Summary: In recent years, there has been a growing emphasis placed on reducing length of hospital stay and health costs associated with breast surgery. Adequate pain control is an essential component of enhanced recovery after surgery. Postoperative pain management strategies include use of narcotic analgesia, non-narcotic analgesia, and local anesthetics. However, these forms of pain control have relatively brief durations of action and multiple-associated side effects. Intraoperative regional blocks have been effectively utilized in other areas of surgery but have been understudied in breast surgery. The aim of this article was to review various intraoperative techniques for regional anesthesia and local pain control in breast surgery and to highlight areas of future technique development.Τετάρτη 13 Δεκεμβρίου 2017
Intraoperative Techniques for the Plastic Surgeon to Improve Pain Control in Breast Surgery
Summary: In recent years, there has been a growing emphasis placed on reducing length of hospital stay and health costs associated with breast surgery. Adequate pain control is an essential component of enhanced recovery after surgery. Postoperative pain management strategies include use of narcotic analgesia, non-narcotic analgesia, and local anesthetics. However, these forms of pain control have relatively brief durations of action and multiple-associated side effects. Intraoperative regional blocks have been effectively utilized in other areas of surgery but have been understudied in breast surgery. The aim of this article was to review various intraoperative techniques for regional anesthesia and local pain control in breast surgery and to highlight areas of future technique development.
Antibiotic Prophylaxis After Immediate Breast Reconstruction: The Reality of its Efficacy
Purpose: Numerous techniques are used to prevent infection after immediate implant-based breast reconstruction. Postoperative antibiotic prophylaxis (PAP) is commonly prescribed to decrease the risk of reconstructive failure, despite conflicting evidence regarding its effectiveness. We sought to determine whether PAP decreases the risk of infection-related explantation in the setting of immediate prosthesis-based breast reconstruction. Methods: Using Truven MarketScan databases, we identified all patients who underwent immediate implant reconstruction between 1/2010-6/2014 with at least 6 months of follow-up. PAP was defined as any oral antibiotic course to be taken postoperatively based on prescriptions filled within 14 days prior to surgery through 24 hours post-discharge. Reconstructive failure defined as explantation due to infection was the primary outcome. Secondary outcomes of interest included wound complications, infection, and readmission for infection. Multivariable regression analyses controlled for demographic variables/comorbidities. Results: Of the 7,443 patients, 6,049 (81%) filled prescriptions for PAP. These patients were equally likely to develop a wound complication (OR=0.93 95%CI:0.71-1.23), infection (OR=0.89 95%CI:0.70-1.14), undergo explantation due to infection (OR=0.82 95%CI: 0.57-1.18), or require readmission for infection (OR=1.21 95%CI:0.82-1.78) compared to those who did not receive PAP. There was no significant difference in the risk of infection-related outcomes based on PAP duration. Conclusion: PAP was not associated with a reduced risk of infection or explantation following prosthesis-based breast reconstruction. Given rising rates of antibiotic resistance, focusing instead on technical considerations and the management of comorbid conditions may more effectively enhance the safety of breast reconstruction. Disclosure: This research was supported by a Mentored Clinical Investigator Award to Dr. Waljee through the Agency for Healthcare Research and Quality (1K08HS023313-01). Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 2K24-AR053120-06 (Dr. Kevin Chung). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was funded by the Chang Gung Memorial Hospital (project CORPG3G0111 and CORPG3G0161). This work was presented at the annual Plastic Surgery Research Council in 2017. Corresponding Author: Jennifer F. Waljee MD, MPH, MS, Michigan Medicine, Section of Plastic Surgery,, 2130 Taubman Center, SPC 5340, Ann Arbor, MI, 48109-5340, filip@med.umich.edu, Phone 734-998-6022, Fax 734-798-6696 ©2017American Society of Plastic Surgeons
Absorbable Antibiotic Beads Prophylaxis in Immediate Breast Reconstruction
Background: Breast reconstruction with tissue expander is the most common mode of reconstruction following mastectomy. Infection necessitating tissue expander removal is a significant complication leading to patient distress as well as increased health care costs. Methods: Over 3 years, 127 breast reconstructions with tissue expanders were performed by a single surgeon. Fifty-nine of these reconstructions were performed using a standardized protocol in which patients washed with chlorhexidine several days prior to surgery and received intravenous antibiotics preoperatively. Intraoperatively, the submuscular pocket was irrigated with triple antibiotic solution and the skin was re-prepped with povidone iodine prior to expander placement. This group was referred to as the preintervention group. Sixty-eight of the reconstructions were performed using the standardized protocol with the addition of biodegradable antibiotic beads (Stimulan ® with vancomycin and gentamicin) in the submuscular pocket. This group made up the post intervention group. The primary outcome was the rate of infection necessitating tissue expander removal. Results: Tissue expander loss due to infection was 11.9% in preintervention group and 1.5% in the post intervention group, (p=0.024). Higher body mass index was associated with a statistically significant increase in infections necessitating implant removal. Conclusions: The use of absorbable antibiotic beads in the submuscular pocket reduced the risk of periprosthetic implant infection necessitating implant removal by 8-fold. Financial Disclosure Statement: The authors have the following to disclose: Nothing Presented at (if applicable): Robert Ivy Plastic Surgery Meeting, Philadelphia, PA on April 22 2017 Absorbable Antibiotic Beads Prophylaxis in Immediate Breast Reconstruction Corresponding Author: Kenna M. Denise M.D F.A.C.S , 2350 Freedom Way Ste 107, York, PA. USA. e-mail address: dmkenna@comcast.net ©2017American Society of Plastic Surgeons
Indocyanine Green Angiography Use in Breast Reconstruction: A National Analysis of Outcomes and Cost in 110,320 Patients
Background: Indocyanine Green (ICG) angiography has gained popularity in breast reconstruction due to its ability to assess the viability of both mastectomy skin and tissue flaps. We aim to analyze trends and outcomes associated with the use of ICG angiography in breast reconstruction. Methods: Using 2012-2014 data from the Healthcare Cost and Utilization Project National Inpatient Sample, Agency for Healthcare Research and Quality, we identified breast reconstructions that were performed with or without the use of ICG angiography. Trends over time were assessed using the Cochran-Armitage test. Outcomes were assessed using logistic regression and generalized linear modeling. Results: Over the study period, 110,320 patients underwent breast reconstruction: 107,005 (97.0%) without the use of ICG and 3,315 (3.0%) with the use of ICG angiography. Indocyanine green angiography use increased over time: 750 patients (1.9%) in 2012, increasing to 1,275 patients (3.7%) in 2013 (p
Low Dose Insulin as an Anti-Scarring Therapy in Breast Surgery: A Randomised Controlled Trial
Background: The role of insulin in expediting wound healing is firmly established within the context of major trauma and burns however only limited clinical evidence exists as to its effects upon scar formation. This study aims to build upon previous laboratory work to examine the potential anti-scarring properties of insulin in a clinical environment. Methods: 91 patients undergoing bilateral aesthetic breast surgeries were recruited to receive low-dose insulin and placebo injections to the medial 3cm of their sub-mammary incisions within the context of a randomised, intra-patient, placebo controlled trial and scar quality was assessed at 3, 6, and 12-month reviews using the Manchester Scar Scale. Results: Across the cohort at 12-month review the insulin-treated scars had lower scar scores (p=0.055) compared to placebo. Sub-group analysis of individuals with heavier scars showed median scar scores were significantly lower for the insulin-treated scars in regards to both scar contour (p=0.048) and scar distortion (p=0.045). Conclusions: Sub-cutaneous insulin injections reduced the appearance of scarring in this study when compared to placebo. The greatest effect was seen in those participants who showed heavier scars and as such insulin has a role as an antiscarring therapy in individuals likely to be affected by heavier scarring. Further research is required to more precisely delineate what subjects may benefit most from this treatment. Acknowledgments: Jon Pleat. Director at Restore Burn & Research Foundation Di Lawrence-Watt. Emeritus Professor Brighton & Sussex Medical School Financial Disclosure Statement: None of the authors have anything to disclose and no funding was received for this article. Presented at: 2016 Winter BAPRAS meeting, London Trial Identification: South East Research Ethics Committee (REC reference 10/H1102/67). Corresponding Author:MJ Hallam, M.D, MRCS, BM, Department of Plastic Surgery, St John's Hospital, Livingston, Edinburgh, EH54 6PP, UK. mj_hallam@hotmail.co.uk ©2017American Society of Plastic Surgeons
The “Boomerang Lift”: A 3-Step Compartment Based Approach to the Youthful Cheek
Background: Autologous fat grafting (AFG) is an important tool for plastic surgeons treating the aging face. Malar augmentation with fat is often targeted to restore the youthful facial contour and provides support to the lower eyelid. The existence of distinct facial fat compartments suggests a step-wise approach may be appropriate in this regard [1]. Here we describe a three-step approach to malar augmentation using targeted deep malar fat compartmental augmentation, termed the "Boomerang Lift". Methods: Clinical patients undergoing AFG for malar augmentation were injected in three distinct deep malar fat compartments: 1. the lateral sub-orbicularis oculi fat (LSOOF), medial sub-orbicularis oculi fat (MSOOF), and lastly to the deep medial cheek (DMC) (n=9). Intra-operative 3D images were taken at baseline and following compartmental injections(Canfield® VECTRA H1). Images were overlaid between the augmented and baseline captures, and the 3D surface changes were analyzed, which represented the resulting "augmentation zone" (AZ). Results: 3D analysis of patients (n=9) demonstrated a unique pattern for AZ consistent across patients. The AZ resembled a boomerang, with the short tail supporting the medial lower lid, and the long tail extending laterally along the zygomatic arch. The upper border was restricted by the level of the naso-jugal interface, and the lower border was defined medially by the nasolabial fold and laterally by the level of the zygomatico-cutaneous ligament. Injections to the lateral and medial SOOF defined the boundaries of the boomerang shape, while the injection to the deep medial cheek provided maximum projection. Conclusions: This is the first description of deep malar augmentation zones described in clinical patients. 3D surface imaging was an ideal method for analyzing the surface change in response to targeted facial fat grafting. Our technique resulted in a reproducible surface shape, which we term the "Boomerang Lift". The authors of this study have no financial disclosures. Corresponding Author: Oren M. Tepper, MD, Assistant Professor, Division of Plastic and Reconstructive Surgery, Director of Aesthetic Surgery, Director of Craniofacial Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, 875 Park Avenue, New York, NY 10075, orenteppermd@yahoo.com ©2017American Society of Plastic Surgeons
Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: A case report and review of the published work
Abstract
Hydroxychloroquine (HCQ) is an effective treatment of lupus erythematosus. Although adverse effects, mainly gastrointestinal and cutaneous manifestations, are rare, they may result in the cessation of medication in some patients with severe reactions. Therefore, the evaluation of a patient's condition is important for a dermatologist to decide whether to cease or continue HCQ. We herein report a case of a 36-year-old Japanese woman with systemic lupus erythematosus and cutaneous eruptions caused by the p.o. administration of HCQ. Because she wanted to continue the medication and had only mild cutaneous eruptions without any adverse effects in other organs, we continued HCQ with careful monitoring. All cutaneous eruptions disappeared within 1 week. We also reviewed published case reports on skin lesions that developed after HCQ treatments, and propose strategies for early cutaneous eruptions after HCQ treatments. When the cutaneous reactions are mild without any reactions in other organs, withdrawal of the drug is not required. However, when cutaneous eruptions are accompanied by some common reactions, HCQ needs to be stopped for a period of time and may subsequently be carefully re-administrated.
Morfea en la infancia: actualización
Publication date: Available online 14 December 2017
Source:Actas Dermo-Sifiliográficas
Author(s): B. Aranegui, J. Jiménez-Reyes
La morfea es una enfermedad de la piel que se manifiesta en forma de inflamación y fibrosis. En niños y jóvenes, también se conoce como esclerodermia juvenil localizada. En edad infantil, afecta con mayor frecuencia al sexo femenino y la edad de comienzo se ha establecido en torno a los 5-7 años. Una clasificación reciente divide la morfea en: circunscrita (en placas), lineal, generalizada, panesclerótica y mixta. Alrededor de un 40% de los pacientes presentan manifestaciones extracutáneas.Los tratamientos empleados en morfea infantil son: fototerapia, calcitriol oral, calcipotriol tópico, tacrolimus 0,1% tópico, metotrexato, glucocorticoides tópicos y sistémicos, mofetil micofenolato, bosentán e imiquimod 5% tópico. Diversas medidas de resultado pueden ayudar a monitorizar el tratamiento. Los estudios pronósticos son escasos, pero apuntan hacia una enfermedad con tendencia a un curso crónico o intermitente-recurrente y una frecuencia considerable de secuelas.Morphea is an inflammatory, fibrosing skin disorder. When it occurs in childhood, it is also known as localized juvenile scleroderma. It is more common in girls and typically appears around the age of 5 to 7 years. According to a recent classification system, morphea is divided into 5 types: circumscribed (plaque), linear, generalized, pansclerotic, and mixed. Approximately 40% of patients present extracutaneous manifestations. Childhood morphea is treated with phototherapy, oral or topical calcitriol, topical tacrolimus 0.1%, methotrexate, topical or systemic corticosteroids, mycophenolate mofetil, bosentán, and topical imiquimod 5%. A variety of measuring tools are used to monitor response to treatment. Few prognostic studies have been conducted, but findings to date suggest that the disease tends to run a chronic or intermittent-recurrent course and frequently causes sequelae.
Graphical abstract
Skin tissue engineering using 3D bioprinting – an evolving research field
Publication date: Available online 13 December 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): S.P. Tarassoli, Z.M. Jessop, A. Al-Sabah, N. Gao, S. Whitaker, S. Doak, I.S. Whitaker
BackgroundCommercially available tissue engineered skin remains elusive despite extensive research because the multi-stratified anisotropic structure is difficult to replicate in vitro using traditional tissue engineering techniques. Bioprinting, involving computer-controlled deposition of cells and scaffolds into spatially controlled patterns, is able to control not only the macro but also micro and nanoarchitecture and could offer the potential to more faithfully replicate native skin.MethodsWe conducted a literature review using PubMed, EMBASE and Web of Science for studies on skin 3D bioprinting between 2009 and 2016, evaluating the bioprinting technique, cell source, scaffold type and in vitro and in vivo outcomes.ResultsWe outline the evolution of biological skin replacements, principles of bioprinting and how they apply to the skin tissue engineering field, potential clinical applications as well the current limitations and future avenues for research. Of the studies analysed, the most common types of bioinks consisted of keratinocytes and fibroblasts combined with collagen, although stem cells are gaining increasing recognition. Laser assisted deposition was the most common printing modality, although ink-jet and pneumatic extrusion have also been tested. Bioprinted skin promoted accelerated wound healing, was able to mimic stratified epidermis but not the thick, elastic, vascular dermis.ConclusionsAlthough 3D bioprinting shows promise in engineering skin, evidenced by large collective investments from the cosmetic industry, the research is still in its infancy. The resolution, vascularity, optimal cell and scaffold combinations and cost of bioprinted skin are hurdles that need to be overcome before the clinical applicability can be realised. Small scale 3D skin tissue models for cosmetics, drug and toxicity testing as well as tumour modelling are likely to be translated first before we see this technology used in reconstructive surgery patients.
Determination of reference values for normal cranial morphology by using mid-sagittal vector analysis in japanese children
Publication date: Available online 13 December 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Takaya Senoo, Eijiro Tokuyama, Kiyoshi Yamada, Yoshihiro Kimata
Mid-Sagittal Vector Analysis (MSVA) is a method of measuring the distance from a defined central point on the skull surface in the entire mid-sagittal plane and provides a clear description of the lateral view of the skull. We used a series of images of normal skulls of Japanese children to determine normal MSVA values.For this cross-sectional study, we first constructed a database of head CT and MRI images of children aged 0–6 years (41.5±24.9 month (mean±SD)) who showed no abnormality of cranial development and growth at the time of imaging. Measurement errors due to lateral shifting of the sagittal plane during MSVA were examined, CT and MRI images taken in the same patients at the same time were compared, and measurement differences were examined. Finally, MSVA was carried out, and the mean of the measured values was calculated according to age group.Two hundred ninety-five images were included in the database. When the lateral shifting of the sagittal plane was within 4 mm from the true midsagittal plane, the mean errors were less than 1 mm at all measurement points. Between the CT and MRI images from the same patients, most differences in MSVA values were within ± 1 mm. These differences were thus acceptable for use in clinical settings. After the above verifications, 220 images were extracted for determination of normal MSVA values. We established a normal dataset of MSVA for Japanese children that can be used effectively for preoperative diagnosis, surgery planning, and postoperative assessment of cranial deformities.
The role of angiogenesis, inflammation and estrogen receptors in breast implant capsules development and remodeling.
Publication date: Available online 13 December 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Francesco Segreto, Simone Carotti, Giovanni Francesco Marangi, Daniele Tosi, Maria Zingariello, Alfonso Luca Pendolino, Laura Sancillo, Sergio Morini, Paolo Persichetti
BackgroundCapsular contracture is the most common complication following breast implant placement. The multiple factors unbalancing the physiological response to the foreign body have not been fully elucidated. The aim of this study was to investigate the role of neo-angiogenesis, inflammation and estrogen receptors in peri-prosthetic tissue development and remodeling.MethodsThe study enrolled 31 women who underwent expander substitution with definitive implant. Specimens were stained with Hematoxylin/Eosin, Masson trichrome, immunohistochemistry and immunofluorescence for alpha-Smooth Muscle Actin, Estrogen Receptor-α (ER-α), Estrogen Receptor-β (ER-β), Collagen type I and III, CD31 (as a marker of neo-angiogenesis) and vascular endothelial growth factor (VEGF). Inflammatory infiltration was quantified and analyzed. Transmission electron microscopy was performed for ultrastructural evaluation.ResultsMyofibroblasts, mainly localized in the middle layer of capsular tissue, expressed VEGF, ER-α and ER-β. ER-β expression positively correlated with Collagen type I deposition (p=0.025). Neo-angiogenesis was predominant in the middle layer. CD31 expression positively correlated with Collagen type I expression (p=0.009) and inflammatory infiltration grade (p=0.004). The degree of inflammatory infiltration negatively correlated with the time from implantation (p=0.022)DiscussionThe middle layer is key in the development and remodeling of capsular tissue. Myofibroblasts produce VEGF, that induces neo-angiogenesis. New vessels formation is also correlated to the inflammatory response. Collagen deposition is associated with ER-β expression and neo-angiogenesis. These findings may prelude to targeted pharmacologic therapies able to control such interactions, thus hampering the self-sustaining loop promoting the progression of physiologic fibrosis towards pathologic contracture.
Smoking as a risk factor for Panniculectomy: An analysis of 7,650 cases
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Carolina Puyana Barcha, Matthew Ranzer
BackgroundPanniculectomy is performed to remove a symptomatic abdominal pannus. Successful surgery can improve quality of life and alleviate numerous health concerns including intertrigo, chronic infection, lumbago, and immobility. This study is aimed to examine smoking as risk factor for post-operative complications in panniculectomy patients. It is the first study to date on this topic.MethodsA retrospective study on 7,650 panniculectomy patients was performed utilizing data from the American College of Surgeons National Surgical Quality Improvement Program, collected from 2005-2015. Patients were identified by Current Procedural Terminology code 15830 and separated into two cohorts based on current smoking status. Cohorts were compared in terms of demographics, preoperative health, operation variables, and 30-day complications. Univariate analysis utilized χ2 or Fisher's exact tests and Wilcoxon rank sum tests. Multivariate logistic regression models were fitted to evaluate the association between smoking and development of wound complications or any complication. Odds ratios were computed at the 95% confidence interval.ResultsThe rate of complications for smokers vs. non-smokers were: deep incisional surgical site infections (2.4 vs. 1.3%; p=0.0162), organ/space surgical site infections (0.8% vs. 0.3%; p=0.026), and return to operating room (4.9% vs. 3.3%; p=0.0185). After adjusting for confounders, smokers had a higher likelihood of developing wound complications (OR 1.332; p=0.0085) or any complications (OR 1.379; p=0.0220) following panniculectomy compared to non-smokers.ConclusionsSmoking confers an increased risk of developing wound complications or any complication for patients undergoing panniculectomy. Smoking cessation should be an important part of the pre-operative workup to reduce complications.
“Long-term craniofacial morphology in young adults treated for a non-syndromal UCLP : a systematic review.”
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Isabelle F.P.M. Kappen, Whitney R. Yoder, Aebele B. Mink van der Molen, Corstiaan C. Breugem
Minimizing mid-facial growth impairment is one of the treatment goals in cleft lip and palate surgery. As growth of the maxilla extends into young adulthood, long-term evaluation is essential to make a comprehensive assessment of a treatment protocol. There are numerous treatment approaches for cleft lip/palate surgery, and most have the characteristic distinction between either an early or a late cleft palate closure. PRISMA guidelines were applied to explore the quality of the current literature and to identify treatment factors influencing long-term cephalometric outcomes. The literature search was conducted in Pubmed, The Cochrane Library and Embase. We included studies evaluating cephalometric outcomes (SNA and ANB values on 2D cephalograms) in UCLP patients with a mean age of 16 years and older. Studies with an inadequate description of the timing of surgery were excluded. 17 studies comprising 906 patients were selected and included for critical appraisal. Treatment protocols differed considerably amongst the included studies and inconsistent methodology was common. Eight studies applied a one-stage procedure, 11 studies performed a two-stage reconstruction, five studies made use of a vomer-flap. Applying a multivariate model, we did not identify any treatment factors that significantly influenced growth (SNA/ANB values), except for the method of inclusion, suggesting the presence of significant selection bias within the studies. The current literature remains inadequate for evidence-based decision making and to advise parents if an early or late palate closure leads to a more favorable maxillary outgrowth. This manuscript will propose guidelines and recommended quality criteria for future studies.
Distribution of the internal nasal branch of the infraorbital nerve to the nasal septum: application to rhinoplasty
Publication date: Available online 13 December 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Joe Iwanaga, Koichi Watanabe, Rod J. Oskouian, R. Shane Tubbs
BackgroundThe course of the nerves along the nasal septum has not been clearly studied, and surgical procedures such as rhinoplasty require a more detailed topography of the nerve supply inside the septum. Therefore, we aimed to investigate the distribution of the internal nasal branch of the infraorbital nerve inside the nasal septum and to define the relationship between it and the nasal cartilages.MethodsFourteen sides from eight fresh frozen and embalmed Caucasian cadaveric heads were dissected. The specimens were derived from three males and five females. The ages of the cadavers at death ranged from 65 to 84 years. The course of the internal nasal branch and its relationship between the nasal cartilages were observed using a surgical microscope.ResultsOn all sides, the internal nasal branch approached the medial crus of the major alar cartilage from behind and traveled anteriorly below the medial crus of the major alar cartilage while giving off anterior inferior septal, middle inferior septal, and posterior inferior septal branches.ConclusionsBased on the results of this study, we suggest that procedures of the nasal cavity such as rhinoplasty could be modified to avoid injuring the main trunk of the internal nasal branch of the infraorbital nerve inside the nasal septum.
Relationship between serum anti-varicella zoster virus antibody titer and time from onset of herpes zoster
Abstract
Herpes zoster is an internal reactivation of varicella zoster virus, and its onset depends on immunity against this virus. We have previously reported that antiviral antibody titers are inversely correlated with patient numbers. In this study, we hypothesized that patients with higher titers may be late visitors to the clinic, whose antibodies were already boosted at presentation because of the time lapse between onset of zoster and measurement of antibodies. We analyzed antibody titers of patients with acute herpes zoster who visited Fukuoka University Hospital from January 2009 to May 2016 (n = 141, 62 males and 79 females). Varicella zoster virus-specific immunoglobulin G, M and complement fixation tests were positive in 93.9%, 12.0% and 64.2% of the patients, respectively. Immunoglobulin G and complement fixation titers were strongly correlated (Spearman's r = 0.8634, P < 0.0001). Patients with high immunoglobulin G and complement fixation titers were immunoglobulin M-negative. Unexpectedly, immunoglobulin G and complement fixation titers showed large inter-subject variation, and were only weakly correlated with onset–measurement time lapse. Patients with consecutive tests tended to show increasing immunoglobulin G and complement fixation titers. Our data suggest that herpes zoster preferentially occurs in patients with low immunoglobulin G and complement fixation titers, and subsequently causes antibody elevation. However, the timing of elevation varies and can be as late as 10 days after zoster. The large variation in antibody titer over the time from onset to testing suggests that some mechanism exists that resists the local breakthrough of virus in the skin, and so delays the onset of blisters.
Affective Personality Traits in Olfactory Dysfunction: the Role of Dysthymia and Arousal
Abstract
Introduction
Olfactory dysfunction can have a negative impact on emotional well-being. The aim of the present study was to examine associations between olfactory deficits and two affective personality characteristics (trait anxiety/trait depression).
Methods
A questionnaire study was conducted with a total of 116 participants (33 classified as anosmic, 40 as hyposmic, and 39 as normosmic). All participants gave self-reports on two facets of trait depression (dysthymia, euthymia) and trait anxiety (arousal, worrying). Due to the fact that in all three groups, trait depression and anxiety were substantially correlated, analyses of covariance were conducted.
Results
After controlling for trait depression, anosmic and hyposmic patients showed lower trait arousal compared to normosmic controls (partial η 2 = .05). After controlling for trait anxiety, patients scored higher on dysthymia (partial η 2 = .06).
Conclusions
This study underlines the importance of statistically isolating specific associations between each of these affective personality characteristics and olfactory dysfunction.
Implications
The present findings suggest that olfactory dysfunction can have opposite effects on facets of trait depression and trait anxiety.
Effect of 670 nm laser photobiomodulation on vascular density and fibroplasia in late stages of tissue repair
This study aimed to investigate the effects of gallium-aluminum-arsenium (GaAlAs) (670 nm) laser therapy on neoangiogenesis and fibroplasia during tissue remodelling. Forty male Wistar rats underwent cutaneous surgery and were divided into 2 experimental groups: the Control and Laser group (9 mW, 670 nm, 0.031 W/cm2, 4 J/cm2). After 14, 21, 28, and 35 days, the animals were euthanised. Descriptive and quantitative analyses were performed in sections stained with haematoxylin-eosin and Sirius Red, respectively. The amounts of VEGF+ and CD31+ cells were evaluated by immunohistochemistry and histomorphometric analysis, respectively. Statistical analysis was performed using the Mann-Whitney, Friedman, and Spearman correlation test, P < 0.05. The collagen expression was significantly higher in the laser group compared with the control group on days 14 and 21 after the creation of the skin wound (P = 0.008; P = 0.016) and in the control group between 14 and 28 and 14 and 35 days (P = 0.001; P = 0.007). There were more blood vessels in three periods of the study only in the (Laser) treated group, with statistical significance at day 14 (P = 0.016). There was no statistically significant difference in VEGF+ cell count in the different experimental groups throughout the study, although a positive correlation was shown with the area of collagen on days 14 and 28 (P = 0.037). Laser treatment had a positive effect in the late course of healing, particularly with regards to collagen expression and the number of newly formed vessels. VEGF+ cells were present in both experimental groups, and VEGF appeared to influence fibroplasia in the treated group.
Postmenopausal craniofacial hyperhidrosis
Summary
Hyperhidrosis is a condition marked by excessive sweating, which can either be localized or generalized. Primary focal hyperhidrosis (PFH) can arise from the palms, plantar feet, axillae and also from the face and scalp. PFH primarily affects a younger population of children and young adults, with the majority presenting before the age of 25 years. We report a distinct subtype of craniofacial hyperhidrosis in 20 postmenopausal women; this subtype is often under-recognized.
Time-varying causality between energy consumption, CO 2 emissions, and economic growth: evidence from US states
Abstract
This study is the first attempt to investigate the relationship between CO2 emissions, energy consumption, and economic growth at a state level, for the 50 US states, through a time-varying causality approach using annual data over the periods 1960–2010. The time-varying causality test facilitates the better understanding of the causal relationship between the covariates owing to the fact that it might identify causalities when the time-constant hypothesis is rejected. Our findings indicate the existence of a time-varying causality at the state level. Specifically, the results probe eight bidirectional time-varying causalities between energy consumption and CO2 emission, six cases of two-way time-varying causalities between economic growth and energy consumption, and five bidirectional time-varying causalities between economic growth and CO2 emission. Moreover, we examine the traditional environmental Kuznets curve hypothesis for the states. Notably, our results do not endorse the validity of the EKC, albeit the majority of states support an inverted N-shaped relationship. Lastly, we can identify multiple policy implications based on the empirical results.
IL-25 is involved in CTCL progression by establishing Th2-dominant microenvironment
Summary
Background
Interleukin (IL)-25 is a member of the IL-17 family which can promote and augment T-helper type (Th) 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases.
Objective
To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL).
Methods
Expression and localization of IL-25 in lesional skin was investigated using immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumor cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in Sézary syndrome patients.
Results
IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL (stage IIB-IV) and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of STAT6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25.
Conclusions
Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may in turn lead to formation of Th2-dominant microenvironment through the direct induction of IL-13 by tumor cells.
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Modeling the impacts of ambient temperatures on cardiovascular mortality in Yinchuan: evidence from a northwestern city of China
Abstract
No evidence is available on whether cardiovascular mortality is affected by the ambient temperatures in Yinchuan, which is located in the northwestern region of China, with a typical continental semi-humid semi-arid climate. Daily data on cardiovascular mortality and meteorological factors was collected from Yinchuan city for the period of 2010–2015. A distributed lag non-linear model with quasi-Poisson link was used to assess the association between daily temperatures and cardiovascular deaths, after controlling for seasonality, day of the week, atmospheric pressure, humidity, sunshine duration, and wind speed. The relationship between ambient temperature and cardiovascular mortality was non-linear, with a U-shaped exposure-response curve. For all cardiovascular mortality, the effects of high temperatures appeared at lag 2–5 days, with the largest hot effect at lag 3 day (RR 1.082, 95% CI 1.021–1.146), while the effects of cold temperatures were insignificant. Both cold and high temperatures have more serious influence on the elderly (age ≥ 65) and males than the youth and females, respectively. The study has shown that both cold and high temperatures affect cardiovascular mortality. The findings may be helpful to identify the susceptible subgroups of cardiovascular mortality induced by temperatures, and to provide useful information for establishing public health programs that would better protect local population health from ambient temperatures.
Evaluation of zinc oxide nanoparticles on lettuce ( Lactuca sativa L.) growth and soil bacterial community
Abstract
The wide spread of nanoparticles (NPs) has caused tremendous concerns on agricultural ecosystem. Some metallic NPs, such as zinc oxide (ZnO), can be utilized as a nano-fertilizer when used at optimal doses. However, little is known about the responses of plant development and concomitant soil bacteria community to ZnO NPs. The present pot experiment studied the impacts of different doses of ZnO NPs and bulk ZnO (0, 1, 10, 100 mg ZnO/kg), on the growth of lettuce (Lactuca sativa L.) and the associated rhizospheric soil bacterial community. Results showed that at a dose of 10 mg/kg, ZnO NPs and bulk ZnO, enhanced the lettuce biomass and the net photosynthetic rate; whereas, the Zn content in plant tissue was higher in NPs treatment than in their bulk counterpart at 10 mg/kg dose or higher. For the underground observations, 10 mg/kg treatment doses (NPs or bulk) significantly changed the soil bacterial community structure, despite the non-significant variations in alpha diversity. Taxonomic distribution revealed that some lineages within Cyanobacteria and other phyla individually demonstrated similar or different responses to ZnO NPs and bulk ZnO. Moreover, some lineages associated with plant growth promotion were also influenced to different extents by ZnO NPs and bulk ZnO, suggesting the distinct microbial processes occurring in soil. Collectively, this study expanded our understanding of the influence of ZnO NPs on plant performance and the associated soil microorganisms.
Green electrochemical modification of RVC foam electrode and improved H 2 O 2 electrogeneration by applying pulsed current for pollutant removal
Abstract
The performance of cathode on H2O2 electrogeneration is a critical factor that limits the practical application of electro-Fenton (EF) process. Herein, we report a simple but effective electrochemical modification of reticulated vitreous carbon foam (RVC foam) electrode for enhanced H2O2 electrogeneration. Cyclic voltammetry, chronoamperometry, and X-ray photoelectron spectrum were used to characterize the modified electrode. Oxygen-containing groups (72.5–184.0 μmol/g) were introduced to RVC foam surface, thus resulting in a 59.8–258.2% higher H2O2 yield. The modified electrodes showed much higher electrocatalytic activity toward O2 reduction and good stability. Moreover, aimed at weakening the extent of electroreduction of H2O2 in porous RVC foam, the strategy of pulsed current was proposed. H2O2 concentration was 582.3 and 114.0% higher than the unmodified and modified electrodes, respectively. To test the feasibility of modification, as well as pulsed current, EF process was operated for removal of Reactive Blue 19 (RB19). The fluorescence intensity of hydroxybenzoic acid in EF with modified electrode is 3.2 times higher than EF with unmodified electrode, illustrating more hydroxyl radicals were generated. The removal efficiency of RB 19 in EF with unmodified electrode, modified electrode, and unmodified electrode assisted by pulsed current was 53.9, 68.9, and 81.1%, respectively, demonstrating that the green modification approach, as well as pulsed current, is applicable in EF system for pollutant removal.
Graphical abstract
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Metal-tolerant thermophiles: metals as electron donors and acceptors, toxicity, tolerance and industrial applications
Abstract
Metal-tolerant thermophiles are inhabitants of a wide range of extreme habitats like solfatara fields, hot springs, mud holes, hydrothermal vents oozing out from metal-rich ores, hypersaline pools and soil crusts enriched with metals and other elements. The ability to withstand adverse environmental conditions, like high temperature, high metal concentration and sometimes high pH in their niche, makes them an interesting subject for understanding mechanisms behind their ability to deal with multiple duress simultaneously. Metals are essential for biological systems, as they participate in biochemistries that cannot be achieved only by organic molecules. However, the excess concentration of metals can disrupt natural biogeochemical processes and can impose toxicity. Thermophiles counteract metal toxicity via their unique cell wall, metabolic factors and enzymes that carry out metal-based redox transformations, metal sequestration by metallothioneins and metallochaperones as well as metal efflux. Thermophilic metal resistance is heterogeneous at both genetic and physiology levels and may be chromosomally, plasmid or transposon encoded with one or more genes being involved. These effective response mechanisms either individually or synergistically make proliferation of thermophiles in metal-rich habitats possibly. This article presents the state of the art and future perspectives of responses of thermophiles to metals at genetic as well as physiological levels.
Methotrexate and azathioprine in severe atopic dermatitis: a 5-year follow up study of a randomised controlled trial
Summary
Background
Systemic treatment is indicated for moderate-to-severe atopic dermatitis (AD), refractory to topical treatment. Long-term evidence, up to 5 years, of off-label prescribed methotrexate (MTX) and azathioprine (AZA) is lacking.
Objectives
To investigate long-term effectiveness, safety and drug survival of MTX and AZA.
Methods
In an open-label follow up phase of a clinical trial patients were seen every 3 months for 5 years. MTX and AZA doses could be in- or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator Global Assessment (IGA) after 5 years compared to baseline. For safety type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan-Meier curves.
Results
Thirty-five of 43 originally included patients participated, of which 27 completed follow up. At year 5 mean relative reduction in SCORAD index was similar in MTX and AZA group: 52.8% and 53.8% by descriptive analysis. Eleven serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTX n=5, AZA n=1).
Conclusion
Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate-to-severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued due to controlled AD.
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“Long-term craniofacial morphology in young adults treated for a non-syndromal UCLP : a systematic review.”
Minimizing mid-facial growth impairment is one of the treatment goals in cleft lip and palate surgery. As growth of the maxilla extends into young adulthood, long-term evaluation is essential to make a comprehensive assessment of a treatment protocol. There are numerous treatment approaches for cleft lip/palate surgery, and most have the characteristic distinction between either an early or a late cleft palate closure. PRISMA guidelines were applied to explore the quality of the current literature and to identify treatment factors influencing long-term cephalometric outcomes.
Determination of reference values for normal cranial morphology by using mid-sagittal vector analysis in japanese children
Mid-Sagittal Vector Analysis (MSVA) is a method of measuring the distance from a defined central point on the skull surface in the entire mid-sagittal plane and provides a clear description of the lateral view of the skull. We used a series of images of normal skulls of Japanese children to determine normal MSVA values.For this cross-sectional study, we first constructed a database of head CT and MRI images of children aged 0–6 years (41.5±24.9 month (mean±SD)) who showed no abnormality of cranial development and growth at the time of imaging.
Skin tissue engineering using 3D bioprinting – an evolving research field
Commercially available tissue engineered skin remains elusive despite extensive research because the multi-stratified anisotropic structure is difficult to replicate in vitro using traditional tissue engineering techniques. Bioprinting, involving computer-controlled deposition of cells and scaffolds into spatially controlled patterns, is able to control not only the macro but also micro and nanoarchitecture and could offer the potential to more faithfully replicate native skin.
Distribution of the internal nasal branch of the infraorbital nerve to the nasal septum: application to rhinoplasty
The course of the nerves along the nasal septum has not been clearly studied, and surgical procedures such as rhinoplasty require a more detailed topography of the nerve supply inside the septum. Therefore, we aimed to investigate the distribution of the internal nasal branch of the infraorbital nerve inside the nasal septum and to define the relationship between it and the nasal cartilages.
The role of angiogenesis, inflammation and estrogen receptors in breast implant capsules development and remodeling.
Capsular contracture is the most common complication following breast implant placement. The multiple factors unbalancing the physiological response to the foreign body have not been fully elucidated. The aim of this study was to investigate the role of neo-angiogenesis, inflammation and estrogen receptors in peri-prosthetic tissue development and remodeling.
Smoking as a risk factor for Panniculectomy: An analysis of 7,650 cases
Panniculectomy is performed to remove a symptomatic abdominal pannus. Successful surgery can improve quality of life and alleviate numerous health concerns including intertrigo, chronic infection, lumbago, and immobility. This study is aimed to examine smoking as risk factor for post-operative complications in panniculectomy patients. It is the first study to date on this topic.
Constructive “Consent”: A Problematic Fiction
Abstract
The law and society occasionally impute consent to an agent despite a clear lack of actual consent. A common type of such 'fictitious consent' is constructive consent. In this practice, we treat an agent as if she consented to Φ because she did Ψ. By examining how constructive consent operates in law (monitoring inmate phone calls and blood alcohol concentration testing on unconscious drivers) and daily life (physical contact in public spaces), I show that our treatment of agents in these cases bears no normatively relevant resemblance to consent because it is grounded in values and concerns other than autonomy. Thus, the practice may diminish the very autonomy consent proper seeks to promote. Hiding this potential for conflict creates the risk moral concerns will not be appropriately balanced when deciding on the permissibility of an action. We thus ought to be explicit that such cases don't involve consent and its common justification.
The small vesicular culprits: the investigation of extracellular vesicles as new targets for cancer treatment
Extracellular vesicles (EVs) are membranous vesicles released from almost all type of cells including cancer cells. EVs transfer their components, such as microRNAs (miRNAs), messenger RNAs, lipids and protein...
Distinctive cutaneous and systemic features associated with specific anti-myositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients
Abstract
Background
Identification of myositis-specific autoantibodies (MSA) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype.
Objective
We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA.
Methods
A 3.5-year multicenter prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSA and the presence of cancer, ILD and calcinosis.
Results
MSA were detected in 47.1% of 117 included patients. Patients with anti-melanoma differentiation-associated protein 5 antibodies (13.7%) had significantly more palmar violaceous macules/papules (odds ratio (OR) 9.9), mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), and articular involvement (OR 15.2), and a higher risk of ILD (OR 25.3). Patients with anti-transcriptional intermediary factor-1 antibodies (11.1%), anti-nuclear matrix protein-2 antibodies (6.8%) and anti-aminoacyl-transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8), and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1).
Conclusion
Recognition of the adult DM phenotype associated with MSA would allow more accurate appraisal of the risk of cancer, ILD and calcinosis.
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Perianal tuberculosis in an immunocompetent patient
Abstract
Tuberculosis (TB) is a major public health problem worldwide, considered to be the main cause of death from infectious diseases, ranking alongside HIV infection. Skin involvement occurs in 1.5% of the cases, and perianal involvement is extremely rare and tends to occur among immunocompromised patients. Due to its heterogeneous clinical presentation, the diagnosis of cutaneous TB is challenging, requiring a high level of suspicion.
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Serum androgens and PSA levels in androgenetic alopecia - is there a difference between frontal and vertex baldness?
Abstract
Background
Androgenetic alopecia (AGA) seems to be a marker of increased risk of prostate cancer (PCa).
Objective
We sought to investigate potential pathophysiological differences between frontal and vertex balding that might have the impact on the incidence of PCa.
Methods
Serum concentrations of testosterone (T), dihydrotestosterone (DHT) and prostate-specific antigen (PSA) were measured in 88 subjects with AGA.
Results
We have examined sixty patients with frontal baldness and 28 patients with vertex baldness. The subgroups did not differ significantly in age, BMI and as regards age of AGA onset, duration of AGA and comorbidities. The mean value of DHT in serum of the men with vertex baldness was higher than those in the men with frontal baldness with statistical significance (p<0,05). The groups did not show significant differences in mean value of serum T and PSA levels, and DHT/T ratio. No correlation was found between the serum PSA level and serum androgen levels as well as DHT/T ratio.
Conclusions
Vertex baldness may signal higher exposures to circulating DHT. Serum PSA level cannot serve as surrogate diagnostic marker of increased androgenic activity in men with AGA.
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Epidermodysplasia verruciformis in an adult patient with a germline ITK mutation and lymphoma: the case of inherited versus acquired
Abstract
Epidermodysplasia verruciformis (EV) is characterized by a clinically distinctive pattern of beta-HPV induced flat warts that may evolve into epithelial skin cancers. The current understanding is that EV encompasses two etiological situations: Classic, inherited type EV (IEV), beginning in childhood or adolescence, due to Trans Membrane Channel (TMC) - 6 and 7 (EVER-1 and 2) gene mutations 75% of patients, or to alterations resulting in T-Cell immune deficiencies (IDs) on Ras Homolog Family Member H (RHOH), Coronin 1A (CORO 1A), Macrophage Stimulating factor 1 (MST-1), or interleukin 7 (IL7) genes.
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Dermoscopy for discriminating between Trichophyton and Microsporum infections in tinea capitis
Abstract
Tinea capitis (TC) is an infection of the scalp, most often observed in pre-school or early school ages. Diagnosis of TC is based on clinical signs and laboratory examinations (direct microscopy and culture). Dermoscopy is a non-invasive diagnostic technique with an already established role in the evaluation of skin tumors, and with a gradually expanding application also in the field of inflammatory and infectious skin diseases.
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Four cases of anti-Mi-2 antibody-positive dermatomyositis: relationship between anti-Mi-2 antibody titer and disease severity and activity
Abstract
Anti-Mi-2 antibody was found to be a specific marker for dermatomyositis (DM) [1, 2]. Patients with anti-Mi-2 antibody generally have a more favorable prognosis, such as milder muscle involvement and a lower risk of interstitial lung disease (ILD) and malignancy [3, 4]. However, it currently remains unclear whether the anti-Mi-2 antibody titer correlates with disease severity and activity, or if repeated testing for disease monitoring is beneficial.
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Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis
Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.
SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.
Cellular and Molecular Analysis of Dendritic Morphogenesis in a Retinal Cell Type That Senses Color Contrast and Ventral Motion
As neuronal dendrites develop, they acquire cell-type-specific features including characteristic size, shape, arborization, location and synaptic patterns. These features, in turn, are major determinants of type-specific neuronal function. Because neuronal diversity complicates the task of relating developmental programs to adult structure and function, we analyzed dendritic morphogenesis in a single retinal ganglion cell (RGC) type in mouse called J-RGC. We documented the emergence of five dendritic features that underlie J-RGC physiology: (1) dendritic field size, which approximate receptive field size; (2) dendritic complexity, which affects how J-RGCs sample space; (3) asymmetry, which contributes to direction-selectivity; (4) restricted lamination within the inner plexiform layer (IPL), which renders J-RGCs responsive to light decrements; and (5) distribution of synaptic inputs, which generate a color-opponent receptive field. We found dendritic growth in J-RGCs is accompanied by a refinement in dendritic self-crossing. Asymmetry arises by a combination of selective pruning and elaboration, whereas laminar restriction results from biased outgrowth toward the outermost IPL. Interestingly, asymmetry develops in a protracted dorsoventral wave, whereas lamination does so in a rapid centrifugal wave. As arbors mature, they acquire excitatory and inhibitory synapses, with the latter forming first and being concentrated in proximal dendrites. Thus, distinct mechanisms operate in different spatiotemporal dimensions of J-RGC dendritic patterning to generate the substrate for specific patterns of synaptogenesis. Finally, we asked whether the defining molecular signature of J-RGCs, the adhesion molecule JAM-B, regulates morphogenesis, and showed that it promotes dendro-dendritic interactions. Our results reveal multiple mechanisms that shape a dendritic arbor.
SIGNIFICANCE STATEMENT Visual perception begins in the retina, where distinct types of retinal ganglion cells (RGCs) are tuned to specific visual features such as direction of motion. The features to which each RGC type responds are determined largely by the number and type of synaptic inputs it receives, and these, in turn, are greatly influenced by the size, shape, arborization pattern, and location of its dendrites. We analyzed dendritic morphogenesis in a functionally characterized RGC type, the J-RGC, demonstrating distinct mechanisms that operate in different dimensions to generate the dendritic scaffold and synaptic patterns for feature detection. Our work elucidates cellular and molecular mechanisms that shape dendritic arbors and synaptic distribution, enabling J-RGC connectivity and thus, function.
The Expanding Toolkit of Translating Ribosome Affinity Purification
Translating ribosome affinity purification is a method initially developed for profiling mRNA from genetically defined cell types in complex tissues. It has been applied both to identify target molecules in cell types that are important for controlling a variety of behaviors in the brain, and to understand the molecular consequences on those cells due to experimental manipulations, ranging from drugs of abuse to disease-causing mutations. Since its inception, a variety of methodological advances are opening new avenues of investigation. These advances include a variety of new methods for targeting cells for translating ribosome affinity purification by features such as their projections or activity, additional tags and mouse reagents increasing the flexibility of the system, and new modifications of the method specifically focused on studying the regulation of translation. The latter includes methods to assess cell type-specific regulation of translation in specific subcellular compartments. Here, I provide a summary of these recent advances and resources, highlighting both new experimental opportunities and areas for future technical development.
Conditional Deletion of Ric-8b in Olfactory Sensory Neurons Leads to Olfactory Impairment
The olfactory system can discriminate a vast number of odorants. This ability derives from the existence of a large family of odorant receptors expressed in the cilia of the olfactory sensory neurons. Odorant receptors signal through the olfactory-specific G-protein subunit, Gαolf. Ric-8b, a guanine nucleotide exchange factor, interacts with Gαolf and can amplify odorant receptor signal transduction in vitro. To explore the function of Ric-8b in vivo, we generated a tissue specific knock-out mouse by crossing OMP-Cre transgenic mice to Ric-8b floxed mice. We found that olfactory-specific Ric-8b knock-out mice of mixed sex do not express the Gαolf protein in the olfactory epithelium. We also found that in these mice, the mature olfactory sensory neuron layer is reduced, and that olfactory sensory neurons show increased rate of cell death compared with wild-type mice. Finally, behavioral tests showed that the olfactory-specific Ric-8b knock-out mice show an impaired sense of smell, even though their motivation and mobility behaviors remain normal.
SIGNIFICANCE STATEMENT Ric-8b is a guanine nucleotide exchange factor (GEF) expressed in the olfactory epithelium and in the striatum. Ric-8b interacts with the olfactory Gαolf subunit, and can amplify odorant signaling through odorant receptors in vitro. However, the functional significance of this GEF in the olfactory neurons in vivo remains unknown. We report that deletion of Ric-8b in olfactory sensory neurons prevents stable expression of Gαolf. In addition, we demonstrate that olfactory neurons lacking Ric-8b (and consequently Gαolf) are more susceptible to cell death. Ric-8b conditional knock-out mice display impaired olfactory guided behavior. Our results reveal that Ric-8b is essential for olfactory function, and suggest that it may also be essential for Gαolf-dependent functions in the brain.
Graded Elevation of c-Jun in Schwann Cells In Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination
Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/+ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/+ mice, in which c-Jun is elevated ~6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyelinating neuropathies. The tumor suppressor P19ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/+ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury.
SIGNIFICANCE STATEMENT In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling beneficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury.
Network Configurations in the Human Brain Reflect Choice Bias during Rapid Face Processing
Network interactions are likely to be instrumental in processes underlying rapid perception and cognition. Specifically, high-level and perceptual regions must interact to balance pre-existing models of the environment with new incoming stimuli. Simultaneous electroencephalography (EEG) and fMRI (EEG/fMRI) enables temporal characterization of brain–network interactions combined with improved anatomical localization of regional activity. In this paper, we use simultaneous EEG/fMRI and multivariate dynamical systems (MDS) analysis to characterize network relationships between constitute brain areas that reflect a subject's choice for a face versus nonface categorization task. Our simultaneous EEG and fMRI analysis on 21 human subjects (12 males, 9 females) identifies early perceptual and late frontal subsystems that are selective to the categorical choice of faces versus nonfaces. We analyze the interactions between these subsystems using an MDS in the space of the BOLD signal. Our main findings show that differences between face-choice and house-choice networks are seen in the network interactions between the early and late subsystems, and that the magnitude of the difference in network interaction positively correlates with the behavioral false-positive rate of face choices. We interpret this to reflect the role of saliency and expectations likely encoded in frontal "late" regions on perceptual processes occurring in "early" perceptual regions.
SIGNIFICANCE STATEMENT Our choices are affected by our biases. In visual perception and cognition such biases can be commonplace and quite curious—e.g., we see a human face when staring up at a cloud formation or down at a piece of toast at the breakfast table. Here we use multimodal neuroimaging and dynamical systems analysis to measure whole-brain spatiotemporal dynamics while subjects make decisions regarding the type of object they see in rapidly flashed images. We find that the degree of interaction in these networks accounts for a substantial fraction of our bias to see faces. In general, our findings illustrate how the properties of spatiotemporal networks yield insight into the mechanisms of how we form decisions.
FGF-FGFR Mediates the Activity-Dependent Dendritogenesis of Layer IV Neurons during Barrel Formation
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known for their potent effects on cell proliferation/differentiation and cortical patterning in the developing brain. However, little is known regarding the roles of FGFs/FGFRs in cortical circuit formation. Here we show that Fgfr1/2/3 and Fgf7/9/10/22 mRNAs are expressed in the developing primary somatosensory (S1) barrel cortex. Barrel cortex layer IV spiny stellate cells (bSCs) are the primary recipients of ascending sensory information via thalamocortical axons (TCAs). Detail quantification revealed distinctive phases for bSC dendritogenesis: orienting dendrites toward TCAs, adding de novo dendritic segments, and elongating dendritic length, while maintaining dendritic patterns. Deleting Fgfr1/2/3 in bSCs had minimal impact on dendritic polarity but transiently increased the number of dendritic segments. However, 6 d later, FGFR1/2/3 loss of function reduced dendritic branch numbers. These data suggest that FGFs/FGFRs have a role in stabilizing dendritic patterning. Depolarization of cultured mouse cortical neurons upregulated the levels of several Fgf/Fgfr mRNAs within 2 h. In vivo, within 6 h of systemic kainic acid administration at postnatal day 6, mRNA levels of Fgf9, Fgf10, Fgfr2c, and Fgfr3b in S1 cortices were enhanced, and this was accompanied by exuberant dendritogenesis of bSCs by 24 h. Deleting Fgfr1/2/3 abolished kainic acid-induced bSC dendritic overgrowth. Finally, FGF9/10 gain of function also resulted in extensive dendritogenesis. Together, our data suggest that FGFs/FGFRs can be regulated by glutamate transmission to modulate/stabilize bSC dendritic complexity. Both male and female mice were used for our study.
SIGNIFICANCE STATEMENT Glutamatergic transmission plays critical roles in cortical circuit formation. Its dysregulation has been proposed as a core factor in the etiology of many neurological diseases. We found that excessive glutamate transmission upregulated mRNA expression of Fgfrs and their ligands Fgfs. Deleting Fgfr1/2/3 not only impaired bSC dendritogenesis but also abolished glutamate transmission-induced dendritic overgrowth. Overexpressing FGF9 or FGF10 in cortical glutamatergic neurons results in excessive dendritic outgrowth within 24 h, resembling the changes induced by excessive glutamate transmission. Our findings provide strong evidence for the physiological role of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in establishing and maintaining cortical circuits. Perturbing the expression levels of FGFs/FGFRs by excessive glutamatergic neurotransmission could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.
Activation of {gamma}-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1
-Secretase is an intramembrane cleaving protease that is responsible for the generation of amyloid-β peptides, which are linked to the pathogenesis of Alzheimer disease. Recently, -secretase modulators (GSMs) have been shown to specifically decrease production of the aggregation-prone and toxic longer Aβ species, and concomitantly increase the levels of shorter Aβ. We previously found that phenylimidazole-type GSMs bind to presenilin 1 (PS1), the catalytic subunit of the -secretase, and allosterically modulate -secretase activity. However, the precise conformational alterations in PS1 remained unclear. Here we mapped the amino acid residues in PS1 that is crucial for the binding and pharmacological actions of E2012, a phenylimidazole-type GSM, using photoaffinity labeling and the substituted cysteine accessibility method. We also demonstrated that a piston-like vertical motion of transmembrane domain (TMD) 1 occurs during modulation of Aβ production. Taking these results together, we propose a model for the molecular mechanism of phenylimidazole-type GSMs, in which the trimming activity of -secretase is modulated by the position of the TMD1 of PS1 in the lipid bilayer.
SIGNIFICANCE STATEMENT Reduction of the toxic longer amyloid-β peptide is one of the therapeutic approaches for Alzheimer disease. A subset of small compounds called -secretase modulators specifically decreases the longer amyloid-β production, although its mechanistic action remains unclear. Here we found that the modulator compound E2012 targets to the hydrophilic loop 1 of presenilin 1, which is a catalytic subunit of the -secretase. Moreover, E2012 triggers the piston movement of the transmembrane domain 1 of presenilin 1, which impacts on the -secretase activity. These results illuminate how -secretase modulators allosterically affect the proteolytic activity, and highlight the importance of the structural dynamics of presenilin 1 in the complexed process of the intramembrane cleavage.
Detailed Dendritic Excitatory/Inhibitory Balance through Heterosynaptic Spike-Timing-Dependent Plasticity
The balance between excitatory and inhibitory inputs is a key feature of cortical dynamics. Such a balance is arguably preserved in dendritic branches, yet its underlying mechanism and functional roles remain unknown. In this study, we developed computational models of heterosynaptic spike-timing-dependent plasticity (STDP) to show that the excitatory/inhibitory balance in dendritic branches is robustly achieved through heterosynaptic interactions between excitatory and inhibitory synapses. The model reproduces key features of experimental heterosynaptic STDP well, and provides analytical insights. Furthermore, heterosynaptic STDP explains how the maturation of inhibitory neurons modulates the selectivity of excitatory neurons for binocular matching in the critical period plasticity. The model also provides an alternative explanation for the potential mechanism underlying the somatic detailed balance that is commonly associated with inhibitory STDP. Our results propose heterosynaptic STDP as a critical factor in synaptic organization and the resultant dendritic computation.
SIGNIFICANCE STATEMENT Recent experimental studies reveal that relative differences in spike timings experienced among neighboring glutamatergic and GABAergic synapses on a dendritic branch significantly influences changes in the efficiency of these synapses. This heterosynaptic form of spike-timing-dependent plasticity (STDP) is potentially important for shaping the synaptic organization and computation of neurons, but its functional role remains elusive. Through computational modeling at the parameter regime where previous experimental results are well reproduced, we show that heterosynaptic plasticity serves to finely balance excitatory and inhibitory inputs on the dendrite. Our results suggest a principle of GABA-driven neural circuit formation.
The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1
Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury.
SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting the TRAF6-Rac1 axis may provide a novel therapeutic strategy for stroke recovery.
Interlayer Repulsion of Retinal Ganglion Cell Mosaics Regulates Spatial Organization of Functional Maps in the Visual Cortex
In higher mammals, orientation tuning of neurons is organized into a quasi-periodic pattern in the primary visual cortex. Our previous model studies suggested that the topography of cortical orientation maps may originate from moiré interference of ON and OFF retinal ganglion cell (RGC) mosaics, but did not account for how the consistent spatial period of maps could be achieved. Here we address this issue with two crucial findings on the development of RGC mosaics: first, homotypic local repulsion between RGCs can develop a long-range hexagonal periodicity. Second, heterotypic interaction restrains the alignment of ON and OFF mosaics, and generates a periodic interference pattern map with consistent spatial frequency. To validate our model, we quantitatively analyzed the RGC mosaics in cat data, and confirmed that the observed retinal mosaics showed evidence of heterotypic interactions, contrary to the previous view that ON and OFF mosaics are developed independently.
SIGNIFICANCE STATEMENT Orientation map is one of the most studied functional maps in the brain, but it has remained unanswered how the consistent spatial periodicity of maps could be developed. In the current study, we address this issue with our developmental model for the retinal origin of orientation map. We showed that local repulsive interactions between retinal ganglion cells (RGCs) can develop a hexagonal periodicity in the RGC mosaics and restrict the alignment between ON and OFF mosaics, so that they generate a periodic pattern with consistent spatial frequency for both the RGC mosaics and the cortical orientation maps. Our results demonstrate that the organization of functional maps in visual cortex, including its structural consistency, may be constrained by a retinal blueprint.
Sleep in Humans Stabilizes Pattern Separation Performance
Replay of hippocampal neural representations during sleep is thought to promote systems consolidation of declarative memory. How this reprocessing of memory during sleep affects the hippocampal representation itself, is unclear. Here we tested hippocampal stimulus processing (i.e., pattern separation) before and after periods of sleep and wakefulness in humans (female and male participants). Pattern separation deteriorated across the wake period but remained stable across sleep (p = 0.013) with this sleep–wake difference being most pronounced for stimuli with low similarity to targets (p = 0.006). Stimuli with the highest similarity showed a reversed pattern with reduced pattern separation performance after sleep (p = 0.038). Pattern separation performance was positively correlated with sleep spindle density, slow oscillation density, and theta power phase-locked to slow oscillations. Sleep, presumably by neural memory replay, shapes hippocampal representations and enhances computations of pattern separation to subsequent presentation of similar stimuli.
SIGNIFICANCE STATEMENT The consolidation of hippocampus-dependent memories is causally related to reactivation during sleep of previously encoded representations. Here, we show that reactivation-based consolidation processes during sleep shape the hippocampal representation itself. We studied the effect of sleep and wakefulness on pattern separation (i.e., orthogonalization of similar representations) and completion performance (i.e., recall of a memory in light of noisy input) that are essential cognitive elements of encoding and retrieval of information by the hippocampus. Our results demonstrate that pattern separation was stabilized after sleep but diminished after wakefulness. We further showed that pattern separation was related to EEG oscillatory parameters of non-REM sleep serving as markers of sleep-dependent memory consolidation and hippocampal reactivation.
Morphological Constraints on Cerebellar Granule Cell Combinatorial Diversity
Combinatorial expansion by the cerebellar granule cell layer (GCL) is fundamental to theories of cerebellar contributions to motor control and learning. Granule cells (GrCs) sample approximately four mossy fiber inputs and are thought to form a combinatorial code useful for pattern separation and learning. We constructed a spatially realistic model of the cerebellar GCL and examined how GCL architecture contributes to GrC combinatorial diversity. We found that GrC combinatorial diversity saturates quickly as mossy fiber input diversity increases, and that this saturation is in part a consequence of short dendrites, which limit access to diverse inputs and favor dense sampling of local inputs. This local sampling also produced GrCs that were combinatorially redundant, even when input diversity was extremely high. In addition, we found that mossy fiber clustering, which is a common anatomical pattern, also led to increased redundancy of GrC input combinations. We related this redundancy to hypothesized roles of temporal expansion of GrC information encoding in service of learned timing, and we show that GCL architecture produces GrC populations that support both temporal and combinatorial expansion. Finally, we used novel anatomical measurements from mice of either sex to inform modeling of sparse and filopodia-bearing mossy fibers, finding that these circuit features uniquely contribute to enhancing GrC diversification and redundancy. Our results complement information theoretic studies of granule layer structure and provide insight into the contributions of granule layer anatomical features to afferent mixing.
SIGNIFICANCE STATEMENT Cerebellar granule cells are among the simplest neurons, with tiny somata and, on average, just four dendrites. These characteristics, along with their dense organization, inspired influential theoretical work on the granule cell layer as a combinatorial expander, where each granule cell represents a unique combination of inputs. Despite the centrality of these theories to cerebellar physiology, the degree of expansion supported by anatomically realistic patterns of inputs is unknown. Using modeling and anatomy, we show that realistic input patterns constrain combinatorial diversity by producing redundant combinations, which nevertheless could support temporal diversification of like combinations, suitable for learned timing. Our study suggests a neural substrate for producing high levels of both combinatorial and temporal diversity in the granule cell layer.
Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities
Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9–11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16–19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.
SIGNIFICANCE STATEMENT The present study proposes a "back translation" of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.
Working Memory and Decision-Making in a Frontoparietal Circuit Model
Working memory (WM) and decision-making (DM) are fundamental cognitive functions involving a distributed interacting network of brain areas, with the posterior parietal cortex (PPC) and prefrontal cortex (PFC) at the core. However, the shared and distinct roles of these areas and the nature of their coordination in cognitive function remain poorly understood. Biophysically based computational models of cortical circuits have provided insights into the mechanisms supporting these functions, yet they have primarily focused on the local microcircuit level, raising questions about the principles for distributed cognitive computation in multiregional networks. To examine these issues, we developed a distributed circuit model of two reciprocally interacting modules representing PPC and PFC circuits. The circuit architecture includes hierarchical differences in local recurrent structure and implements reciprocal long-range projections. This parsimonious model captures a range of behavioral and neuronal features of frontoparietal circuits across multiple WM and DM paradigms. In the context of WM, both areas exhibit persistent activity, but, in response to intervening distractors, PPC transiently encodes distractors while PFC filters distractors and supports WM robustness. With regard to DM, the PPC module generates graded representations of accumulated evidence supporting target selection, while the PFC module generates more categorical responses related to action or choice. These findings suggest computational principles for distributed, hierarchical processing in cortex during cognitive function and provide a framework for extension to multiregional models.
SIGNIFICANCE STATEMENT Working memory and decision-making are fundamental "building blocks" of cognition, and deficits in these functions are associated with neuropsychiatric disorders such as schizophrenia. These cognitive functions engage distributed networks with prefrontal cortex (PFC) and posterior parietal cortex (PPC) at the core. It is not clear, however, what the contributions of PPC and PFC are in light of the computations that subserve working memory and decision-making. We constructed a biophysical model of a reciprocally connected frontoparietal circuit that revealed shared and distinct functions for the PFC and PPC across working memory and decision-making tasks. Our parsimonious model connects circuit-level properties to cognitive functions and suggests novel design principles beyond those of local circuits for cognitive processing in multiregional brain networks.
Neural Representations of Hierarchical Rule Sets: The Human Control System Represents Rules Irrespective of the Hierarchical Level to Which They Belong
Humans use rules to organize their actions to achieve specific goals. Although simple rules that link a sensory stimulus to one response may suffice in some situations, often, the application of multiple, hierarchically organized rules is required. Recent theories suggest that progressively higher level rules are encoded along an anterior-to-posterior gradient within PFC. Although some evidence supports the existence of such a functional gradient, other studies argue for a lesser degree of specialization within PFC. We used fMRI to investigate whether rules at different hierarchical levels are represented at distinct locations in the brain or encoded by a single system. Thirty-seven male and female participants represented and applied hierarchical rule sets containing one lower-level stimulus–response rule and one higher-level selection rule. We used multivariate pattern analysis to investigate directly the representation of rules at each hierarchical level in absence of information about rules from other levels or other task-related information, thus providing a clear identification of low- and high-level rule representations. We could decode low- and high-level rules from local patterns of brain activity within a wide frontoparietal network. However, no significant difference existed between regions encoding representations of rules from both levels except for precentral gyrus, which represented only low-level rule information. Our findings show that the brain represents conditional rules regardless of their level in the explored hierarchy, so the human control system did not organize task representation according to this dimension. Our paradigm represents a promising approach to identifying critical principles that shape this control system.
SIGNIFICANCE STATEMENT Several recent studies investigating the organization of the human control system propose that rules at different control levels are organized along an anterior-to-posterior gradient within PFC. In this study, we used multivariate pattern analysis to explore independently the representation of formally identical conditional rules belonging to different levels of a cognitive hierarchy and provide for the first time a clear identification of low- and high-level rule representations. We found no major spatial differences between regions encoding rules from different hierarchical levels. This suggests that the human brain does not use levels in the investigated hierarchy as a topographical organization principle to represent rules controlling our behavior. Our paradigm represents a promising approach to identifying which principles are critical.
Extensive Tonotopic Mapping across Auditory Cortex Is Recapitulated by Spectrally Directed Attention and Systematically Related to Cortical Myeloarchitecture
Auditory selective attention is vital in natural soundscapes. But it is unclear how attentional focus on the primary dimension of auditory representation—acoustic frequency—might modulate basic auditory functional topography during active listening. In contrast to visual selective attention, which is supported by motor-mediated optimization of input across saccades and pupil dilation, the primate auditory system has fewer means of differentially sampling the world. This makes spectrally-directed endogenous attention a particularly crucial aspect of auditory attention. Using a novel functional paradigm combined with quantitative MRI, we establish in male and female listeners that human frequency-band-selective attention drives activation in both myeloarchitectonically estimated auditory core, and across the majority of tonotopically mapped nonprimary auditory cortex. The attentionally driven best-frequency maps show strong concordance with sensory-driven maps in the same subjects across much of the temporal plane, with poor concordance in areas outside traditional auditory cortex. There is significantly greater activation across most of auditory cortex when best frequency is attended, versus ignored; the same regions do not show this enhancement when attending to the least-preferred frequency band. Finally, the results demonstrate that there is spatial correspondence between the degree of myelination and the strength of the tonotopic signal across a number of regions in auditory cortex. Strong frequency preferences across tonotopically mapped auditory cortex spatially correlate with R1-estimated myeloarchitecture, indicating shared functional and anatomical organization that may underlie intrinsic auditory regionalization.
SIGNIFICANCE STATEMENT Perception is an active process, especially sensitive to attentional state. Listeners direct auditory attention to track a violin's melody within an ensemble performance, or to follow a voice in a crowded cafe. Although diverse pathologies reduce quality of life by impacting such spectrally directed auditory attention, its neurobiological bases are unclear. We demonstrate that human primary and nonprimary auditory cortical activation is modulated by spectrally directed attention in a manner that recapitulates its tonotopic sensory organization. Further, the graded activation profiles evoked by single-frequency bands are correlated with attentionally driven activation when these bands are presented in complex soundscapes. Finally, we observe a strong concordance in the degree of cortical myelination and the strength of tonotopic activation across several auditory cortical regions.
Firefighter Skin Cancer and Sun Protection Practices
This survey study examines skin cancer history, skin cancer screening, and sun protection habits among active Florida firefighters.
Clinical Findings and Gene Expression in Balloon Cell Melanoma
This case series describes 2 patients with balloon cell melanoma to evaluate the association of clinical and histopathologic characteristics with findings of gene expression profiling tests.
Tender Nodules on the Lower Legs
A man in his 20s with panhypopituitarism, septo-optic dysplasia, developmental delay, duodenal stricture, and a history of pancreatitis presented with a painful eruption on both lower legs. What is your diagnosis?
Noninvasive Gene Expression Testing in Amelanotic Melanoma
This case report describes noninvasive gene expression testing in a patient with amelanotic melanoma.
Hypercoagulable Conditions and Calciphylaxis in Renal Disease
This case-control study compares the hypercoagulability status of patients with calciphylaxis and renal disease with controls to identify conditions that are risk factors for developing calciphylaxis while controlling for chronic kidney disease.
Rational evaluation of the therapeutic effect and dosimetry of auger electrons for radionuclide therapy in a cell culture model
Abstract
Objective
Radionuclide therapy with low-energy auger electron emitters may provide high antitumor efficacy while keeping the toxicity to normal organs low. Here we evaluated the usefulness of an auger electron emitter and compared it with that of a beta emitter for tumor treatment in in vitro models and conducted a dosimetry simulation using radioiodine-labeled metaiodobenzylguanidine (MIBG) as a model compound.
Methods
We evaluated the cellular uptake of 125I-MIBG and the therapeutic effects of 125I- and 131I-MIBG in 2D and 3D PC-12 cell culture models. We used a Monte Carlo simulation code (PHITS) to calculate the absorbed radiation dose of 125I or 131I in computer simulation models for 2D and 3D cell cultures. In the dosimetry calculation for the 3D model, several distribution patterns of radionuclide were applied.
Results
A higher cumulative dose was observed in the 3D model due to the prolonged retention of MIBG compared to the 2D model. However, 125I-MIBG showed a greater therapeutic effect in the 2D model compared to the 3D model (respective EC50 values in the 2D and 3D models: 86.9 and 303.9 MBq/cell), whereas 131I-MIBG showed the opposite result (respective EC50 values in the 2D and 3D models: 49.4 and 30.2 MBq/cell). The therapeutic effect of 125I-MIBG was lower than that of 131I-MIBG in both models, but the radionuclide-derived difference was smaller in the 2D model. The dosimetry simulation with PHITS revealed the influence of the radiation quality, the crossfire effect, radionuclide distribution, and tumor shape on the absorbed dose. Application of the heterogeneous distribution series dramatically changed the radiation dose distribution of 125I-MIBG, and mitigated the difference between the estimated and measured therapeutic effects of 125I-MIBG.
Conclusions
The therapeutic effect of 125I-MIBG was comparable to that of 131I-MIBG in the 2D model, but the efficacy was inferior to that of 131I-MIBG in the 3D model, since the crossfire effect is negligible and the homogeneous distribution of radionuclides was insufficient. Thus, auger electrons would be suitable for treating small-sized tumors. The design of radiopharmaceuticals with auger electron emitters requires particularly careful consideration of achieving a homogeneous distribution of the compound in the tumor.
Combination of UVC-LEDs and ultrasound for peroxymonosulfate activation to degrade synthetic dye: influence of promotional and inhibitory agents and application for real wastewater
Abstract
Several efforts have been carried out to present an efficient method for PMS activation. This work presented the use of UVC-LEDs (light emitting diodes) and US (ultrasound) to activate PMS for decolorization of Direct Orange 26 (DO26). The performance of UVC-LEDs/US/PMS process was effective in a broad range of pH (3.0–9.0). Complete decolorization was obtained in only 12 min in pH = 7.0 and 1.5 mM PMS. Bicarbonate and nitrite ions showed inhibitory effect on decolorization while sulfate, chloride, and nitrate had no significant effect on the performance of the process. Transition metals in homogenous (Fe2+ and Co2+) and heterogeneous forms (Fe3O4 and Co3O4) accelerated decolorization in UVC-LEDs/US/PMS system. The presence of turbidity declined the performance of UVC-LEDs/US/PMS through the prevention of PMS activation by UV and US. Compared to other oxidants (S2O82−, H2O2 and 2Na2CO3.3H2O2), PMS proved the higher function in decolorization of DO26 in UVC-LEDs/US/oxidant system. Scavenging experiments showed that 1O2, HO•, and SO4•- contributed in the degradation of DO26. Moreover, the UVC-LEDs/US/PMS system could markedly increase the biodegradability of real textile wastewater. These results promised an effective process for degradation of organic pollutants from aquatic environment.
Legal regulations of restrictions of air pollution made by non-road mobile machinery—the case study for Europe: a review
Abstract
The high awareness of intensification and frequency of smog phenomenon all over the world in XXI age makes for detailed analyses of the reasons of its formation and prevention. The governments of the developed countries and conscious of real hazards, including many European countries, aim to restrict the emission of harmful gases. In literature, we can find the discussions on the influence of this phenomenon on the health and life of inhabitants of contaminated areas. Some elaborations of prognostic models, descriptions of pollution sources, the manner of their restriction, and the analysis of causal-consecutive correlation are also popular. The influence of pollutions resulting from the operation of vehicles, planes, and the industry are well described. However, every machine and device which is driven with a combustion engine has the effect on the general level of anthropogenic pollutions. These drives are subject of different regulations limiting their emission for service conditions and applications. One of the groups of such machines described in European and American regulations is non-road mobile machinery. The aim of this paper is the presentation of the problem of weak analysis and application of engineering and technological tools for machinery drive emission, despite of many publications on hazards and problems of emission. These machines have the influence on both the increase of global contamination and the machine users. The regulations of the European Union take into consideration the generated hazards and restrict the emission of machine exhaust gases by approval tests—these regulations are continually improved, and the effects of these works are new emission limits in 2019. However, these activities seem to be liberal as opposed to limits of the emission for passenger and goods vehicles where the technological development of the construction is greater and the regulations are the most rigorous. During the analysis of the development of non-road mobile machinery in the correlation with automotive vehicles, we can indicate engineering and technological solutions which are limiting the emission of non-road mobile machinery, but which are not applied. Due to liberal regulations for this group of machinery, the producers do not apply innovative solutions which can be found in road vehicles. The paper presents the synthetic review of existing EU regulations concerning limits of the emission of harmful exhaust gases which are generated by spark-ignition combustion engines of non-road mobile machinery. The authors show the divergences between the limits of the emission of harmful exhaust gases generated by road vehicles and non-road mobile machinery (boats and railway engines are not taken into account). The authors present the directions of the development of the combustion process control and systems limiting the emission of harmful exhaust gases. High innovative automotive industry was indicated as the direction of the development for limiting the influence of the emission on the environment by non-road mobile machinery.
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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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https://www.youtube.com/watch?v=DFOhpBjLqN4&t=1s , Η ΘΕΡΑΠΕΙΑ ΓΙΑ ΟΛΕΣ ΤΙΣ ΑΣΘΕΝΕΙΕΣ 1 Περιεχόμενα Σύντομο βιογραφικό Πρόλογος μεταφραστ...
