Τετάρτη 20 Ιουνίου 2018
Environmentally persistent free radicals and particulate emissions from the thermal degradation of Croton megalocarpus biodiesel
Abstract
Pyrolysis of biodiesel at high temperatures may result in the formation of transient and stable free radicals immobilized on particulate emissions. Consequently, free radicals adsorbed on particulates are believed to be precursors for health-related illnesses such as cancer, cardiac arrest, and oxidative stress. This study explores the nature of free radicals and particulate emissions generated when Croton megalocarpus biodiesel is pyrolyzed at 600 °C in an inert environment of flowing nitrogen at a residence time of 0.5 s at 1 atm. The surface morphology of thermal emissions were imaged using a field emission gun scanning electron microscope (FEG SEM) while the radical characteristics were investigated using an electron paramagnetic resonance spectrometer (EPR). A g-value of 2.0024 associated with a narrow ∆Hp-p of 3.65 G was determined. The decay rate constant for the radicals was low (1.86 × 10−8 s−1) while the half-life was long ≈ 431 days. The observed EPR characterization of Croton megalocarpus thermal particulates revealed the existence of free radicals typical of those found in coal. The low g-value and low decay rate constant suggests that the free radicals in particulates are possibly carbon-centered. The mechanistic channel for the formation of croton char from model biodiesel component (9-dodecenoic acid, methyl ester) has been proposed in this study.
The environmental characteristics and applications of biochar
Abstract
The environmental deterioration is in a grave situation, and it is urgent to restore the environment. Biochar is a carbon-rich pyrolysis product of feedstock, which has aroused extensive concern due to its broad application potential for getting rid of pollutants and rehabilitating environment. This review generalizes three aspects on biochar, including production and properties, applications and mechanisms, and its modifications. Firstly, the production and characteristics have been summarized, because the practical applications of biochar are highly related to the special characteristics of biochar. Secondly, this paper outlines the latest applications of biochar for environmental remediation, and further provides a critical review on the application mechanisms in environmental restoration. Thirdly, the modification methods and applications of modified biochar are summarized, and all of the ways can be classified into two types: pretreatment of feedstock and modification of primitive biochar. Furthermore, the possible improvements and outlooks of applying biochar in environmental remediation are proposed. This review provides useful information for the application of biochar in environmental restoration.
Environmental genotoxicity and risk assessment in the Gulf of Riga (Baltic Sea) using fish, bivalves, and crustaceans
Abstract
Environmental genotoxicity in the Gulf of Riga was assessed using different bioindicators (fish, clams, and isopods) collected from 14 study stations. Comparison of genotoxicity responses (micronuclei (MN) and nuclear buds (NB)) in blood erythrocytes of herring (Clupea harengus), eelpout (Zoarces viviparous), and flounder (Platichthys flesus) revealed the species- and site-specific differences. For the first time, the analysis of genotoxicity was carried out in gill cells of isopods Saduria entomon. The highest inductions of MN and NB in gill cells of investigated S. entomon and clams (Macoma balthica) were evaluated in specimens from station 111A (offshore zone). In fish, the highest incidences of MN were measured in eelpout and in herring collected in the southern part of Gulf of Riga (station GOR3/41S). Moreover, in the southern coastal area, the assessment of genotoxicity risk (according to micronuclei levels) indicated exceptionally high risk for flounder, eelpout, and clams.
Antialgal effects of α-linolenic acid on harmful bloom-forming Prorocentrum donghaiense and the antialgal mechanisms
Abstract
Harmful algal blooms (HABs) induced by Prorocentrum donghaiense occur frequently and cause a serious threat to the marine ecosystem. In this study, antialgal effects of α-linolenic acid (ALA) that is generally extracted from diverse macroalga on P. donghaiense were investigated. Specifically, the growth, cellular morphology and ultrastructure, reactive oxygen species (ROS) content, mitochondrial membrane potential (MMP), cytochrome C (Cyt-C), and caspase-9,3 activity of untreated and treated P. donghaiense were investigated. The results showed that ALA significantly inhibited the growth of P. donghaiense. Under ALA exposure, the cellular morphology and ultrastructure were damaged. ALA also induced ROS overproduction in the algal cells, decreased MMP, induced Cyt-C release, and activated caspase-9,3, which strongly relates to algal apoptosis. In summary, this study revealed the responses of morphology and physiology of P. donghaiense when exposed under ALA, and shows the potential of biotechnology on controlling P. donghaiense.
Linear IgA bullous dermatosis induced by diclofenac sodium
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):496-497
Paradigm shift in antinuclear antibody negative lupus: Current evidence
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):384-387
Generalized multinucleate cell angiohistiocytoma with involvement of palms and soles: An unusual manifestation
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):468-470
Updates on the use of vaccines in dermatological conditions
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):388-402
Numerous vaccines are being actively developed for use in dermatologic diseases. Advances in the fields of immunotherapy, genetics and molecular medicine have allowed for the design of prophylactic and therapeutic vaccines with immense potential in managing infections and malignancies of the skin. This review addresses the different vaccines available for use in dermatological diseases and those under development for future potential use. The major limitation of our review is its complete reliance on published data. Our review is strictly limited to the availability of published research online through available databases. We do not cite any of the authors' previous publications nor have we conducted previous original research studies regarding vaccines in dermatology. Strength would have been added to our paper had we conducted original studies by our research team regarding the candidate vaccines delineated in the paper.
Giant eccrine porocarcinoma in an unusual location
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):521-521
Incidence of leprosy in Firozabad district (Uttar Pradesh)
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):403-407
Objective: To assess incidence of leprosy in Firozabad District (U.P.). Materials and Methods: A random sample of 148,061 population was covered by this second survey, spread over 259 units (230 rural/29 urban). The survey was conducted between March 2011 and November 2012. Clinically confirmed cases detected in known disease-free population were labeled as incident cases and treated. Results: The overall incidence rate of leprosy was found to be 3.4 per 10,000 person years; In healthy contacts it was 3.1, in paucibacillary contacts 29.7 while it was 89.3 in multibacillary contacts. The differences in incidence rate of these three groups were significant (P < 0.001). Incidence rate was significantly higher by age; 1.1 in persons <15 years to 8.0 in those >44 years of age, and in high endemicity areas with three or more cases. In terms of incidence rate ratio (95% confidence interval), the incidence for ages 15–24 years was 3.2 times significantly higher than for those under 15 years, 5.3 times (4.3–6.5) in ages 30–44 years and 7.0 times (5.6–8.7) for age ≥45 years. Incidence rate ratio was also significantly higher in paucibacillary contacts, by 9.5 times (7.0–13.0) and 27.7 times (18.8–40.6) in multibacillary contacts, as compared to healthy controls. Incidence rate ratio (95% confidence interval) was significantly higher by 2.9 times (2.4–3.5) in areas with endemicity status of 3 to 5 cases and by 2.0 times (1.6–2.5) in areas with >5 cases as compared to areas with no endemicity. It was 2.4 times more (1.6–3.5) in Narkhi, 2.4 times higher (1.7–3.5) in Tundla and 3.0 times higher (2.1–4.5) in Aravon blocks than in Aeka block of the district. Incidence rate was also found to be significantly higher (3.7) among females, 1.3 times higher (1.1–1.5) than in males (2.9). Incidence rate ratio (95% confidence interval) was also 2.5 times higher (1.2–5.1) among persons having reported disease of greater than 4 years in comparison to 1.5 in persons having disease for 2 to 3 years. Limitations of Study: None to the best of our knowledge. Conclusion: The present study suggests that incidence rate of leprosy is significantly higher among persons of above 15 years, in females, among contacts of paucibacillary/multibacillary disease, in areas where >3 leprosy cases were found and in Tundla, Narkhi and Aravon blocks in Firozabad district.
Ulcerated necrobiosis lipoidica: A cutaneous granulomatous reaction associated with systemic B-cell lymphoma
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):481-484
Clinical, immunological profile and follow up of patients with pemphigus: A study from India
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):408-413
Background: Pemphigus has a protracted course and multiple factors influence its prognosis. The objective of this study was to describe the epidemiology and clinical profile of pemphigus patients and to study its influence on treatment end points. Methods: This was a retrospective chart review done in an Indian tertiary care hospital from December 1991 to December 2013. Patients with less than 3 months' follow up and those who had paraneoplastic pemphigus were excluded. Results: There were 132 patients with pemphigus, of which 118 (89.4%) had pemphigus vulgaris and 14 (10.6%) had pemphigus foliaceous. The time to disease control (TDC) was available for 100 patients (n = 100, 75.7%); patients with a minimum follow up of 3 months (n = 80) were included for studying the end points like time to first disease remission (TDR) and time to first disease relapse (TDRe). The median period of follow up was 23 months (range 3–245). Out of the 100 patients, 61.9% were on oral steroids with adjuvant therapy. The steroid dose required for disease control for n = 100, ranged from 0.2 to 1.5 mg/kg body weight. Of these, 60% were treated with steroid dose of 1 mg/kg, 22% with >1 mg/kg, and 18% with <1 mg/kg. The mean time to disease control (in months) in the group which received <1 mg/kg steroid was 1.02 ± 0.68, 1 mg/kg was 0.72 ± 0.51, and >1 mg/kg was 1.02 ± 0.62 (P = 0.017); with a significant difference between the groups 2 and 3 (P = 0.007), implying a faster disease control in those who received 1 mg/kg dose. This difference was significant after adjusting for the steroid sparing drugs taken at baseline (P = 0.009, C.I. - 1.44-13.59). The mean time to first disease remission (TDR) was 11.46 ± 2.06 months. Out of the 80 patients with a minimum follow up of 3 months, 75% had achieved either partial or complete remission. None of the other epidemiological, clinical or immunological parameters had an impact on the TDC or TDR. Conclusions: The epidemiological, clinical or immunological parameters had no impact on the treatment end points like time to disease control and time to first disease remission. The dose of steroids required for disease control higher than 1 mg/kg offered no advantage in the time to disease control as compared to 1 mg/kg. Limitations: The study was retrospective and disease severity scores were not applied. In view of the shorter follow up period, long term prognostic end points and mortality could not be well represented. The median period of follow up was 23 months. The serum anti- desmoglein antibody titres were not available at various treatment end points for correlation at different time intervals.
Plica polonica: from national plague to death of the disease in the nineteenth-century Vilnius
Eglė Sakalauskaitė-Juodeikienė, Dalius Jatužis, Saulius Kaubrys
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):510-514
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):510-514
Is there a correlation of serum and tissue T helper-1 and -2 cytokine profiles with psoriasis activity and severity? A cross-sectional study
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):414-418
Background: Previous studies correlating Th1 and Th2 cytokine profiles with psoriasis activity provided inconsistent results. Correlation of tissue cytokine levels with psoriasis severity has not been studied till now. Objective: To compare serum and tissue Th1 and Th2 cytokine profiles of patients with active and stable psoriasis as well as healthy controls, and to correlate them with psoriasis severity. Methodology: This was a cross-sectional study involving adult patients with 'active' psoriasis (untreated progressive chronic plaque psoriasis, guttate psoriasis, and erythrodermic psoriasis), 'stable' psoriasis (stable plaque psoriasis or those with completely resolved lesions) and healthy subjects with non-inflammatory skin lesions as controls. Mean levels of Th1 and Th2 cytokines in serum [interleukin 2 (IL-2), interferon-gamma (IFN-γ), IL-4, IL-10] and tissue mRNA expression (IFN-γ, IL-4) were compared among these three groups. Results: There were 30 patients each in active and stable psoriasis groups, and 15 in the control group. Mean serum IL-2, IFN-γ, and IL-10 levels of patients with psoriasis patients were significantly higher than the controls (P < 0.001 for both active and stable psoriasis), whereas mean serum IL-4 level of patients was significantly lower than the controls (P < 0.001). However, there was no statistically significant difference of serum cytokine levels between active and stable psoriasis groups. Mean quantitative tissue mRNA expression of IFN-γ and IL-4 of patients with active and stable psoriasis were significantly lower than the controls (P < 0.001 and <0.01, respectively), but were not significantly different between active and stable psoriasis groups. Serum and tissue cytokines showed weak correlation with psoriasis area and severity index. Limitations: Small sample size and heterogenous nature of patients with psoriasis in terms of disease activity, morphology and treatment are limitations of this study. Conclusions: There is no significant change in the serum or tissue levels of Th1 and Th2 cytokines with activity or severity of psoriasis.
Rational use of laboratory tests in dermatology
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):377-383
Intramatricial injections for nail psoriasis: An open-label comparative study of triamcinolone, methotrexate, and cyclosporine
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):419-423
Background: One of the most effective options available for treating psoriatic fingernails is intramatricial injection of triamcinolone acetonide. Efficacies of intramatricial methotrexate and cyclosporine have not been comparatively evaluated to date. Methods: Ninety fingernails in 17 patients were assigned to three groups of thirty nails each, and treated with intramatricial injections of triamcinolone acetonide (10 mg/ml), methotrexate (25 mg/ml) and cyclosporine (50 mg/ml) respectively. Each nail was given two injections with a 6-week interval, and graded at 24 weeks using the Nail Psoriasis Severity Index. Results: In both triamcinolone acetonide and methotrexate groups, 15 (50%) nails out of 30 showed >75% improvement. In the cyclosporine group, only ten (33%) nails showed >75% improvement. Side effects were most in the nails treated with cyclosporine. Limitations: The limited follow-up period of 24 weeks may have been insufficient for detecting delayed remissions. The number of patients was small and there was no randomization or blinding. The lack of a placebo/ no- treatment arm can be considered a limitation. Conclusions: Amongst the three drugs studied, intramatricial methotrexate injection yielded the most improvement with minimum side effects, results being comparable to intramatricial triamcinolone acetonide injection. Cyclosporine was the least effective drug, with the most side effects. Intramatricial injection therapy is a safe, economical, simple and effective therapeutic modality in the management of nail psoriasis.
Mongolian spots combined with halo-like disappearance surrounding café au lait spots
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):474-477
Eruptive pseudoangiomatosis - cherry angiomas with perilesional halo
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):424-430
Eruptive pseudoangiomatosis is a rare viral exanthem characterized by acute onset of hemangiomata-like lesions, however, histological findings are distinct from that of true angiomas. This entity has been reported from Europe, North America, Japan, and Korea till date. Here, we report 12 cases of eruptive pseudoangiomatosis from a tertiary care hospital in Punjab.
Topical timolol in PHACES syndrome: Is it safe?
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):488-491
Chinese version of the treatment of autoimmune bullous disease quality of life questionnaire: Reliability and validity
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):431-436
Background: Treatments for autoimmune blistering disease carry significant risks of medical complications and can affect the patient's quality of life. Recently, the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire was developed in Australia. Objective: The objective of this study was to evaluate the reliability and validity of the Chinese version of the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire in Chinese patients with autoimmune blistering diseases. Methods: The Chinese version of the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire was produced by forward-backward translation and cross-cultural adaptation of the original English version. Autoimmune blistering disease patients recruited in the study self-administered the Chinese Treatment of Autoimmune Bullous Disease Quality of Life questionnaire, the Dermatology Life Quality Index and the 36-item Short-Form Health Survey. Reliability of the Chinese Treatment of Autoimmune Bullous Disease Quality of Life was evaluated using internal consistency and test-retest (days 0 and 7) methods. Validity was analyzed by face, content, construct, convergent and discriminant validity measures. Results: A total of 86 autoimmune blistering disease patients were recruited for the study. Cronbach's alpha coefficient was 0.883 and the intraclass correlation coefficient was 0.871. Face and content validities were satisfactory. Convergent validity testing revealed correlation coefficients of 0.664 for the Treatment of Autoimmune Bullous Disease Quality of Life and Dermatology Life Quality Index and –0.577 for the Treatment of Autoimmune Bullous Disease Quality of Life and 36-item Short-Form Health Survey. With respect to discriminant validity, no significant differences were observed in the Treatment of Autoimmune Bullous Disease Quality of Life scores of men and women (t = 0.251, P = 0.802), inpatients and outpatients (t = 0.447, P = 0.656), patients on steroids and steroid-sparing medications (t = 0.672, P = 0.503) and patients with different autoimmune blistering disease subtypes (F = 0.030, P = 0.971). Limitations: Illiterate patients were excluded from the study. The patients were from a single hospital and most of their conditions were in a relatively stable status. Conclusion: The Chinese version of the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire is a reliable and valid instrument to measure treatment burden and to serve as an end point in clinical trials in Chinese autoimmune blistering disease patients.
The strawberry tongue: What, how and where?
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):500-505
Solitary dome-shaped erythematous lump of long duration on the palm
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):437-439
Multiple inflamed cutaneous nodules in an elderly female
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):518-520
A creeping eruption of the buttocks
Indian Journal of Dermatology, Venereology, and Leprology 2018 84(4):440-440
A case of adult onset folliculocentric Langerhans cell histiocytosis
Journal of Cutaneous Pathology, Volume 45, Issue 7, Page 469-472, July 2018.
An unusual case of a systemic delayed hypersensitivity reaction to sodium metabisulfite
Contact Dermatitis, EarlyView.
Hand eczema and occupational contact allergies in healthcare workers with a focus on rubber additives
Contact Dermatitis, EarlyView.
Psoriasis: implication to disease and therapeutic strategies, with an emphasis on drug delivery approaches
International Journal of Dermatology, EarlyView.
Case of infective endocarditis caused by implanted artificial hair pyoderma
The Journal of Dermatology, EarlyView.
Incontinentia pigmenti in a Japanese female infant with a novel frame‐shift mutation in the IKBKG gene
The Journal of Dermatology, EarlyView.
Two cases of dabrafenib and trametinib therapy‐failed advanced melanoma successfully controlled by nivolumab monotherapy
The Journal of Dermatology, EarlyView.
Novel mutation c.263A>G in the ACVRL1 gene in a Japanese patient with hereditary hemorrhagic telangiectasia 2
The Journal of Dermatology, EarlyView.
Vitiligo at a keloid scar: A possible case of Koebner phenomenon
The Journal of Dermatology, EarlyView.
Association of human beta‐defensin 1 gene polymorphisms with nonsegmental vitiligo
Clinical and Experimental Dermatology, EarlyView.
Aciclovir for treatment of pityriasis lichenoides?
Clinical and Experimental Dermatology, EarlyView.
Actinic Keratosis Area Severity Index (AKASI): reproducibility study and comparison with total lesion count
British Journal of Dermatology, EarlyView.
Clinical and dermoscopic features of Spitz naevus by sex, age and anatomical site: a study of 913 Spitz naevi
British Journal of Dermatology, EarlyView.
Hyperspectral imaging system in the delineation of Ill‐defined basal cell carcinomas: a pilot study
Journal of the European Academy of Dermatology and Venereology, EarlyView.
Biologic switching between interleukin 17A antagonists secukinumab and ixekizumab: a 12‐week, multicenter, retrospective study
Journal of the European Academy of Dermatology and Venereology, EarlyView.
Dermoscopic clues in Pagetoid reticulosis Woringer–Kolopp type
Journal of the European Academy of Dermatology and Venereology, EarlyView.
Primary and secondary prevention of skin cancer in mountain guides: attitude and motivation for or against participation
Journal of the European Academy of Dermatology and Venereology, EarlyView.
Impossible obligations and the non-identity problem
Abstract
In a common example of the non-identity problem (NIP), a person (call her Wilma) deliberately conceives a child (call her Pebbles) who she knows will have incurable blindness but a life well worth living. Although Wilma's decision seems wrong, it is difficult to say why. This paper develops and defends a version of the "indirect strategy" for solving the NIP. This strategy rests on the idea that it is wrong to deliberately make it impossible to fulfill an obligation; consequently, it is wrong for Wilma to create Pebbles because doing so makes it impossible to fulfill her obligation to protect her child from harms like blindness. A challenge for the indirect strategy is the well-known "rights waiver problem": Since Pebbles's very existence depends on Wilma's having made herself unable to fulfill an obligation to Pebbles, Pebbles is likely to waive that obligation. I address this problem by recasting the indirect strategy in terms of a non-grievance evil. I argue that deliberately making it impossible to fulfill a moral obligation manifests a defective attitude toward morality—an attitude which sees moral obligations as things to be dodged whenever they are inconvenient. Next, I argue that acting on this attitude is a wrong-making feature that is independent of any wrong that might be done to Pebbles. I conclude that Wilma's decision remains wrong even if Pebbles waives any objection to it.
Optogenetic Inhibition of CGRP{alpha} Sensory Neurons Reveals Their Distinct Roles in Neuropathic and Incisional Pain
Cutaneous somatosensory neurons convey innocuous and noxious mechanical, thermal, and chemical stimuli from peripheral tissues to the CNS. Among these are nociceptive neurons that express calcitonin gene-related peptide-α (CGRPα). The role of peripheral CGRPα neurons (CANs) in acute and injury-induced pain has been studied using diphtheria toxin ablation, but their functional roles remain controversial. Because ablation permanently deletes a neuronal population, compensatory changes may ensue that mask the physiological or pathophysiological roles of CANs, particularly for injuries that occur after ablation. Therefore, we sought to define the role of intact CANs in vivo under baseline and injury conditions by using noninvasive transient optogenetic inhibition. We assessed pain behavior longitudinally from acute to chronic time points. We generated adult male and female mice that selectively express the outward rectifying proton pump archaerhodopsin-3 (Arch) in CANs, and inhibited their peripheral cutaneous terminals in models of neuropathic (spared nerve injury) and inflammatory (skin-muscle incision) pain using transdermal light activation of Arch. After nerve injury, brief activation of Arch reversed the chronic mechanical, cold, and heat hypersensitivity, alleviated the spontaneous pain, and reversed the sensitized mechanical currents in primary afferent somata. In contrast, Arch inhibition of CANs did not alter incision-induced hypersensitivity. Instead, incision-induced mechanical and heat hypersensitivity was alleviated by peripheral blockade of CGRPα peptide-receptor signaling. These results reveal that CANs have distinct roles in the time course of pain during neuropathic and incisional injuries and suggest that targeting peripheral CANs or CGRPα peptide-receptor signaling could selectively treat neuropathic or postoperative pain, respectively.
SIGNIFICANCE STATEMENT The contribution of sensory afferent CGRPα neurons (CANs) to neuropathic and inflammatory pain is controversial. Here, we left CANs intact during neuropathic and perioperative incision injury by using transient transdermal optogenetic inhibition of CANs. We found that peripheral CANs are required for neuropathic mechanical, cold, and heat hypersensitivity, spontaneous pain, and sensitization of mechanical currents in afferent somata. However, they are dispensable for incisional pain transmission. In contrast, peripheral pharmacological inhibition of CGRPα peptide-receptor signaling alleviated the incisional mechanical and heat hypersensitivity, but had no effect on neuropathic pain. These results show that CANs have distinct roles in neuropathic and incisional pain and suggest that their targeting via novel peripheral treatments may selectively alleviate neuropathic versus incisional pain.
Neural Dynamics of Variable Grasp-Movement Preparation in the Macaque Frontoparietal Network
Our voluntary grasping actions lie on a continuum between immediate action and waiting for the right moment, depending on the context. Therefore, studying grasping requires an investigation into how preparation time affects this process. Two macaque monkeys (Macaca mulatta; one male, one female) performed a grasping task with a short instruction followed by an immediate or delayed go cue (0–1300 ms) while we recorded in parallel from neurons in the grasp preparation relevant area F5 that is part of the ventral premotor cortex, and the anterior intraparietal area (AIP). Initial population dynamics followed a fixed trajectory in the neural state space unique to each grip type, reflecting unavoidable movement selection, then diverged depending on the delay, reaching unique states not achieved for immediately cued movements. Population activity in the AIP was less dynamic, whereas F5 activity continued to evolve throughout the delay. Interestingly, neuronal populations from both areas allowed for a readout tracking subjective anticipation of the go cue that predicted single-trial reaction time. However, the prediction of reaction time was better from F5 activity. Intriguingly, activity during movement initiation clustered into two trajectory groups, corresponding to movements that were either "as fast as possible" or withheld movements, demonstrating a widespread state shift in the frontoparietal grasping network when movements must be withheld. Our results reveal how dissociation between immediate and delay-specific preparatory activity, as well as differentiation between cortical areas, is possible through population-level analysis.
SIGNIFICANCE STATEMENT Sometimes when we move, we consciously plan our movements. At other times, we move instantly, seemingly with no planning at all. Yet, it's unclear how preparation for movements along this spectrum of planned and seemingly unplanned movement differs in the brain. Two macaque monkeys made reach-to-grasp movements after varying amounts of preparation time while we recorded from the premotor and parietal cortex. We found that the initial response to a grasp instruction was specific to the required movement, but not to the preparation time, reflecting required movement selection. However, when more preparation time was given, neural activity achieved unique states that likely related to withholding movements and anticipation of movement, shedding light on the roles of the premotor and parietal cortex in grasp planning.
Metaplasticity in the Visual Cortex: Crosstalk Between Visual Experience and Reactive Oxygen Species
Metaplasticity is the regulation of synaptic plasticity based on the history of previous synaptic activation. This concept was formulated after observing that synaptic changes in the visual cortex are not fixed, but dynamic and dependent on the history of visual information flux. In visual cortical neurons, sustained synaptic stimulation activate the enzymatic complex NOX2, resulting in the generation of reactive oxygen species (ROS). NOX2 is the main molecular structure responsible for translating neural activity into redox modulation of intracellular signaling pathways involved in plastic changes. Here, we studied the interaction between NOX2 and visual experience as metaplastic factors regulating synaptic plasticity at the supergranular layers of the mouse visual cortex. We found that genetic inhibition of NOX2 reverses the polarizing effects of dark rearing from LTP to LTD. In addition, we demonstrate that this process relies on changes in the NMDA receptor functioning. Altogether, this work indicates a role of ROS in the activity-dependent regulation of cortical synaptic plasticity.
SIGNIFICANCE STATEMENT Synaptic plasticity in the visual cortex is modulated by the history of sensory experience and this modulation has been defined as metaplasticity. Dark rearing facilitates synaptic potentiation as a mechanism optimizing the range of synaptic modification. This process requires the production of reactive oxygen species mediated by the enzymatic complex NOX2. If the activity of NOX2 is inhibited, then visual deprivation results in synaptic depression. These findings increase our knowledge about metaplasticity and help in our understanding of how neural activity modulates cellular mechanisms of synaptic change.
Cortical Oscillatory Mechanisms Supporting the Control of Human Social-Emotional Actions
The human anterior prefrontal cortex (aPFC) is involved in regulating social–emotional behavior, presumably by modulating effective connectivity with downstream parietal, limbic, and motor cortices. Regulating that connectivity might rely on theta-band oscillations (4–8 Hz), a brain rhythm known to create overlapping periods of excitability between distant regions by temporally releasing neurons from inhibition. Here, we used MEG to understand how aPFC theta-band oscillations implement control over prepotent social–emotional behaviors; that is, the control over automatically elicited approach and avoidance actions. Forty human male participants performed a social approach–avoidance task in which they approached or avoided visually displayed emotional faces (happy or angry) by pulling or pushing a joystick. Approaching angry and avoiding happy faces (incongruent condition) requires rapid application of cognitive control to override prepotent habitual action tendencies to approach appetitive and to avoid aversive situations. In the time window before response delivery, trial-by-trial variations in aPFC theta-band power (6 Hz) predicted reaction time increases during emotional control and were inversely related to beta-band power (14–22 Hz) over parietofrontal cortex. In sensorimotor areas contralateral to the moving hand, premovement gamma-band rhythms (60–90 Hz) were stronger during incongruent than congruent trials, with power increases phase locked to peaks of the aPFC theta-band oscillations. These findings define a mechanistic relation between cortical areas involved in implementing rapid control over human social–emotional behavior. The aPFC may bias neural processing toward rule-driven actions and away from automatic emotional tendencies by coordinating tonic disinhibition and phasic enhancement of parietofrontal circuits involved in action selection.
SIGNIFICANCE STATEMENT Being able to control social–emotional behavior is crucial for successful participation in society, as is illustrated by the severe social and occupational difficulties experienced by people suffering from social motivational disorders such as social anxiety. In this study, we show that theta-band oscillations in the anterior prefrontal cortex (aPFC), which are thought to provide temporal organization for neural firing during communication between distant brain areas, facilitate this control by linking aPFC to parietofrontal beta-band and sensorimotor gamma-band oscillations involved in action selection. These results contribute to a mechanistic understanding of cognitive control over automatic social–emotional action and point to frontal theta-band oscillations as a possible target of rhythmic neurostimulation techniques during treatment for social anxiety.
WT1-Expressing Interneurons Regulate Left-Right Alternation during Mammalian Locomotor Activity
The basic pattern of activity underlying stepping in mammals is generated by a neural network located in the caudal spinal cord. Within this network, the specific circuitry coordinating left–right alternation has been shown to involve several groups of molecularly defined interneurons. Here we characterize a population of spinal neurons that express the Wilms' tumor 1 (WT1) gene and investigate their role during locomotor activity in mice of both sexes. We demonstrate that WT1-expressing cells are located in the ventromedial region of the spinal cord of mice and are also present in the human spinal cord. In the mouse, these cells are inhibitory, project axons to the contralateral spinal cord, terminate in close proximity to other commissural interneuron subtypes, and are essential for appropriate left–right alternation during locomotion. In addition to identifying WT1-expressing interneurons as a key component of the locomotor circuitry, this study provides insight into the manner in which several populations of molecularly defined interneurons are interconnected to generate coordinated motor activity on either side of the body during stepping.
SIGNIFICANCE STATEMENT In this study, we characterize WT1-expressing spinal interneurons in mice and demonstrate that they are commissurally projecting and inhibitory. Silencing of this neuronal population during a locomotor task results in a complete breakdown of left–right alternation, whereas flexor-extensor alternation was not significantly affected. Axons of WT1 neurons are shown to terminate nearby commissural interneurons, which coordinate motoneuron activity during locomotion, and presumably regulate their activity. Finally, the WT1 gene is shown to be present in the spinal cord of humans, raising the possibility of functional homology between these species. This study not only identifies a key component of the locomotor circuitry but also begins to unravel the connectivity among the growing number of molecularly defined interneurons that comprise this neural network.
Optogenetic Activation of Colon Epithelium of the Mouse Produces High-Frequency Bursting in Extrinsic Colon Afferents and Engages Visceromotor Responses
Epithelial cells of the colon provide a vital interface between the internal environment (lumen of the colon) and colon parenchyma. To examine epithelial–neuronal signaling at this interface, we analyzed mice in which channelrhodopsin (ChR2) was targeted to either TRPV1-positive afferents or to villin-expressing colon epithelial cells. Expression of a ChR2-EYFP fusion protein was directed to either primary sensory neurons or to colon epithelial cells by crossing Ai32 mice with TRPV1-Cre or villin-Cre mice, respectively. An ex vivo preparation of the colon was used for single-fiber analysis of colon sensory afferents of the pelvic nerve. Afferents were characterized using previously described criteria as mucosal, muscular, muscular-mucosal, or serosal and then tested for blue light-induced activation. Light activation of colon epithelial cells produced robust firing of action potentials, similar to that elicited by physiologic stimulation (e.g., circumferential stretch), in 50.5% of colon afferents of mice homozygous for ChR2 expression. Light-induced activity could be reduced or abolished in most fibers using a cocktail of purinergic receptor blockers suggesting ATP release by the epithelium contributed to generation of sensory neuron action potentials. Using electromyographic recording of visceromotor responses we found that light stimulation of the colon epithelium evoked behavioral responses in Vil-ChR2 mice that was similar to that seen with balloon distension of the colon. These ex vivo and in vivo data indicate that light stimulation of colon epithelial cells alone, without added mechanical or chemical stimuli, can directly activate colon afferents and elicit behavioral responses.
SIGNIFICANCE STATEMENT Abdominal pain that accompanies inflammatory diseases of the bowel is particularly vexing because it can occur without obvious changes in the structure or inflammatory condition of the colon. Pain reflects abnormal sensory neuron activity that may be controlled in part by release of substances from lining epithelial cells. In support of this mechanism we determined that blue-light stimulation of channelrhodopsin-expressing colon epithelial cells could evoke action potential firing in sensory neurons and produce changes in measures of behavioral sensitivity. Thus, activity of colon epithelial cells alone, without added mechanical or chemical stimuli, is sufficient to activate pain-sensing neurons.
Voltage-Gated Calcium Influx Modifies Cholinergic Inhibition of Inner Hair Cells in the Immature Rat Cochlea
Until postnatal day (P) 12, inner hair cells of the rat cochlea are invested with both afferent and efferent synaptic connections. With the onset of hearing at P12, the efferent synapses disappear, and afferent (ribbon) synapses operate with greater efficiency. This change coincides with increased expression of voltage-gated potassium channels, the loss of calcium-dependent electrogenesis, and the onset of graded receptor potentials driven by sound. The transient efferent synapses include near-membrane postsynaptic cisterns thought to regulate calcium influx through the hair cell's α9-containing and α10-containing nicotinic acetylcholine receptors. This influx activates small-conductance Ca2+-activated K+ (SK) channels. Serial-section electron microscopy of inner hair cells from two 9-d-old (male) rat pups revealed many postsynaptic efferent cisterns and presynaptic afferent ribbons whose average minimal separation in five cells ranged from 1.1 to 1.7 μm. Efferent synaptic function was studied in rat pups (age, 7–9 d) of either sex. The duration of these SK channel-mediated IPSCs was increased by enhanced calcium influx through L-type voltage-gated channels, combined with ryanodine-sensitive release from internal stores—presumably the near-membrane postsynaptic cistern. These data support the possibility that inner hair cell calcium electrogenesis modulates the efficacy of efferent inhibition during the maturation of inner hair cell synapses.
SIGNIFICANCE STATEMENT Strict calcium buffering is essential for cellular function. This problem is especially acute for compact hair cells where increasing cytoplasmic calcium promotes the opposing functions of closely adjoining afferent and efferent synapses. The near-membrane postsynaptic cistern at efferent synapses segregates synaptic calcium signals by acting as a dynamic calcium store. The hair cell serves as an informative model for synapses with postsynaptic cisterns (C synapses) found in central neurons.
Identification and Characterization of a Novel Spontaneously Active Bursty GABAergic Interneuron in the Mouse Striatum
The recent availability of different transgenic mouse lines coupled with other modern molecular techniques has led to the discovery of an unexpectedly large cellular diversity and synaptic specificity in striatal interneuronal circuitry. Prior research has described three spontaneously active interneuron types in mouse striatal slices: the cholinergic interneuron, the neuropeptide Y-low threshold spike interneuron, and the tyrosine hydroxylase interneurons (THINs). Using transgenic Htr3a-Cre mice, we now characterize a fourth population of spontaneously active striatal GABAergic interneurons termed spontaneously active bursty interneurons (SABIs) because of their unique burst-firing pattern in cell-attached recordings. Although they bear some qualitative similarity in intrinsic electrophysiological properties to THINs in whole-cell recordings, detailed analysis revealed significant differences in many intrinsic properties and in their morphology. Furthermore, all previously identified striatal GABAergic interneurons have been shown to innervate striatal spiny projection neurons (SPNs), contributing to the suggestion that the principal function of striatal GABAergic interneurons is to provide feedforward inhibition to SPNs. Here, very surprisingly, paired recordings show that SABIs do not innervate SPNs significantly. Further, optogenetic inhibition of striatal Htr3a-Cre interneurons triggers barrages of IPSCs in SPNs. We hypothesize that these IPSCs result from disinhibition of a population of GABAergic interneurons with activity that is constitutively suppressed by the SABIs. We suggest that the SABIs represent the first example of a striatal interneuron-selective interneuron and, further, that their existence, along with previously defined interneuronal networks, may participate in the formation of SPN ensembles observed by others.
SIGNIFICANCE STATEMENT Before ~2010, the main function of the three known subtypes of striatal GABAergic interneurons was assumed to mediate feedforward inhibition of the spiny neurons (SPNs). During the past decade, we and others have described several novel populations of striatal GABAergic interneurons and their synaptic connections and have shown that striatal interneurons and SPNs interact through extensive and highly cell-type-specific connections that form specialized networks. Here, we describe a novel population of striatal GABAergic interneuron and provide several lines of evidence suggesting that it represents the first interneuron-selective interneuron in striatum. Striatal interneurons and their synaptic connections are suggested to play an important role in the formation of ensembles of striatal SPNs interconnected by inhibitory axon collaterals.
Persistent but Labile Synaptic Plasticity at Excitatory Synapses
Short-term synaptic plasticity contributes to many computations in the brain and allows synapses to keep a finite record of recent activity. Here we have investigated the mechanisms underlying an intriguing form of short-term plasticity termed labile LTP, at hippocampal and PFC synapses in male rats and male and female mice. In the hippocampus, labile LTP is triggered by high-frequency activation of presynaptic axons and is rapidly discharged with further activation of those axons. However, if the synapses are quiescent, they remain potentiated until further presynaptic activation. To distinguish labile LTP from NMDAR-dependent forms of potentiation, we blocked NMDARs in all experiments. Labile LTP was synapse-specific and was accompanied by a decreased paired pulse ratio, consistent with an increased release probability. Presynaptic Ca2+ and protein kinase activation during the tetanus appeared to be required for its initiation. Labile LTP was not reversed by a PKC inhibitor and did not require either RIM1α or synaptotagmin-7, proteins implicated in other forms of presynaptic short-term plasticity. Similar NMDAR-independent potentiation could be elicited at synapses in mPFC. Labile LTP allows for rapid information storage that is erased under controlled circumstances and could have a role in a variety of hippocampal and prefrontal cortical computations related to short-term memory.
SIGNIFICANCE STATEMENT Changes in synaptic strength are thought to represent information storage relevant to particular nervous system tasks. A single synapse can exhibit multiple overlapping forms of plasticity that shape information transfer from presynaptic to postsynaptic neurons. Here we investigate the mechanisms underlying labile LTP, an NMDAR-independent form of plasticity induced at hippocampal synapses. The potentiation is maintained for long periods as long as the synapses are infrequently active, but with regular activation, the synapses are depotentiated. Similar NMDAR-independent potentiation can also be induced at L2/3-to-L5 synapses in mPFC. Labile LTP requires a rise in presynaptic Ca2+ and protein kinase activation but is unaffected in RIM1α or synaptotagmin-7 mutant mice. Labile LTP may contribute to short-term or working memory in hippocampus and mPFC.
Ischemic Brain Injury Leads to Brain Edema via Hyperthermia-Induced TRPV4 Activation
Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain largely unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which male mouse brain slices were treated with oxygen-glucose deprivation (OGD) to mimic ischemia. We continuously measured the cross-sectional area of the brain slice for 150 min under macroscopic microscopy, finding that OGD induces swelling of brain slices. OGD-induced swelling was prevented by pharmacologically blocking or genetically knocking out the transient receptor potential vanilloid 4 (TRPV4), a member of the thermosensitive TRP channel family. Because TRPV4 is activated at around body temperature and its activation is enhanced by heating, we next elevated the temperature of the perfusate in the recording chamber, finding that hyperthermia induces swelling via TRPV4 activation. Furthermore, using the temperature-dependent fluorescence lifetime of a fluorescent-thermosensitive probe, we confirmed that OGD treatment increases the temperature of brain slices through the activation of glutamate receptors. Finally, we found that brain edema following traumatic brain injury was suppressed in TRPV4-deficient male mice in vivo. Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia.
SIGNIFICANCE STATEMENT Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which mouse brain slices were treated with oxygen-glucose deprivation. Using this system, we showed that the increase in brain temperature and the following activation of the thermosensitive cation channel TRPV4 (transient receptor potential vanilloid 4) are involved in the pathology of edema. Finally, we confirmed that TRPV4 is involved in brain edema in vivo using TRPV4-deficient mice, concluding that hyperthermia activates TRPV4 and induces brain edema after ischemia.
Correlated Gene Expression and Anatomical Communication Support Synchronized Brain Activity in the Mouse Functional Connectome
Cognition and behavior depend on synchronized intrinsic brain activity that is organized into functional networks across the brain. Research has investigated how anatomical connectivity both shapes and is shaped by these networks, but not how anatomical connectivity interacts with intra-areal molecular properties to drive functional connectivity. Here, we present a novel linear model to explain functional connectivity by integrating systematically obtained measurements of axonal connectivity, gene expression, and resting-state functional connectivity MRI in the mouse brain. The model suggests that functional connectivity arises from both anatomical links and inter-areal similarities in gene expression. By estimating these effects, we identify anatomical modules in which correlated gene expression and anatomical connectivity support functional connectivity. Along with providing evidence that not all genes equally contribute to functional connectivity, this research establishes new insights regarding the biological underpinnings of coordinated brain activity measured by BOLD fMRI.
SIGNIFICANCE STATEMENT Efforts at characterizing the functional connectome with fMRI have risen exponentially over the last decade. Yet despite this rise, the biological underpinnings of these functional measurements are still primarily unknown. The current report begins to fill this void by investigating the molecular underpinnings of the functional connectome through an integration of systematically obtained structural information and gene expression data throughout the rodent brain. We find that both white matter connectivity and similarity in regional gene expression relate to resting-state functional connectivity. The current report furthers our understanding of the biological underpinnings of the functional connectome and provides a linear model that can be used to streamline preclinical animal studies of disease.
Functional Consequences of Synapse Remodeling Following Astrocyte-Specific Regulation of Ephrin-B1 in the Adult Hippocampus
Astrocyte-derived factors can control synapse formation and functions, making astrocytes an attractive target for regulating neuronal circuits and associated behaviors. Abnormal astrocyte-neuronal interactions are also implicated in neurodevelopmental disorders and neurodegenerative diseases associated with impaired learning and memory. However, little is known about astrocyte-mediated mechanisms that regulate learning and memory. Here, we propose astrocytic ephrin-B1 as a regulator of synaptogenesis in adult hippocampus and mouse learning behaviors. We found that astrocyte-specific ablation of ephrin-B1 in male mice triggers an increase in the density of immature dendritic spines and excitatory synaptic sites in the adult CA1 hippocampus. However, the prevalence of immature dendritic spines is associated with decreased evoked postsynaptic firing responses in CA1 pyramidal neurons, suggesting impaired maturation of these newly formed and potentially silent synapses or increased excitatory drive on the inhibitory neurons resulting in the overall decreased postsynaptic firing. Nevertheless, astrocyte-specific ephrin-B1 knock-out male mice exhibit normal acquisition of fear memory but enhanced contextual fear memory recall. In contrast, overexpression of astrocytic ephrin-B1 in the adult CA1 hippocampus leads to the loss of dendritic spines, reduced excitatory input, and impaired contextual memory retention. Our results suggest that astrocytic ephrin-B1 may compete with neuronal ephrin-B1 and mediate excitatory synapse elimination through its interactions with neuronal EphB receptors. Indeed, a deletion of neuronal EphB receptors impairs the ability of astrocytes expressing functional ephrin-B1 to engulf synaptosomes in vitro. Our findings demonstrate that astrocytic ephrin-B1 regulates long-term contextual memory by restricting new synapse formation in the adult hippocampus.
SIGNIFICANCE STATEMENT These studies address a gap in our knowledge of astrocyte-mediated regulation of learning and memory by unveiling a new role for ephrin-B1 in astrocytes and elucidating new mechanisms by which astrocytes regulate learning. Our studies explore the mechanisms underlying astrocyte regulation of hippocampal circuit remodeling during learning using new genetic tools that target ephrin-B signaling in astrocytes in vivo. On a subcellular level, astrocytic ephrin-B1 may compete with neuronal ephrin-B1 and trigger astrocyte-mediated elimination of EphB receptor-containing synapses. Given the role EphB receptors play in neurodevelopmental disorders and neurodegenerative diseases, these findings establish a foundation for future studies of astrocyte-mediated synaptogenesis in clinically relevant conditions that can help to guide the development of clinical applications for a variety of neurological disorders.
Neuroanatomy of the vmPFC and dlPFC Predicts Individual Differences in Cognitive Regulation During Dietary Self-Control Across Regulation Strategies
Making healthy food choices is challenging for many people. Individuals differ greatly in their ability to follow health goals in the face of temptation, but it is unclear what underlies such differences. Using voxel-based morphometry, we investigated in healthy humans (i.e., men and women) the links between structural variation in gray matter volume and individuals' level of success in shifting toward healthier food choices. We combined MRI and choice data into a joint dataset by pooling across three independent studies that used a task prompting participants to explicitly focus on the healthiness of food items before making their food choices. Within this dataset, we found that individual differences in gray matter volume in the ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) predicted regulatory success. We extended and confirmed these initial findings by predicting regulatory success out of sample and across tasks in a second dataset requiring participants to apply a different regulation strategy that entailed distancing from cravings for unhealthy, appetitive foods. Our findings suggest that neuroanatomical markers in the vmPFC and dlPFC generalized to different forms of dietary regulation strategies across participant groups. They provide novel evidence that structural differences in neuroanatomy of two key regions for valuation and its control, the vmPFC and dlPFC, predict an individual's ability to exert control in dietary choices.
SIGNIFICANCE STATEMENT Dieting involves regulating food choices to eat healthier foods and fewer unhealthy foods. People differ dramatically in their ability to achieve or maintain this regulation, but it is unclear why. Here, we show that individuals with more gray matter volume in the dorsolateral and ventromedial prefrontal cortex are better at exercising dietary self-control. This relationship was observed across four different studies examining two different forms of dietary self-regulation, suggesting that neuroanatomical differences in the ventromedial prefrontal cortex and dorsolateral prefrontal cortex may represent a general marker for self-control abilities. These results identify candidate neuroanatomical markers for dieting success and failure, and suggest potential targets for therapies aimed at preventing or treating obesity and related eating disorders.
The Interplay Between Spike-Time and Spike-Rate Modes in the Auditory Nerve Encodes Tone-In-Noise Threshold
Auditory nerve fibers (ANFs) encode pure tones through two modes of coding, spike time and spike rate, depending on the tone frequency. In response to a low-frequency tone, ANF firing is phase locked to the sinusoidal waveform. Because time coding vanishes with an increase in the tone frequency, high-frequency tone coding relies on the spike rate of the ANFs. Adding a continuous broadband noise to a tone compresses the rate intensity function of ANFs and shifts its dynamic range toward higher intensities. Therefore, the ANFs with high-threshold/low-spontaneous rate (SR) are thought to contribute to behavioral tone detection in noise. However, this theory relies on the discharge rate of the ANFs. The direct comparison with the masking threshold through spike timing, irrespective of the spontaneous rate, has not so far been investigated. Taking advantage of a unique proxy to quantify the spike synchrony (i.e., the shuffle autocorrelogram), we show in female gerbils that high-SR ANFs are more adapted to encode low-frequency thresholds through temporal code, giving them a strong robustness in noise. By comparing behavioral thresholds measured using prepulse inhibition of the acoustical startle reflex with population thresholds calculated from ANFs pooled per octave band, we show that threshold-based spike timing provides a better estimate of behavioral thresholds in the low-frequency range, whereas the high-frequency behavioral thresholds rely on the spiking rate, particularly in noise. This emphasizes the complementarity of temporal and rate modes to code tone-in-noise thresholds over a large range of frequencies.
SIGNIFICANCE STATEMENT There is a general agreement that high-threshold/low-spontaneous rate (SR) auditory nerve fibers (ANFs) are of prime importance for tone detection in noise. However, this theory is based on the discharge rate of the fibers. Comparing the behavioral thresholds and single ANF thresholds shows that this is only true in the high-frequency range of tone stimulations. In the low-frequency range of tones (up to 2.7 kHz in the gerbil), the most sensitive ANFs (high-SR fibers) carry neural information through a spike-timing mode, even for noise in which tones do not induce a noticeable increment in the spike rate. This emphasizes the interplay between spike-time and spike-rate modes in the auditory nerve to encode tone-in-noise threshold over a large range of tone frequencies.
Age Differentiation within Gray Matter, White Matter, and between Memory and White Matter in an Adult Life Span Cohort
It is well established that brain structures and cognitive functions change across the life span. A long-standing hypothesis called "age differentiation" additionally posits that the relations between cognitive functions also change with age. To date, however, evidence for age-related differentiation is mixed, and no study has examined differentiation of the relationship between brain and cognition. Here we use multigroup structural equation models (SEMs) and SEM trees to study differences within and between brain and cognition across the adult life span (18–88 years) in a large (N > 646, closely matched across sexes), population-derived sample of healthy human adults from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.org). After factor analyses of gray matter volume (from T1- and T2-weighted MRI) and white matter organization (fractional anisotropy from diffusion-weighted MRI), we found evidence for the differentiation of gray and white matter, such that the covariance between brain factors decreased with age. However, we found no evidence for age differentiation among fluid intelligence, language, and memory, suggesting a relatively stable covariance pattern among cognitive factors. Finally, we observed a specific pattern of age differentiation between brain and cognitive factors, such that a white matter factor, which loaded most strongly on the hippocampal cingulum, became less correlated with memory performance in later life. These patterns are compatible with the reorganization of cognitive functions in the face of neural decline, and/or with the emergence of specific subpopulations in old age.
SIGNIFICANCE STATEMENT The theory of age differentiation posits age-related changes in the relationships among cognitive domains, either weakening (differentiation) or strengthening (dedifferentiation), but evidence for this hypothesis is mixed. Using age-varying covariance models in a large cross-sectional adult life span sample, we found age-related reductions in the covariance among both brain measures (neural differentiation), but no covariance change among cognitive factors of fluid intelligence, language, and memory. We also observed evidence of uncoupling (differentiation) between a white matter factor and cognitive factors in older age, most strongly for memory. Together, our findings support age-related differentiation as a complex, multifaceted pattern that differs for brain and cognition, and discuss several mechanisms that might explain the changing relationship between brain and cognition.
Distinguishing Mild, Moderate, and Severe Hidradenitis Suppurativa
In Reply We are grateful for the very constructive and positive feedback from Kokolakis and Sabat regarding our newly proposed Severity Assessment of Hidradenitis Suppurativa (SAHS) score.
A Twitter Analysis of the #DontFryDay Campaign
This study assessed the reach of the "Don't Fry Day" campaign on Twitter, using the hashtag #DontFryDay, and identified what types of individuals and/or tweeters are engaging in the campaign.
Persistent Malar Erythema With Atrophy in a Young Woman
A young woman had asymptomatic, facial redness that flared in sunlight, previously treated with doxycycline and topical sulfacetamide with no effect; on her cheeks and nasal bridge there were multiple erythematous, annular plaques with focal areas of atrophy. What is your diagnosis?
Distinguishing Mild, Moderate, and Severe Hidradenitis Suppurativa
To the Editor We read with great interest the article by Hessam and colleagues published in a recent issue of JAMA Dermatology describing the evaluation of a novel comprehensive score for hidradenitis suppurativa (HS) severity assessment. A highly inflammatory destructive disease, HS mainly affects axillary, inguinal, and perianal body areas. Patients with HS show signs of systemic inflammation and additionally often have metabolic syndrome, spondyloarthritis, or inflammatory bowel disease. Furthermore, HS has a tremendous negative effect on life quality and leads to reduced life expectancy.
Assessment of a Predictive Scoring Model for Dermoscopy of Subungual Melanoma In Situ
This cohort study identifies the dermoscopic features of subungual melanoma in situ in a Korean population and assesses a predictive scoring model that distinguishes the diagnosis of subungual melanoma in situ from longitudinal melanonychia in patients with pigmented nails.
Dietary Recommendations for Adults With Psoriasis or Psoriatic Arthritis
This systematic review presents evidence-based dietary recommendations for adults with psoriasis or psoriatic arthritis from the Medical Board of the National Psoriasis Foundation.
High Time for Hair Cells: An introduction to the symposium on sensory hair cells
Synopsis
Sensory hair cells are highly specialized cells that form the basis for our senses of hearing, orientation to gravity, and perception of linear acceleration (head translation in space) and angular acceleration (head rotation). In many species of fish and aquatic amphibians, hair cells mediate perception of water movement through the lateral line system, and electroreceptors derived from hair cell precursors mediate electric field detection. In tunicates, cells of the mechanosensory coronal organ on the incurrent siphon meet the structural, functional and developmental criteria to be described as hair cells, and they function to deflect large particles from entering the animal. The past two decades have witnessed significant breakthroughs in our understanding of hair cell biology and how their specialized structures influence their functions. This symposium combines the approaches of developmental biology, evolutionary biology, and physiology to share the gains of recent research in understanding hair cell function in different model systems. We brought together researchers working on sensory hair cells in organisms spanning the chordates in order to examine the depth and breadth of hair cell evolution. It is clear that these specialized cells serve a range of functions in different animals, due to evolutionary tinkering with a basic specialized cell type. This collection of papers will serve to mark the progress that has been made in this field and also stimulate the next wave of progress in this exciting field.Transcriptomic insights into the loss of vision in Molnár János Cave’s crustaceans
Abstract
Animals that inhabit subterranean environments often undergo various distinct phenotypic modifications (referred to as "troglomorphy") as they transition to life in perpetual darkness. However, the molecular basis behind troglomorphy remains poorly understood, particularly in regards to the mechanisms involved in the reduction and/or loss of traits at the transcriptomic level. In this study we investigate the transcriptional basis behind vision loss in populations of cave-dwelling crustaceans. We employ phylogenetic and transcriptomic methods on surface and cave-adapted populations of an emerging model species for biospeleology, the isopod Asellus aquaticus (Linnaeus, 1758), and the amphipod Niphargus hrabei S. Karaman, 1932. These two species show contrasting directionality in the surface-cave transition, which positions them as ideal study subjects. A. aquaticus is common in surface waters and is only occasionally found in caves, where its populations present different degrees of eye reduction and pigmentation. On the other hand, the eyeless N. hrabei has successfully colonized surface environments despite belonging to an almost exclusively cave-dwelling genus. By sequencing and assembling robust de novo transcriptomes we characterized differences in visual genes and pathways among surface and cave populations of the aforementioned species. Our results indicate that despite having reduced eyes, recent cave colonizer A. aquaticus is still capable of expressing functional visual opsins and major components of the phototransduction pathway within the cave. Niphargus hrabei, a species with an ancient cave origin, shows no clear indication of being capable of sight. However, the expression of putative functional visual opsins and other phototransduction genes was maintained, which suggests that this eyeless species might be capable of extraocular photoreception. With the present study, we aim to bring forth the Molnár János Cave system as a promising research avenue to improve our understanding of patterns of reduction and loss of vision in caves and other aphotic environments.Assessment of MRI Safety Issues for Stainless Steel Sutures used for Microtia Reconstruction
Publication date: Available online 19 June 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): TL Kraai, RB Loch, FG Shellock
IntroductionPotential magnetic resonance imaging issues for stainless steel sutures used for microtia reconstruction could be clinically significant from safety and diagnostic yield considerations. Therefore, the purpose of this investigation was to assess magnetic resonance issues (magnetic field interactions, heating, and artifacts) for different types of stainless steel sutures used for microtia reconstruction.MethodsSmall gauge, commonly used stainless steel sutures from four different manufacturers (5/-0 Steelex, Aesculap/B. Braun Medical, Inc.; Nagata 38 Gauge Microtia Wire, Bear Medical Corporation; Auricular Reco Wire, Medicon Surgical Inc.; and 5-0 B&S 35 Surgical Steel Suture, Ethicon, Inc.) were tested using standardized, ex vivo techniques to assess magnetic field interactions, heating, and artifacts at 3 Tesla. Prior to testing, the stainless steel sutures were configured as they would be for cartilage reconstruction used to treat microtia.ResultsEach stainless steel suture exhibited minor magnetic field interactions at 3 Tesla (translational attraction, deflection angle <10 degrees and no torque). Heating associated with a whole body averaged SAR of 2.9 W/kg was not excessive (highest temperature changes, ≤1.8°C). Artifacts were relatively minor in relation to the size and shape of each stainless steel suture (artifact size in relation to the size and shape of each stainless steel suture extending ≤ 5 mm).ConclusionsThe stainless steel sutures that underwent testing do not present additional risks to patients in a 3 Tesla or less setting (i.e., magnetic resonance conditional). Artifacts for these sutures may only be an issue within close proximity to the reconstructed ear.
Auricular Reconstruction of Congenital Microtia Using Modified Nagata Method: Personal 10-Year Experience with 1350 Cases
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Qiang Li, Xu Zhou, Yue Wang, Jin Qian, Qingguo Zhang
BackgroundTotal auricular reconstruction is currently one of the most challenging plastic procedures. Herein, we present our 10-year experience with 1350 cases of ear reconstruction using Nagata method with necessary improvement.MethodsBefore operation, factors related to ear reconstruction were carefully evaluated. These factors were remnant ear, mastoid skin, adjacent scalp, rib cartilages, normal ear, and mastoid process. An individualized design and precise framework fabricating were performed for each patient. Necessary modifications in fabricating base frame, helix, tragus, and antihelix were introduced to achieve a stable and individualized framework. These efforts also reduced the quantity of required cartilage for ear reconstruction.ResultsFollow-up time ranged from one month to five years, and 1217 (90.1%) patients were satisfied with the reconstructed ears, which showed appropriate color, texture, size, and location. The modifications made conferred a harmonious and individualized contour of the reconstructed ears. Complication incidences such as hematoma, skin necrosis, and framework absorption were all very low.ConclusionsBased on preoperative assessment, individualized design, and precise sculpting, a harmonious and individual auricle with detailed anatomical structures was achieved using our modified Nagata method. A stable and sophisticated framework can be fabricated with less cartilage requirement in this method.
A New Method for Mild Blepharoptosis Correction using Orbital Septum
Publication date: Available online 19 June 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Gaofeng Li, Wei Ding, Jun Tan, Bo Zhang, Xin Chen, Bin He
Cosmetic and structural outcomes of two different techniques of medial epicanthoplasty according to epicanthal fold classification and severity: a cohort study
Publication date: Available online 19 June 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Guanhuier Wang, Song Zhang, Jianxun Ma, Dong Li, Hongyu Xue
AimThis study aimed to compare the cosmetic and structural outcomes of two techniques for medial epicanthoplasty of the epicanthal fold, which varied in classification and severity.MethodsMedical records and photographs of 106 patients (212 eyes) who underwent medial epicanthoplasty using the modified Z-plasty or the modified redraping technique were reviewed retrospectively. They underwent surgery from January 2009 to June 2017, and had completed the follow-up of 6 months. The cosmetic outcome was evaluated in satisfactory, symmetry, smoothness, and scarring using a four-point scoring method, and the structural outcome was assessed by the ratio of intercanthal distance (ICD) and interpupillary distance (IPD). The two surgical techniques in the same epicanthal classification and severity were compared and analyzed.ResultsThe modified Z-plasty and the modified redraping technique had similar outcomes in satisfaction level in all types of epicanthal folds. The modified Z-plasty scored significantly higher in scarring in mild, moderate, and severe epicanthus palpebralis (p=0.034, 0.028, 0.013, respectively). The modified redraping technique scored significantly higher in smoothness in mild epicanthus tarsalis (p=0.025). In epicanthus palpebralis, the postoperative ICD/IPD ratio in the redraping technique was significantly lower (p=0.001, 0.000, respectively) while the preoperative ratio showed no significant difference. In epicanthus tarsalis, the postoperative ICD/IPD ratio showed no significantly difference while the preoperative ratio was significantly difference (p=0.011, 0.002, respectively).ConclusionsThe modified Z-plasty provided less scar in epicanthus palpebralis. The modified redraping technique provided more smoothness in mild epicanthus tarsalis, and it was more efficient in shortening the intercanthal distance.
BAPRAS and BAAPS Scientific Meetings: Are we sticking our noses up at rhinoplasty?
Publication date: Available online 19 June 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Zeeshaan Arshad, Tasneem Pope, Raina Zarb-Adami, Charles M Malata
Anatomical Variability of the Infra-mammary Fold and its Dynamics in Relation to Lejour Mammoplasty
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Hesham A. Helal, Nada A. Mahmoud
Scents in the stack: olfactometric proficiency testing with an emission simulation apparatus
Abstract
Olfactometry is globally acknowledged as a technique to determine odor concentrations, which are used to characterize odors for regulatory purposes, e.g., to protect the general public against harmful effects of air pollution. Although the determination procedure for odor concentrations is standardized in some countries, continued research is required to understand uncertainties of odor monitoring and prediction. In this respect, the present paper strives to provide answers of paramount importance in olfactometry. To do so, a wealth of measurement data originating from six large-scale olfactometric stack emission proficiency tests conducted from 2015 to 2017 was retrospectively analyzed. The tests were hosted at a unique emission simulation apparatus—a replica of an industry chimney with 23 m in height—so that for the first time, conventional proficiency testing (no sampling) with real measurements (no reference concentrations) was combined. Surprisingly, highly variable recovery rates of the odorants were observed—no matter, which of the very different odorants was analyzed. Extended measurement uncertainties with roughly 30–300% up to 20–520% around a single olfactometric measurement value were calculated, which are way beyond the 95% confidence interval given by the widely used standard EN 13725 (45–220%) for assessment and control of odor emissions. Also, no evidence has been found that mixtures of odorants could be determined more precisely than single-component odorants. This is an important argument in the intensely discussed topic, whether n-butanol as current reference substance in olfactometry should be replaced by multi-component odorants. However, based on our data, resorting to an alternative reference substance will not solve the inherent problem of high uncertainty levels in dynamic olfactometry. Finally, robust statistics allowed to calculate reliable odor thresholds, which are an important prerequisite to convert mass concentrations to odor concentrations and vice versa.
Pilot study of the feasibility of a double‐blind, randomized, placebo‐controlled localized area ultraviolet phototherapy trial methodology
Skin Research and Technology, EarlyView.
The revised EEMCO guidance for the in vivo measurement of water in the skin
Skin Research and Technology, EarlyView.
Household air pollution from cooking fuel and respiratory health risks for children in Pakistan
Abstract
Around 2.7 billion people in the world cook with polluting fuels, such as wood, crop residue, animal dung, charcoal, coal, and kerosene. Household air pollution from cooking with polluting fuels is recognized as a major risk factor for the disease burden. In this study, we examine the effect of using polluting fuels for cooking on the respiratory health of children in Pakistan. This study uses cross-sectional data from Pakistan Demographic and Health Survey 2012–13, with the sample size of 11,040 children under 5 years of age. Using logistic regression model, we control for factors such as averting activities, child characteristics, household characteristics, mother characteristics, and the unobserved factors using fixed effects. The results show that children in households using polluting fuels are 1.5 times more likely to have symptoms of acute respiratory infection (ARI) than children in households using cleaner fuels.
P-239Impact of adding oxaliplatin to fluoropyrimidines in the adjuvant therapy in stage II in colon cancer: Experience in Ramon y Cajal Universitary Hospital
Introduction: The addition of oxaliplatin to fluorouracil and leucovorin as adjuvant chemotherapy (AC) for patients with stage II and III colon cancer (CC) has been analyzed in two large, randomized trials, MOSAIC and C-07 trials. The updated results of these studies showed that the addition of oxaliplatin enhances overall survival by approximately 5% in patients with stage III disease but has no effect in patients with stage II disease.
P-170Management of patients with unresectable HCC: A simulation-based assessment of medical oncologists’ practice choices
Introduction: For the first time in a decade the hepatocellular carcinoma (HCC) treatment algorithm is undergoing significant change, challenging oncologists to assimilate evidence into practice.
O-002Geographic variation in systemic treatment of metastatic pancreatic adenocarcinoma (mPAC) patients in real world across Europe
Introduction: mPAC remains associated with poor outcomes. While new compounds/combinations continue to be explored, treatment options are still limited. Data on systemic treatment choices in mPAC and outcomes outside clinical trials are scarce. The goal of this pan-European project was to generate data on diagnosis, treatment patterns and outcomes from the records of patients who completed first-line mPAC treatment across Europe.
P-306The relationship between primary tumor regression grade and lymph nodes status in local advanced rectal cancer after neoadjuvant chemoradiation therapy
Introduction: Neoadjuvant chemoradiation therapy may affect the lymph node status in local advanced rectal cancer. In this study, we evaluate the relationship between tumor regression grade and lymph nodes status and prognosis value in local advanced rectal cancer after neoadjuvant chemoradiation therapy.
O-003Gemcitabine with nab-paclitaxel in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC): A quality of life randomized cross-over study (QOLINPAC)
Introduction: Nab-paclitaxel added to standard gemcitabine significantly improves overall survival, progression-free survival and response rates when compared to gemcitabine alone in metastatic PDAC. Baseline quality of life (QOL) indicators such as global health status (GHS) may be predictive for survival in this disease setting, together with clinical variables and tumour markers.
P-206Intensive first line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in RAS wild-type metastatic colorectal cancer patients: Preliminary phase II data and individual limiting toxicity syndromes prediction by pharmacogenomic biomarkers
Introduction: Intensive triplet chemotherapy/bevacizumab significantly increased MCRC outcome. Phase II study investigated safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first line RAS wild-type and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.
O-004Selected subgroup analyses of liposomal irinotecan (nal-IRI) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the global NAPOLI-1 phase III trial
Introduction: NAPOLI1 (NCT01494506; Wang-Gillam et al., Lancet 2016;387:545-57) was a global phase 3 study of patients with mPDAC who progressed following gemcitabine-based therapy. In patients receiving nalIRI+5FU/LV, median overall survival (mOS) was significantly higher (6.1 months) compared with 5FU/LV (4.2 months; unstratified HR = 0.67; P = 0.012). Here, we summarise four separate NAPOLI-1 subgroup analyses investigating the effect of selected baseline parameters.
P-273Recruitment for a survey on the unmet needs of patients living with metastatic colorectal cancer (mCRC): Lessons from a European study
Introduction: Colorectal cancer is still a taboo for many patients and there is little information about the patient's experience in general practice. Much of what is known about their quality-of-life comes from clinical trials – that are not representative of everyday patient experience. To fill this gap, EuropaColon, a European CRC patient organisation, planned and carried out a survey on the Unmet Needs of Patients Living with Metastatic Colorectal Cancer (mCRC). The aim of the survey was to better understand the challenges and needs of those living with mCRC as well as to understand their quality-of-life.
O-005A multicentre, prospective clinical evaluation study for analyzing RAS mutational status utilizing plasma circulating tumor DNA in patients with metastatic colorectal cancer
Introduction: Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness. The OncoBEAM RAS kit is a circulating tumor DNA (ctDNA) test intended for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted multicentre, prospective clinical evaluation study investigating the concordance of RAS mutational status between plasma ctDNA and tumor tissue DNA in patients with mCRC.
PD-014Survival following curative indented treatment of brain metastases from colorectal cancer: A Danish population-based cohort study
Introduction: Brain metastases (BM) are an uncommon presentation of metastatic colorectal cancer (mCRC) with reported incidence of about 2-4%. Previously, the focus has been on a palliative treatment course with whole brain radiation, corticosteroids and supportive care, resulting in an expected survival of a few months. Today, there is an increased awareness towards a localized curative intended treatment approach with either surgical resection, stereotactic body radiotherapy (SBRT) or both. We examined the survival for patients treated with a localized modality for BM from CRC in a nationwide population-based study.
O-006Ultra-selection of metastatic colorectal cancer patients using next generation sequencing platform to improve clinical efficacy of anti-EGFR therapy
Introduction: Extended RAS and BRAF analysis is mandatory in metastatic colorectal cancer (mCRC) patients to establish the best therapeutic strategy. Recent studies aimed to determine the optimal threshold of RAS mutated subclones to identify patients most likely to benefit from anti-EGFR treatment (Laurent-Puig, CCR 2015; Santos C. Molec Can Ther 2017). Our aim is to assess the clinical relevance of highly sensitive Next Generation Sequencing (NGS) technology to detect point mutations in KRAS, NRAS, BRAF, and EGFR S492R in tissue tumor samples and its correlation with clinical outcome in terms of progression-free survival (PFS), overall response rate (ORR) and overall survival (OS) in mCRC patients treated with chemotherapy plus anti-EGFR or anti-VEGF therapy.
P-189Retinoic acid-induced 2 (RAI2) is a potential tumor suppressor and RAI2 promoter methylation is a poor prognostic marker in colorectal cancer
Introduction: Retinoic acid (RA) plays an important role in development, adult hematopoiesis and cell differentiation. Retinoic acid induced 2 (RAI2) was originally discovered to be induced by retinoic acid in embryonal carcinoma cells. Low retinoic acid induced 2 (RAI2) expression was found in breast cancer as an independent poor prognostic factor, promoting early hematogenous dissemination of human breast cancer cells to bone marrow. The expression of Retinoic acid induced 2 (RAI2) was found reduced in colorectal cancer (CRC) by searching The Cancer Genome Atlas (TCGA) database. The regulation and function of RAI2 in human cancer remain unclear. In this study, we focused on the epigenetic regulation and function of RAI2 in colorectal cancer (CRC).
O-007Liquid biopsy allows predicting benefit from rechallenge with cetuximab(cet)+irinotecan(iri) in RAS/BRAF wild-type mCRC patients(pts) with resistance to 1st-line cet+iri: Final results and translational analyses of the CRICKET study by GONO
Introduction: CRICKET (NCT02296203) was designed to investigate the activity of the rechallenge with cet and iri as 3 rd -line treatment in RAS/BRAF wild-type mCRC pts with acquired resistance to 1st-line cet- and iri-based therapy. The role of liquid biopsies as a tool to identify pts more likely to benefit from this strategy was investigated.
P-223NORTH/HGCSG1003: A phase II study evaluating the safety and efficacy of FOLFOX as adjuvant chemotherapy for patients with stage III colon cancer: Comparison with medical oncologists and surgeons
Introduction: The efficacy of oxaliplatin containing regimens were confirmed in large randomized phase III trials in which they were superior to fluorouracil and leucovorin as adjuvant setting for patients with stage III colon cancer. In Japan, not only medical oncologists but also surgeons practice chemotherapy. In this analysis, we investigated differences in safety and efficacy between surgeons and medical oncologists from NORTH/HGCSG1003 study.
O-008The prognostic role of microsatellite status, tumor mutational burden and protein expression in CRC
Introduction: Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death. Microsatellite instability (MSI) is prognostic in CRC and is used to select patients for immunotherapy. High tumor mutational burden (TMB) is associated with genomic instability and is prognostic in melanoma. Expression of p16 protein is prognostic in many tumor types. We used proteomic and genomic profiling to measure MSI, TMB and p16 in CRC tumors and to assess associations with patient survival. The global proteome data was also used to identify potentially prognostic protein biomarkers.
P-257Improvement of metastatic colorectal cancer patient survival: Single institution experience
Introduction: The outcome of patients with metastatic colorectal cancer (mCRC) has significantly improved over the last two decades, reaching a median overall survival (mOS) of around 30 months, more than double that 20 years ago. Both surgery and a more aggressive systemic approach may have contributed to this result. The aim of this study is to describe the evolution of survival of mCRC patients followed at a single institution over the past 17 years, investigating the possible influence of tumour characteristics, as well as the changes in treatment practice through the years.
O-009A Phase II multi institutional study of nivolumab in patients with advanced refractory biliary tract cancers (BTC)
Introduction: Biliary tract cancers (BTC) typically include intra and extrahepatic cholangiocarcinoma and cancers of the gallbladder. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. There are pre-clinical and small series of clinical data which supports the usage of immune modulatory agents in BTC. Therefore we propose to evaluate the anti-PD1 agent nivolumab in advanced, refractory BTC.
P-290Simultaneous versus staged resections of liver metastases in patients with advanced colorectal cancer
Introduction: Surgical management of metastatic colorectal cancer remains the best method to use which significantly improves overall 5-year survival. There are two well-known possible approaches of surgical treatment of patients with synchronous colorectal liver metastasis. The former includes synchronous resection of the colorectal primary with the following resection of the liver metastases and the latter is a staged resection approach. However, at present the issue of feasibility and effectiveness of simultaneous operations for metastatic liver lesions in patients with synchronous metastatic colorectal cancer (SMCLC) is negotiated and remains uncertain. This study aimed to compare the surgical outcomes and survival benefit between synchronous and staged resections of the colorectal liver metastases.
O-010Cisplatin/5-fluorouracil +/- panitumumab for patients with non-resectable, advanced or metastatic esophageal squamous cell cancer: A randomized phase III AIO/EORTC trial with an extensive biomarker program
Introduction: Most esophageal squamous cell cancer (ESCC) patients (pts) have advanced disease at time of diagnosis. Chemotherapy (CTX) improved overall survival (OS), but still with limited impact. Prior studies suggested increased efficacy of EGFR antibodies (AB) combined with cisplatin (C) / 5-fluorouracil (F).
P-322First study in North Africa: Screening colorectal cancer
Introduction: In Algeria in 2015 colorectal cancer represents the 2nd cause of cancer mortality after lung cancer in men and after breast cancer in women. The increasing CRC incidence and mortality can be reduced by screening and treating adenomas and early cancers. A pilot CRC screening programme using immunochemical faecal occult blood testing (iFOBT) and colonoscopy for test-positives were implemented in Béjaia a northeast district of Algeria. This study aims to evaluate the acceptability, feasibility, validity of screening tests, and scaling-up of screening in Algeria. This report describes the implementation, coverage and performance indicators of this pilot project.
Improvement in Both Primary and Eccentric Ocular Alignment After Thyroid Eye Disease-Strabismus Surgery With Tenon’s Recession
Purpose: To evaluate the improvement in primary and eccentric gaze ocular alignment in thyroid eye disease (TED) patients undergoing horizontal strabismus surgery with Tenon's recession. Methods: This is an Institutional Review Board-approved retrospective analysis of TED patients undergoing horizontal strabismus surgery for esotropia. The study included all patients from 2007 to 2016 operated on by a single surgeon at Columbia University Medical Center. Surgical success was defined as the ability to fuse at both near and distance either without prismatic correction or with less than 10 prism diopters (PD) of correction. Measurements of ocular alignment were also made in eccentric fields of gaze. This study was Health Insurance Portability and Accountability Act compliant with protection of individually identifiable information. Results: Thirty-eight patients with TED and restrictive horizontal strabismus underwent unilateral or bilateral medial rectus recession to relieve diplopia. All patients underwent Tenon's recession with dissection of Tenon's from the overlying conjunctiva permitting it to retract into the orbit. Overall the success rate was 87% with a reoperation rate of 7.9%. The improvement in horizontal deviation in both primary and eccentric gaze was statistically significant (p
Revision Surgery for Undercorrected Blepharoptosis After Frontalis Sling Operation Using Autogenous Fascia Lata
Purpose: Undercorrected blepharoptosis can be encountered after frontalis sling operation. Revision surgery for undercorrection has commonly involved introducing a new sling material. We describe and evaluate a simple surgical technique to correct undercorrection by adjusting preexisting fascia. Methods: This is a retrospective interventional case series of patients undergoing sling revision between February 2010 and February 2017. Skin incision was made on the previous incision line. Careful dissection was performed superiorly to identify a preexisting fascia, and the dissected fascia was reattached to the tarsal plate using nonabsorbable sutures with adjustments for eyelid height and contour. The success of the procedure was defined as less than 1 mm of difference in the marginal reflex distance 1 of both eyes without any contour deformity. Results: Twenty-one eyelids in 18 patients were included with a mean follow-up of 17.5 months (range 6–48) and a mean age of 14.7 years (range 5–57). All patients had undergone frontalis sling with autogenous fascia lata for congenital ptosis. Undercorrection due to recurrent ptosis was found in 12 eyelids, and contour deformity such as temporal ptosis was found in 9 eyelids. The mean time interval between previous frontalis sling operation and sling revision was 6.8 years. Nineteen patients (90.5%) achieved surgical success and a cosmetically acceptable appearance. Conclusion: Sling revision is a simple and effective method with low perioperative morbidity for cases of undercorrection or contour deformity following frontalis sling operation using autogenous fascia lata, even long after the primary procedure. Accepted for publication April 14, 2018. Presentation at the American Society of Ophthalmic Plastic and Reconstructive Surgery Fall Scientific Symposium on October 16–17, 2014 in Chicago, IL. The authors have no financial or conflicts of interest to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.op-rs.com.). Address correspondence and reprint requests to Kyung In Woo, M.D., Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: eyeminded@skku.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
Expression of Surfactant Proteins in the Human Canaliculus: Evidence and Potential Insights Into the Tear Flow Dynamics
Purpose: To investigate the presence and distribution patterns of 6 surfactant proteins (SPs) in the human lacrimal canaliculus. Methods: The study was performed on fresh frozen cadaveric samples of canaliculi. Immunohistochemical labeling was performed for assessing the presence and distribution of SP: SP-A, SP-B, SP-C, SP-D, SP-G/SFTA2, and SP-H/SFTA3. Immunofluorescence double staining was performed using the respective fluorescein-conjugated antibodies and the results were scored as positive or negative and the distribution pattern within the canalicular system was assessed. Western blot analysis was performed on the protein content which was resolved by reducing 15% sodium dodecyl sulfate-polyacrylamide electrophoresis and bands were studied following staining with primary and secondary antibodies. Human lung tissues were used as controls. Results: Fluorescence double staining with 4,6-diamidino 2-pheynlindole and SPs showed strong immunostaining for SP-A, SP-B, SP-C, SP-D, and SP-H/SFTA3. The positive immunofluorescence was noticed across all the layers of the epithelium but not the subepithelial structures. The expression was noted on the surfaces and superficial cytoplasm of the superficial and deep epithelial cells. There was no expression of SP-G/SFTA2 across the canalicular system. Western blot analysis of the proteins confirmed and concurred with the immunofluorescence findings. Conclusions: This study provides a proof of principle for the presence of SPs known from lungs in the canalicular system and hypothesizes their possible functions and also their potential role in the tear flow dynamics between the ocular surface and the lacrimal drainage system. Accepted for publication April 24, 2018. M.J.A. received support from the Alexander von Humboldt Foundation for his research and he also receives royalties from Springer for the textbook Principles and Practice of Lacrimal Surgery and treatise Atlas of Lacrimal Drainage Disorders and is a registered PhD student at the University of Hyderabad. F.P. was supported by Deutsche Forschungsgemeinschaft (DFG) grants PA738/1-1 to 1–5 as well as PA738/2-1. He receives royalties from Elsevier for the anatomy atlas Sobotta and the Sobotta Textbook of Anatomy. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Mohammad Javed Ali, F.R.C.S., Institute of Anatomy II, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany. E-mail: drjaved007@gmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
Efficacy and Safety of Immunosuppressive Agents for Thyroid Eye Disease
Purpose: To present an update on the efficacy and safety of immunosuppressive therapy for thyroid eye disease (TED) and to offer a general recommendation for management of TED, in light of these reports. Methods: Data were retrieved from a literature search on PubMed, using the following words: thyroid eye disease, immunosuppressant, corticosteroid, methotrexate, azathioprine, cyclosporine, cyclophosphamide, rituximab, etanercept, adalimumab, tocilizumab, teprotumumab, adverse effects, side effects, and complications. Results: Corticosteroids continue to be the primary medical therapy for TED. Recent research has offered insight into potential differences between oral corticosteroid and intravenous corticosteroid treatment regimens in terms of efficacy and side-effect profiles, which proved more favorable for the latter. The use of some traditional immunosuppressive agents, such as methotrexate and mycophenolate, seems suitable as steroid-sparing medications. In recent years, many scientific reports demonstrated the effectiveness of biologic immunosuppressive agents in the management of TED. Etanercept, adalimumab, and tocilizumab have been shown to be effective in reduction of the inflammatory signs with the possible added advantage of preventing relapse of the disease. Teprotumumab may control the disease activity, and it seems to be very effective in preventing disease progression. Infliximab might be useful in severe TED resistant to steroids and orbital decompression. Conclusions: Steroid therapy remains the first-line therapy for moderate/severe and severe vision-threatening TED. The biological agents may provide a deep and long-standing block of inflammatory activity in TED, with the hope to lower the risk of recurrences and to reduce the need of surgical intervention in moderate-to-severe disease. Indeed, the actual incidence of adverse effects is not yet well assessed because of the paucity of studies. Therefore, their use should be limited to those cases that really need an alternative therapy to steroids, handled by expert physician in this field. Accepted for publication March 24, 2018. Presented at the 4th International ITEDS Course and Symposium on June 24 and 25, 2016 in London, United Kingdom. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Diego Strianese, M.D., Ph.D., King Khaled Eye Specialist Hospital, KSA Central Province Riyadh City, King Khaled Road, P.O. Box 7191, Riyadh 11462, Saudi Arabia. E-mail: dstrianese@kkesh.med.sa © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
Orbital Mass With Features of Both Kimura Disease and Immunoglobulin G4-Related Disease
Kimura disease has been known as a chronic inflammatory disease of unknown etiology, since the first report in 1937 and characterized by an increased eosinophil fraction in peripheral blood, increased serum immunoglobulin E (IgE) levels, and lymphoid granuloma with eosinophilic infiltration on histopathological examination. The authors present a 30-year-old man who visited their clinic with a 3-month history of protrusion and conjunctival injection of the right eye. Surgical mass resection was performed, and initial histopathology revealed Kimura disease. Additional immunohistochemical examination revealed IgG4-related disease in another hospital, which showed more than 80 IgG4-positive plasma cells per high-power field and an IgG4+/IgG+ ratio more than 40%. There are histopathological similarities, and several reports have suggested a relationship between Kimura disease and IgG4-related disease. Thus, it is difficult to classify them as completely different diseases. Kimura disease and IgG4 can be considered a part of a clinical spectrum of abnormal immune reactions. Accepted for publication March 25, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Sung Chul Kim, M.D., HanGil Eye Hospital, Incheon 21388, South Korea. E-mail: hapto@daum.net © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
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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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Publication date: Available online 28 September 2017 Source: Actas Dermo-Sifiliográficas Author(s): F.J. Navarro-Triviño
