduction surgery to establish proper indications for revision, seek adequate surgical strategies, and share the results from revision surgical cases.
METHODS: A retrospective review was conducted involving 341 patients who underwent malar reduction reoperation between March 2010 and June 2015. Surgical strategies were decided based upon specific problems and complaints from the previous surgery. Facial photographs, cephalography, and computed tomography images were analyzed, and a patient satisfaction survey was conducted before and after the surgery.
RESULTS: A total of 341 patients (321 women, 20 men; average age, 26.6 years, range 18-40 years) were included. The main causes of reoperations were subjective dissatisfaction and nonunion-related symptoms. Undercorrection of the zygomatic body and arch (n = 175, 51.3%) was the most frequent reason for dissatisfaction. The patients underwent revision surgeries via different techniques and strategies based on previous problems from primary surgery, and postoperative patient satisfaction was high. Complications occurred in 35 patients (10.3%) after revision.
CONCLUSIONS: Based on the results of this study, patient dissatisfaction with the procedure can be minimized beforehand through accurate goal identification and careful planning. Bone nonunion is usually due to excessive bone resection during zygoma reduction surgery. Careful selection of the reposition site and appropriate fixation based on a thorough understanding of masseter action are essential in ensuring satisfactory outcomes without adverse side effects.
LEVEL OF EVIDENCE IV: 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 http://ift.tt/18t7xNj .
PMID: 28032152 [PubMed - indexed for MEDLINE]
EANO guidelines for the diagnosis and treatment of ependymal tumors
Abstract
Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level of evidence of diagnostic and therapeutic interventions is higher in the pediatric compared with the adult patient population.The diagnosis and disease staging is performed by craniospinal MRI. Tumor classification is achieved by histological and molecular diagnostic assessment of tissue specimens according to the World Health Organization (WHO) classification 2016. Surgery is the crucial initial treatment in both children and adults. In pediatric patients with intracranial ependymomas of WHO grades II or III, surgery is followed by local radiotherapy regardless of residual tumor volume. In adults, radiotherapy is employed in patients with anaplastic ependymoma WHO grade III, and in case of incomplete resection of WHO grade II ependymoma. Chemotherapy alone is reserved for young children <12 months and for adults with recurrent disease when further surgery and irradiation are no longer feasible. A gross total resection is the mainstay of treatment in spinal ependymomas, and radiotherapy is reserved for incompletely resected tumors. Nine subgroups of ependymal tumors across different anatomical compartments (supratentorial, posterior fossa, spinal) and patient ages have been identified with distinct genetic and epigenetic alterations, and with distinct outcomes. These findings may lead to more precise diagnostic and prognostic assessments, molecular subgroup-adapted therapies, and eventually new recommendations pending validation in prospective studies.ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma
Abstract
The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.2017 Reviewer Acknowledgment List
The editors of Clinical Infectious Diseases thank the following reviewers for their time and efforts. The quality of the journal depends in large part on their expertise.
2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea
Abstract
These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea. They are not intended to replace physician judgement regarding specific patients or clinical or public health situations. This document does not provide detailed recommendations on infection prevention and control aspects related to infectious diarrhea.Erratum
An error appeared in the 1 September 2016 issue of the journal [Kalil AC, Metersky ML, Klompas M, et al. Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016; 63(5):e61–e111]. The online supplementary data file was not uploaded with the published articles. The supplementary data files are now available at http://ift.tt/2h95bN3.
A Population-Based Study of Recurrent Symptomatic Bordetella pertussis Infections in Children in California, 2010–2015
Abstract
Background
Natural infection with Bordetella pertussis is thought to result in 4–20 years of immunity against subsequent symptomatic pertussis infection. However, these estimates are based on studies in unvaccinated or whole-cell pertussis–vaccinated children. We conducted a population-based study of pertussis infection and reinfection during a 5-year period in California in an cohort vaccinated exclusively with acellular pertussis (aP) vaccine. Methods
California surveillance data were reviewed to identify all children with 2 reported incidents of pertussis with symptom onset between 1 January 2010 and 31 December 2015. Case investigation reports were reviewed, and children with ≥2 episodes of symptomatic pertussis infection that met the case definition were included. Results
Of 26259 pertussis cases reported in children (aged <18 years), 27 children met the inclusion criteria. Recurrent cases occurred among children of all ages; 5 (19%) were <6 months of age at the time of their first illness. The time from initial infection to reinfection was <1 year in 11 (41%) cases. Twenty-one children (78%) had received ≥3 doses of diphtheria and tetanus toxoids and aP vaccine at the time of their first pertussis infection, 1 (4%) had received 1 dose, and 5 (19%) were unvaccinated. Conclusions
Recurrent cases of pertussis infection are extremely rare. Based on this surveillance data, approximately 0.1% of children who were infected with pertussis experienced a clinically significant second episode of pertussis within 4 years. More research is needed to understand the immune response to B. pertussis infection in children vaccinated with aP vaccines.Undiagnosed Diabetes Mellitus in Community-Acquired Pneumonia: A Prospective Cohort Study
Abstract
Background
Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort. Methods
This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus. Results
Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35–4.45]), body mass index ≥25 kg/m2 (OR, 2.64 [95% CI, 1.48–4.72]), and hyperglycemia at admission (6–11 mM: OR, 2.93 [95% CI, 1.54–5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58–113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001). Conclusions
Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus.
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Publication date: Available online 25 July 2018 Source: Journal of Photochemistry and Photobiology B: Biology Author(s): Marco Ballestr...
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Editorial AJR Reviewers: Heartfelt Thanks From the Editors and Staff Thomas H. Berquist 1 Share + Affiliation: Citation: American Journal...
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