A 64-year-old woman presented with a 1 year history of progressive left proptosis and "blurry vision." Imaging studies revealed a left superior orbital mass distorting the optic nerve and superior rectus muscle. Excisional biopsy established the diagnosis of hobnail hemangioma. This report describes the first case of an orbital hobnail hemangioma, a lesion that more commonly presents in the dermis. Accepted for publication January 29, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Paul D. Langer, M.D., F.A.C.S., Rutgers New Jersey Medical School, Doctors Office Center, Suite 6100, P.O. Box 1709, Newark, NJ 07101-1709. E-mail: planger@njms.rutgers.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
Τετάρτη 28 Φεβρουαρίου 2018
Fibrous Histiocytoma of the Lacrimal Sac in an 11-Year-Old Male
Fibrous histiocytoma is a soft tissue tumor with cells resembling both fibroblasts and histiocytes. Occasionally in the orbit, they rarely arise in the lacrimal sac. Similar to prior cases described, the patient presented with symptoms of epiphora and a slowly enlarging mass inferior to the right medial canthus. Imaging demonstrated a circumscribed 1.2 cm × 1.1 cm × 1.1 cm mass within the lacrimal sac without surrounding bony destruction. Grossly, the tumor appeared homogenous and rubbery. Pathologic study results from the case demonstrated zones of hypercellularity and hypocellularity with a fibrous appearance, admixed with spindle cells and collections of foamy histiocytes. A diagnosis of benign fibrous histiocytoma was rendered, with the patient experiencing a complete resolution of symptoms at subsequent follow up. To the authors' knowledge, this is the first reported solitary case report of a fibrous histiocytoma of the lacrimal sac in a pediatric patient. Accepted for publication January 5, 2018. The authors have no financial or conflict of interest to disclose. Address correspondence and reprint requests to Joseph A. Santamaria, M.D., San Antonio Military Medical Center, San Antonio, TX 78234. E-mail: joesantam3@gmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
Inverse-Probability-Weighted Estimation for Monotone and Nonmonotone Missing Data
Abstract
Missing data is a common occurrence in epidemiologic research. In this paper, 3 data sets with induced missing values from the Collaborative Perinatal Project, a multisite US study conducted from 1959 to 1974, are provided as examples of prototypical epidemiologic studies with missing data. Our goal was to estimate the association of maternal smoking behavior with spontaneous abortion while adjusting for numerous confounders. At the same time, we did not necessarily wish to evaluate the joint distribution among potentially unobserved covariates, which is seldom the subject of substantive scientific interest. The inverse probability weighting (IPW) approach preserves the semiparametric structure of the underlying model of substantive interest and clearly separates the model of substantive interest from the model used to account for the missing data. However, IPW often will not result in valid inference if the missing-data pattern is nonmonotone, even if the data are missing at random. We describe a recently proposed approach to modeling nonmonotone missing-data mechanisms under missingness at random to use in constructing the weights in IPW complete-case estimation, and we illustrate the approach using 3 data sets described in a companion article (Am J Epidemiol. 2018;187(3):568–575).Principled Approaches to Missing Data in Epidemiologic Studies
Abstract
Principled methods with which to appropriately analyze missing data have long existed; however, broad implementation of these methods remains challenging. In this and 2 companion papers (Am J Epidemiol. 2018;187(3):576–584 and Am J Epidemiol. 2018;187(3):585–591), we discuss issues pertaining to missing data in the epidemiologic literature. We provide details regarding missing-data mechanisms and nomenclature and encourage the conduct of principled analyses through a detailed comparison of multiple imputation and inverse probability weighting. Data from the Collaborative Perinatal Project, a multisite US study conducted from 1959 to 1974, are used to create a masked data-analytical challenge with missing data induced by known mechanisms. We illustrate the deleterious effects of missing data with naive methods and show how principled methods can sometimes mitigate such effects. For example, when data were missing at random, naive methods showed a spurious protective effect of smoking on the risk of spontaneous abortion (odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.19, 0.93), while implementation of principled methods multiple imputation (OR = 1.30, 95% CI: 0.95, 1.77) or augmented inverse probability weighting (OR = 1.40, 95% CI: 1.00, 1.97) provided estimates closer to the "true" full-data effect (OR = 1.31, 95% CI: 1.05, 1.64). We call for greater acknowledgement of and attention to missing data and for the broad use of principled missing-data methods in epidemiologic research.Multiple Imputation for Incomplete Data in Epidemiologic Studies
Abstract
Epidemiologic studies are frequently susceptible to missing information. Omitting observations with missing variables remains a common strategy in epidemiologic studies, yet this simple approach can often severely bias parameter estimates of interest if the values are not missing completely at random. Even when missingness is completely random, complete-case analysis can reduce the efficiency of estimated parameters, because large amounts of available data are simply tossed out with the incomplete observations. Alternative methods for mitigating the influence of missing information, such as multiple imputation, are becoming an increasing popular strategy in order to retain all available information, reduce potential bias, and improve efficiency in parameter estimation. In this paper, we describe the theoretical underpinnings of multiple imputation, and we illustrate application of this method as part of a collaborative challenge to assess the performance of various techniques for dealing with missing data (Am J Epidemiol. 2018;187(3):568–575). We detail the steps necessary to perform multiple imputation on a subset of data from the Collaborative Perinatal Project (1959–1974), where the goal is to estimate the odds of spontaneous abortion associated with smoking during pregnancy.Sex Differences in the Association of Diabetes With Cardiovascular Disease Outcomes Among African-American and White Participants in the Atherosclerosis Risk in Communities Study
Abstract
A sex × diabetes interaction in cardiovascular disease (CVD) has been established among white persons; however, it is unknown whether this interaction occurs among African Americans. We hypothesized that there was a multiplicative sex × diabetes interaction for CVD among African Americans participating in the Atherosclerosis Risk in Communities Study (1987–2013). Race-specific Cox models were run in three stages: Stage 1 examined baseline diabetes status; stage 2 examined baseline diabetes status with the competing risk of non-CVD death; and stage 3 examined time-varying diabetes status with a competing risk of non-CVD death. There were 1,073 incident CVD events among 3,767 African Americans and 2,475 among 10,291 white persons. Among African Americans, in stage 1 analysis, the hazard ratio for women with diabetes was 2.3 (95% confidence interval (CI): 2.0, 2.7) compared with women without diabetes after adjustment for age, and the corresponding hazard ratio for men was 1.8 (95% CI: 1.5, 2.1) (P for interaction = 0.014). After full adjustment, the diabetes hazard ratio was attenuated to 2.0 (95% CI: 1.8, 2.3) among women and remained 1.8 (95% CI: 1.5, 2.1) for men (P for interaction = 0.058). A synergistic influence on CVD risk between being a black woman and having diabetes was consistent across stage 2 and stage 3 analyses, with marginally significant interaction, mirroring sex differences seen in whites.Invited Commentary: Sex and Race Differences in Diabetes and Cardiovascular Disease—Achieving the Promise of Sex and Race Subgroup Analyses in Epidemiologic Research
Abstract
Diabetes confers a higher risk of cardiovascular disease on women than on men. The reasons for these sex differences, such as poorer cardiovascular risk factor profiles, have received considerable attention. However, a recent report on sex × diabetes interactions on cardiovascular disease identified that few if any prior studies have confirmed these sex differences in black individuals, despite known diabetes-related disparities. In this issue of the Journal, George et al. (Am J Epidemiol. 2018;187(3):403–410.) found marginally significant multiplicative sex × diabetes interactions in black but not white study participants after adjustments for traditional and behavioral risk factors, competing risk, and change in diabetes status over time. This study is notable for its attempt to fill an important literature gap, and it elegantly addressed multiple statistical considerations in assessing sex × diabetes interactions according to race strata. The findings also highlighted several important considerations for conducting race and sex subgroup analyses.Breast Cancer Incidence and Exposure to Metalworking Fluid in a Cohort of Female Autoworkers
Abstract
Breast cancer is the leading cancer diagnosed among women, and environmental studies have produced few leads on modifiable risk factors for breast cancer. Following an Institute of Medicine recommendation for occupational studies of women highly exposed to potential breast cancer risk factors, we took advantage of an existing cohort of 4,503 female autoworkers in Michigan exposed to metalworking fluid (MWF), complex mixtures of oils and chemicals widely used in metal manufacturing worldwide. Cox proportional hazards models were fit to estimate hazard ratios for incident breast cancer (follow-up, 1985–2013) and cumulative exposure (20-year lag) to straight mineral oils (a known human carcinogen) and water-based soluble and synthetic MWF. Because the state cancer registry began decades after the cohort was defined, we restricted our analyses to subcohorts of women hired closer to the start of follow-up. Among those hired after 1969, the hazard ratio associated with a 1 interquartile-range increase in straight MWF exposure was 1.13 (95% confidence interval: 1.03, 1.23). In separate analyses of premenopausal breast cancer, defined by age at diagnosis, the hazard ratio was elevated for exposure to synthetic MWF (chemical lubricants with no oil content), possibly suggesting a different mechanism in the younger women with breast cancer. This study adds to the limited literature regarding quantitative chemical exposures and breast cancer risk.Association of DNA Methylation-Based Biological Age With Health Risk Factors and Overall and Cause-Specific Mortality
Abstract
Measures of biological age based on blood DNA methylation, referred to as age acceleration (AA), have been developed. We examined whether AA was associated with health risk factors and overall and cause-specific mortality. At baseline (1990–1994), blood samples were drawn from 2,818 participants in the Melbourne Collaborative Cohort Study (Melbourne, Victoria, Australia). DNA methylation was determined using the Infinium HumanMethylation450 BeadChip array (Illumina Inc., San Diego, California). Mixed-effects models were used to examine the association of AA with health risk factors. Cox models were used to assess the association of AA with mortality. A total of 831 deaths were observed during a median 10.7 years of follow-up. Associations of AA were observed with male sex, Greek nationality (country of birth), smoking, obesity, diabetes, lower education, and meat intake. AA measures were associated with increased mortality, and this was only partly accounted for by known determinants of health (hazard ratios were attenuated by 20%–40%). Weak evidence of heterogeneity in the association was observed by sex (P = 0.06) and cause of death (P = 0.07) but not by other factors. DNA-methylation-based AA measures are associated with several major health risk factors, but these do not fully explain the association between AA and mortality. Future research should investigate what genetic and environmental factors determine AA.Possible Mediation by Methylation in Acute Inflammation Following Personal Exposure to Fine Particulate Air Pollution
Abstract
Air pollution may increase cardiovascular and respiratory risk through inflammatory pathways, but evidence for acute effects has been weak and indirect. Between December 2014 and July 2015, we enrolled 36 healthy, nonsmoking college students for a panel study in Shanghai, China, a city with highly variable levels of air pollution. We measured personal exposure to particulate matter with an aerodynamic diameter less than or equal to 2.5 μm (PM2.5) continuously for 72 hours preceding each of 4 clinical visits that included phlebotomy. We measured 4 inflammation proteins and DNA methylation at nearby regulatory cytosine-phosphate-guanine (CpG) loci. We applied linear mixed-effect models to examine associations over various lag times. When results suggested mediation, we evaluated methylation as mediator. Increased PM2.5 concentration was positively associated with all 4 inflammation proteins and negatively associated with DNA methylation at regulatory loci for tumor necrosis factor alpha (TNF-α) and soluble intercellular adhesion molecule-1. A 10-μg/m3 increase in average PM2.5 during the 24 hours preceding blood draw corresponded to a 4.4% increase in TNF-α and a statistically significant decrease in methylation at one of the two studied candidate CpG loci for TNF-α. Epigenetics may play an important role in mediating effects of PM2.5 on inflammatory pathways.Sickle Cell Trait and Heat Injury Among US Army Soldiers
Abstract
There is concern that sickle cell trait (SCT) increases risk of exertional collapse, a primary cause of which is heat injury. However, to our knowledge, no population-based studies among active individuals have addressed this, representing a critical evidence gap. We conducted a retrospective cohort study of SCT-tested African-American soldiers who were on active duty in the US Army anytime between January 2011 and December 2014. Using Cox proportional hazards models and adjusting for demographic and medical factors, we observed no significant associations between SCT and either mild heat injury (hazard ratio (HR) = 1.15, 95% confidence interval (CI): 0.84, 1.56; n = 45,999) or heat stroke (HR = 1.11, 95% CI: 0.44, 2.79; n = 46,183). Risk of mild heat injury was substantially higher among soldiers with recent prescriptions for antipsychotic agents (HR = 3.25, 95% CI: 1.33, 7.90). Risk of heat stroke was elevated among those with a prior mild heat injury (HR = 17.7, 95% CI: 8.50, 36.7) and among overweight and obese individuals (HR = 2.91 (95% CI: 1.38, 6.17) and HR = 4.04 (95% CI: 1.72, 9.45), respectively). In a setting where universal precautions are utilized to mitigate risk of exertion-related illnesses, SCT is not associated with either mild heat injury or heat stroke.The Role of Mobile Genetic Elements in the Spread of Antimicrobial-Resistant Escherichia coli From Chickens to Humans in Small-Scale Production Poultry Operations in Rural Ecuador
Abstract
Small-scale production poultry operations are increasingly common worldwide. To investigate how these operations influence antimicrobial resistance and mobile genetic elements (MGEs), Escherichia coli isolates were sampled from small-scale production birds (raised in confined spaces with antibiotics in feed), household birds (no movement constraints; fed on scraps), and humans associated with these birds in rural Ecuador (2010–2012). Isolates were screened for genes associated with MGEs as well as phenotypic resistance to 12 antibiotics. Isolates from small-scale production birds had significantly elevated odds of resistance to 7 antibiotics and presence of MGE genes compared with household birds (adjusted odds ratio (OR) range = 2.2–87.9). Isolates from humans associated with small-scale production birds had elevated odds of carrying an integron (adjusted OR = 2.0; 95% confidence interval (CI): 1.06, 3.83) compared with humans associated with household birds, as well as resistance to sulfisoxazole (adjusted OR = 1.9; 95% CI: 1.01, 3.60) and trimethoprim/sulfamethoxazole (adjusted OR = 2.1; 95% CI: 1.13, 3.95). Stratifying by the presence of MGEs revealed antibiotic groups that are explained by biological links to MGEs; in particular, resistance to sulfisoxazole, trimethoprim/sulfamethoxazole, or tetracycline was highest among birds and humans when MGE exposures were present. Small-scale production poultry operations might select for isolates carrying MGEs, contributing to elevated levels of resistance in this setting.Understanding Causal Distributional and Subgroup Effects With the Instrumental Propensity Score
Abstract
To address issues with measured and unmeasured confounding in observational studies, we developed a unified approach to using an instrumental variable in more flexible ways to evaluate treatment effects. The approach is based on an instrumental propensity score conditional on baseline variables, which can then be incorporated in matching, regression, subclassification, or weighting along with various parametric, semiparametric, or nonparametric methods for the assessment of treatment effects. Therefore, the application of the instrumental propensity score allows different methods for outcome effect evaluations in addition to standard 2-stage least square models while controlling for unmeasured confounders. Several properties of the instrumental propensity score are discussed. The approach is then illustrated using subclassification along with a semiparametric density ratio model and empirical likelihood. This method allows us to evaluate distributional and subgroup treatment effects in addition to the overall average treatment effect. Simulation studies showed that the method works well. We applied our method to a study of the effects of attending a Catholic school versus a public school and found that attending a Catholic school had significant beneficial effects on subsequent wages among a subgroup of subjects.The Mental Health Benefits of Acquiring a Home in Older Age: A Fixed-Effects Analysis of Older US Adults
Abstract
Homeownership is consistently associated with better mental health, but whether becoming a homeowner in later in life has positive psychological benefits has not, to our knowledge, been examined. We assessed whether acquiring a home after age 50 years was associated with depression in a representative sample of older US adults. We used individual fixed-effects models based on data from 20,524 respondents aged ≥50 years from the Health and Retirement Study, who were interviewed biennially during 1993–2010. Depressive symptoms were measured using the 8-item Center for Epidemiologic Studies Depression Scale. Controlling for confounders, becoming a homeowner in later life predicted a decline in depressive symptoms in the same year (β = −0.0768, 95% confidence interval (CI): −0.152, −0.007). The association remained significant after 2 years (β = −0.0556, 95% CI: −0.134, −0.001) but weakened afterward. Buying a home for reasons associated with positive characteristics of the new house or neighborhood drove this association (β = −0.426, 95% CI: −0.786, −0.066), while acquiring a home for reasons associated with characteristics of the previous home or neighborhood, the desire to be closer to relatives, downsizing, or upsizing did not predict mental health improvements. Findings suggest that there are small but significant benefits for mental health associated with acquiring a home in older age.When to Censor?
Abstract
Loss to follow-up is an endemic feature of time-to-event analyses that precludes observation of the event of interest. To our knowledge, in typical cohort studies with encounters occurring at regular or irregular intervals, there is no consensus on how to handle person-time between participants' last study encounter and the point at which they meet a definition of loss to follow-up. We demonstrate, using simulation and an example, that when the event of interest is captured outside of a study encounter (e.g., in a registry), person-time should be censored when the study-defined criterion for loss to follow-up is met (e.g., 1 year after last encounter), rather than at the last study encounter. Conversely, when the event of interest must be measured within the context of a study encounter (e.g., a biomarker value), person-time should be censored at the last study encounter. An inappropriate censoring scheme has the potential to result in substantial bias that may not be easily corrected.Invited Commentary: “Bedroom Light Exposure at Night and the Incidence of Depressive Symptoms: A Longitudinal Study of the HEIJO-KYO Cohort”
Abstract
In modern society, we are increasingly disconnected from natural light/dark cycles and beset by round-the-clock exposure to artificial light. Light has powerful effects on physical and mental health, in part via the circadian system, and thus the timing of light exposure dictates whether it is helpful or harmful. In their compelling paper, Obayashi et al. (Am J Epidemiol. 2018;187(3):427–434.) offer evidence that light at night can prospectively predict an elevated incidence of depressive symptoms in older adults. Strengths of the study include the longitudinal design and direct, objective assessment of light levels, as well as accounting for multiple plausible confounders during analyses. Follow-up studies should address the study's limitations, including reliance on a global self-report of sleep quality and a 2-night assessment of light exposure that may not reliably represent typical light exposure. In addition, experimental studies including physiological circadian measures will be necessary to determine whether the light effects on depression are mediated through the circadian system or are so-called "direct" effects of light. In any case, these exciting findings could inform novel approaches to preventing depressive disorders in older adults.Bedroom Light Exposure at Night and the Incidence of Depressive Symptoms: A Longitudinal Study of the HEIJO-KYO Cohort
Abstract
Previous studies have indicated that minimal exposure to light at night (LAN) increases depression risk, even at 5 lux, in nocturnal and diurnal mammals. Although such low-level LAN may affect human circadian physiology, the association between exposure to LAN and depressive symptoms remains uncertain. In the present study, bedroom light intensity was measured objectively, and depressive symptoms were assessed, during 2010–2014 in Nara, Japan. Of 863 participants (mean age = 71.5 years) who did not have depressive symptoms at baseline, 73 participants reported development of depressive symptoms during follow-up (median, 24 months). Compared with the "dark" group (average of <5 lux; n = 710), the LAN group (average of ≥5 lux; n = 153) exhibited a significantly higher depression risk (hazard ratio = 1.89; 95% CI: 1.13, 3.14), according to a Cox proportional hazards model adjusting for age, sex, body mass index, and economic status. Further, the significance remained in a multivariable model adjusting for hypertension, diabetes, and sleep parameters (hazard ratio = 1.72; 95% CI: 1.03, 2.89). Sensitivity analyses using bedroom light data with a cutoff value of ≥10 lux suggested consistent results. In conclusion, these results indicated that exposure to LAN in home settings was independently associated with subsequent depression risk in an elderly general population.Cumulative effects of cascade hydropower stations on total dissolved gas supersaturation
Abstract
Elevated levels of total dissolved gas (TDG) may occur downstream of dams during the spill process. These high levels would increase the incidence of gas bubble disease in fish and cause severe environmental impacts. With increasing numbers of cascade hydropower stations being built or planned, the cumulative effects of TDG supersaturation are becoming increasingly prominent. The TDG saturation distribution in the downstream reaches of the Jinsha River was studied to investigate the cumulative effects of TDG supersaturation resulting from the cascade hydropower stations. A comparison of the effects of the joint operation and the single operation of two hydropower stations (XLD and XJB) was performed to analyze the risk degree to fish posed by TDG supersaturation. The results showed that water with supersaturated TDG generated at the upstream cascade can be transported to the downstream power station, leading to cumulative TDG supersaturation effects. Compared with the single operation of XJB, the joint operation of both stations produced a much higher TDG saturation downstream of XJB, especially during the non-flood discharge period. Moreover, the duration of high TDG saturation and the lengths of the lethal and sub-lethal areas were much higher in the joint operation scenario, posing a greater threat to fish and severely damaging the environment. This work provides a scientific basis for strategies to reduce TDG supersaturation to the permissible level and minimize the potential risk of supersaturated TDG.
Fabrication and characterization of β-cypermethrin-loaded PLA microcapsules prepared by emulsion-solvent evaporation: loading and release properties
Abstract
Microcapsulses can be designed to effectively encapsulate, protect, and control the release of pesticides. In this study, emulsion-solvent evaporation method was used to fabricate microcapsules using dichloromethane as the solvent, polylactic acid (PLA) as the carrier materials, poly(vinyl alcohol) as the emulsifier, and β-cypermethrin as the entrapped pesticide. The effects of process parameters on the microcapsules characteristics (size, loading content, and encapsulation efficiency) were investigated. Also, the release behavior of the β-cypermethrin was measured experimentally and modeled mathematically. Kinetic analysis indicated that release mechanism of β-cypermethrin was compatible to Fickian diffusion. By optimizing the process parameters, β-cypermethrin-loaded microcapsules were successfully produced with spherical shape, smooth surface, high encapsulation efficiency (> 80%), and a range of pesticide contents. These parameters could be adjusted to achieve delivery systems with desirable release profiles. The results are beneficial to develop delivery systems for rational and effective usage of pesticides.
Experimental investigation on emission reduction in neem oil biodiesel using selective catalytic reduction and catalytic converter techniques
Abstract
In the present study, non-edible seed oil namely raw neem oil was converted into biodiesel using transesterification process. In the experimentation, two biodiesel blends were prepared namely B25 (25% neem oil methyl ester with 75% of diesel) and B50 (50% neem oil methyl ester with 50% diesel). Urea-based selective catalytic reduction (SCR) technique with catalytic converter (CC) was fixed in the exhaust tail pipe of the engine for the reduction of engine exhaust emissions. Initially, the engine was operated with diesel as a working fluid and followed by refilling of biodiesel blends B25 and B50 to obtain the baseline readings without SCR and CC. Then, the same procedure was repeated with SCR and CC technique for emission reduction measurement in diesel, B25 and B50 sample. The experimental results revealed that the B25 blend showed higher break thermal efficiency (BTE) and exhaust gas temperature (EGT) with lower break-specific fuel consumption (BSFC) than B50 blend at all loads. On comparing with biodiesel blends, diesel experiences increased BTE of 31.9% with reduced BSFC of 0.29 kg/kWh at full load. A notable emission reduction was noticed for all test fuels in SCR and CC setup. At full load, B25 showed lower carbon monoxide (CO) of 0.09% volume, hydrocarbon (HC) of 24 ppm, and smoke of 14 HSU and oxides of nitrogen (NOx) of 735 ppm than diesel and B50 in SCR and CC setup. On the whole, the engine with SCR and CC setup showed better performance and emission characteristics than standard engine operation.
Impact of military on biofuels consumption and GHG emissions: the evidence from G7 countries
Abstract
It was aimed to test the relation among the greenhouse gases emissions, economic growth, biofuels consumption, and militarization in G7 countries during the 1985–2015 period by Pedroni 1995 and panel Johansen tests and two long-run estimators—dynamic OLS and fully modified OLS. Long-run estimators found that economic growth and militarization have statistically significant positive impact on CO2 emission of G7 countries. Furthermore, the panel causality tests were applied: Dumitrescu and Hurlin (Econ Model 29(4):1450–1460, 2012) and panel Granger causality. These tests determined the causal relationship between the variables. The results of this paper implied that economic growth and biofuels consumption depend on militarization, and economic growth and militarization are granger causes of the greenhouse gases emissions.
Removing polycyclic aromatic hydrocarbons from water using granular activated carbon: kinetic and equilibrium adsorption studies
Abstract
Polycyclic aromatic hydrocarbons (PAHs) constitute a group of highly persistent, toxic and widespread environmental micropollutants that are increasingly found in water. A study was conducted in removing five PAHs, specifically naphthalene, acenaphthylene, acenaphthene, fluorene and phenanthrene, from water by adsorption onto granular activated carbon (GAC). The pseudo-first-order (PFO) model satisfactorily described the kinetics of adsorption of the PAHs. The Weber and Morris diffusion model's fit to the data showed that there were faster and slower rates of intra-particle diffusion probably into the mesopores and micropores of the GAC, respectively. These rates were negatively related to the molar volumes of the PAHs. Batch equilibrium adsorption data fitted well to the Langmuir, Freundlich and Dubinin–Radushkevich models, of which the Freundlich model exhibited the best fit. The adsorption affinities were related to the hydrophobicity of the PAHs as determined by the log Kow values. Free energies of adsorption calculated from the Dubinin–Radushkevich model and the satisfactory kinetic data fitting to the PFO model suggested physical adsorption of the PAHs. Adsorption of naphthalene, acenaphthylene and acenaphthene in fixed-bed columns containing a mixture of GAC (0.5 g) + sand (24.5 g) was satisfactorily simulated by the Thomas model.
Assessment and identification of nitrogen pollution sources in the Cheongmi River with intensive livestock farming areas, Korea
Abstract
This study aimed to develop methods for assessing and identifying nitrogen sources in the Cheongmi River, Korea, that has intensive livestock farming areas (ILFA) in its watershed. The assessment focused on the feasibility of the simultaneous use of stable isotopic compositions of ammonium (δ15NNH4) and nitrate (δ15NNO3) for identifying the main nitrogen pollution sources in the Cheongmi River watershed. Our results suggested that the organic nitrogen (Org-N) to total nitrogen (T-N) ratio could be used as an indicator for assessing the effect of livestock excreta on waterways in ILFA. We observed that the T-N concentration was much more strongly affected by livestock excreta than the T-P concentration in the mainstream of the Cheongmi River. The positive correlation was more significant between δ15NNH4 and NH4-N than that between δ15NNO3 and NO3-N for river water samples. Furthermore, the use of δ15NNH4 was more effective than that of δ15NNO3 in evaluating nitrogen variations between May and August in the Cheongmi River because the differences in δ15NNH4 between May and August were more remarkable compared to those in δ15NNO3. Finally, the simultaneous use of δ15NNH4 and δ15NNO3 showed that the dominant nitrogen source at sites M3, M4, M5, and M6, specifically in May, was livestock excreta in the Cheongmi River. The results of this study could be used for sustainable water quality management in the Cheongmi River watershed.
3 tesla MRI assisted detection of compression points in ulnar neuropathy at the elbow in correlation with intraoperative findings
Releasing the ulnar nerve from all entrapments is the primary objective of every surgical method in ulnar neuropathy at the elbow (UNE). The aim of this retrospective diagnostic study was to validate preoperative 3 Tesla MRI results by comparing the MRI findings with the intraoperative aspects during endoscopic-assisted or open surgery.
‘Investigation of the activation of temporalis and masseter muscles in voluntary and spontaneous smile production.’
Masticatory muscles or their nerve supply are options for facial reanimation surgery but their ability to create spontaneous smile has been questioned. This study assessed the percentage of healthy adults who activate temporalis and masseter during voluntary and spontaneous smile.
Orthotopic transfer of vascularized groin lymph node flap in the treatment of breast cancer-related lymphedema: clinical results, lymphoscintigraphy findings and proposed mechanism
Vascularized lymph node transfer (VLNT) has become more popular in treating secondary lymphedema. However, the mechanism has not been clearly elucidated.The purpose of this study were (1) to evaluate the outcome of vascularized groin lymph node (VGLN) transfer using axilla as a recipient site in patients with breast cancer-related lymphedema (BCRL) and (2) to provide radiological evidence of lymphangiogenesis in VLNT.
Polychlorinated biphenyls in the Yellow River of Henan section: occurrence, composition, and impact factors
Abstract
The levels, spatial variation, congener profiles, impact factors, and ecological risk of polychlorinated biphenyls (PCBs) in the sediment from the Yellow River of Henan section, China, were investigated in this paper. Total concentration of 31 PCBs and seven indicator PCBs varied from ND to 1015 pg g−1 and ND to 423 pg g−1, respectively. Compared with other aquatic environments around China, PCB levels in the studied area were relatively low. Spatial variations revealed that tributaries possessed higher PCB levels, in comparison to mainstream, which acted as input sources of PCBs in the mainstream. The homolog profiles were dominated by lighter PCBs (Tri–PentaCBs), contributing above 70% of total PCBs. Correlation analysis between PCB concentrations and total organic carbon indicated that local input or atmospheric deposition was the primary controls of spatial variation of PCBs. According to simple sediment quality guidelines (SQG), the risks posed by PCBs in the sediments might be negligible.
Reduction of N-nitrosodimethylamine formation from ranitidine by ozonation preceding chloramination: influencing factors and mechanisms
Abstract
Formation of toxic N-nitrosodimethylamine (NDMA) by chloramination of ranitidine, a drug to block histamine, was still an ongoing issue and posed a risk to human health. In this study, the effect of ozonation prior to chloramination on NDMA formation and the transformation pathway were determined. Influencing factors, including ozone dosages, pH, hydroxyl radical scavenger, bromide, and NOM, were studied. The results demonstrated that small ozone dosage (0.5 mg/L) could effectively control NDMA formation from subsequent chloramination (from 40 to 0.8%). The NDMA molar conversion was not only influenced by pH but also by ozone dosages at various pre-ozonation pH (reached the highest value of 5% at pH 8 with 0.5 mg/L O3 but decreased with the increasing pH with 1 mg/L O3). The NDMA molar yield by chloramination of ranitidine without pre-ozonation was reduced by the presence of bromide ion due to the decomposition of disinfectant. However, due to the formation of brominated intermediate substances (i.e., dimethylamine (DMA), dimethyl-aminomethyl furfuryl alcohol (DFUR)) with higher NDMA molar yield than their parent substances, more NDMA was formed than that without bromide ion upon ozonation. Natural organic matter (NOM) and hydroxyl radical scavenger (tert-butyl alcohol, tBA) enhanced NDMA generation because of the competition of ozone and more ranitidine left. The NDMA reduction mechanism by pre-ozonation during chloramination of ranitidine may be due to the production of oxidation products with less NDMA yield (such as DMA) than parent compound. Based on the result of Q-TOF and GC-MS/MS analysis, three possible transformation pathways were proposed. Different influences of oxidation conditions and water quality parameters suggest that strategies to reduce NDMA formation should vary with drinking water sources and choose optimal ozone dosage.
Behavioral and neurochemical consequences of perinatal exposure to lead in adult male Wistar rats: protective effect by Centella asiatica
Abstract
The present study evaluated the protective effects of Centella asiatica (CA) leaf extract on behavioral deficits and neurotoxicity in adult rat exposed to lead during perinatal period. Adult Wistar rats were exposed to 0.15% lead acetate (Pb) from gestation day 6 through drinking water and the pups were exposed lactationally to Pb till weaning. Significant perturbations in locomotor activity and exploratory behavior were observed in rats exposed to Pb during perinatal period. The levels of lipid peroxidation increased significantly with a reduction in levels of glutathione and activity levels of acetylcholinesterase and antioxidant enzymes in hippocampus, cerebrum, cerebellum, and medulla of brains excised from Pb-exposed rats. Oral supplementation of CA during postweaning period provided significant protection against Pb-induced behavioral impairments and neurotoxicity, without chelating tissue Pb levels. The possible neuroprotective efficacy of CA may be due to its antioxidant potential but not by lowering effects of brain Pb content.
Dynamic Interactions between Top-Down Expectations and Conscious Awareness
It is well known that top–down expectations affect perceptual processes. Yet, remarkably little is known about the relationship between expectations and conscious awareness. We address three crucial outstanding questions: (1) how do expectations affect the likelihood of conscious stimulus perception?; (2) does the brain register violations of expectations nonconsciously?; and (3) do expectations need to be conscious to influence perceptual decisions? Using human participants, we performed three experiments in which we manipulated stimulus predictability within the attentional blink paradigm, while combining visual psychophysics with electrophysiological recordings. We found that valid stimulus expectations increase the likelihood of conscious access of stimuli. Furthermore, our findings suggest a clear dissociation in the interaction between expectations and consciousness: conscious awareness seems crucial for the implementation of top–down expectations, but not for the generation of bottom-up stimulus-evoked prediction errors. These results constrain and update influential theories about the role of consciousness in the predictive brain.
SIGNIFICANCE STATEMENT While the relationship between expectations and conscious awareness plays a major role in many prediction-based theories of brain functioning, thus far few empirical studies have examined this relationship. Here, we address this gap in knowledge in a set of three experiments. Our results suggest that the effect of expectations on conscious awareness varies between different steps of the hierarchy of predictive processing. While the active use of top–down expectations for perceptual decisions requires conscious awareness, prediction errors can be triggered outside of conscious awareness. These results constrain and update influential theories about the role of consciousness in the predictive brain.
The Axon Initial Segment: An Updated Viewpoint
At the base of axons sits a unique compartment called the axon initial segment (AIS). The AIS generates and shapes the action potential before it is propagated along the axon. Neuronal excitability thus depends crucially on the AIS composition and position, and these adapt to developmental and physiological conditions. The AIS also demarcates the boundary between the somatodendritic and axonal compartments. Recent studies have brought insights into the molecular architecture of the AIS and how it regulates protein trafficking. This Viewpoints article summarizes current knowledge about the AIS and highlights future challenges in understanding this key actor of neuronal physiology.
Role of Anterior Intralaminar Nuclei of Thalamus Projections to Dorsomedial Striatum in Incubation of Methamphetamine Craving
Relapse to methamphetamine (Meth) seeking progressively increases after withdrawal from drug self-administration (incubation of Meth craving). We previously demonstrated a role of dorsomedial striatum (DMS) dopamine D1 receptors (D1Rs) in this incubation. Here, we studied the role of afferent glutamatergic projections into the DMS and local D1R–glutamate interaction in this incubation in male rats. We first measured projection-specific activation on day 30 relapse test by using cholera toxin b (retrograde tracer) + Fos (activity marker) double-labeling in projection areas. Next, we determined the effect of pharmacological reversible inactivation of lateral or medial anterior intralaminar nuclei of thalamus (AIT-L or AIT-M) on incubated Meth seeking on withdrawal day 30. We then used an anatomical asymmetrical disconnection procedure to determine whether an interaction between AIT-L->DMS glutamatergic projections and postsynaptic DMS D1Rs contributes to incubated Meth seeking. We also determined the effect of unilateral inactivation of AIT-L and D1R blockade of DMS on incubated Meth seeking, and the effect of contralateral disconnection of AIT-L->DMS projections on nonincubated Meth seeking on withdrawal day 1. Incubated Meth seeking was associated with selective activation of AIT->DMS projections; other glutamatergic projections to DMS were not activated. AIT-L (but not AIT-M) inactivation or anatomical disconnection of AIT-L->DMS projections decreased incubated Meth seeking. Unilateral inactivation of AIT-L or D1R blockade of the DMS had no effect on incubated Meth craving, and contralateral disconnection of AIT-L->DMS projections had no effect on nonincubated Meth seeking. Our results identify a novel role of AIT-L and AIT-L->DMS glutamatergic projections in incubation of drug craving and drug seeking.
SIGNIFICANCE STATEMENT Methamphetamine seeking progressively increases after withdrawal from drug self-administration, a phenomenon termed incubation of methamphetamine craving. We previously found that D1R-mediated dopamine transmission in the dorsomedial striatum plays a critical role in this incubation phenomenon. Here, we used neuroanatomical and neuropharmacological methods in rats to demonstrate that an interaction between the glutamatergic projection from the lateral anterior intralaminar nuclei of the thalamus to the dorsomedial striatum and local dopamine D1 receptors plays a critical role in relapse to methamphetamine seeking after prolonged withdrawal. Our study identified a novel motivation-related thalamostriatal projection critical to relapse to drug seeking.
Endoplasmic Reticulum Stress Contributes to the Loss of Newborn Hippocampal Neurons after Traumatic Brain Injury
Adult hippocampal neurogenesis has been shown to be required for certain types of cognitive function. For example, studies have shown that these neurons are critical for pattern separation, the ability to store similar experiences as distinct memories. Although traumatic brain injury (TBI) has been shown to cause the loss of newborn hippocampal neurons, the signaling pathway(s) that triggers their death is unknown. Endoplasmic reticulum (ER) stress activates the PERK-eIF2α pathway that acts to restore ER function and improve cell survival. However, unresolved/intense ER stress activates C/EBP homologous protein (CHOP), leading to cell death. We show that TBI causes the death of hippocampal newborn neurons via CHOP. Using CHOP KO mice, we show that loss of CHOP markedly reduces newborn neuron loss after TBI. Injured CHOP mice performed significantly better in a context fear discrimination task compared with injured wild-type mice. In contrast, the PERK inhibitor GSK2606414 exacerbated doublecortin cell loss and worsened contextual discrimination. Administration of guanabenz (which reduces ER stress) to injured male rats reduced the loss of newborn neurons and improved one-trial contextual fear memory. Interestingly, we also found that the surviving newborn neurons in brain-injured animals had dendritic loss, which was not observed in injured CHOP KO mice or in animals treated with guanabenz. These results indicate that ER stress plays a key role in the death of newborn neurons after TBI. Further, these findings indicate that ER stress can alter dendritic arbors, suggesting a role for ER stress in neuroplasticity and dendritic pathologies.
SIGNIFICANCE STATEMENT The hippocampus, a structure in the temporal lobe, is critical for learning and memory. The hippocampus is one of only two areas in which neurons are generated in the adult brain. These newborn neurons are required for certain types of memory, and are particularly vulnerable to traumatic brain injury (TBI). However, the mechanism(s) that causes the loss of these cells after TBI is poorly understood. We show that endoplasmic reticulum (ER) stress pathways are activated in newborn neurons after TBI, and that manipulation of the CHOP cascade improves newborn neuron survival and cognitive outcome. These results suggest that treatments that prevent/resolve ER stress may be beneficial in treating TBI-triggered memory dysfunction.
An Interaction between Serotonin Receptor Signaling and Dopamine Enhances Goal-Directed Vigor and Persistence in Mice
The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti–depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.
SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.
Differential Sampling of Visual Space in Ventral and Dorsal Early Visual Cortex
A fundamental feature of cortical visual processing is the separation of visual processing for the upper and lower visual fields. In early visual cortex (EVC), the upper visual field is processed ventrally, with the lower visual field processed dorsally. This distinction persists into several category-selective regions of occipitotemporal cortex, with ventral and lateral scene-, face-, and object-selective regions biased for the upper and lower visual fields, respectively. Here, using an elliptical population receptive field (pRF) model, we systematically tested the sampling of visual space within ventral and dorsal divisions of human EVC in both male and female participants. We found that (1) pRFs tend to be elliptical and oriented toward the fovea with distinct angular distributions for ventral and dorsal divisions of EVC, potentially reflecting a radial bias; and (2) pRFs in ventral areas were larger (~1.5x) and more elliptical (~1.2x) than those in dorsal areas. These differences potentially reflect a tendency for receptive fields in ventral temporal cortex to overlap the fovea with less emphasis on precise localization and isotropic representation of space compared with dorsal areas. Collectively, these findings suggest that ventral and dorsal divisions of EVC sample visual space differently, likely contributing to and/or stemming from the functional differentiation of visual processing observed in higher-level regions of the ventral and dorsal cortical visual pathways.
SIGNIFICANCE STATEMENT The processing of visual information from the upper and lower visual fields is separated in visual cortex. Although ventral and dorsal divisions of early visual cortex (EVC) are commonly assumed to sample visual space equivalently, we demonstrate systematic differences using an elliptical population receptive field (pRF) model. Specifically, we demonstrate that (1) ventral and dorsal divisions of EVC exhibit diverging distributions of pRF angle, which are biased toward the fovea; and (2) ventral pRFs exhibit higher aspect ratios and cover larger areas than dorsal pRFs. These results suggest that ventral and dorsal divisions of EVC sample visual space differently and that such differential sampling likely contributes to different functional roles attributed to the ventral and dorsal pathways, such as object recognition and visually guided attention, respectively.
Antagonistic Interactions Between Microsaccades and Evidence Accumulation Processes During Decision Formation
Despite their small size, microsaccades can impede stimulus detections if executed at inopportune times. Although it has been shown that microsaccades evoke both inhibitory and excitatory responses across different visual regions, their impact on the higher-level neural decision processes that bridge sensory responses to action selection has yet to be examined. Here, we show that when human observers monitor stimuli for subtle feature changes, the occurrence of microsaccades long after (up to 800 ms) change onset predicts slower reaction times and this is accounted for by momentary suppression of neural signals at each key stage of decision formation: visual evidence encoding, evidence accumulation, and motor preparation. Our data further reveal that, independent of the timing of the change events, the onset of neural decision formation coincides with a systematic inhibition of microsaccade production, persisting until the perceptual report is executed. Our combined behavioral and neural measures highlight antagonistic interactions between microsaccade occurrence and evidence accumulation during visual decision-making tasks.
SIGNIFICANCE STATEMENT When fixating on a location in space, we frequently make tiny eye movements called microsaccades. In the present study, we show that these microsaccades impede our ability to make perceptual decisions about visual stimuli and this impediment specifically occurs via the disruption of several processing levels of the sensorimotor network: the encoding of visual evidence itself, the accumulation of visual evidence toward a response, and effector-selective motor preparation. Furthermore, we show that the production of microsaccades is inhibited during the perceptual decision, possibly as a counteractive measure to mitigate their negative effect on behavior in this context. The combined behavioral and neural measures used in this study provide strong and novel evidence for the interaction of fixational eye movements and the perceptual decision-making process.
Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis
Loss-of-function mutations in progranulin, a lysosomal glycoprotein, cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency causes CLN11 neuronal ceroid lipofuscinosis (NCL). Progranulin replacement is a rational therapeutic strategy for these disorders, but there are critical unresolved mechanistic questions about a progranulin gene therapy approach, including its potential to reverse existing pathology. Here, we address these issues using an AAV vector (AAV-Grn) to deliver progranulin in Grn–/– mice (both male and female), which model aspects of NCL and FTD pathology, developing lysosomal dysfunction, lipofuscinosis, and microgliosis. We first tested whether AAV-Grn could improve preexisting pathology. Even with treatment after onset of pathology, AAV-Grn reduced lipofuscinosis in several brain regions of Grn–/– mice. AAV-Grn also reduced microgliosis in brain regions distant from the injection site. AAV-expressed progranulin was only detected in neurons, not in microglia, indicating that the microglial activation in progranulin deficiency can be improved by targeting neurons and thus may be driven at least in part by neuronal dysfunction. Even areas with sparse transduction and almost undetectable progranulin showed improvement, indicating that low-level replacement may be sufficiently effective. The beneficial effects of AAV-Grn did not require progranulin binding to sortilin. Finally, we tested whether AAV-Grn improved lysosomal function. AAV-derived progranulin was delivered to the lysosome, ameliorated the accumulation of LAMP-1 in Grn–/– mice, and corrected abnormal cathepsin D activity. These data shed light on progranulin biology and support progranulin-boosting therapies for NCL and FTD due to GRN mutations.
SIGNIFICANCE STATEMENT Heterozygous loss-of-function progranulin (GRN) mutations cause frontotemporal dementia (FTD) and homozygous mutations cause neuronal ceroid lipofuscinosis (NCL). Here, we address several mechanistic questions about the potential of progranulin gene therapy for these disorders. GRN mutation carriers with NCL or FTD exhibit lipofuscinosis and Grn–/– mouse models develop a similar pathology. AAV-mediated progranulin delivery reduced lipofuscinosis in Grn–/– mice even after the onset of pathology. AAV delivered progranulin only to neurons, not microglia, but improved microgliosis in several brain regions, indicating cross talk between neuronal and microglial pathology. Its beneficial effects were sortilin independent. AAV-derived progranulin was delivered to lysosomes and corrected lysosomal abnormalities. These data provide in vivo support for the efficacy of progranulin-boosting therapies for FTD and NCL.
Altered Baseline and Nicotine-Mediated Behavioral and Cholinergic Profiles in ChAT-Cre Mouse Lines
The recent development of transgenic rodent lines expressing cre recombinase in a cell-specific manner, along with advances in engineered viral vectors, has permitted in-depth investigations into circuit function. However, emerging evidence has begun to suggest that genetic modifications may introduce unexpected caveats. In the current studies, we sought to extensively characterize male and female mice from both the ChAT(BAC)-Cre mouse line, created with the bacterial artificial chromosome (BAC) method, and ChAT(IRES)-Cre mouse line, generated with the internal ribosome entry site (IRES) method. ChAT(BAC)-Cre transgenic and wild-type mice did not differ in general locomotor behavior, anxiety measures, drug-induced cataplexy, nicotine-mediated hypolocomotion, or operant food training. However, ChAT(BAC)-Cre transgenic mice did exhibit significant deficits in intravenous nicotine self-administration, which paralleled an increase in vesicular acetylcholine transporter and choline acetyltransferase (ChAT) hippocampal expression. For the ChAT(IRES)-Cre line, transgenic mice exhibited deficits in baseline locomotor, nicotine-mediated hypolocomotion, and operant food training compared with wild-type and hemizygous littermates. No differences among ChAT(IRES)-Cre wild-type, hemizygous, and transgenic littermates were found in anxiety measures, drug-induced cataplexy, and nicotine self-administration. Given that increased cre expression was present in the ChAT(IRES)-Cre transgenic mice, as well as a decrease in ChAT expression in the hippocampus, altered neuronal function may underlie behavioral phenotypes. In contrast, ChAT(IRES)-Cre hemizygous mice were more similar to wild-type mice in both protein expression and the majority of behavioral assessments. As such, interpretation of data derived from ChAT-Cre rodents must consider potential limitations dependent on the line and/or genotype used in research investigations.
SIGNIFICANCE STATEMENT Altered baseline and/or nicotine-mediated behavioral profiles were discovered in transgenic mice from the ChAT(BAC)-Cre and ChAT(IRES)-Cre lines. Given that these cre-expressing mice have become increasingly used by the scientific community, either independently with chemicogenetic and optogenetic viral vectors or crossed with other transgenic lines, the current studies highlight important considerations for the interpretation of data from previous and future experimental investigations. Moreover, the current findings detail the behavioral effects of either increased or decreased baseline cholinergic signaling mechanisms on locomotor, anxiety, learning/memory, and intravenous nicotine self-administration behaviors.
Inhalation Frequency Controls Reformatting of Mitral/Tufted Cell Odor Representations in the Olfactory Bulb
In mammals, olfactory sensation depends on inhalation, which controls activation of sensory neurons and temporal patterning of central activity. Odor representations by mitral and tufted (MT) cells, the main output from the olfactory bulb (OB), reflect sensory input as well as excitation and inhibition from OB circuits, which may change as sniff frequency increases. To test the impact of sampling frequency on MT cell odor responses, we obtained whole-cell recordings from MT cells in anesthetized male and female mice while varying inhalation frequency via tracheotomy, allowing comparison of inhalation-linked responses across cells. We characterized frequency effects on MT cell responses during inhalation of air and odorants using inhalation pulses and also "playback" of sniffing recorded from awake mice. Inhalation-linked changes in membrane potential were well predicted across frequency from linear convolution of 1 Hz responses; and, as frequency increased, near-identical temporal responses could emerge from depolarizing, hyperpolarizing, or multiphasic MT responses. However, net excitation was not well predicted from 1 Hz responses and varied substantially across MT cells, with some cells increasing and others decreasing in spike rate. As a result, sustained odorant sampling at higher frequencies led to increasing decorrelation of the MT cell population response pattern over time. Bulk activation of sensory inputs by optogenetic stimulation affected MT cells more uniformly across frequency, suggesting that frequency-dependent decorrelation emerges from odor-specific patterns of activity in the OB network. These results suggest that sampling behavior alone can reformat early sensory representations, possibly to optimize sensory perception during repeated sampling.
SIGNIFICANCE STATEMENT Olfactory sensation in mammals depends on inhalation, which increases in frequency during active sampling of olfactory stimuli. We asked how inhalation frequency can shape the neural coding of odor information by recording from projection neurons of the olfactory bulb while artificially varying odor sampling frequency in the anesthetized mouse. We found that sampling an odor at higher frequencies led to diverse changes in net responsiveness, as measured by action potential output, that were not predicted from low-frequency responses. These changes led to a reorganization of the pattern of neural activity evoked by a given odorant that occurred preferentially during sustained, high-frequency inhalation. These results point to a novel mechanism for modulating early sensory representations solely as a function of sampling behavior.
Prepubertal Development of GABAergic Transmission to Gonadotropin-Releasing Hormone (GnRH) Neurons and Postsynaptic Response Are Altered by Prenatal Androgenization
Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction through pulsatile GnRH release. Women with polycystic ovary syndrome (PCOS) have persistently elevated luteinizing hormone release frequency, reflecting GnRH release; this exacerbates hyperandrogenemia and disrupted reproductive cycles that are characteristic of this disorder. Clinical evidence suggests that neuroendocrine features of PCOS may manifest peripubertally. Adult mice prenatally exposed to androgens (PNA) mimic several reproductive features of PCOS. GnRH neurons from these mice have increased firing activity and receive increased GABAergic transmission, which is excitatory. When changes emerge during development is unknown. To study the typical postnatal development of GABAergic transmission and the effects of PNA treatment and sex, whole-cell voltage-clamp recordings were made of GABAergic postsynaptic currents (PSCs) in GnRH neurons in brain slices from prepubertal through adult control and PNA female and male mice. GABAergic transmission was present by 1 week of age in females and males and increased in frequency, reaching adult levels at 3 and 4 weeks, respectively. GABAergic PSC frequency was elevated in 3-week-old PNA versus control females. PSC frequency in both controls and PNA mice was activity independent, suggesting that PNA induces changes in synapse organization. PNA also alters the functional response of GnRH neurons to GABA. GABA induced firing in fewer neurons from 3-week-old PNA than control females; membrane potential depolarization induced by GABA was also reduced in cells from PNA mice at this age. PNA thus induces changes during development in the presynaptic organization of the GABAergic network afferent to GnRH neurons as well as the postsynaptic GnRH neuron response, both of which may contribute to adult reproductive dysfunction.
SIGNIFICANCE STATEMENT The central neuronal network that regulates reproduction is overactive in polycystic ovary syndrome (PCOS), a leading cause of infertility. Recent evidence of neuroendocrine dysfunction in midpubertal girls suggests that the pathophysiological mechanisms underlying PCOS may arise before pubertal maturation. Prenatal exposure to androgens (PNA) in mice mimics several neuroendocrine features of PCOS. GABAergic transmission to gonadotropin-releasing hormone (GnRH) neurons is important for reproduction and is increased in adult PNA mice. The typical development of this network and when changes with PNA and sex arise relative to puberty are unknown. These studies provide evidence that PNA alters prepubertal development of the GABAergic network afferent to GnRH neurons, including both the presynaptic organization and postsynaptic response. These changes may contribute to reproductive dysfunction in adults.
A Unique Homeostatic Signaling Pathway Links Synaptic Inactivity to Postsynaptic mTORC1
mTORC1-dependent translational control plays a key role in several enduring forms of synaptic plasticity such as long term potentiation (LTP) and mGluR-dependent long term depression. Recent evidence demonstrates an additional role in regulating synaptic homeostasis in response to inactivity, where dendritic mTORC1 serves to modulate presynaptic function via retrograde signaling. Presently, it is unclear whether LTP and homeostatic plasticity use a common route to mTORC1-dependent signaling or whether each engage mTORC1 through distinct pathways. Here, we report a unique signaling pathway that specifically couples homeostatic signaling to postsynaptic mTORC1 after loss of excitatory synaptic input. We find that AMPAR blockade, but not LTP-inducing stimulation, induces phospholipase D (PLD)-dependent synthesis of the lipid second messenger phosphatidic acid (PA) in rat cultured hippocampal neurons of either sex. Pharmacological blockade of PLD1/2 or pharmacogenetic disruption of PA interactions with mTOR eliminates mTORC1 signaling and presynaptic compensation driven by AMPAR blockade, but does not alter mTORC1 activation or functional changes during chemical LTP (cLTP). Overexpression of PLD1, but not PLD2, recapitulates both functional synaptic changes as well as signature cellular adaptations associated with homeostatic plasticity. Finally, transient application of exogenous PA is sufficient to drive rapid presynaptic compensation requiring mTORC1-dependent translation of BDNF in the postsynaptic compartment. These results thus define a unique homeostatic signaling pathway coupling mTORC1 activation to changes in excitatory synaptic drive. Our results further imply that more than one canonical mTORC1 activation pathway may be relevant for the design of novel therapeutic approaches against neurodevelopmental disorders associated with mTORC1 dysregulation.
SIGNIFICANCE STATEMENT Homeostatic and Hebbian forms of synaptic plasticity are thought to play complementary roles in regulating neural circuit function, but we know little about how these forms of plasticity are distinguished at the single neuron level. Here, we define a signaling pathway that uniquely links mTORC1 with homeostatic signaling in neurons.
Timescales of Intrinsic BOLD Signal Dynamics and Functional Connectivity in Pharmacologic and Neuropathologic States of Unconsciousness
Environmental events are processed on multiple timescales via hierarchical organization of temporal receptive windows (TRWs) in the brain. The dependence of neural timescales and TRWs on altered states of consciousness is unclear. States of reduced consciousness are marked by a shift toward slowing of neural dynamics (<1 Hz) in EEG/ECoG signals. We hypothesize that such prolongation of intrinsic timescales are also seen in blood-oxygen-level-dependent (BOLD) signals. To test this hypothesis, we measured the timescales of intrinsic BOLD signals using mean frequency (MF) and temporal autocorrelation (AC) in healthy volunteers (n = 23; male/female 14/9) during graded sedation with propofol. We further examined the relationship between the intrinsic timescales (local/voxel level) and its regional connectivity (across neighboring voxels; regional homogeneity, ReHo), global (whole-brain level) functional connectivity (GFC), and topographical similarity (Topo). Additional results were obtained from patients undergoing deep general anesthesia (n = 12; male/female: 5/7) and in patients with disorders of consciousness (DOC) (n = 21; male/female: 14/7). We found that MF, AC, and ReHo increased, whereas GFC and Topo decreased, during propofol sedation. The local alterations occur before changes of distant connectivity. Conversely, all of these parameters decreased in deep anesthesia and in patients with DOC. We conclude that propofol synchronizes local neuronal interactions and prolongs the timescales of intrinsic BOLD signals. These effects may impede communication among distant brain regions. Furthermore, the intrinsic timescales exhibit distinct dynamic signatures in sedation, deep anesthesia, and DOC. These results improve our understanding of the neural mechanisms of unconsciousness in pharmacologic and neuropathologic states.
SIGNIFICANCE STATEMENT Information processing in the brain occurs through a hierarchy of temporal receptive windows (TRWs) in multiple timescales. Anesthetic drugs induce a reversible suppression of consciousness and thus offer a unique opportunity to investigate the state dependence of neural timescales. Here, we demonstrate for the first time that sedation with propofol is accompanied by the prolongation of the timescales of intrinsic BOLD signals presumably reflecting enlarged TRWs. We show that this is accomplished by an increase of local and regional signal synchronization, effects that may disrupt information exchange among distant brain regions. Furthermore, we show that the timescales of intrinsic BOLD signals exhibit distinct dynamic signatures in sedation, deep anesthesia, and disorders of consciousness.
Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals
Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague Dawley rats, the effect of local administration of agents that reverse type I (protein translation) or type II [combination of Src and mitogen-activated protein kinase (MAPK)] priming. At the central terminal, priming induced by systemic, intradermal, or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, but at the peripheral terminal, it was reversed by the protein translation inhibitor. Mu-opioid receptor (MOR) antisense prevented fentanyl hyperalgesia and priming. To determine whether type I and II priming occur in the same population of neurons, we used isolectin B4–saporin or [Sar9, Met(O2)11]-substance P–saporin to deplete nonpeptidergic or peptidergic nociceptors, respectively. Following intrathecal fentanyl, central terminal priming was prevented by both saporins, whereas that in peripheral terminal was not attenuated even by their combination. However, after intradermal fentanyl, priming in the peripheral terminal requires both peptidergic and nonpeptidergic nociceptors, whereas that in the central terminal is dependent only on peptidergic nociceptors. Pretreatment with dantrolene at either terminal prevented fentanyl-induced priming in both terminals, suggesting communication between central and peripheral terminals mediated by intracellular Ca2+ signaling. In vitro application of fentanyl increased cytoplasmic Ca2+ concentration in dorsal root ganglion neurons, which was prevented by pretreatment with dantrolene and naloxone. Therefore, acting at MOR in the nociceptor, fentanyl induces hyperalgesia and priming rapidly at both the central (type II) and peripheral (type I) terminal and this is mediated by Ca2+ signaling.
SIGNIFICANCE STATEMENT Fentanyl, acting at the μ-opioid receptor (MOR), induces hyperalgesia and hyperalgesic priming at both the central and peripheral terminal of nociceptors and this is mediated by endoplasmic reticulum Ca2+ signaling. Priming in the central terminal is type II, whereas that in the peripheral terminal is type I. Our findings may provide useful information for the design of drugs with improved therapeutic profiles, selectively disrupting individual MOR signaling pathways, to maintain an adequate long-lasting control of pain.
Corticosterone Production during Repeated Social Defeat Causes Monocyte Mobilization from the Bone Marrow, Glucocorticoid Resistance, and Neurovascular Adhesion Molecule Expression
Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged anxiety-like behavior. Physiological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57BL/6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress-induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule intercellular cell adhesion molecule-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression.
SIGNIFICANCE STATEMENT Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune, and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress.
Notch Suppression Collaborates with Ascl1 and Lin28 to Unleash a Regenerative Response in Fish Retina, But Not in Mice
Müller glial (MG) cells in the zebrafish retina respond to injury by acquiring retinal stem-cell characteristics. Thousands of gene expression changes are associated with this event. Key among these changes is the induction of Ascl1a and Lin28a, two reprogramming factors whose expression is necessary for retina regeneration. Whether these factors are sufficient to drive MG proliferation and subsequent neuronal-fate specification remains unknown. To test this, we conditionally expressed Ascl1a and Lin28a in the uninjured retina of male and female fish. We found that together, their forced expression only stimulates sparse MG proliferation. However, in combination with Notch signaling inhibition, widespread MG proliferation and neuron regeneration ensued. Remarkably, Ascl1 and Lin28a expression in the retina of male and female mice also stimulated sparse MG proliferation, although this was not enhanced when combined with inhibitors of Notch signaling. Lineage tracing in both fish and mice suggested that the proliferating MG generated multipotent progenitors; however, this process was much more efficient in fish than mice. Overall, our studies suggest that the overexpression of Ascl1a and Lin28a in zebrafish, in combination with inhibition of Notch signaling, can phenocopy the effects of retinal injury in Müller glia. Interestingly, Ascl1 and Lin28a seem to have similar effects in fish and mice, whereas Notch signaling may differ. Understanding the different consequences of Notch signaling inhibition in fish and mice, may suggest additional strategies for enhancing retina regeneration in mammals.
SIGNIFICANCE STATEMENT Mechanisms underlying retina regeneration in fish may suggest strategies for stimulating this process in mammals. Here we report that forced expression of Ascl1 and Lin28a can stimulate sparse MG proliferation in fish and mice; however, only in fish does Notch signaling inhibition collaborate with Ascl1a and Lin28a to stimulate widespread MG proliferation in the uninjured retina. Discerning differences in Notch signaling between fish and mice MG may reveal strategies for stimulating retina regeneration in mammals.
Age-Dependent Decline in Fate Switch from NG2 Cells to Astrocytes After Olig2 Deletion
NG2 cells are a resident glial progenitor cell population that is uniformly distributed throughout the developing and mature mammalian CNS. Those in the postnatal CNS generate exclusively myelinating and non-myelinating oligodendrocytes and are thus equated with oligodendrocyte precursor cells. Prenatally, NG2 cells in the ventral gray matter of the forebrain generate protoplasmic astrocytes as well as oligodendrocytes. The fate conversion from NG2 cells into protoplasmic astrocytes is dependent on downregulation of the key oligodendrocyte transcription factor Olig2. We showed previously that constitutive deletion of Olig2 in NG2 cells converts NG2 cells in the neocortex into protoplasmic astrocytes at the expense of oligodendrocytes. In this study, we show that postnatal deletion of Olig2 caused NG2 cells in the neocortex but not in other gray matter regions to become protoplasmic astrocytes. However, NG2 cells in the neocortex became more resistant to astrocyte fate switch over the first 3 postnatal weeks. Fewer NG2 cells differentiated into astrocytes and did so with longer latency after Olig2 deletion at postnatal day 18 (P18) compared with deletion at P2. The high-mobility group transcription factor Sox10 was not downregulated for at least 1 month after Olig2 deletion at P18 despite an early transient upregulation of the astrocyte transcription factor NFIA. Furthermore, inhibiting cell proliferation in slice culture reduced astrocyte differentiation from Olig2-deleted perinatal NG2 cells, suggesting that cell division might facilitate nuclear reorganization needed for astrocyte transformation.
SIGNIFICANCE STATEMENT NG2 cells are glial progenitor cells that retain a certain degree of lineage plasticity. In the normal postnatal neocortex, they generate mostly oligodendrocyte lineage cells. When the oligodendrocyte transcription factor Olig2 is deleted in NG2 cells in the neocortex, they switch their fate to protoplasmic astrocytes. However, the efficiency of the fate switch decreases with age over the first 3 postnatal weeks and is reduced when cell proliferation is inhibited. As the neocortex matures, sustained expression of the oligodendrocyte lineage-specific key transcription factor Sox10 becomes less dependent on Olig2. Together, our findings suggest a gradual stabilization of the oligodendrocyte lineage genes and loss of lineage plasticity during the first 3 weeks after birth, possibly due to nuclear reorganization.
A Collaborator's Reputation Can Bias Decisions and Anxiety under Uncertainty
Informational social influence theory posits that under conditions of uncertainty, we are inclined to look to others for advice. This leaves us remarkably vulnerable to being influenced by others' opinions or advice. Rational agents, however, do not blindly seek and act on arbitrary information, but often consider the quality of its source before committing to a course of action. Here, we ask the question of whether a collaborator's reputation can increase their social influence and, in turn, bias perception and anxiety under changing levels of uncertainty. Human male and female participants were asked to provide estimations of dot direction using the random dot motion (RDM) perceptual discrimination task and were paired with transient collaborators of high or low reputation whom provided their own estimations. The RDM varied in degrees of uncertainty and joint performance accuracy was linked to risk of an electric shock. Despite providing identical information, we show that collaborating with a high reputation compared with a low reputation partner, led to significantly more conformity during the RDM task for uncertain perceptual decisions. Consequently, high reputation partners decreased the subjects' anxiety during the anticipatory shock periods. fMRI data showed that parametric changes in conformity resulted in increased activity in the ventromedial PFC, whereas dissent was associated with increased in activity in the dorsal anterior cingulate cortex (dACC). Furthermore, the dACC and insula, regions involved in anticipatory pain, were significantly more active when collaborating with a low reputation partner. These results suggest that information about reputation can influence both cognitive and affective processes and in turn alter the neural circuits that underlie decision-making and emotion.
SIGNIFICANCE STATEMENT Humans look to others for advice when making decisions under uncertainty. Rational agents, however, do not blindly seek information, but often consider the quality of its source before committing to a course of action. Here, we ask the question of whether a collaborators' reputation can increase social influence and in turn bias perception and anxiety in the context of perceptual uncertainty. We show that when subjects are partnered with collaborators with a high reputation, this leads to increased conformity during uncertain perceptual decision-making and reduces anxiety when joint performance accuracy leads to an electric shock. Furthermore, our results show that information about reputation alters the neural circuits that underlie decision-making and emotion.
Exploring the in situ expression of vascular endothelial growth factor and endoglin in pemphigus foliaceus variants and pemphigus vulgaris
Abstract
Background
Erythroderma is a severe manifestation of pemphigus foliaceus (PF), a blistering disease mediated by IgG autoantibodies against desmoglein-1. Increasing evidence supports the contribution of angiogenic mediators in the pathogenesis of erythroderma.
Objective
To evaluate the in situ expression of vascular endothelial growth factor (VEGF) and endoglin in PF patients with erythroderma.
Methods
Formalin-fixed paraffin-embedded skin samples obtained from patients with erythrodermic PF (n=19; 12 patients with endemic PF), non-erythrodermic PF (n=17), pemphigus vulgaris (PV; n=10), psoriasis (n=10), and healthy individuals (HI; n=10) were processed in an automated immunohistochemistry platform utilizing anti-VEGF and anti-endoglin as primary antibodies. Reactivity was evaluated both manually (0=negative; 1+=mild; 2+=intense) and through an automated microvessel analysis algorithm.
Results
VEGF expression in erythrodermic PF was higher than in non-erythrodermic PF (p=0.034) and in HI (p=0.004), and similar to psoriasis (p=0.667) and PV (p=0.667). In non-erythrodermic PF, VEGF positivity was similar to HI (p=0.247), and lower than psoriasis (p=0.049) and PV (p=0.049). Both erythrodermic and non-erythrodermic PF presented similar endoglin expression (p=0.700). In addition, endoglin positivity during erythrodermic PF was similar to psoriasis (p=0.133) and lower than PV (p=0.0009). Increased expression of in situ VEGF suggests that healing processes are triggered in response to tissue damage led by autoantibodies in PF, especially during erythroderma. Reduced endoglin positivity suggests that an unbalanced angiogenesis may occur during erythrodermic PF. Further studies may help to confirm if the regulation of VEGF and endoglin expression in patients with PF can contribute to control the healing process and enable disease remission.
Conclusion
Overexpression of VEGF in erythrodermic PF as well as in PV and psoriasis points out a dysregulated repair process in severe forms of these diseases, and suggests VEGF and endoglin could act as prognostic markers and future therapeutic targets to enable proper healing in PF.
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Reply to Happle R. And al. Koebner's sheep in Wolf's clothing: does the isotopic response exist as a distinct phenomenon?
Abstract
We read with interest the issues raised by Happle and Kluger. The Koebner phenomenon is well-established and the number of diseases apparently showing this phenomenon has grown so much that a classification of subtypes exists. The concept of locus minoris resistentiae (lmr), which helps us explain why certain disorders occur in certain locations, appears to underlie both Koebner phenomenon and Wolf isotopic response. The isotopic response was initially defined as "the occurrence of a new disorder at the site of another, unrelated and already healed skin disease". Wolf himself cited lmr as a putative explanation for the occurrence of the isotopic response. Certain questions arise from the initial definition by Wolf and the ever growing extensions of the isotopic response we see today.
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Answer to Nwabudike LC and al. Koebner's sheep in Wolf's clothing: does the isotopic response exist as a distinct phenomenon?
Abstract
We thank Dr. Nwabudike for his interest in our article. We fully agree with him that the "isotopic response" is merely a variant of Koebner reaction. In fact, all forms of Koebner reaction can be taken as variants from each other.
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Hereditary palmoplantar keratodermas. Part I. Non-syndromic palmoplantar keratodermas: classification, clinical and genetic features
Abstract
The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the epidermis of palms and soles, and includes genetic as well as acquired conditions. We review the nosology of hereditary PPKs that comprise an increasing number of entities with different prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be divided into: i. non-syndromic, isolated PPKs, which are characterized by a unique or predominant palmoplantar involvement; ii. non-syndromic PPKs with additional distinctive cutaneous and adnexal manifestations, here named complex PPKs; iii. syndromic PPKs, in which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis of the different hereditary PPKs is based mainly on clinical history and features combined with histopathological findings. In recent years, the exponentially increasing use of next generation sequencing technologies has led to the identification of several novel disease genes, and thus substantially contributed to elucidate the molecular basis of such a heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where other well-defined genetic diseases, which may present PPK among their phenotypic manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are summarized.
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The depth of follicular extension in actinic keratosis correlates with the depth of invasion in squamous cell carcinoma: implication for clinical treatment
Abstract
Background
Actinic keratosis (AK) may show extension down follicules, not only in cases with full-thickness epidermal atypia ("bowenoid" AK), but also in cases with atypia limited to the epidermal basalis. Previous studies have demonstrated that in bowenoid AK, follicular extension is usually superficial, being limited to the upper follicular segment. Little is known about the depth of follicular involvement in cases of iSCC arising from AK and the role of the follicle in iSCC pathogenesis.
Objective
This study investigated the relationship between follicular extension of atypical keratinocytes in an AK and the development of iSCC from the follicular wall. The depth of follicular extension was correlated with the depth invasion of iSCC. Differences between the differentiated and classical pathways of iSCC were also examined.
Methods
We performed a retrospective histologic review of 193 biopsy specimens of iSCC with an associated AK. We assessed the presence and depth of follicular extension of atypical keratinocytes in the AK, using tumor (Breslow) thickness and the follicular unit level (infundibular, isthmic and sub-isthmic), as well as iSCC being present directly adjacent to the follicular basalis.
Results
Follicular extension was present in 25.9% of the cases (50 cases), usually extending into the lower follicular segment. The iSCC was present directly adjacent to the follicular basalis in 58% of the cases (29 cases), correlating highly with the depth of follicular extension (infundibular: 3/12; isthmic: 21/33; sub-isthmic 5/5).
Conclusion
The depth of follicular extension of atypical keratinocytes in an AK correlates with the development of depth of invasion of an associated iSCC, irrespective of the pathway of origin. It is therefore important to note the presence and the depth of follicular extension when diagnosing an AK, since follicular extension likely accounts for a significant proportion of recurrent AK and the development of iSCC following superficial treatment modalities.
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Orthotopic transfer of vascularized groin lymph node flap in the treatment of breast cancer-related lymphedema: clinical results, lymphoscintigraphy findings and proposed mechanism
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Hin-Lun Liu, Suet-Ying Pang, Chung-Ching Lee, Melody Man-Kuen Wong, Hon-Ping Chung, Yu-Wai Chan
IntroductionVascularized lymph node transfer (VLNT) has become more popular in treating secondary lymphedema. However, the mechanism has not been clearly elucidated.The purpose of this study were (1) to evaluate the outcome of vascularized groin lymph node (VGLN) transfer using axilla as a recipient site in patients with breast cancer-related lymphedema (BCRL) and (2) to provide radiological evidence of lymphangiogenesis in VLNT.MethodsBetween August 2013 and June 2016, 30 consecutive patients with a mean age of 60 years underwent VGLN transfer for BCRL. A skinless VGLN flap nourished by the superficial circumflex iliac vessels was transferred to the axillary region of lymphedematous limb. The outcomes were assessed clinically with limb circumference measurement and radiologically with lymphoscintigraphy.ResultsAt a mean follow-up of 22.11 ± 7.83 months, 21 (70%) patients had reduction in limb circumference. The mean circumference reduction rate of the lymphedematous limb was 47.06 ± 27.92% (range, 0 to 100%).Eleven (37%) patients showed radiological improvement in post-operative lymphoscintigraphy that included 7 cases of faster contrast transport and 4 cases of visualization of transplanted lymph node.ConclusionPatients with BCRL can benefit from orthotopic VGLN transfer. Lymphangiogenesis is supported by the visualization of transplanted lymph node in post-operative lymphoscintigraphy.
Morphological changes of hair melanosomes by aging
Summary
Various changes appear in hair by aging and graying is the most remarkable one. Changes in melanocytes have been well studied as the cause, however, little is known about the change of melanosomes which have a role of carrying melanin pigments into hair shafts. Using pigmented hairs of Japanese females from their age of 4 to 75, I isolated melanosomes and observed them. As a result, I found a significant change in the morphology of hair melanosomes with age. They were ellipsoidal on the whole and there was no age dependence in the major axis, while the minor axis significantly increased and its frequency distribution broadened with age. The anticipated volume of the melanosome of the oldest person hairs was about twice larger than that of child hairs. This enlargement of melanosome seems to be a cause of the age-related color change of pigmented hairs from brown to black.
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“This Is a White Space”: On Restorative Possibilities of Hospitality in a Raced Space
Abstract
In a restorative classroom inspired by a vision of racial equity, race consciousness is a necessity and a restorative outcome is conceptualized in terms of a sustainable interdependent right-relation, a species of racial justice. Yet, regardless of intent, the constructed space is white. Race-based inequity is reproduced as White students get more of everything from class than do students of Color. What made the space white? How might hospitality affect the restorative possibilities of and in the space? I explore these questions and reconceptualize right-relation as that which necessitates hospitality.
Source apportionments of PM 2.5 organic carbon during the elevated pollution episodes in the Ordos region, Inner Mongolia, China
Abstract
The Ordos region in the southwestern part of Inner Mongolia experiences frequent PM concentrations in excess of the national PM2.5 air quality standards. In order to determine the key sources of PM2.5 contributing to these pollution episodes, the main sources of PM2.5 OC during elevated PM episodes in the Inner Mongolia were analyzed and compared with non-polluted days. This will provide insight to the main sources of particulate matter pollution during the high-pollution episodes and the effective seasonal strategies to control sources of particulate matter during months and with the highest PM concentrations that need to be controlled. The PMF source contributions to OC demonstrated that the industrial/coal combustion (4762.77 ± 1061.54 versus 2726.49 ± 469.75 ng/m3; p < 0.001) and mobile source factors (4651.14 ± 681.82 versus 2605.55 ± 276.50 ng/m3; p value < 0.001) showed greater contributions to the elevated concentrations during the episode. The spatial analysis of secondary organic carbon (SOC) factors, regional biomass burning, and biogenic sources did not show significant difference in the pollution episodes and the non-polluted months. In addition, the bivariate polar plots and CWT maps of the industrial/coal combustion and mobile illustrated a regional long-range transport patterns from the external sources to the study area, however, adjacent areas were mostly controlling the contributions of these factors during the PM elevated episodes. The SOC sources, regional biomass burning, and biogenic sources illustrated a regional long-range transport with similar locations found during the elevated pollution episodes compared to the normal situations.
Evaluating gas chromatography with a halogen-specific detector for the determination of disinfection by-products in drinking water
Abstract
The occurrence of disinfection by-products (DBPs) in drinking water has become an issue of concern during the past decades. The DBPs pose health risks and are suspected to cause various cancer forms, be genotoxic, and have negative developmental effects. The vast chemical diversity of DBPs makes comprehensive monitoring challenging. Only few of the DBPs are regulated and included in analytical protocols. In this study, a method for simultaneous measurement of 20 DBPs from five different structural classes (both regulated and non-regulated) was investigated and further developed for 11 DBPs using solid-phase extraction and gas chromatography coupled with a halogen-specific detector (XSD). The XSD was highly selective towards halogenated DBPs, providing chromatograms with little noise. The method allowed detection down to 0.05 μg L−1 and showed promising results for the simultaneous determination of a range of neutral DBP classes. Compounds from two classes of emerging DBPs, more cytotoxic than the "traditional" regulated DBPs, were successfully determined using this method. However, haloacetic acids (HAAs) should be analyzed separately as some HAA methyl esters may degrade giving false positives of trihalomethanes (THMs). The method was tested on real water samples from two municipal waterworks where the target DBP concentrations were found below the regulatory limits of Sweden.
Enhanced algae removal by Ti-based coagulant: comparison with conventional Al- and Fe-based coagulants
Abstract
The water eutrophication caused by cyanobacteria seasonally proliferates, which is a hot potato to be resolved for water treatment plants. This study firstly investigated coagulation performance of titanium tetrachloride (TiCl4) for Microcystis aeruginosa synthetic water treatment. Results show complete algal cell removal by TiCl4 coagulation without damage to cell membrane integrity even under harsh conditions; 60 mg/L TiCl4 was effective in removing the microcystins up to 85%. Furthermore, besides having stronger UV254 removal capability and the higher removal of fluorescent substances over Al- and Fe-based coagulants, TiCl4 coagulant required more compact coagulation and sedimentation tanks due to its significantly improved floc growth and sedimentation speed. Meanwhile, its' short hydraulic retention time avoided algal cell breakage and subsequent algal organic matter release. Microcystin concentrations were kept at a low level during sludge storage period, indicating that the TiCl4 flocs could prevent algal cells from natural lysis. To facilitate water recycling without secondary contamination, the algae-containing sludge after TiCl4 coagulation ought to be disposed within 12 days at 20 °C and 8 days at 35 °C.
Anoxic conditions are beneficial for abiotic diclofenac removal from water with manganese oxide (MnO 2 )
Abstract
This is the first study examining pharmaceutical removal under anoxic conditions with MnO2. This study compares the abiotic removal of seven pharmaceuticals with reactive MnO2 particles in the presence of oxygen (oxic conditions) and in the absence of oxygen (anoxic conditions). Due to the novelty of pharmaceutical removal under anoxic conditions, the influence of phosphate buffer, pH, and MnO2 morphologies is also examined. Results show that over 90% of diclofenac is removed under anoxic conditions. Additionally, we found that (1) anoxic conditions are beneficial for diclofenac removal with MnO2, (2) phosphate buffer affects the pharmaceutical removal efficiencies, (3) higher pharmaceutical removal is obtained at acidic pH compared to that at neutral or alkaline conditions, and (4) amorphous MnO2 removes pharmaceuticals better than crystalline MnO2. The pharmaceutical molecular structure and properties, MnO2 properties especially reactive sites of the MnO2 surface, are important for degradation kinetics. This study provides a fundamental basis towards understanding pharmaceutical degradation with MnO2 under anoxic conditions, and development of a cost-effective, sustainable technology for removal of pharmaceuticals from water.
Impact of Previous Biologic Use on Efficacy and Safety of Brodalumab and Ustekinumab in Patients with Moderate-to-Severe Plaque Psoriasis: Integrated Analysis of AMAGINE-2 and AMAGINE-3
Abstract
Background
Biologics used increasingly used for treating moderate-to-severe psoriasis. Efficacy may differ in patients with previous biologics exposure.
Objective
To investigate the impact of previous biologic exposure on efficacy and safety of brodalumab and ustekinumab in moderate-to-severe plaque psoriasis.
Methods
Two placebo- and ustekinumab-controlled phase 3 clinical trials. Initial 12-week induction phase where patients were treated with brodalumab (210mg Q2W or 140mg Q2W), ustekinumab or placebo. Efficacy endpoints included: Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment (sPGA 0/1) versus placebo, PASI 100 versus ustekinumab, Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Inventory (PSI). Adverse events were monitored throughout.
Results
493 patients (334 [27%] brodalumab 210 mg Q2W and 159 [26%] ustekinumab) received prior biologics exposure; 150 (12%) and 62 (10%) reporting previously failed biologic. Brodalumab efficacy in patients with or without previous biologics exposure was statistically equivalent; 40.9% and 39.5% of bio-naïve and -experienced patients achieved PASI 100 at Week 12, compared with 21.1% and 17.0% with ustekinumab (both P<0.001). In patients where prior biologics had been successful or failed, 41.7% and 32.0% achieved PASI 100, compared with 21.1% and 11.3% with ustekinumab. Tolerability was similar, and did not appear to be influenced by previous biologic treatment.
Conclusions
Efficacy of brodalumab 210 mg Q2W was similar regardless of prior biologic therapy (P=0.31, 0.32 and 0.64 for PASI 75, 90, and 100 respectively). Almost twice as many patients achieved PASI 100 or complete clearance at Week 12 compared with ustekinumab; differences most noticeable where previous biologics had failed. Both treatments were well tolerated.
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Publication date: Available online 28 September 2017 Source: Actas Dermo-Sifiliográficas Author(s): F.J. Navarro-Triviño
