Abstract
The correct name of the 5th Author is Jiabin Chen.
Τετάρτη 11 Απριλίου 2018
Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma
Abstract
Background
As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and Methods
From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were performed of imaging outcomes. Results
170 patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56% - 83%. Negative scans had predictive values of 89% - 96% for true non-recurrence (negative predictive values (NPV)) until the next scan. A negative PET at 18 months had NPVs of 80% - 84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions
Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.Cytology cell blocks are suitable for immunohistochemical testing for PD-L1 in lung cancer
Abstract
Background
PD-L1 immunohistochemistry (IHC) testing is usually performed on tissue blocks from core needle biopsy or surgical resections. In this study, we assessed the feasibility of using cytology cell blocks for PD-L1 IHC assay. Methods
A total of 1419 consecutive cases of non-small cell lung cancer (NSCLC), including 371 cytology cell blocks, 809 small biopsies, and 239 surgical specimens, were included in the study. The cytology cell blocks were prepared with formalin only, methanol/alcohol only or both. PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as < 1%, 1-49% and ≥ 50% tumor cells. A total of 100 viable tumor cells were required for adequacy. Results
Of the cytology cell blocks, 92% of the specimens had an adequate number of tumor cells, not significantly different from small biopsies. The rate of TPS ≥ 50% differed between sample types and was observed in 42% of cytology cell blocks versus 36% of small biopsies (P=0.04), and 29% of surgical resections (P=0.001). The fixative methods did not affect the immunostaining, with overall PD-L1 high expression (TPS≥50%) rates of 42% in formalin-fixed specimens versus 40% in specimens with combined fixation by methanol/alcohol and formalin (NS). The PD-L1 high expression rate was not associated with EGFR, ALK or KRAS molecular alterations. Higher stage (IV) was associated with higher PD-L1 TPS (P= 0.001). Conclusion
Our results show that when the TPS ≥50% is used as the endpoint, PD-L1 IHC performs well with cytology cell blocks. Cell blocks should be considered as a valuable resource for PD-L1 testing in advanced NSCLC. The clinical significance of higher PD-L1 IHC scores in cytology specimens needs to be evaluated prospectively.Study on sandstorm PM 10 exposure assessment in the large-scale region: a case study in Inner Mongolia
Abstract
The current exposure-effect curves describing sandstorm PM10 exposure and the health effects are drawn roughly by the outdoor concentration (OC), which ignored the exposure levels of people's practical activity sites. The main objective of this work is to develop a novel approach to quantify human PM10 exposure by their socio-categorized micro-environment activities-time weighed (SCMEATW) in strong sandstorm period, which can be used to assess the exposure profiles in the large-scale region. Types of people's SCMEATW were obtained by questionnaire investigation. Different types of representatives were trackly recorded during the big sandstorm. The average exposure levels were estimated by SCMEATW. Furthermore, the geographic information system (GIS) technique was taken not only to simulate the outdoor concentration spatially but also to create human exposure outlines in a visualized map simultaneously, which could help to understand the risk to different types of people. Additionally, exposure-response curves describing the acute outpatient rate odds by sandstorm were formed by SCMEATW, and the differences between SCMEATW and OC were compared. Results indicated that acute outpatient rate odds had relationships with PM10 exposure from SCMEATW, with a level less than that of OC. Some types of people, such as herdsmen and those people walking outdoors during a strong sandstorm, have more risk than office men. Our findings provide more understanding of human practical activities on their exposure levels; they especially provide a tool to understand sandstorm PM10 exposure in large scale spatially, which might help to perform the different categories population's risk assessment regionally.
Genetic aberrations of the K-ras proto-oncogene and in bladder cancer in relation to pesticide exposure
Abstract
In Egypt, bladder cancer is one of the most popular cancer, accounting for 31% of all cancer cases. It ranks first in males about 16.2% of male cancer. The incidence in rural areas among males is near 32 per 100,000. The exact etiology of bladder cancer is still unknown; K-ras gene is known as a critical DNA target for chemical carcinogens as a pesticide. Some occupational hazard exposure is thought to be directly genotoxic, while others might enhance the mutagenicity and carcinogenicity of directly acting genotoxic agents. Analysis of the relationship between pesticide exposure and mutation in the K-ras gene in human bladder cancer. One hundred patients were diagnosed with bladder cancer and one hundred controls attended the outpatient clinic; after taking consent and filling a questionnaire for age, sex, occupation and pesticide exposure, surgically resected specimens were collected and the samples were used to determine the k-ras mutation. Blood samples were taken to analyze the level of acetylcholinesterase enzyme and level of P53. The present study indicated that pesticide exposure may play a great role in malignant transformation of the bladder cells through mutation in the K-ras gene; there was a significant correlation between the acetylcholinesterase enzyme level and k-ras mutation (p < 0.001). The results revealed that the level of P53 was significantly high in comparison with the control group (p < 0.001). These findings give an alarm to decrease the amount of pesticides used in our area; also, p53 may be used as an indicator to bladder cancer.
The effect of cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, on human hair growth with the dual promoting mechanisms
Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, increases the intracellular level of cyclic adenosine monophosphate to cause vasodilation. Topical application of cilostazol is reported to improve local blood flow and enhance wound healing; however, its effect on human hair follicles is unknown.
Does intraoperative navigation improve the accuracy of mandibular angle osteotomy: comparison between augmented reality navigation, individualised templates, and free-hand techniques
Augmented reality (AR)-based navigation surgery has evolved to be an advanced assisted technology. The aim of this study is to manifest the accuracy of AR navigation for the intraoperative mandibular angle osteotomy by comparing the navigation with other interventional techniques.
A systematic review and meta-analysis of comparison of autologous costal cartilage and alloplastic materials in rhinoplasty
Both autologous costal cartilage (ACC) and alloplastic materials are widely used in rhinoplasty. However, there is controversy regarding which material can offer the ideal outcome and fewer complications.
The modified bull's horn upper lip lift
The upper lip is often neglected when considering overall facial rejuvenation. With aging, the cutaneous lip elongates, the vermilion loses it volume and inverts, and there is loss of dental show. An upper lip lift can help reverse these changes. In this correspondence, we describe our modified bull's horn technique, which builds on the original description by Cardoso and Sperli1, in which only skin and subcutaneous tissue are removed. Our procedure is a simple, reliable, and effective method of improving upper lip shape.
Anaphylaxis Knowledge in Camp Personnel
Publication date: Available online 11 April 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Margaret Redmond, Michael Pistiner, Rebecca Scherzer, David Stukus, Frank J. Twarog, John Lee
Comparing ran-out status of inhaled short-acting beta-agonists in emergency department patients with acute asthma: 1996-1998 versus 2015-2017
Publication date: Available online 11 April 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Tadahiro Goto, Carlos A. Camargo, Catalina Gimenez-Zapiola, Daniel J. Pallin, Nathan I. Shapiro, Thomas J. Ferro, Carolyn Rainville, Stanislav Stoyanov, Kohei Hasegawa
BackgroundMedication non-adherence including running out of inhaled asthma medications, is an important problem.ObjectiveTo examine the changes in the proportion of adults with acute asthma who ran out of their short-acting beta-agonist (SABA) inhalers before presenting to the emergency department (ED) between 1996-1998 and 2015-2017.MethodsWe analyzed data from prospective multicenter observational cohort studies of ED adult patients (aged 18-54 years) with acute asthma. Within the same three EDs, we performed a structured interview during two time periods: 1996-1998 and 2015-2017. We fitted multivariable models to compare ran-out status between the two periods, adjusting for the baseline patient demographics, socioeconomic status, chronic asthma factors, and healthcare utilization factors. We further adjusted for the presence of a written action plan – an intervenable factor.ResultsThe analytic cohort comprised 353 patients (150 from the 1996-1998 studies and 203 from the 2015-2017 study). Over the ∼20-year period, the proportion of patients who ran out of SABA inhalers increased (18% in 1996-1998 vs 26% in 2015-2017). In the multivariable model, compared to patients in 1996-1998, those in 2015-2017 had a significantly higher risk of running out of their SABA inhalers (adjusted OR 2.01; 95%CI 1.06-3.81; P=0.03). With further adjustment for the presence of a written action plan, this difference attenuated (adjusted OR 1.66; 95%CI 0.75-3.68; P=0.21).ConclusionBetween 1996 and 2017, the proportion of ED patients with asthma who ran out of SABA inhalers significantly increased. The increase was explained, at least partially, by a lack of written action plan.
Assessment of the inhalation risks associated with working in printing rooms: a study on the staff of eight printing rooms in Beijing, China
Abstract
The concentration of pollution directly determines the occupational health risk, and the exposure time is an important influencing factor. We evaluated the inhalation risks of working in a printing room. Eight units with centralized printing rooms were randomly selected. Formaldehyde, ozone, benzene, toluene, xylene, and fine particulate matter were detected by spectrophotometry, gas chromatography, and direct reading instruments, respectively. The U.S. EPA inhalation risk assessment model was used to assess cancer and non-cancer risks. The formaldehyde inhalation cancer risk value was 1.35–3.45 × 10−6, which is greater than the limit of 1 × 10−6, suggesting a risk of squamous cell carcinoma. The benzene inhalation cancer risk in five of the rooms was 1.09–4.65 × 10−6, which is greater than the limit of 1 × 10−6, suggesting a risk of leukemia. In terms of non-cancer risk, in five of the rooms, the hazard quotient (HQ) was > 1 (range 1.99–4.69) due to benzene pollution, suggesting a risk of reduced lymphocyte count. In one room, due to benzene and xylene pollution, the HQ was > 1, suggesting a risk of lymphocyte count drop and motor coordination impairment. Collectively, the study concludes that staff members of printing rooms are exposed to both cancer and non-cancer occupational health risks.
Comparison of pathogen-derived ‘total risk’ with indicator-based correlations for recreational (swimming) exposure
Abstract
Typical recreational water risk to swimmers is assessed using epidemiologically derived correlations by means of fecal indicator bacteria (FIB). It has been documented that concentrations of FIB do not necessarily correlate well with protozoa and viral pathogens, which pose an actual threat of illness and thus sometimes may not adequately assess the overall microbial risks from water resources. Many of the known pathogens have dose-response relationships; however, measuring water quality for all possible pathogens is impossible. In consideration of a typical freshwater receiving secondarily treated effluent, we investigated the level of consistency between the indicator-derived correlations and the sum of risks from six reference pathogens using a quantitative microbial risk assessment (QMRA) approach. Enterococci and E. coli were selected as the benchmark FIBs, and norovirus, human adenovirus (HAdV), Campylobacter jejuni, Salmonella enterica, Cryptosporidium spp., and Giardia spp. were selected as the reference pathogens. Microbial decay rates in freshwater and uncertainties in exposure relationships were considered in developing our analysis. Based on our exploratory assessment, the total risk was found within the range of risk estimated by the indicator organisms, with viral pathogens as dominant risk agents, followed by protozoan and bacterial pathogens. The risk evaluated in this study captured the likelihood of gastrointestinal illnesses only, and did not address the overall health risk potential of recreational waters with respect to other disease endpoints. Since other highly infectious pathogens like hepatitis A and Legionella spp. were not included in our analysis, these estimates should be interpreted with caution.
Low-level concentrations of aminoglycoside antibiotics induce the aggregation of cyanobacteria
Abstract
The interactions between antibiotics and microorganisms have attracted enormous research attentions. In this study, we investigated the effects of two typical aminoglycoside antibiotics on the aggregation of the model cyanobacterium, Synechococcus elongatus, and the dominating strain in algal blooms, Microcystis aeruginosa, via the analysis of zeta potentials, hydrophobicity, and extracellular polymeric substances (EPS) secretion. The results showed that low-level antibiotics promoted the aggregation of S. elongatus and M. aeruginosa by 40 and 18% under 0.10 and 0.02 μg/mL of kanamycin, respectively, which was mainly attributed to the combined effects of increased zeta potentials and the ratio between extracellular proteins and polysaccharides. Tobramycin exerted similar effects. Additionally, we discovered that at low pH (pH 5) and ionic strength (1 mM Na+ and 2 mM Mg2+), the inducing effects of antibiotics would be even larger than those with higher pH and ionic strength. As aggregation is important to cyanobacteria in either the basic physiology of biofilm formation or the algal bloom, our study demonstrated that low-level antibiotics exert ecological impacts via interfered aggregation. We believe this study will shed light on the mechanisms underlying antibiotic-induced biofilm formation and help with the evaluation of the environmental and ecological risks of antibiotics and other emerging pollutants.
Blue light decreases tanshinone IIA content in Salvia miltiorrhiza hairy roots via genes regulation
Publication date: Available online 11 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Ing-Gin J. Chen, Meng-Shiou Lee, Ming-Kuem Lin, Chia-Yun Ko, Wen-Te Chang
The effect of light-emitting diodes (LEDs) on the production of secondary metabolites in medicinal plants and hairy roots is receiving much attention. The roots and rhizomes of the traditional Chinese medicinal plant Salvia miltiorrhiza Bunge are widely used for treating cardiovascular and cerebrovascular diseases. The main components are liposoluble tanshinones and hydrophilic phenolic acids. Moreover, hairy root culture of S. miltiorrhiza has been used in research of valuable plant-derived secondary metabolites. In this study, we examined the effect of LEDs with different combinations of wavelengths on the content of the main components in hairy roots of S. miltiorrhiza. Tanshinone IIA (TSIIA) content in hairy roots was significantly decreased with all light treatments containing blue light by >60% and was 9 times lower with LED treatment duration changed from 1 week to 3 weeks. HMGR, DXS2, DXR, GGPPS, CPS and CYP76AH1 genes involved in the tanshinone biosynthesis pathway were downregulated by blue light. Furthermore, light quality treatments have different effect on the accumulation of phenolic acids in hairy roots of S. miltiorrhiza. The light treatments 6R3B, 6B3IR, 7RGB and 2R6BUV for 3 weeks could increase rosmarinic acid (RA) content slightly but not salvianolic acid B (SAB) content. Different secondary metabolite contents could be regulated by different wavelength combinations of LEDs. Blue light could reduce TSIIA content in hairy roots of S. miltiorrhiza via gene regulation.
Towards better microbial safety of fresh produce: Chlorophyllin-based photosensitization for microbial control of foodborne pathogens on cherry tomatoes
Publication date: Available online 11 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Egle Paskeviciute, Bernadeta Zudyte, Zivile Luksiene
The aim of this study is to evaluate the antimicrobial efficiency of Chlorophyllin-based photosensitization for microbial control of cherry tomatoes.Chlorophyllin-based photosensitization (1.5 × 10−4 M, 3 J/cm2) significantly (2.4 log) reduced the population of naturally distributed surface attached various mesophilic bacteria (microbiota) on tomatoes. Moreover, the population of thermoresistant strains of food pathogens Bacillus cereus and Listeria monocytogenes inoculated on tomatoes was reduced by 1.5 log and 1.6 log respectively after this treatment. Conventional washing with water reduced the population of Listeria on tomato by 0.6 log and Bacillus by 0.8 log. In comparison, hypochlorite treatment reduced Listeria on tomatoes by 1.4 log and Bacillus by 1.6 log. The regrowth of mesophilic bacteria and thermoresistant Listeria on the surface of tomatoes after photosensitization was delayed for 28 days and 14 days respectively. Moreover, photosensitization did not induce harmful effects on main parameter of nutritional quality of tomatoes, i.e. antioxidant activity of tomatoes remained unchanged (27.5 mM Fe2+/kg). Eventually, this treatment did not induce visible thermal effects in fruit matrix and prolonged the shelf-life of tomatoes by 4 days. In our opinion, chlorophyllin-based photosensitization has a huge potential as alternative to not-chemical food preservation technology, saving water and energy. In addition, fast development of light emitting diodes (LED's) and light sources based on LED technologies make this treatment low cost, environmentally friendly and easy to maintain.
Interhelical interactions between D92 and C218 in the cytoplasmic domain regulate proton uptake upon N-decay in the proton transport of Acetabularia rhodopsin II
Publication date: Available online 11 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Jun Tamogami, Takashi Kikukawa, Keisuke Ohkawa, Noboru Ohsawa, Toshifumi Nara, Makoto Demura, Seiji Miyauchi, Tomomi Kimura-Someya, Mikako Shirouzu, Shigeyuki Yokoyama, Kazumi Shimono, Naoki Kamo
Acetabularia rhodopsin II (ARII or Ace2), an outward light-driven algal proton pump found in the giant unicellular marine alga Acetabularia acetabulum, has a unique property in the cytoplasmic (CP) side of its channel. The X-ray crystal structure of ARII in a dark state suggested the formation of an interhelical hydrogen bond between C218ARII and D92ARII, an internal proton donor to the Schiff base (Wada et al., 2011). In this report, we investigated the photocycles of two mutants at position C218ARII: C218AARII which disrupts the interaction with D92ARII, and C218SARII which potentially forms a stronger hydrogen bond. Both mutants exhibited slower photocycles compared to the wild-type pump. Together with several kinetic changes of the photoproducts in the first half of the photocycle, these replacements led to specific retardation of the N-to-O transition in the second half of the photocycle. In addition, measurements of the flash-induced proton uptake and release using a pH-sensitive indium-tin oxide electrode revealed a concomitant delay in the proton uptake. These observations strongly suggest the importance of a native weak hydrogen bond between C218ARII and D92ARII for proper proton translocation in the CP channel during N-decay. A putative role for the D92ARII-C218ARII interhelical hydrogen bond in the function of ARII is discussed.
Graphical abstract
Full color emitting fluorescent carbon material as reversible pH sensor with multicolor live cell imaging
Publication date: Available online 11 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Vinay Sharma, Navpreet Kaur, Pranav Tiwari, Shaikh M. Mobin
Carbon-based nano materials are developed as a cytocompatible alternative to semiconducting quantum dots for bioimaging and fluorescence-based sensing. The green alternatives for the synthesis of carbon materials are imminent. The present study demonstrates microwave based one step quick synthesis of fluorescent carbon material (FCM) having three variants: (i) un-doped fluorescent carbon material (UFCM) (ii) nitrogen doped FCM (N@FCM), and (iii) nitrogen & phosphorus co-doped FCM (N-P@FCM) using sugarcane extract as a carbon source. The N doping was performed using ethylenediamine and phosphoric acid was used for P doping. The heteroatom doped FCM were synthesized due to insolubility of UFCM in water. Unlike, UFCM, the N@FCM and N-P@FCM were found to be highly soluble in water. The N-P@FCM shows highest quantum yield among the three. The N-P@FCM was explored for alkaline pH sensing and it shows a quenching of fluorescence in the pH range 09–14. The sensing behaviour shows reversibility and high selectivity. Further, the sensor was also investigated for their biocompatibility and hence employed as a promising multicolour probe for cancer cell imaging. The generality in cell imaging was investigated by flow cytometry. The hetero-atom doped green carbon-dots may open new avenues for sensing and selective cellular targeting.
Graphical abstract
Mercury species accumulation and distribution in Typha domingensis under real field conditions (Almadén, Spain)
Abstract
Monomethylmercury (MeHg) is one of the most toxic and the most commonly occurring organomercury compound and the wetlands are one of the main areas of generation of this Hg form. Concretely, it is in the macrophyte root system where better conditions are given for its generation. However, the knowledge of absorption and subsequent distribution of mercury (Hg) and monomethylmercury in aquatic plants is still limited. Mercury mining district such as Almadén (Ciudad Real, Spain) is a natural laboratory where different rivers flow and the species Typha domingensis Pers. is a common macrophyte which grows in their riverbanks. The aim of the present work is to apply a recently developed method specially designed to analyze Hg species in plant tissues to the different fractions of T. domingensis under real field conditions and to study the accumulation and distribution of Hg species (inorganic Hg and MeHg) within the plant. The results proved that whatever Hg species has preference to be accumulated in the belowground fractions and demonstrated a high efficiency in the accumulation of MeHg.
X-ray fluorescence spectrometry characteristics of oily waste water from steel processing and an evaluation of its impact on the environment
Abstract
Metal-cutting fluids, one of the most consumed materials in the metallurgy industry, turn into oily wastewater after being used in the metalworking processes. The amount of cutting fluids used can reach up to millions of tons. And these invaluable fluids are difficult to distil and expensive, and impossible to store. Even after it is disposed and recaptured, the end product has no commercial value. In this study, the effect of this mixture was examined on the ecosystem using the Allium cepa test system in which onion root tips were treated with three different concentrations of waste-cutting fluid, based on a 24- and 48-h cell cycle. The oily wastewater exhibited a mechanism which triggered the chromosomal and nuclear abnormalities in the onion root-tip meristem and reduced the mitotic index. Common abnormalities observed in the experimental groups based on the water concentration were chromosome stickiness, c-mitosis, and micronuclei formation. In the experimental group with the lowest water concentration, budding nuclei were observed at a different level than all of the other experimental groups. The x-ray fluorescence analysis showed that the concentrations of elements, such as silicon, calcium, iron, and zinc, were higher in the oily wastewater than those in the unused cutting oil.
Tissue distribution and oral exposure risk assessment of heavy metals in an urban bird: magpie from Central Iran
Abstract
Direct ingestion of soil and/or soil attached to the food items is a potential rout for wildlife exposure to contaminants. In this study, bioaccumulation of five heavy metals (HMs) in internal tissues of an urban bird (Pica pica) collected from Aran-O-Bidgol City, Central Iran and their related soil were investigated. A total of 15 magpie specimens were collected in autumn 2013 and then their internal tissues were digested using a mixture of HNO3 and H2O2, and finally, concentrations of HMs were detected by ICP-OES. In addition, in order to show level of HM exposure risk to magpie, an exposure risk assessment was modeled. Results indicated that HMs were accumulated as follows: liver > kidney > muscle. Zn and Cu were significantly higher in magpie's tissues collected from agricultural site; on the other hand, Pb and Cd were significantly higher in industrial site (p < 0.05). Level of Cd in male's livers (2.11 μg/g dw) was significantly higher than in females (1.85 μg/g dw) (p < 0.05). Levels of Cd, Pb, and Ni in liver, muscle, and kidney, respectively, were significantly higher in adults than in subadults (p < 0.05). Soil exposure doses of all HMs were lower than tolerable daily intake (Zn 4.35, Cu 1.34, Ni 5.65, Pb 0.35, and Cd 0.53). The calculated hazard quotations (HQs) for HMs were as follows: Pb > Zn > Cu > Ni > Cd and for all HMs were at no risk level (HQ < 1). The amounts of hazard index for three sites were as follows: urban (1.032) > agriculture (0.943) ≥ industry (0.941) and only for urban area was at low risk (1 < HQ < 2). It seemed that birds living in a safe environment and/or HM contaminations in soil separately had no negative effects on magpies. We can also suggest that low levels of HMs in magpie's tissues can be due to low levels of HMs in soil.
Linguistic labor and its division
Abstract
This paper exposes a common mistake concerning the division of linguistic labor. I characterize the mistake as an overgeneralization from natural kind terms; this misleads philosophers about (1) which terms are subject to the division of linguistic labor, (2) what linguistic labor is, (3) how linguistic labor is divided, and (4) how the extensions of non-natural kind terms subject to the division of linguistic labor are determined. I illustrate these points by considering Sally Haslanger's account of the division of linguistic labor for social kind terms and raising an objection to it. Then, I draw on Tyler Burge's work to characterize a conception of the division of linguistic labor that (a) avoids the mistaken overgeneralization and (b) grounds 1–4 above in social norms and practices.
Electrophysiological Evidence for the Development of a Self-Sustained Large-Scale Epileptic Network in the Kainate Mouse Model of Temporal Lobe Epilepsy
Most research on focal epilepsy focuses on mechanisms of seizure generation in the primary epileptic focus (EF). However, neurological deficits that are not directly linked to seizure activity and that may persist after focus removal are frequent. The recruitment of remote brain regions of an epileptic network (EN) is recognized as a possible cause, but a profound lack of experimental evidence exists concerning their recruitment and the type of pathological activities they exhibit. We studied the development of epileptic activities at the large-scale in male mice of the kainate model of unilateral temporal lobe epilepsy using high-density surface EEG and multiple-site intracortical recordings. We show that, along with focal spikes and fast ripples that remain localized to the injected hippocampus (i.e., the EF), a subpopulation of spikes that propagate across the brain progressively emerges even before the expression of seizures. The spatiotemporal propagation of these generalized spikes (GSs) is highly stable within and across animals, defining a large-scale EN comprising both hippocampal regions and frontal cortices. Interestingly, GSs are often concomitant with muscular twitches. In addition, while fast ripples are, as expected, highly frequent in the EF, they also emerge in remote cortical regions and in particular in frontal regions where GSs propagate. Finally, we demonstrate that these remote interictal activities are dependent on the focus in the early phase of the disease but continue to be expressed after focus silencing at later stages. Our results provide evidence that neuronal networks outside the initial focus are progressively altered during epileptogenesis.
SIGNIFICANCE STATEMENT It has long been held that the epileptic focus is responsible for triggering seizures and driving interictal activities. However, focal epilepsies are associated with heterogeneous symptoms, calling into question the concept of a strictly focal disease. Using the mouse model of hippocampal sclerosis, this work demonstrates that focal epilepsy leads to the development of pathological activities specific to the epileptic condition, notably fast ripples, that appear outside of the primary epileptic focus. Whereas these activities are dependent on the focus early in the disease, focus silencing fails to control them in the chronic stage. Thus, dynamical changes specific to the epileptic condition are built up outside of the epileptic focus along with disease progression, which provides supporting evidence for network alterations in focal epilepsy.
BMP-Responsive Protease HtrA1 Is Differentially Expressed in Astrocytes and Regulates Astrocytic Development and Injury Response
Astrocytes perform a wide array of physiological functions, including structural support, ion exchange, and neurotransmitter uptake. Despite this diversity, molecular markers that label subpopulations of astrocytes are limited, and mechanisms that generate distinct astrocyte subtypes remain unclear. Here we identified serine protease high temperature requirement A 1 (HtrA1), a bone morphogenetic protein 4 signaling regulated protein, as a novel marker of forebrain astrocytes, but not of neural stem cells, in adult mice of both sexes. Genetic deletion of HtrA1 during gliogenesis accelerates astrocyte differentiation. In addition, ablation of HtrA1 in cultured astrocytes leads to altered chondroitin sulfate proteoglycan expression and inhibition of neurite extension, along with elevated levels of transforming growth factor-β family proteins. Brain injury induces HtrA1 expression in reactive astrocytes, and loss of HtrA1 leads to an impairment in wound closure accompanied by increased proliferation of endothelial and immune cells. Our findings demonstrate that HtrA1 is differentially expressed in adult mouse forebrain astrocytes, and that HtrA1 plays important roles in astrocytic development and injury response.
SIGNIFICANCE STATEMENT Astrocytes, an abundant cell type in the brain, perform a wide array of physiological functions. Although characterized as morphologically and functionally diverse, molecular markers that label astrocyte subtypes or signaling pathways that lead to their diversity remain limited. Here, after examining the expression profile of astrocytes generated in response to bone morphogenetic protein signaling, we identify high temperature requirement A 1 (HtrA1) as an astrocyte-specific marker that is differentially expressed in distinct adult mouse brain regions. HtrA1 is a serine protease that has been linked to cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a small blood vessel disease in humans. Understanding the role of HtrA1 during development and after injury will provide insights into how distinct astrocyte populations are generated and their unique roles in injury and disease.
Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease
In toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SPNs (iSPNs), whereas spine loss and hyperexcitability persist in direct pathway SPNs (dSPNs). These alterations have only been characterized in toxin-based models of PD, raising the possibility that they are an artifact of exposure to the toxin, which may engage compensatory mechanisms independent of the PD-like pathology or due to the loss of dopaminergic afferents. To test all these, we studied the synaptic remodeling in Pitx3–/– or aphakia mice, a genetic model of PD, in which most of the dopamine neurons in the substantia nigra fail to fully differentiate and to innervate the striatum. We made 3D reconstructions of the dendritic arbor and measured excitability in identified SPNs located in dorsal striatum of BAC-Pitx3–/– mice treated with saline or l-DOPA. Both dSPNs and iSPNs from BAC-Pitx3–/– mice had shorter dendritic trees, lower spine density, and more action potentials than their counterparts from WT mice. Chronic l-DOPA treatment restored spine density and firing rate in iSPNs. By contrast, in dSPNs, spine loss and hyperexcitability persisted following l-DOPA treatment, which is similar to what happens in 6-OHDA WT mice. This indicates that dopamine-mediated synaptic remodeling and plasticity is independent of dopamine innervation during SPN development and that Pitx3–/– mice are a good model because they develop the same pathology described in the toxins-based models and in human postmortem studies of advanced PD.
SIGNIFICANCE STATEMENT As the only genetic model of Parkinson's disease (PD) that develops dyskinesia, Pitx3–/– mice reproduce the behavioral effects seen in humans and are a good system for studying dopamine-induced synaptic remodeling. The studies we present here establish that the structural and functional synaptic plasticity that occur in striatal projection neurons in PD and in l-DOPA-induced dyskinesia are specifically due to modulation of the neurotransmitter dopamine and are not artifacts of the use of chemical toxins in PD models. In addition, our findings provide evidence that synaptic plasticity in the Pitx3–/– mouse is similar to that seen in toxin models despite its lack of dopaminergic innervation of the striatum during development. Pitx3–/– mice reproduced the alterations described in patients with advanced PD and in well accepted toxin-based models of PD and dyskinesia. These results further consolidate the fidelity of the Pitx3–/– mouse as a PD model in which to study the morphological and physiological remodeling of striatal projection neurons by administration of l-DOPA and other drugs.
Convergence and Divergence of CRH Amacrine Cells in Mouse Retinal Circuitry
Inhibitory interneurons sculpt the outputs of excitatory circuits to expand the dynamic range of information processing. In mammalian retina, >30 types of amacrine cells provide lateral inhibition to vertical, excitatory bipolar cell circuits, but functional roles for only a few amacrine cells are well established. Here, we elucidate the function of corticotropin-releasing hormone (CRH)-expressing amacrine cells labeled in Cre-transgenic mice of either sex. CRH cells costratify with the ON alpha ganglion cell, a neuron highly sensitive to positive contrast. Electrophysiological and optogenetic analyses demonstrate that two CRH types (CRH-1 and CRH-3) make GABAergic synapses with ON alpha cells. CRH-1 cells signal via graded membrane potential changes, whereas CRH-3 cells fire action potentials. Both types show sustained ON-type responses to positive contrast over a range of stimulus conditions. Optogenetic control of transmission at CRH-1 synapses demonstrates that these synapses are tuned to low temporal frequencies, maintaining GABA release during fast hyperpolarizations during brief periods of negative contrast. CRH amacrine cell output is suppressed by prolonged negative contrast, when ON alpha ganglion cells continue to receive inhibitory input from converging OFF-pathway amacrine cells; the converging ON- and OFF-pathway inhibition balances tonic excitatory drive to ON alpha cells. Previously, it was demonstrated that CRH-1 cells inhibit firing by suppressed-by-contrast (SbC) ganglion cells during positive contrast. Therefore, divergent outputs of CRH-1 cells inhibit two ganglion cell types with opposite responses to positive contrast. The opposing responses of ON alpha and SbC ganglion cells are explained by differing excitation/inhibition balance in the two circuits.
SIGNIFICANCE STATEMENT A goal of neuroscience research is to explain the function of neural circuits at the level of specific cell types. Here, we studied the function of specific types of inhibitory interneurons, corticotropin-releasing hormone (CRH) amacrine cells, in the mouse retina. Genetic tools were used to identify and manipulate CRH cells, which make GABAergic synapses with a well studied ganglion cell type, the ON alpha cell. CRH cells converge with other types of amacrine cells to tonically inhibit ON alpha cells and balance their high level of excitation. CRH cells diverge to different types of ganglion cell, the unique properties of which depend on their balance of excitation and inhibition.
Activity-Dependent Myelination of Parvalbumin Interneurons Mediated by Axonal Morphological Plasticity
Axonal myelination of neocortical pyramidal neurons is modulated dynamically by neuronal activity. Recent studies have shown that a substantial proportion of neocortical myelin content is contributed by fast-spiking, parvalbumin (PV)-positive interneurons. However, it remains unknown whether the myelination of PV+ interneurons is also modulated by intrinsic activity. Here, we used cell-type-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in adult mice to activate a sparse population of medial prefrontal cortex (mPFC) PV+ interneurons. Using single-cell axonal reconstructions, we found that DREADD-stimulated PV+ interneurons exhibited a nearly two-fold increase in total length of myelination, predominantly mediated by a parallel increase of axonal arborization and number of internodes. In contrast, the distribution of axonal interbranch segment distance and myelin internode length were not altered significantly. Topographical analysis revealed that myelination of DREADD-stimulated cells extended to higher axonal branch orders while retaining a similar interbranch distance threshold for myelination. Together, our results demonstrate that chemogenetically induced neuronal activity increases the myelination of neocortical PV+ interneurons mediated at least in part by an elaboration of their axonal morphology.
SIGNIFICANCE STATEMENT Myelination is the wrapping of an axon to optimize conduction velocity in an energy-efficient manner. Previous studies have shown that myelination of neocortical pyramidal neurons is experience and activity dependent. We now show that activity-dependent myelin plasticity in the adult neocortex extends to parvalbumin (PV)-expressing fast-spiking interneurons. Chemogenetic stimulation of PV interneurons in the medial prefrontal cortex (mPFC) significantly enhanced axonal myelination, which was paralleled by an increase in axonal arborization. This suggests that activity-dependent axonal plasticity may involve changes in both structural morphology and myelination. Such multicomponent plasticity reveals an unexpected repertoire of anatomical parameters available for optimizing and adapting neuronal networks in response to experience.
Autophagy Enhances Memory Erasure through Synaptic Destabilization
There is substantial interest in memory reconsolidation as a target for the treatment of anxiety disorders, such as post-traumatic stress disorder. However, its applicability is restricted by reconsolidation-resistant boundary conditions that constrain the initial memory destabilization. In this study, we investigated whether the induction of synaptic protein degradation through autophagy modulation, a major protein degradation pathway, can enhance memory destabilization upon retrieval and whether it can be used to overcome these conditions. Here, using male mice in an auditory fear reconsolidation model, we showed that autophagy contributes to memory destabilization and its induction can be used to enhance erasure of a reconsolidation-resistant auditory fear memory that depended on AMPAR endocytosis. Using male mice in a contextual fear reconsolidation model, autophagy induction in the amygdala or in the hippocampus enhanced fear or contextual memory destabilization, respectively. The latter correlated with AMPAR degradation in the spines of the contextual memory-ensemble cells. Using male rats in an in vivo LTP reconsolidation model, autophagy induction enhanced synaptic destabilization in an NMDAR-dependent manner. These data indicate that induction of synaptic protein degradation can enhance both synaptic and memory destabilization upon reactivation and that autophagy inducers have the potential to be used as a therapeutic tool in the treatment of anxiety disorders.
SIGNIFICANCE STATEMENT It has been reported that inhibiting synaptic protein degradation prevents memory destabilization. However, whether the reverse relation is true and whether it can be used to enhance memory destabilization are still unknown. Here we addressed this question on the behavioral, molecular, and synaptic levels, and showed that induction of autophagy, a major protein degradation pathway, can enhance memory and synaptic destabilization upon reactivation. We also show that autophagy induction can be used to overcome a reconsolidation-resistant memory, suggesting autophagy inducers as a potential therapeutic tool in the treatment of anxiety disorders.
Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice
The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8–/– mice exhibited a fall of 0.7°C in core body temperature when housed at cold temperatures, and a deep hypothermia (<30°C) during food deprivation. In both situations, TRPM8 deficiency induced an increase in tail heat loss. This, together with the presence of TRPM8-sensory fibers innervating the main tail vessels, unveils a major role of this ion channel in tail vasomotor regulation. Finally, TRPM8 deficiency had a remarkable impact on energy balance. Trpm8–/– mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity.
SIGNIFICANCE STATEMENT The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures.
Human V4 Activity Patterns Predict Behavioral Performance in Imagery of Object Color
Color is special among basic visual features in that it can form a defining part of objects that are engrained in our memory. Whereas most neuroimaging research on human color vision has focused on responses related to external stimulation, the present study investigated how sensory-driven color vision is linked to subjective color perception induced by object imagery. We recorded fMRI activity in male and female volunteers during viewing of abstract color stimuli that were red, green, or yellow in half of the runs. In the other half we asked them to produce mental images of colored, meaningful objects (such as tomato, grapes, banana) corresponding to the same three color categories. Although physically presented color could be decoded from all retinotopically mapped visual areas, only hV4 allowed predicting colors of imagined objects when classifiers were trained on responses to physical colors. Importantly, only neural signal in hV4 was predictive of behavioral performance in the color judgment task on a trial-by-trial basis. The commonality between neural representations of sensory-driven and imagined object color and the behavioral link to neural representations in hV4 identifies area hV4 as a perceptual hub linking externally triggered color vision with color in self-generated object imagery.
SIGNIFICANCE STATEMENT Humans experience color not only when visually exploring the outside world, but also in the absence of visual input, for example when remembering, dreaming, and during imagery. It is not known where neural codes for sensory-driven and internally generated hue converge. In the current study we evoked matching subjective color percepts, one driven by physically presented color stimuli, the other by internally generated color imagery. This allowed us to identify area hV4 as the only site where neural codes of corresponding subjective color perception converged regardless of its origin. Color codes in hV4 also predicted behavioral performance in an imagery task, suggesting it forms a perceptual hub for color perception.
The Role of the Mechanotransduction Ion Channel Candidate Nanchung-Inactive in Auditory Transduction in an Insect Ear
Insect auditory receivers provide an excellent comparative resource to understand general principles of auditory transduction, but analysis of the electrophysiological properties of the auditory neurons has been hampered by their tiny size and inaccessibility. Here we pioneer patch-clamp recordings from the auditory neurons of Müller's organ of the desert locust Schistocerca gregaria to characterize dendritic spikes, axonal spikes, and the transduction current. We demonstrate that dendritic spikes, elicited by sound stimuli, trigger axonal spikes, and that both types are sodium and voltage dependent and blocked by TTX. Spontaneous discrete depolarizations summate upon acoustic stimulation to produce a graded transduction potential that in turn elicits the dendritic spikes. The transduction current of Group III neurons of Müller's organ, which are broadly tuned to 3 kHz, is blocked by three ion channel blockers (FM1-43, streptomycin, and 2-APB) that are known to block mechanotransduction channels. We investigated the contribution of the candidate mechanotransduction ion channel Nanchung-Inactive—which is expressed in Müller's organ—to the transduction current. A specific agonist of Nanchung-Inactive, pymetrozine, eliminates the sound-evoked transduction current while inducing a tonic depolarizing current of comparable amplitude. The Nanchung-Inactive ion channels, therefore, have the required conductance to carry the entire transduction current, and sound stimulation appears not to open any additional channels. The application of three mechanotransduction ion channel blockers prevented the pymetrozine-induced depolarizing current. This implies that either Nanchung-Inactive is, or forms part of, the mechanotransduction ion channel or it amplifies a relatively small current (<30 pA) produced by another mechanotransduction ion channel such as NompC.
SIGNIFICANCE STATEMENT The mechanically activated ion channel underpinning hearing is not known. We have pioneered intracellular patch-clamp recordings from locust auditory neurons to unravel the role of the candidate mechanotransduction ion channel Nanchung-Inactive in auditory transduction in insects.
Bilateral Tactile Input Patterns Decoded at Comparable Levels But Different Time Scales in Neocortical Neurons
The presence of contralateral tactile input can profoundly affect ipsilateral tactile perception, and unilateral stroke in somatosensory areas can result in bilateral tactile deficits, suggesting that bilateral tactile integration is an important part of brain function. Although previous studies have shown that bilateral tactile inputs exist and that there are neural interactions between inputs from the two sides, no previous study explored to what extent the local neuronal circuitry processing contains detailed information about the nature of the tactile input from the two sides. To address this question, we used a recently introduced approach to deliver a set of electrical, reproducible, tactile afferent, spatiotemporal activation patterns, which permits a high-resolution analysis of the neuronal decoding capacity, to the skin of the second forepaw digits of the anesthetized male rat. Surprisingly, we found that individual neurons of the primary somatosensory can decode contralateral and ipsilateral input patterns to comparable extents. Although the contralateral input was stronger and more rapidly decoded, given sufficient poststimulus processing time, ipsilateral decoding levels essentially caught up to contralateral levels. Moreover, there was a weak but significant correlation for neurons with high decoding performance for contralateral tactile input to also perform well on decoding ipsilateral input. Our findings shed new light on the brain mechanisms underlying bimanual haptic integration.
SIGNIFICANCE STATEMENT Here we demonstrate that the spiking activity of single neocortical neurons in the somatosensory cortex of the rat can be used to decode patterned tactile stimuli delivered to the distal ventral skin of the second forepaw digits on both sides of the body. Even though comparable levels of decoding of the tactile input were achieved faster for contralateral input, given sufficient integration time each neuron was found to decode ipsilateral input with a comparable level of accuracy. Given that the neocortical neurons could decode ipsilateral inputs with such small differences between the patterns suggests that S1 cortex has access to very precise information about ipsilateral events. The findings shed new light on possible network mechanisms underlying bimanual haptic processing.
Ventromedial Prefrontal Cortex Is Necessary for Normal Associative Inference and Memory Integration
The ability to flexibly combine existing knowledge in response to novel circumstances is highly adaptive. However, the neural correlates of flexible associative inference are not well characterized. Laboratory tests of associative inference have measured memory for overlapping pairs of studied items (e.g., AB, BC) and for nonstudied pairs with common associates (i.e., AC). Findings from functional neuroimaging and neuropsychology suggest the ventromedial prefrontal cortex (vmPFC) may be necessary for associative inference. Here, we used a neuropsychological approach to test the necessity of vmPFC for successful memory-guided associative inference in humans using an overlapping pairs associative memory task. We predicted that individuals with focal vmPFC damage (n = 5; 3F, 2M) would show impaired inferential memory but intact non-inferential memory. Performance was compared with normal comparison participants (n = 10; 6F, 4M). Participants studied pairs of visually presented objects including overlapping pairs (AB, BC) and nonoverlapping pairs (XY). Participants later completed a three-alternative forced-choice recognition task for studied pairs (AB, BC, XY) and inference pairs (AC). As predicted, the vmPFC group had intact memory for studied pairs but significantly impaired memory for inferential pairs. These results are consistent with the perspective that the vmPFC is necessary for memory-guided associative inference, indicating that the vmPFC is critical for adaptive abilities that require application of existing knowledge to novel circumstances. Additionally, vmPFC damage was associated with unexpectedly reduced memory for AB pairs post-inference, which could potentially reflect retroactive interference. Together, these results reinforce an emerging understanding of a role for the vmPFC in brain networks supporting associative memory processes.
SIGNIFICANCE STATEMENT We live in a constantly changing environment, so the ability to adapt our knowledge to support understanding of new circumstances is essential. One important adaptive ability is associative inference which allows us to extract shared features from distinct experiences and relate them. For example, if we see a woman holding a baby, and later see a man holding the same baby, then we might infer that the two adults are a couple. Despite the importance of associative inference, the brain systems necessary for this ability are not known. Here, we report that damage to human ventromedial prefrontal cortex (vmPFC) disproportionately impairs associative inference. Our findings show the necessity of the vmPFC for normal associative inference and memory integration.
SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy
Hyperacetylation of tau has been implicated in neurodegeneration and cognitive decline in tauopathy brains. The nicotinamide adenosine dinucleotide-dependent class-III protein deacetylase SIRT1 is one of the major enzymes involved in removal of acetyl groups from tau in vitro. However, whether SIRT1 regulates acetylation of pathogenic tau and ameliorates tau-mediated pathogenesis remains unclear. Here, we report deacetylating activity of SIRT1 for acetylated Lys174 (K174) of tau in tauP301S transgenic mice with a brain-specific SIRT1 deletion. We show that SIRT1 deficiency leads to exacerbation of premature mortality, synapse loss, and behavioral disinhibition in tauP301S transgenic mice of both sexes. By contrast, SIRT1 overexpression by stereotaxic delivery of adeno-associated virus that encodes SIRT1 into the hippocampus reduces acetylated K174 tau. Furthermore, SIRT1 overexpression significantly attenuates the spread of tau pathology into anatomically connected brain regions of tauP301S transgenic mice of both sexes. These findings suggest the functional importance of SIRT1 in regulating pathogenic tau acetylation and in suppressing the spread of tau pathology in vivo.
SIGNIFICANCE STATEMENT In neurodegenerative disorders with inclusions of microtubule-associated protein tau, aberrant lysine acetylation of tau plays critical roles in promoting tau accumulation and toxicity. Identifying strategies to deacetylate tau could interfere with disease progression; however, little is known about how pathogenic tau is deacetylated in vivo. Here we show that the protein deacetylase SIRT1 reduces tau acetylation in a mouse model of neurodegeneration. SIRT1 deficiency in the brain aggravates synapse loss and behavioral disinhibition, and SIRT1 overexpression ameliorates propagation of tau pathology.
EEG Correlates of Preparatory Orienting, Contextual Updating, and Inhibition of Sensory Processing in Left Spatial Neglect
Studies with event-related potentials have highlighted deficits in the early phases of orienting to left visual targets in right-brain-damaged patients with left spatial neglect (N+). However, brain responses associated with preparatory orienting of attention, with target novelty and with the detection of a match/mismatch between expected and actual targets (contextual updating), have not been explored in N+. Here in a study in healthy humans and brain-damaged patients of both sexes we demonstrate that frontal activity that reflects supramodal mechanisms of attentional orienting (Anterior Directing Attention Negativity, ADAN) is entirely spared in N+. In contrast, posterior responses that mark the early phases of cued orienting (Early Directing Attention Negativity, EDAN) and the setting up of sensory facilitation over the visual cortex (Late Directing Attention Positivity, LDAP) are suppressed in N+. This uncoupling is associated with damage of parietal-frontal white matter. N+ also exhibit exaggerated novelty reaction to targets in the right side of space and reduced novelty reaction for those in the left side (P3a) together with impaired contextual updating (P3b) in the left space. Finally, we highlight a drop in the amplitude and latency of the P1 that over the left hemisphere signals the early blocking of sensory processing in the right space when targets occur in the left one: this identifies a new electrophysiological marker of the rightward attentional bias in N+. The heterogeneous effects and spatial biases produced by localized brain damage on the different phases of attentional processing indicate relevant functional independence among their underlying neural mechanisms and improve the understanding of the spatial neglect syndrome.
SIGNIFICANCE STATEMENT Our investigation answers important questions: are the different components of preparatory orienting (EDAN, ADAN, LDAP) functionally independent in the healthy brain? Is preparatory orienting of attention spared in left spatial neglect? Does the sparing of preparatory orienting have an impact on deficits in reflexive orienting and in the assignment of behavioral relevance to the left space? We show that supramodal preparatory orienting in frontal areas is entirely spared in neglect patients though this does not counterbalance deficits in preparatory parietal-occipital activity, reflexive orienting, and contextual updating. This points at relevant functional dissociations among different components of attention and suggests that improving voluntary attention in N+ might be behaviorally ineffective unless associated with stimulations boosting the response of posterior parietal-occipital areas.
Functional MRI Responses to Passive, Active, and Observed Touch in Somatosensory and Insular Cortices of the Macaque Monkey
Neurophysiological data obtained in primates suggests that merely observing others' actions can modulate activity in the observer's motor cortices. In humans, it has been suggested that these multimodal vicarious responses extend well beyond the motor cortices, including somatosensory and insular brain regions, which seem to yield vicarious responses when witnessing others' actions, sensations, or emotions (Gazzola and Keysers, 2009). Despite the wealth of data with respect to shared action responses in the monkey motor system, whether the somatosensory and insular cortices also yield vicarious responses during observation of touch remains largely unknown. Using independent tactile and motor fMRI localizers, we first mapped the hand representations of two male monkeys' primary (SI) and secondary (SII) somatosensory cortices. In two subsequent visual experiments, we examined fMRI brain responses to (1) observing a conspecific's hand being touched or (2) observing a human hand grasping or mere touching an object or another human hand. Whereas functionally defined "tactile SI" and "tactile SII" showed little involvement in representing observed touch, vicarious responses for touch were found in parietal area PFG, consistent with recent observations in humans (Chan and Baker, 2015). Interestingly, a more anterior portion of SII, and posterior insular cortex, both of which responded when monkeys performed active grasping movements, also yielded visual responses during different instances of touch observation.
SIGNIFICANCE STATEMENT Common coding of one's own and others' actions, sensations, and emotions seems to be widespread in the brain. Although it is currently unclear to what extent human somatosensory cortices yield vicarious responses when observing touch, even less is known about the presence of similar vicarious responses in monkey somatosensory cortex. We therefore localized monkey somatosensory hand representations using fMRI and investigated whether these regions yield vicarious responses while observing various instances of touch. Whereas "tactile SI and SII" did not elicit responses during touch observation, a more anterior portion of SII, in addition to area PFG and posterior insular cortex, all of which responded during monkeys' own grasping movements, yielded vicarious responses during observed touch.
ACC to Dorsal Medial Striatum Inputs Modulate Histaminergic Itch Sensation
Itch is an unpleasant sensation that initiates scratching behavior. The itch–scratch reaction is a complex phenomenon that implicates supraspinal structures required for regulation of sensory, emotional, cognitive, and motivational aspects. However, the central mechanisms underlying the processing of itch and the interplay of the supraspinal regions and spinal cord in regulating itch–scratch processes are poorly understood. Here, we have shown that the neural projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a critical circuit element for regulating itch-related behaviors in the brains of male C57BL/6J mice. Moreover, we demonstrate that ACC-DMS projections selectively modulate histaminergic, but not nonhistaminergic, itch-related behavior. Furthermore, photoactivation of ACC-DMS projections has also no significant effects on pain behavior induced by thermal, mechanical, and chemical stimuli except for a relief on inflammatory pain evoked by formalin and complete Freund's adjuvant. We further demonstrate that the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons, which represent a population of spinal inhibitory interneurons that mediate the inhibition of itch. Therefore, this study presents the first evidence that the ACC-DMS projections modulate histaminergic itch-related behavior and reveals an interplay between the supraspinal and spinal levels in histaminergic itch regulation.
SIGNIFICANCE STATEMENT This study reveals that the projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a supraspinal circuit for modulation of histaminergic, but not nonhistaminergic, itch. Manipulation of ACC-DMS projections has no effect on acute pain sensation. Furthermore, the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons. Understanding the supraspinal itch circuits is of great significance in the development of new therapies for chronic itch-related intractable diseases.
JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory
The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JNK-interacting protein 1 (JIP1) scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDAR currents, increased NMDAR-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse model that suppresses JNK activity. Together, these observations establish that JIP1-mediated JNK activation contributes to the regulation of hippocampus-dependent, NMDAR-mediated synaptic plasticity and learning.
SIGNIFICANCE STATEMENT The results of this study demonstrate that c-Jun N-terminal kinase (JNK) activation induced by the JNK-interacting protein 1 (JIP1) scaffold protein negatively regulates the threshold for induction of long-term synaptic plasticity through the NMDA-type glutamate receptor. This change in plasticity threshold influences learning. Indeed, mice with defects in JIP1-mediated JNK activation display enhanced memory in hippocampus-dependent tasks, such as contextual fear conditioning and Morris water maze, indicating that JIP1-JNK constrains spatial memory. This study identifies JIP1-mediated JNK activation as a novel molecular pathway that negatively regulates NMDAR-dependent synaptic plasticity and memory.
Inequalities in child immunization coverage in Ghana: evidence from a decomposition analysis
Childhood vaccination has been promoted as a global intervention aimed at improving child survival and health, through the reduction of vaccine preventable deaths. However, there exist significant inequalities...
Intertriginous Multiple Reddish-Brown Papulonodules
A teenaged male with a 7-year medical history of polydipsia and polyuria, central diabetes insipidus, growth retardation, and hypothyroidism presented with numerous asymptomatic reddish-brownish papules, nodules, and plaques over his whole body. What is your diagnosis?
Thyroid Function Screening in Children With Alopecia Areata—Reply
In Reply We appreciate the interest of Drs Rustagi and Weiss in our proposed screening guidelines for thyroid function in children with alopecia. We have noted that many blood tests are performed in children with alopecia areata who have no symptoms outside of their hair loss, and so the goal of our article was to suggest a reduction in the number of patients who are being screened for thyroid disease when they present with alopecia areata. We stand by our conclusions that the specific subpopulation of patients who have both alopecia areata and trisomy 21 should undergo thyroid screening at the occurrence of new-onset alopecia areata if they have not had recent screening. The association between Down syndrome and thyroid disorders is well recognized, and patients with Down syndrome have an increased prevalence of both congenital hypothyroidism and acquired thyroid dysfunction, with hypothyroidism being most common. The American Academy of Pediatrics recommends screening at age 6 months, age 12 months, and annually thereafter or at the development of new symptoms. We found a statistically significant association between Down syndrome in patients with alopecia areata who also had thyroid abnormalities.
Tax as a Measure of Health Policy Association With Indoor Tanning, 2011-2016-
This study examines the association between excise tax collections from indoor tanning facilities and use of the facilities since institution of the Affordable Care Act.
The Dangers of Black Salve
This case report describes a patient who experienced painful eruptions following the application of nonprescription black salve.
Thyroid Function Screening in Children With Alopecia Areata
To the Editor In their recent article in JAMA Dermatology, Patel et al describe the prevalence of thyroid disorders among subgroups of children with alopecia areata (eg, those with Down syndrome), and interpret the findings as justification for screening such children. Unfortunately, the authors did not attempt to exclude children presenting with symptoms of thyroid dysfunction (eg, heat or cold intolerance, fatigue, growth abnormalities). Indeed, a category of thyroid dysfunction among the 59 patients with abnormal results was "subclinical thyroid dysfunction," implying that the other patients may have had clinical signs or symptoms of thyroid disease. Since screening, by definition, is conducted among asymptomatic individuals, the results reported by Patel et al cannot be interpreted to support or refute screening guidelines. Children with symptoms of thyroid dysfunction are more likely to receive thyroid function tests and are also more likely to have thyroid dysfunction; therefore, the true prevalence of thyroid disorders among asymptomatic children with alopecia areata who receive thyroid screening is expected to be lower than the estimates in this study. Whether the true prevalence is high enough in certain subgroups to justify screening cannot be determined from the data presented.
Endocrine Therapy–Induced Alopecia in Patients With Breast Cancer
This cohort study describes clinical features, quality of life, and response to minoxidil among female patients with breast cancer who have endocrine therapy–induced alopecia.
Catalyzing Future Drug, Device, and Information Technology Breakthroughs in Dermatology
This Viewpoint announces the creation of the Advancing Innovation in Dermatology Accelerator Fund and describes its aims.
Anhydramnios in Patients With Pemphigoid Gestationis
This case report describes the occurrence of anhydramnios in 2 patients with pemphigoid gestationis.
Iododerma (?) in Cancer Treated With Complementary and Alternative Medicine—Reply
In Reply We thank Dr Nwabudike for his kind remarks regarding our recent Observation. Herein, we provide additional details concerning our diagnosis of iododerma while expanding our opinion on the role of Hoxsey herbal therapy in the outcome of this case.
Dermatologists Should Speak Out Against a Word Ban at CDC
This Viewpoint details why dermatologists must speak out against the current US political administration's word ban at the Centers for Disease Control and Prevention.
Diagnosis uPGrade—Advances in Pyoderma Gangrenosum
In this issue of JAMA Dermatology, 2 large, well-constructed studies remind dermatologists that even though pyoderma gangrenosum (PG) is a quintessential disease in medical dermatology, we still need data to better define the disease and reduce the risk of cognitive biases. We know the results of these biases well; even at referral centers and in clinical trials, alternative diagnoses can prevail 7% to 20% of the time. In these articles, one of the largest retrospective PG databases and a new tool for PG diagnosis validation are presented.
Methotrexate-Associated B-Cell Lymphoproliferative Disease in Cutaneous T-Cell Lymphoma
This case report describes a patient with cutaneous T-cell lymphoma who developed methotrexate-associated B-cell lymphoproliferative disease.
Dermoscopy and Overdiagnosis of Melanoma In Situ
In this issue of JAMA Dermatology, Lallas et al state that "our goal today is to detect melanoma, if possible, before it becomes invasive." Given the challenges related to the early detection of melanoma faced by clinicians and patients alike, this goal can only be achieved through further improving clinical training of clinicians, allied health care workers, and consumers alike, combined with heightened individual awareness and advanced imaging technologies.
Theodore Lawless—African American Physician and Philanthropist
Theodore Lawless, MD, MS, DSc, LLD, was an African American dermatologist and scientist who was born in Louisiana in 1892 and received his medical degree from Northwestern University in 1919.
JAMA Dermatology—The Year in Review, 2017
JAMA Dermatology continues to enhance our digital presence, which serves to inform physicians and the public about advances in treatment of skin conditions. The journal content is available online ahead of print, and we connect with our readers via the electronic table of contents and through social media. Each weekly online issue of the journal offers an article free to be downloaded for 1 week; thus, the public has free access to selected articles. Our reach extended to 3.4 million people in 2017 with full-text downloads. Our online presence is international, with more than 100 000 users in Canada, India, the United Kingdom, and the United States.
Association of Patient Satisfaction With Medical Scribe Use in Dermatology
This survey study examines the the association of using medical scribes in an academic dermatology practice with patient satisfaction.
Age and Pyoderma Gangrenosum Presentation and Comorbidities
This cohort study evaluates the association of age with the clinical presentation and disease associations of pyoderma gangrenosum.
Lenalidomide Treatment for Recurrent Erythema Multiforme
This case report describes 3 patients treated with lenalidomide as an alternative to thalidomide for recurrent erythema multiforme.
Accuracy of Dermoscopic Criteria for the Diagnosis of Melanoma In Situ
This diagnostic accuracy study compares dermoscopic criteria for diagnosis of melanoma in situ.
Blaschkoid Acute Graft-vs-Host Disease
This case report describes a patient who developed acute graft-vs-host disease along the lines of Blaschko.
Patient Follow-up Preferences After Excision of Localized Melanoma
This telephone survey study determined the proportion of adults treated for localized melanoma who prefer the standard scheduled visit frequency, according to Australian guideline recommendations, or fewer scheduled visits.
The Vedic View of Vitiligo
Throughout antiquity, many causes of leukoderma, including vitiligo and leprosy, were thought to be the negative result of a prior action in life. In the Old Testament Book of Leviticus, "white spots" were arguably considered as a punishment by God for having committed a mortal sin, and the consequence for that was to be an outcaste. Around the same time period, in his book Clio, the Greek historian Herodotus wrote "if a Persian has leprosy or white sickness he is not allowed to enter into a city or to have dealings with other Persians [for] he must have sinned against the sun." This all-too-familiar theme appeared again a thousand years later in the ancient Hindu texts, the Puranas, when Samba, the son of Lord Krishna, is cursed with "white leprosy" by the sage Durvasa for mocking him, or, depending on which version of the Puranas you read, is cursed by Lord Krishna for lack of propriety. Regardless of the inciting insult, all versions of the Puranas note that Samba was cured of "white leprosy" after he worshipped the sun god, Surya. Although it is impossible to be certain, it is likely that the Persian "white sickness" and Hindu "white leprosy" refer to vitiligo.
Four Staging Systems for Cutaneous Squamous Cell Carcinoma
This nested case-control study assesses the validity and usefulness of 4 staging systems for cutaneous squamous cell carcinoma using population-based data.
Albert Sézary—The Man, the Cell, and the Syndrome
Albert Sézary, the notable French dermatologist, was born on December 26, 1880, in Algiers. Sézary first trained in general medicine and neurology under Joseph Déjerine and Fulgence Raymond and then underwent his dermatological training with Edouard Jeanselme and Lucien Jacquet. Sézary became physician of the hospitals of Paris in 1921, served as the head of department in Hôpital Broca from 1925 to 1929, and then was the head of Pavillon Brocq at l'Hôpital Saint-Louis from 1929 to 1945. He was appointed professor of medicine at the University of Paris in 1927.
Pemphigus and Solid Cancers
This cross-sectional study estimates the association between pemphigus and a wide range of nonhematologic malignancies by examining a large cohort of patients with pemphigus.
Reclamation of a lignite combustion waste disposal site with alders ( Alnus sp.): assessment of tree growth and nutrient status within 10 years of the experiment
Abstract
Combustion wastes are characterised by extremely low N contents. Therefore, introduction of nitrogen-fixing species at the first stage of their biological reclamation is required. This paper presents an assessment of the growth parameters of alders (Alnus sp.) 10 years after their introduction to a disposal site of lignite combustion waste in Central Poland. Black (Alnus glutinosa) and grey alders (Alnus incana) were planted directly in the combustion waste. The soil amendment included three variants: control with pure combustion waste, admixture of lignite culm and addition of acid sand. Both alder species displayed good growth parameters comparable to those of alders in natural habitats. However, black alder had better growth parameters, such as stand density index (SDI), diameter at breast height (DBH) and height (H) than grey alder. The lignite amendment exerted a positive effect on tree growth, reflected in a higher SDI and H, whereas the acid sand amendment did not affect any of the growth parameters of the studied alder species. Despite the good growth parameters, the measured N:P and N:K ratios in the alder leaves largely differed from the optimal values indicating insufficient P and K supply at the combustion waste disposal site. This may pose a threat to further development of the introduced tree plantings. The introduction of alders along with the lignite addition into the planting holes seems to be a successful method of combustion waste revegetation.
Thermal effects from the release of selenium from a coal combustion during high-temperature processing: a review
Abstract
The release of selenium (Se) during coal combustion can have serious impacts on the ecological environment and human health. Therefore, it is very important to study the factors that concern the release of Se from coal combustion. In this paper, the characteristics of the release of Se from coal combustion, pyrolysis, and gasification of different coal species under different conditions are studied. The results show that the amount of released Se increases at higher combustion temperatures. There are obvious increases in the amount of released Se especially in the temperature range of 300 to 800 °C. In addition, more Se is released from the coal gasification than coal combustion process, but more Se is released from coal combustion than pyrolysis. The type of coal, rate of heating, type of mineral ions, and combustion atmosphere have different effects on the released percentage of Se. Therefore, having a good understanding of the factors that surround the release of Se during coal combustion, and then establishing the combustion conditions can reduce the impacts of this toxic element to humans and the environment.
A new marine sediment certified reference material (CRM) for the determination of persistent organic contaminants: IAEA-459
Abstract
A new marine sediment certified reference material (IAEA 459) with very low concentrations (μg kg−1) for a variety of persistent organic contaminants (POPs) listed by the Stockholm Convention, as well as other POPs and priority substances (PSs) listed in many environmental monitoring programs was developed by the IAEA. The sediment material was collected from the Ham River estuary in South Korea, and the assigned final values were derived from robust statistics on the results provided by selected laboratories which demonstrated technical and quality competence, following the guidance given in ISO Guide 35. The robust mean of the laboratory means was assigned as certified values, for those compounds where the assigned value was derived from at least five datasets and its relative expanded uncertainty was less than 40% of the assigned value (most of the values ranging from 8 to 20%). All the datasets were derived from at least two different analytical techniques which have allowed the assignment of certified concentrations for 22 polychlorinated biphenyl (PCB) congeners, 6 organochlorinated (OC) pesticides, 5 polybrominated diphenyl ethers (PBDEs), and 18 polycyclic aromatic hydrocarbon (PAHs). Mass fractions of compounds that did not fulfill the criteria of certification are considered information values, which include 29 PAHs, 11 PCBs, 16 OC pesticides, and 5 PBDEs. The extensive characterization and associated uncertainties at concentration levels close to the marine sediment quality guidelines will make CRM 459 a valuable matrix reference material for use in marine environmental monitoring programs.
River habitat assessment for ecological restoration of Wei River Basin, China
Abstract
As an important composition component of river ecosystems, river habitats must undergo quality assessment to potentially provide scientific basis for river ecological restoration. Substrate composition, habitat complexity, bank erosion degree, river meandering degree, human activity intensity, vegetation buffer width, water quality, and water condition were determined as indicators for river habitat assessment. The comprehensive habitat quality index (CHQI) was established for the Wei River Basin. In addition, the indicator values were determined on the basis of a field investigation at 12 national hydrological stations distributed across the Wei, Jing, and Beiluo Rivers. The analytic hierarchy process was used to determine the indicator weights and thus distinguish the relative importance of the assessment indicator system. Results indicated that the average CHQIs for the Wei, Jing, and Beiluo Rivers were 0.417, 0.508, and 0.304, respectively. The river habitat quality for the three rivers was well. As for the whole river basin, the river habitat quality for 25% of the cross section was very well, the other 25% was well, and the 50% remaining was in critical state. The river habitat quality of the Jing River was better than that of the Wei and Beiluo Rivers.
Assessment of intake of copper and lead by sheep grazing on a shooting range for small arms: a case study
Abstract
The Norwegian Armed Forces' shooting ranges contain contamination by metals such as lead (Pb) and copper (Cu) and are often used as grazing pastures for livestock. To determine whether the sheep were at risk from grazing at a shooting range in Nord-Trøndelag (the Leksdalen shooting field), a study was conducted wherein the aim was to determine the amount of soil the sheep were eating, the accumulation of Cu and Pb in the livers of lambs grazing on the shooting ranges, and the accumulation of Pb and Cu in the grass. The grazing behavior of the sheep was mapped using GPS tracking and wildlife cameras. Soil, grass, feces, and liver samples were collected. All the samples were analyzed for Pb, Cu, and molybdenum (Mo), and soil and feces were also analyzed for titanium (Ti). Mean concentrations in grass, soil, feces, and liver was 41–7189, 1.3–29, 4–5, and 0.3 mg/kg Pb, respectively, and 42–580, 4.2–11.9, 19–23, and 273 mg/kg Cu, respectively. The soil ingestion rate was calculated using Ti in feces and soil. From these results, the theoretical dose of Cu and Pb ingested by grazing sheep was calculated. The soil ingestion rate was found to be 0.1–0.4%, significantly lower than the soil ingestion rate of 5–30% usually used for sheep. Little or no accumulation of Cu and Pb in the grass was found. There was no difference between the metal concentrations in the washed and unwashed grass. According to the calculated dose, the sheep were at little or no risk of acute or chronic Pb and Cu poisoning from grazing on the Leksdalen shooting range. The analysis of liver samples showed that lambs grazing on the shooting range did not have higher levels of Cu or Pb than lambs grazing elsewhere. None of the lambs had concentrations of Cu or Pb in their livers indicating poisoning.
Groundwater nitrate pollution and climate change: learnings from a water balance-based analysis of several aquifers in a western Mediterranean region (Catalonia)
Abstract
Climate change will affect the dynamics of the hydrogeological systems and their water resources quality; in particular nitrate, which is herein taken as a paradigmatic pollutant to illustrate the effects of climate change on groundwater quality. Based on climatic predictions of temperature and precipitation for the horizon of 2021 and 2050, as well as on land use distribution, water balances are recalculated for the hydrological basins of distinct aquifer systems in a western Mediterranean region as Catalonia (NE Spain) in order to determine the reduction of available water resources. Besides the fact that climate change will represent a decrease of water availability, we qualitatively discuss the modifications that will result from the future climatic scenarios and their impact on nitrate pollution according to the geological setting of the selected aquifers. Climate effects in groundwater quality are described according to hydrological, environmental, socio-economic, and political concerns. Water reduction stands as a major issue that will control stream-aquifer interactions and subsurface recharge, leading to a general modification of nitrate in groundwater as dilution varies. A nitrate mass balance model provides a gross estimation of potential nitrate evolution in these aquifers, and it points out that the control of the fertilizer load will be crucial to achieve adequate nitrate content in groundwater. Reclaimed wastewater stands as local reliable resource, yet its amount will only satisfy a fraction of the loss of available resources due to climate change. Finally, an integrated management perspective is necessary to avoid unplanned actions from private initiatives that will jeopardize the achievement of sustainable water resources exploitation under distinct hydrological scenarios.
The Impact of Obesity on Breast Cancer
Abstract
The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances—such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden.
Monitoring and Management of Toxicities of Novel B Cell Signaling Agents
Abstract
Purpose review
B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management.
Recent findings
Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis.
Summary
Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.
Emerging Therapies in Metastatic Prostate Cancer
Abstract
Purpose of Review
In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy.
Recent Findings
Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals.
Summary
Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.
Electrophysiologic Toxicity of Chemoradiation
Abstract
Purpose of Review
There is growing awareness of the link between oncology treatments and cardiovascular (CV) complications. This has led to the development of cardio-oncology, a specialty aimed at managing CV risk and disease in cancer patients and survivors. Cardiac arrhythmias are potential adverse CV complications of cancer treatments; however, these cardiotoxicities are often underappreciated due to the uncertain arrhythmogenic mechanisms of various chemotherapeutic agents.
Recent Findings
Chemotherapeutic agents can induce arrhythmias via direct electrophysiological effects on ion channels or intracellular signaling pathways, or indirectly from cardiac tissue damage.
Summary
As more drugs are being linked to the development of arrhythmias, a deeper understanding of the pathophysiology of their electrophysiological (EP) effects will be necessary. Expanding research in this field has allowed for the identification of novel agents with potential arrhythmogenic properties and the development of preventative measures, early recognition, and closer surveillance of patients more susceptible to these EP side effects.
Emerging Role of Immunotherapy in Advanced Urothelial Carcinoma
Abstract
Purpose of Review
Advanced urothelial carcinoma (aUC) has long been treated preferably with cisplatin-based chemotherapy, but many patients are cisplatin-ineligible whereas for those who progress on a platinum-based regimen treatment options are limited. We review key recent data regarding immune checkpoint inhibitors that are changing this treatment landscape.
Recent Findings
Since May 2016, five different agents targeting the PD-1/PD-L1 pathway (atezolizumab, pembrolizumab, nivolumab, avelumab, durvalumab) have received FDA approval for the treatment of aUC in the platinum-refractory setting, while pembrolizumab and atezolizumab are FDA-approved for cisplatin-ineligible patients in the first-line setting. Clinical outcomes and safety profiles of these agents appear relatively comparable across separate trials; however, only pembrolizumab is supported by level I evidence from a large randomized phase III trial showing overall survival benefit over conventional cytotoxic salvage chemotherapy in the platinum-refractory setting.
Summary
Pembrolizumab has the highest level of evidence in platinum-refractory aUC, whereas pembrolizumab and atezolizumab have comparable level of evidence in the frontline setting in cisplatin-ineligible patients. Ongoing research is evaluating novel agents, various rational combinations, and sequences, as well as predictive and prognostic biomarkers.
Neutrophilic dermatoses. Part II. Pyoderma gangrenosum and other bowel and arthritis associated neutrophilic dermatoses
Publication date: Available online 11 April 2018
Source:Journal of the American Academy of Dermatology
Author(s): Hovik J. Ashchyan, Caroline A. Nelson, Sasha Stephen, William D. James, Robert G. Micheletti, Misha Rosenbach
Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders that present with unique clinical features, but are unified by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. The morphology of cutaneous lesions associated with these disorders is heterogeneous, which renders diagnosis challenging. Moreover, a thorough evaluation is required to exclude diseases that mimic these disorders and to diagnose potential associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatoses may resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality. Therapeutic modalities range from systemic corticosteroids to novel biologic agents, and the treatment literature is rapidly expanding. Part II of this continuing medical education activity reviews the epidemiology, clinical characteristics, histopathological features, diagnosis, and management of pyoderma gangrenosum as well as bowel-associated dermatosis-arthritis syndrome and the arthritis-associated neutrophilic dermatoses: rheumatoid neutrophilic dermatitis and adult Still disease.
Neutrophilic dermatoses. Part I. Pathogenesis, Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet’s disease
Publication date: Available online 11 April 2018
Source:Journal of the American Academy of Dermatology
Author(s): Caroline A. Nelson, Sasha Stephen, Hovik J. Ashchyan, William D. James, Robert G. Micheletti, Misha Rosenbach
Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders that present with unique clinical features, but are unified by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. The morphology of cutaneous lesions associated with these disorders is heterogeneous, which renders diagnosis challenging. Moreover, a thorough evaluation is required to exclude diseases that mimic these disorders and to diagnose potential associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatoses may resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality. Therapeutic modalities range from systemic corticosteroids to novel biologic agents, and the treatment literature is rapidly expanding. Part I of this continuing medical education activity explores the pathogenesis of neutrophilic dermatoses and reviews the epidemiology, clinical and histopathological features, diagnosis, and management of Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet's disease.
Improving classification of melanocytic nevi: BRAF V600E expression associated with distinct histomorphologic features
Publication date: Available online 11 April 2018
Source:Journal of the American Academy of Dermatology
Author(s): Maija Kiuru, Danielle M. Tartar, Lihong Qi, Danyang Chen, Lan Yu, Thomas Konia, John D. McPherson, William J. Murphy, Maxwell A. Fung
BackgroundA subset of melanomas carrying a BRAF V600E mutation, the most common targetable mutation in melanoma, arises in association with a melanocytic nevus also harboring a BRAF V600E mutation. The detailed histomorphologic characteristics of BRAF V600E–positive nevi are not systematically documented.ObjectiveTo identify histomorphologic features correlating with BRAF V600E status in nevi.MethodsWe retrospectively identified melanocytic nevi from our laboratory reporting system. We performed a histomorphologic analysis and BRAF V600E expression analysis by immunohistochemistry.ResultsThirteen (14.8%) nevi were wild type (WT) and 76 (86.4%) positive for BRAF V600E. BRAF V600E nevi were predominantly dermal (BRAF V600E 55.3% vs. BRAF WT 15.4%, p=0.01) and showed congenital growth pattern (BRAF V600E 51.3% vs. BRAF WT 15.4%, p=0.02). BRAF V600E nevi often exhibited predominantly nested intraepidermal melanocytes, larger junctional nests, abrupt lateral circumscription, and larger cell size. Architectural disorder and inflammatory infiltrates were more often seen in BRAF WT nevi. BRAF sequencing of a subset of nevi confirmed immunohistochemical results.LimitationsLimitations include retrospective design and a small sample size of BRAF WT nevi.ConclusionsBRAF V600E is associated with distinct histomorphologic features in nevi. This may contribute to improving the accuracy of classification and diagnosis of melanocytic neoplasms.
Teaser
BRAF V600E mutation is a common genetic driver of melanocytic nevi and melanoma. BRAF V600E is associated with distinct histomorphologic features in melanocytic nevi, including dermal and congenital growth patterns. Understanding the genetic-morphologic correlates in melanocytic nevi may facilitate a more accurate classification and improved diagnosis of melanocytic neoplasms.Dermoscopy is a useful bedside tool for the evaluation of cutaneous Loxoscelism
Publication date: Available online 11 April 2018
Source:Journal of the American Academy of Dermatology
Author(s): Cristián Navarrete-Dechent, Sergio Álvarez-Véliz
Cardiotoxicity of Immunotherapy: Incidence, Diagnosis, and Management
Abstract
Purpose of review
This review describes cardiotoxicity associated with adoptive T cell therapy and immune checkpoint blockade.
Recent findings
Cardiotoxicity is a rare but potentially fatal complication associated with novel immunotherapies. Both affinity-enhanced and chimeric antigen receptor T cells have been reported to cause hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Immune checkpoint inhibitors are generally well-tolerated but have the potential to cause myocarditis, with clinical presentations ranging from asymptomatic cardiac biomarker elevation to heart failure, arrhythmia, and cardiogenic shock. Electrocardiography, cardiac biomarker measurement, and cardiac imaging are key components of the diagnostic evaluation. For suspected myocarditis, endomyocardial biopsy is recommended if the diagnosis remains unclear after initial testing.
Summary
The incidence of immunotherapy-associated cardiotoxicity is likely underestimated and may increase as adoptive T cell therapy and immune checkpoint inhibitors are used in larger populations and for longer durations of therapy. Baseline and serial cardiac evaluation is recommended to facilitate early identification and treatment of cardiotoxicity.
The Selective Use of Radiation Therapy in Rectal Cancer Patients
Abstract
Purpose of Review
Colorectal cancer has a high global incidence, and standard treatment employs a multimodality approach. In addition to cure, minimizing treatment-related toxicity and improving the therapeutic ratio is a common goal. The following article addresses the potential of omitting radiotherapy in select rectal cancer patients.
Recent Findings
Omission of radiotherapy in rectal cancer is analyzed in the context of historical findings, as well as more recent data describing risk stratification of stage II–III disease, surgical optimization, imaging limitations, improvement in systemic chemotherapeutic agents, and contemporary studies evaluating selective omission of radiotherapy.
Summary
A subset of rectal cancer patients exists that may be considered low to intermediate risk for locoregional recurrence. With appropriate staging, surgical technique, and possibly improved systemic therapy, it may be feasible to selectively omit radiotherapy in these patients. Current imaging limitations as well as evidence of increased locoregional recurrence following radiotherapy omission lend us to continue supporting the standard treatment of approach of neoadjuvant chemoradiation therapy followed by surgical resection until additional improvements and prospective evidence can support otherwise.
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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
