Applicability of Kd for modelling dissolved 137Cs concentrations in Fukushima river water: Case study of the upstream Ota River

Publication date: April 2018
Source:Journal of Environmental Radioactivity, Volumes 184–185
Author(s): Kazuyuki Sakuma, Hideki Tsuji, Seiji Hayashi, Hironori Funaki, Alex Malins, Kazuya Yoshimura, Hiroshi Kurikami, Akihiro Kitamura, Kazuki Iijima, Masaaki Hosomi
A study is presented on the applicability of the distribution coefficient (Kd) absorption/desorption model to simulate dissolved ¹³⁷Cs concentrations in Fukushima river water. The upstream Ota River basin was simulated using GEneral-purpose Terrestrial Fluid-flow Simulator (GETFLOWS) for the period 1 January 2014 to 31 December 2015. Good agreement was obtained between the simulations and observations on water and suspended sediment fluxes, and on particulate bound ¹³⁷Cs concentrations under both base and high flow conditions. By contrast the measured concentrations of dissolved ¹³⁷Cs in the river water were much harder to reproduce with the simulations. By tuning the Kd values for large particles, it was possible to reproduce the mean dissolved ¹³⁷Cs concentrations during base flow periods (observation: 0.32 Bq/L, simulation: 0.36 Bq/L). However neither the seasonal variability in the base flow dissolved ¹³⁷Cs concentrations (0.14–0.53 Bq/L), nor the peaks in concentration that occurred during storms (0.18–0.88 Bq/L, mean: 0.55 Bq/L), could be reproduced with realistic simulation parameters. These discrepancies may be explained by microbial action and leaching from organic matter in forest litter providing an additional input of dissolved ¹³⁷Cs to rivers, particularly over summer, and limitations of the Kd absorption/desorption model. It is recommended that future studies investigate these issues in order to improve simulations of dissolved ¹³⁷Cs concentrations in Fukushima rivers.



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Monitoring of soil radon by SSNTD in Eastern India in search of possible earthquake precursor

Publication date: April 2018
Source:Journal of Environmental Radioactivity, Volumes 184–185
Author(s): Argha Deb, Mahasin Gazi, Jayita Ghosh, Saheli Chowdhury, Chiranjib Barman
The present paper deals with monitoring soil radon-222 concentration at two different locations, designated Site A and Site B, 200 m apart at Jadavpur University campus, Kolkata, India, with a view to find possible precursors for the earthquakes that occurred within a few hundred kilometers from the monitoring site. The solid state nuclear track detector CR-39 has been used for detection of radon gas coming out from soil. Radon-222 time series at both locations during the period August 2012–December 2013 have been analysed. Distinct anomalies in the soil radon time series have been observed for seven earthquakes of magnitude greater than 4.0 M that occurred during this time. Of these, radon anomalies for two earthquakes have been observed at both locations A and B. Absence of anomalies for some other earthquakes has been discussed, and the observations have been compared with some earthquake precursor models.



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Volumetric assessment of tumor size changes in pediatric low-grade gliomas: feasibility and comparison with linear measurements

Abstract

Purpose

We report a retrospective comparison between bi-dimensional RANO criteria and manual volumetric segmentation (MVS) in pediatric low-grade gliomas.

Methods

MRI FLAIR or T1 post contrast images were used for assessment of tumor response. Seventy patients were included in this single center study, for each patient two scans were assessed ("time 0" and "end of therapy") and response to therapy was evaluated for both methods. Inter-reader variability and average time for volumetric assessment were also calculated.

Results

Fourteen (20%) of the 70 patients had discordant results in terms of response assessment between the bi-dimensional measurements and MVS. All volumetric response assessments were in keeping with the subjective analysis of tumor (radiology report). Of the 14 patients, 6 had stable disease (SD) on MVS and progressive disease (PD) on 2D assessment, 5 patients had SD on MVS and partial response (PR) on 2D assessment, 2 patients had PD on MVS and SD on 2D assessment, and 1 patient had PR on MVS and SD on 2D analysis. The number of discordant results rises to 21(30%) if minor response is integrated in the response assessment. MVS was relatively fast and showed high inter-reader concordance.

Conclusion

Our analysis shows that therapeutic response classification may change in a significant number of children by performing a volumetric tumor assessment. Furthermore, MVS is not particularly time consuming and has very good inter-reader concordance.

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Age-related early/late variations of functional connectivity across the human lifespan

Abstract

Purpose

Many questions remain regarding how the brain develops, matures, and ages across the lifespan. The functional connectivity networks in the resting-state brain can reflect many of the characteristic changes in the brain that are associated with increasing age. Functional connectivity has been shown to be time-dependent over the course of a lifespan and even over the course of minutes. The lifespan strategies of all cognitive networks and how dynamic functional connectivity is associated with age are unclear.

Methods

In this paper, studies employing both linear and quadratic models to define new specific lifespan strategies, including early/late increase/decrease models, were conducted to explore the lifespan functional changes. A large data sample was retrieved from the publicly available data from the Nathan Kline Institute (N = 149 and ages 9–85). Both static and dynamic functional connectivity indexes were calculated including the static functional connectivity, the mean of the dynamic functional connectivity and variations in dynamic functional connectivity.

Results

The between-network connectivity results revealed early increases in the default-mode (DF) and cingulo-opercular network (CO)-associated network connectivities and a late increase in the fronto-parietal (FP)-associated network connectivity. These results depicted various lifespan strategies for different development stages and different cognitive networks across the lifespan. Additionally, the static FC and mean dynamic FC exhibited consistent results, and their variation exhibited a constant decrease with age across the entire age range.

Conclusion

These results (FDR-corrected p value < 0.05) suggest that the early/late variations in lifespan strategies could reflect an association between varied and complex circumstances and brain development.

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Thoracic Imaging of Solid Tumor Patients Treated with Immune Checkpoint Inhibitors

Abstract

Purpose of Review

Immune checkpoint inhibitors harness the patient's own immune system to fight cancer. They are now approved for treating a number of solid malignancies, with more agents and indications expected in the coming months and years. Because of their unique mechanism of action, these agents may lead to unusual imaging appearances.

Recent Findings

Rare patients may experience pseudoprogression, whereby tumors may initially increase in size or number despite response to therapy. Many patients will experience autoimmune side effects including pneumonitis, which may lead to respiratory compromise and will necessitate cessation of therapy. Occasionally pneumonitis or a sarcoid-like reaction can mimic metastatic disease.

Summary

It is imperative that radiologists be aware of these unusual imaging manifestations in patients on immunotherapy so that they are able to assist oncologists in appropriately treating these patients. In particular, we urge caution in interpreting new or enlarging lesions, since these may not always mean progression of disease. Additionally, radiologists should look out for potential immune-related side effects of these therapies.

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What Happens after a Diagnosis of High-Risk Breast Lesion at Stereotactic Vacuum-assisted Biopsy? An Observational Study of Postdiagnosis Management and Imaging Adherence.

What Happens after a Diagnosis of High-Risk Breast Lesion at Stereotactic Vacuum-assisted Biopsy? An Observational Study of Postdiagnosis Management and Imaging Adherence.

Radiology. 2018 Jan 29;:171665

Authors: Gao Y, Albert M, Young Lin LL, Lewin AA, Babb JS, Heller SL, Moy L

Abstract
Purpose To assess adherence with annual or biennial screening mammography after a diagnosis of high-risk lesion(s) at stereotactic biopsy with or without surgical excision and to identify clinical factors that may affect screening adherence after a high-risk diagnosis. Materials and Methods This institutional review board-approved HIPAA-compliant retrospective study included 208 patients who underwent stereotactic biopsy between January 2012 and December 2014 that revealed a high-risk lesion. Whether the patient underwent surgical excision and/or follow-up mammography was documented. Adherence of these women to a protocol of subsequent mammography within 1 year (9-18 months) or within 2 years (9-30 months) was compared with that of 45 508 women with normal screening mammograms who were imaged during the same time period at the same institution. Possible factors relevant to postdiagnosis management and screening adherence were assessed. Consultation with a breast surgeon was identified by reviewing clinical notes. Uptake of pharmacologic chemoprevention following diagnosis (patient decision to take chemopreventive medications) was assessed. The Fisher exact test was used to compare annual or biennial screening adherence rates. Binary logistic regression was used to identify factors predictive of whether women returned for screening within selected time frames. Results In total, 913 (1.3%) of 67 874 women were given a recommendation to undergo stereotactic biopsy, resulting in diagnosis of 208 (22.8%) of 913 high-risk lesions. Excluding those with a prior personal history of breast cancer or upgrade to cancer at surgery, 124 (66.7%) of 186 women underwent surgery and 62 (33.3%) did not. Overall post-high-risk diagnosis adherence to annual or biennial mammography was similar to that in control subjects (annual, 56.4% vs 50.8%, P = .160; biennial, 62.0% vs 60.1%, P = .630). Adherence was significantly better in the surgical group than in the nonsurgical group for annual mammography (70.0% vs 32.0%; odds ratio [OR] = 5.0; 95% confidence interval [CI]: 2.4, 10.1; P < .001) and for biennial mammography (74.3% vs 40.0%; OR = 4.3; 95% CI: 2.1, 8.8; P < .001). Among the patients in the nonsurgical group, those adherent to annual or biennial mammography were significantly more likely to have seen a breast surgeon than the nonadherent women (annual, 77.3% vs 35.7%, P = .005; biennial, 67.9% vs 36.4%, P = .045). All patients receiving chemopreventive agents underwent a surgical consultation (100%; n = 21). Conclusion Although diagnosis of a high-risk lesion at stereotactic breast biopsy did not compromise overall adherence to subsequent mammographic screening, patients without surgical excision, particularly those who did not undergo a surgical consultation, had significantly lower imaging adherence and chemoprevention uptake as compared with their counterparts who underwent surgery, suggesting that specialist care may be important in optimizing management. © RSNA, 2018.

PMID: 29378151 [PubMed - as supplied by publisher]

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EAACI Guidelines on Allergen Immunotherapy: Executive Statement

Abstract

The allergist's community has recently celebrated 100 year of Allergen Immunotherapy (AIT). Unfortunately the implemention of this treatment is still impaired by some challenges. With the diversity of definitions, methodology and different allergen products used, research studies have produced conflicting outcomes. This has resulted in confusion about the benefits and risks of AIT amongst policymakers and professionals, as well as in the variable availability of AIT products, regulation and reimbursement policies globally. In 2015 EAACI initiated the AIT Guidelines project as part of the Presidential plan in order to settle the controversies.

This article is protected by copyright. All rights reserved.

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Prediction of the severity of allergic reactions to foods

Abstract

Background

There is currently considerable uncertainty regarding what the predictors of the severity of diagnostic or accidental food allergic reactions are, and to what extent the severity of such reactions can be predicted.

Objective

To identify predictors for the severity of diagnostic and accidental food allergic reactions and to quantify their impact.

Methods

The study population consisted of children with a double-blind, placebo-controlled food challenge (DBPCFC) confirmed food allergy to milk, egg, peanut, cashew nut and/or hazelnut. The data was analyzed using multiple linear regression analysis. Missing values were imputed using multiple imputation techniques. Two scoring systems were used to determine the severity of the reactions.

Results

734 children were included. Independent predictors for the severity of the DBPCFC reaction were: age (B=0.04, p=0.001), skin prick test ratio (B=0.30, p<0.001), eliciting dose (B=-0.09, p<0.001), level of specific immunoglobulin E (B=0.15, p<0.001), reaction time during the DBPCFC (B=-0.01, p=0.004), and severity of accidental reaction (B=0.08, p=0.015). The total explained variance of this model was 23.5%, and the eliciting dose only contributed 4.4% to the model. Independent predictors for more severe accidental reactions with an explained variance of 7.3% were: age (B=0.03, p=0.014), milk as causative food (B=0.77, p<0.001), cashew as causative food (B=0.54, p<0.001), history of atopic dermatitis (B=-0.47, p=0.006), and severity of DBPCFC reaction (B=0.12, p=0.003).

Conclusions

The severity of DBPCFCs and accidental reactions to food remain largely unpredictable. Clinicians should not use the eliciting dose obtained from a graded food challenge for the purposes of making risk-related management decisions.

This article is protected by copyright. All rights reserved.

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Isolation of Extracellular Vesicles: General Methodologies and Latest Trends

Background. Extracellular vesicles (EVs) play an essential role in the communication between cells and transport of diagnostically significant molecules. A wide diversity of approaches utilizing different biochemical properties of EVs and a lack of accepted protocols make data interpretation very challenging. Scope of Review. This review consolidates the data on the classical and state-of-the-art methods for isolation of EVs, including exosomes, highlighting the advantages and disadvantages of each method. Various characteristics of individual methods, including isolation efficiency, EV yield, properties of isolated EVs, and labor consumption are compared. Major Conclusions. A mixed population of vesicles is obtained in most studies of EVs for all used isolation methods. The properties of an analyzed sample should be taken into account when planning an experiment aimed at studying and using these vesicles. The problem of adequate EVs isolation methods still remains; it might not be possible to develop a universal EV isolation method but the available protocols can be used towards solving particular types of problems. General Significance. With the wide use of EVs for diagnosis and therapy of various diseases the evaluation of existing methods for EV isolation is one of the key problems in modern biology and medicine.

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Variation of Pore Water Pressure in Tailing Sand under Dynamic Loading

Intense vibration affects the pore water pressure in a tailing dam, with the tendency to induce dam liquefaction. In this study, experiments were performed wherein model tailing dams were completely liquefied by sustained horizontal dynamic loading to determine the effects of the vibration frequency, vibration amplitude, and tailing density on the pore water pressure. The results revealed four stages in the increase of the tailing pore water pressure under dynamic loading, namely, a slow increase, a rapid increase, inducement of structural failure, and inducement of complete liquefaction. A lower frequency and smaller amplitude of the vibration were found to increase the time required to achieve a given pore water pressure in dense tailings. Under the effect of these three factors—vibration frequency and amplitude and tailing density—the tailing liquefaction time varied nonlinearly with the height from the base of the tailing dam, with an initial decrease followed by an increase. The pore pressure that induced structural failure also gradually decreased with increasing height. The increase in the tailing pore pressure could be described by an S-shaped model. A complementary multivariate nonlinear equation was also derived for predicting the tailing pore water pressure under dynamic loading.

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SEISGAMA: A Free C# Based Seismic Data Processing Software Platform

Seismic reflection is one of the most popular methods in geophysical prospecting. Nevertheless, obtaining high resolution and accurate results requires a sophisticated processing stage. There are many open-source seismic reflection data processing software programs available; however, they often use a high-level programming language that decreases its overall performance, lacks intuitive user-interfaces, and is limited to a small set of tasks. These shortcomings reveal the need to develop new software using a programming language that is natively supported by Windows® operating systems, which uses a relatively medium-level programming language (such as C#) and can be enhanced by an intuitive user interface. SEISGAMA was designed to address this need and employs a modular concept, where each processing group is combined into one module to ensure continuous and easy development and documentation. SEISGAMA can perform basic seismic reflection processes. This ability is very useful, especially for educational purposes or during a quality control process (in the acquisition stage). Those processes can be easily carried out by users via specific menus on SEISGAMA’s main user interface. SEISGAMA has been tested, and its results have been verified using available theoretical frameworks and by comparison to similar commercial software.

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Nephroprotective Effect of Zingerone against CCl4-Induced Renal Toxicity in Swiss Albino Mice: Molecular Mechanism

The protective effects of Zingerone against CCl4 induced nephrotoxicity in Swiss albino mice via modulation of metabolizing enzyme, oxidative stress, inflammatory cytokines, and apoptosis. The biochemical estimation indicated that the BUN and creatinine were significantly increased in group 2 (CCl4) compared to group 1 (normal) which was significantly reduced after treatment with Zingerone in group 3 when compared with group 2. The CCl4 treatment has significantly increased TBARS levels and reduced the antioxidant enzyme such as GSH, GPx, GR, GST, CAT, and SOD in group 2 compared to group 1, while the Zingerone treatment showed significant reduction in TBARS levels and increased the antioxidant enzymes in group 3 (CCl4 + Zingerone) as compared to group 2. Similarly, it was observed that CCl4 significantly increased the cytokines such as IL-1β, IL-2, and TNFα levels in group 2 as compared to group 1. The treatment with Zingerone significantly attenuated the levels of IL-1β, IL-2, and TNFα in group 3 compared to group 2. Caspase 3 and caspase 9 were also significantly increased in CCl4-treated group 2, whereas Zingerone treatment significantly reduced the elevated levels of caspases 3 and 9 in group 3 compared to group 2.

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Oxidative Stress Markers Patients with Parotid Gland Tumors: A Pilot Study

Salivary gland tumors account for 3–6% of tumors of the head and neck. About 80% of salivary gland tumors occur in parotid glands. Oxidative stress (OS) is implicated in the origin, development, and whole-body effects of various tumors. There are no data on the occurrence of OS in the parotid gland tumors. The aim of this study was to ascertain if whole-body OS accompanies parotid gland tumors, based first of all on oxidative modifications of blood serum proteins and other markers of OS in the serum of the patients. The group studied included 17 patients with pleomorphic adenoma, 9 patients with Warthin’s tumor, 8 patients with acinic cell carcinoma, and 24 age-matched controls. We found increased concentration of interleukin 4 in patients with acinic cell carcinoma, decreased plasma thiols, increased AOPP concentration, and decreased FRAP of blood serum in all groups of the patients while protein oxidative modifications assessed fluorimetrically, protein carbonyls, protein nitration, malondialdehyde concentration, and serum ABTS-scavenging capacity were unchanged. These data indicate the occurrence of OS in patients with parotid gland tumors and point to various sensitivities of OS markers.

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Bus Route Design with a Bayesian Network Analysis of Bus Service Revenues

A Bayesian network is used to estimate revenues of bus services in consideration of the effect of bus travel demands, passenger transport distances, and so on. In this research, the area X in Beijing has been selected as the study area because of its relatively high bus travel demand and, on the contrary, unsatisfactory bus services. It is suggested that the proposed Bayesian network approach is able to rationally predict the probabilities of different revenues of various route services, from the perspectives of both satisfying passenger demand and decreasing bus operation cost. This way, the existing bus routes in the studied area can be optimized for their most probable high revenues.

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Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide

Background. After perinatal asphyxia, the cerebellum presents more damage than previously suggested. Objectives. To explore if the antioxidant N-acetylcysteine amide (NACA) could reduce cerebellar injury after hypoxia-reoxygenation in a neonatal pig model. Methods. Twenty-four newborn pigs in two intervention groups were exposed to 8% oxygen and hypercapnia, until base excess fell to −20 mmol/l or the mean arterial blood pressure declined to

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Shaofu Zhuyu Decoction Regresses Endometriotic Lesions in a Rat Model

The current therapies for endometriosis are restricted by various side effects and treatment outcome has been less than satisfactory. Shaofu Zhuyu Decoction (SZD), a classic traditional Chinese medicinal (TCM) prescription for dysmenorrhea, has been widely used in clinical practice by TCM doctors to relieve symptoms of endometriosis. The present study aimed to investigate the effects of SZD on a rat model of endometriosis. Forty-eight female Sprague-Dawley rats with regular estrous cycles went through autotransplantation operation to establish endometriosis model. Then 38 rats with successful ectopic implants were randomized into two groups: vehicle- and SZD-treated groups. The latter were administered SZD through oral gavage for 4 weeks. By the end of the treatment period, the volume of the endometriotic lesions was measured, the histopathological properties of the ectopic endometrium were evaluated, and levels of proliferating cell nuclear antigen (PCNA), CD34, and hypoxia inducible factor- (HIF-) 1α in the ectopic endometrium were detected with immunohistochemistry. Furthermore, apoptosis was assessed using the terminal deoxynucleotidyl transferase (TdT) deoxyuridine 5′-triphosphate (dUTP) nick-end labeling (TUNEL) assay. In this study, SZD significantly reduced the size of ectopic lesions in rats with endometriosis, inhibited cell proliferation, increased cell apoptosis, and reduced microvessel density and HIF-1α expression. It suggested that SZD could be an effective therapy for the treatment and prevention of endometriosis recurrence.

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From Localized Scleroderma to Systemic Sclerosis: Coexistence or Possible Evolution

Background. Systemic sclerosis (SSc) and localized scleroderma (LoS) are two different diseases that may share some features. We evaluated the relationship between SSc and LoS in our case series of SSc patients. Methods. We analysed the clinical records of 330 SSc patients, in order to find the eventual occurrence of both the two diseases. Results. Eight (2.4%) female patients presented both the two diagnoses in their clinical histories. Six developed LoS prior to SSc; in 4/6 cases, the presence of autoantibodies was observed before SSc diagnosis. Overall, the median time interval between LoS and SSc diagnosis was 18 (range 0–156) months. Conclusions. LoS and SSc are two distinct clinical entities that may coexist. Moreover, as anecdotally reported in pediatric populations, we suggested the possible development of SSc in adult patients with LoS, particularly in presence of Raynaud’s phenomenon or antinuclear antibodies before the SSc onset.

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Serum Cytokine Profiles in Patients with Dengue Fever at the Acute Infection Phase

Background. Dengue virus (DENV) is transmitted by mosquito and has been circulating in Guangdong, China, for over 30 years. Dengue infection causes mild to severe disease symptoms in human. Cytokine profiles were suggested to be crucial especially during the acute stage in the dengue infection. Aim. To determine the cytokine profiles at the acute stage in patients with primary or secondary dengue infection in Guangzhou city in the 2014 outbreak. Methods. We investigated 23 inflammatory cytokines in serum collected from dengue-infected patients and analyzed their correlations with their clinical indexes. Results. The concentrations of CXCL9, IP-10, CXCL11, IL-8, IL-10, and CCL2 in serum were significantly higher in the groups of DENV-infected patients during the first two weeks than those of control group while CCL17 and CXCL5 showed lower expression level in the patients. Among these cytokines, CXCL9, CCL17, and CXCL5 showed statistical difference between the groups of primary and secondary infections. The platelet count and lactate dehydrogenase were correlated with the level of CCL17 and MIP-1α/CXCL5, respectively, in the group of secondary infection. Conclusions. We determined the cytokine profiles in serum of the patients during the 2014 dengue outbreak. The expression of specific cytokines was associated with the secondary infection.

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Hepatitis B Virus Infection in Tanzania: Current Status and Challenges

Hepatitis B is one of the most common infectious diseases in the world with high prevalence in most of sub-Saharan Africa countries. The complexity in its diagnosis and treatment poses a significant management challenge in the resource-limited settings including Tanzania, where most of the tests and drugs are either unavailable or unaffordable. This mini review aims at demonstrating the current status of the disease in the country and discussing the concomitant challenges in diagnosis, treatment, and prevention.

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Early Factors Associated with the Development of Chronic Pain in Trauma Patients

Objective. To identify factors, available at the time of trauma admission, associated with the development of chronic pain to allow testing of preventive approaches. Methods. In a retrospective observational cohort study, we included all patients ≥ 18 years old admitted for injury in 57 adult trauma centers in the province of Quebec (Canada) between 2004 and 2014. Chronic pain was defined as follows: treated in a chronic pain clinic, diagnosed with chronic pain, or received at least 2 prescriptions of chronic pain medications 3 to 12 months postinjury. Results. A total of 95,134 patients were retained for analysis. Mean age was 59.8 years (±21.7), and 52% were men. The causes of trauma were falls (63%) and motor vehicle accidents (22%). We identified 14,518 patients (15.3%; 95% CI: 15.1–15.5) who developed chronic pain. After controlling for confounding factors, the variables associated with chronic pain were spinal cord injury (OR = 3.9; 95% CI: 3.4–4.6), disc-vertebra trauma (OR = 1.6; 95% CI: 1.5–1.7), history of alcoholism (OR = 1.4; 95% CI: 1.2–1.7), history of anxiety (OR = 1.4; 95% CI: 1.2–1.5), history of depression (OR = 1.3; 95% CI: 1.1–1.4), and being female (OR = 1.3; 95% CI: 1.2–1.3). The area under the receiving operating characteristic curve derived from the model was 0.80. Conclusions. We identified risk factors present on hospital admission that can predict trauma patients who will develop chronic pain. These factors should be prospectively validated.

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Identification of Common Genes Refers to Colorectal Carcinogenesis with Paired Cancer and Noncancer Samples

Colorectal cancer is a malignant tumor which harmed human beings’ health. The aim of this study was to explore common biomarkers associated with colorectal carcinogenesis in paired cancer and noncancer samples. At first, fifty-nine pairs of colorectal cancer and noncancer samples from three gene expression datasets were collected and analyzed. Then, 181 upregulation and 282 downregulation common differential expression genes (DEGs) were found. Next, functional annotation was performed in the DAVID database with the DEGs. Finally, real-time polymerase chain reaction (PCR) assay was conducted to verify the analyses in sixteen colorectal cancer and individual-matched adjacent mucosa samples. Real-time PCR showed that MCM2, RNASEH2A, and TOP2A were upregulated in colorectal cancer compared with adjacent mucosa samples (MCM2, ; RNASEH2A, ; TOP2A, ). These suggested that 463 DEGs might contribute to colorectal carcinogenesis.

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Choriocapillaris Loss in Advanced Age-Related Macular Degeneration

The purpose of this review is to summarize the current knowledge on choriocapillaris loss in advanced age macular degeneration (AMD). Several histopathological studies in animal models and human eyes had showed that the choriocapillaris density decreases with age. However, the role of choriocapillaris loss is still unclear in AMD and its advanced forms, either choroidal neovascularization (CNV) or geographic atrophy (GA). Some authors have hypothesized that choriocapillaris loss might precede overt retinal pigment epithelium atrophy. Others have hypothesized that deposition of complement complexes on and around the choriocapillaris could be related to the tissue loss observed in early AMD. The development of imaging modalities, such as optical coherence tomography angiography (OCTA), have led to a better understanding of underlying physiopathological mechanisms in AMD. OCTA showed atrophy of choriocapillaris underneath and beyond the region of photoreceptors and RPE loss, in agreement with previous histopathologic studies. The evolution of OCTA technology suggests that CNV seems to originate from regions of severe choriocapillaris alteration. Significant progress has been made in the understanding of development and progression of GA and CNV. In vivo investigation of the choriocapillaris using OCTA may lead to new insights related to underlying disease mechanisms in AMD.

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Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V

Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases. The exact cause for the observed clinical heterogeneity within the family is unknown. One explanation is that there are modifier genes that affect the phenotype. These cases highlight the possibility of considering pathogenic variants in the GARS gene as a potential cause of early onset axonal polyneuropathy with atypical presentation.

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Effect of N-Acetylcysteine on Antioxidant Defense, Oxidative Modification, and Salivary Gland Function in a Rat Model of Insulin Resistance

Oxidative stress plays a crucial role in the salivary gland dysfunction in insulin resistance (IR). It is not surprising that new substances are constantly being sought that will protect against the harmful effects of IR in the oral cavity environment. The purpose of this study was to evaluate the effect of N-acetylcysteine (NAC) on oxidative stress and secretory function of salivary glands in a rat model of insulin resistance. Rats were divided into 4 groups: C—normal diet, C + NAC—normal diet + NAC, HFD—high-fat diet, and HFD + NAC. We have demonstrated that NAC elevated enzymatic (superoxide dismutase, catalase, and peroxidase) and nonenzymatic antioxidants (reduced glutathione (GSH) and total antioxidant capacity (TAS)) in the parotid glands of HFD + NAC rats, while in the submandibular glands increased only GSH and TAS levels. NAC protects against oxidative damage only in the parotid glands and increased stimulated salivary secretion; however, it does not increase the protein secretion in the both salivary glands. Summarizing, NAC supplementation prevents the decrease of stimulated saliva secretion, seen in the HFD rats affected. NAC improves the antioxidative capacity of the both glands and protects against oxidative damage to the parotid glands of IR rats.

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Recovery of Chronic Stress-Triggered Changes of Hippocampal Glutamatergic Transmission

Chronic stress results in neurochemical, physiological, immune, molecular, cellular, and structural changes in the brain and often dampens the cognition. The hippocampus has been one major focus in studying the stress responsivity and neural mechanisms underlying depression. Both acute and chronic stress stimuli lead to dynamic changes in excitatory transmission in the hippocampus. The present study examined the potential effects of spontaneous recovery after chronic stress on spatial memory function and glutamatergic transmission in the hippocampus. The results showed that chronic unpredicted mild stress transiently increased AMPA receptor GluA2/3 subunit expression, together with elevated PICK-1 protein expression. Spontaneous recovery restored the behavioral deficits in Barnes maze test, as well as the glutamate receptor expression changes. In conclusion, spontaneous recovery acts as an important mechanism in system homeostasis.

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Structural Basis for pH-Dependent Oligomerization of Dihydropyrimidinase from Pseudomonas aeruginosa PAO1

Dihydropyrimidinase, a dimetalloenzyme containing a carboxylated lysine within the active site, is a member of the cyclic amidohydrolase family, which also includes allantoinase, dihydroorotase, hydantoinase, and imidase. Unlike all known dihydropyrimidinases, which are tetrameric, pseudomonal dihydropyrimidinase forms a dimer at neutral pH. In this paper, we report the crystal structure of P. aeruginosa dihydropyrimidinase at pH 5.9 (PDB entry 5YKD). The crystals of P. aeruginosa dihydropyrimidinase belonged to space group C2221 with cell dimensions of a = 108.9, b = 155.7, and c = 235.6 Å. The structure of P. aeruginosa dihydropyrimidinase was solved at 2.17 Å resolution. An asymmetric unit of the crystal contained four crystallographically independent P. aeruginosa dihydropyrimidinase monomers. Gel filtration chromatographic analysis of purified P. aeruginosa dihydropyrimidinase revealed a mixture of dimers and tetramers at pH 5.9. Thus, P. aeruginosa dihydropyrimidinase can form a stable tetramer both in the crystalline state and in the solution. Based on sequence analysis and structural comparison of the dimer-dimer interface between P. aeruginosa dihydropyrimidinase and Thermus sp. dihydropyrimidinase, different oligomerization mechanisms are proposed.

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Nocardia spp. Pneumonia in a Solid Organ Recipient: Role of Linezolid

We describe a rare infection with Nocardia spp. (N. pseudobrasiliensis species identification based on high-performance liquid chromatography analysis) in a 68-year-old renal transplant recipient. He presented with pneumonia complicated by hypoxic respiratory failure. He was allergic to sulphonamides. He was initially successfully treated with linezolid. However, he suffered severe sensory neuropathy after 4 months of therapy, necessitating linezolid cessation and completion of treatment with azithromycin. He had clinical and radiological resolution of his pneumonia and was disease free at subsequent follow-up 4 years later. This case highlights the need for alternative therapies for nocardiosis for patients that cannot be treated with sulphonamides due to allergies or/and infection with multidrug-resistant pathogens. It also illustrates the treatment limiting side effects of long-term therapy with linezolid.

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Four Plasma Glucose and Insulin Responses to a 75 g OGTT in Healthy Young Japanese Women

The incidence of diabetes has been gradually increasing, not only in middle-aged individuals but also in young individuals. However, insulin and glucose patterns have not been investigated in apparently healthy young individuals, as they are typically grouped as controls. In this study, we investigated and classified glucose and insulin patterns in healthy young women. Sixty-two nonobese women without metabolic disease were recruited. The subjects underwent a 75 g oral glucose tolerance test (OGTT), physical measurements, and a biochemical examination. Two subjects displayed impaired glucose tolerance. The 62 subjects were categorized into four patterns by plasma glucose and insulin peak time during OGTT: normal type (), insulin-late type (), insulin- and glucose-late type (), and insulin-very late type (). OGTT glucose and insulin levels at all time points, insulinogenic index, HOMA-IR, and glucose area under the curve (AUC) significantly differed among the four groups. However, insulin AUC did not significantly differ. We did not detect significant differences in body condition or biochemical measurements. Our study demonstrated that some healthy young individuals might have delayed insulin secretion by OGTT. Early detection of altered glucose metabolism might be helpful to improve lifestyle choices and prevent progression to diabetes.

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Proteomics for synaptic markers of cognitive decline in neurodegenerative diseases

This scientific commentary refers to ‘Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach’ by Bereczki et al. (doi:10.1093/brain/awx352).

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Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study

Abstract

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen’s d = −0.24 to −0.73; P < 1.49 × 10⁻⁴), and lower thickness in the precentral gyri bilaterally (d = −0.34 to −0.52; P < 4.31 × 10⁻⁶). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = −1.73 to −1.91, P < 1.4 × 10⁻¹⁹), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = −0.36 to −0.52; P < 1.49 × 10⁻⁴). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = −0.29 to −0.54; P < 1.49 × 10⁻⁴). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = −0.27 to −0.51; P < 1.49 × 10⁻⁴). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < −0.0018; P < 1.49 × 10⁻⁴). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

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Multimodal neuroimaging provides insights into the biology of Alzheimer’s disease

This scientific commentary refers to ‘Networks of tau distribution in Alzheimer’s disease’ by Hoenig et al. (doi:10.1093/brain/awx353).

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Rest in peace FTDP-17

This scientific commentary refers to ‘Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies’ by Forrest et al. (doi:10.1093/brain/awx328).

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Editorial

The cover of this issue relates to one of five articles on tau. Using ¹⁸F-AV-1451 PET scanning, Merle Hoenig and colleagues report that tau pathology expands along independent pathways that correspond to functional networks known to be impaired in Alzheimer’s disease, including the default mode network and the frontal control network. Thomas Cope and co-workers also show that highly connected networks are susceptible to tau pathology in Alzheimer’s disease. Such a relationship was, however, not seen in progressive supranuclear palsy, where the burden appears to correlate instead with increased metabolic demand or lack of trophic support. The pathogenic role of tau remains at the centre of much research published in Brain. Marie d’Orange and colleagues compare the effect of viral expression of either wild-type tau or a chimeric protein designed to aggregate tau in rat brain, and conclude that potentiating tangle formation reduces acute toxicity of soluble tau species. Shelley Forrest and co-workers show that distinct mutations of the MAPT gene that encodes tau result in pathologies that strongly resemble sporatic sporadic frontotemporal tauopathies. Finally, Chad Tagge, Andrew Fisher, Olga Minaeva and colleagues report that impact head injury can result in early phosphorylated tau pathology in experimental models, and identify similar changes in a small number of young athletes who died suddenly within 4 months of a closed-head injury.

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Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model

Abstract

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood–brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood–brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001

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A brain-based pain facilitation mechanism contributes to painful diabetic polyneuropathy

Abstract

The descending pain modulatory system represents one of the oldest and most fundamentally important neurophysiological mechanisms relevant to pain. Extensive work in animals and humans has shown how a functional imbalance between the facilitatory and inhibitory components is linked to exacerbation and maintenance of persistent pain states. Forward translation of these findings into clinical populations is needed to verify the relevance of this imbalance. Diabetic polyneuropathy is one of the most common causes of chronic neuropathic pain; however, the reason why ∼25–30% of patients with diabetes develop pain is not known. The current study used a multimodal clinical neuroimaging approach to interrogate whether the sensory phenotype of painful diabetic polyneuropathy involves altered function of the ventrolateral periaqueductal grey—a key node of the descending pain modulatory system. We found that ventrolateral periaqueductal grey functional connectivity is altered in patients suffering from painful diabetic polyneuropathy; the magnitude of which is correlated to their spontaneous and allodynic pain as well as the magnitude of the cortical response elicited by an experimental tonic heat paradigm. We posit that ventrolateral periaqueductal grey-mediated descending pain modulatory system dysfunction may reflect a brain-based pain facilitation mechanism contributing to painful diabetic polyneuropathy.

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Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study

Abstract

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.

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Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach

Abstract

See Attems and Jellinger (doi:10.1093/brain/awx360) for a scientific commentary on this article.Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson’s disease dementia, dementia with Lewy bodies, and Alzheimer’s disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson’s disease dementia from Alzheimer’s disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.

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Historical crossroads in the conceptual delineation of apathy in Parkinson’s disease

Apathy is now viewed as an independent symptom at the crossroads between neurology and psychiatry. Prange et al. identify seven conceptual breakthroughs from 1817 to the present day that led to the delineation of apathy in its cognitive, motivational and emotional dimensions in Parkinson’s disease and other basal ganglia disorders.

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Networks of tau distribution in Alzheimer’s disease

Abstract

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer’s disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two ¹⁸F-AV-1451 PET scans of patients with amnestic Alzheimer’s disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer’s disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13–0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42–0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer’s disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer’s disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer’s disease.

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Reply: Non-freezing cold injury: a multi-faceted syndrome

Sir,

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Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy

Abstract

Alzheimer’s disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer’s disease, neuropathology and atrophy preferentially affect ‘hub’ brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer’s disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer’s disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer’s disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker ‘small-world’ properties. Conversely, in PSP, unlike in Alzheimer’s disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer’s disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.

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Non-freezing cold injury: a multi-faceted syndrome

Sir

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A widespread visually-sensitive functional network relates to symptoms in essential tremor

Abstract

Essential tremor is a neurological syndrome of heterogeneous pathology and aetiology that is characterized by tremor primarily in the upper extremities. This tremor is commonly hypothesized to be driven by a single or multiple neural oscillator(s) within the cerebello-thalamo-cortical pathway. Several studies have found an association of blood-oxygen level-dependent (BOLD) signal in the cerebello-thalamo-cortical pathway with essential tremor, but there is behavioural evidence that also points to the possibility that the severity of tremor could be influenced by visual feedback. Here, we directly manipulated visual feedback during a functional MRI grip force task in patients with essential tremor and control participants, and hypothesized that an increase in visual feedback would exacerbate tremor in the 4–12 Hz range in essential tremor patients. Further, we hypothesized that this exacerbation of tremor would be associated with dysfunctional changes in BOLD signal and entropy within, and beyond, the cerebello-thalamo-cortical pathway. We found that increases in visual feedback increased tremor in the 4–12 Hz range in essential tremor patients, and this increase in tremor was associated with abnormal changes in BOLD amplitude and entropy in regions within the cerebello-thalamo-motor cortical pathway, and extended to visual and parietal areas. To determine if the tremor severity was associated with single or multiple brain region(s), we conducted a birectional stepwise multiple regression analysis, and found that a widespread functional network extending beyond the cerebello-thalamo-motor cortical pathway was associated with changes in tremor severity measured during the imaging protocol. Further, this same network was associated with clinical tremor severity measured with the Fahn, Tolosa, Marin Tremor Rating Scale, suggesting this network is clinically relevant. Since increased visual feedback also reduced force error, this network was evaluated in relation to force error but the model was not significant, indicating it is associated with force tremor but not force error. This study therefore provides new evidence that a widespread functional network is associated with the severity of tremor in patients with essential tremor measured simultaneously at the hand during functional imaging, and is also associated with the clinical severity of tremor. These findings support the idea that the severity of tremor is exacerbated by increased visual feedback, suggesting that designers of new computing technologies should consider using lower visual feedback levels to reduce tremor in essential tremor.

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Motor learning and metaplasticity in striatal neurons: relevance for Parkinson’s disease

Abstract

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson’s disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson’s disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson’s disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson’s disease, and that might be relevant for other striatal pathologies, such as drug abuse.

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Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration

Abstract

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using ¹¹C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, ¹¹C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater ¹¹C-PBR28 binding. Minocycline reduced ¹¹C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.

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The importance of early immunotherapy in patients with faciobrachial dystonic seizures

Abstract

Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to understand clinical, therapeutic and serological differences between those with and without cognitive impairment, and to determine whether cessation of faciobrachial dystonic seizures can prevent cognitive impairment. The 22/103 patients without cognitive impairment typically had normal brain MRI, EEGs and serum sodium levels (P < 0.0001). Overall, cessation of faciobrachial dystonic seizures with antiepileptic drugs alone occurred in only 9/89 (10%) patients. By contrast, 51% showed cessation of faciobrachial dystonic seizures 30 days after addition of immunotherapy (P < 0.0001), with earlier cessation in cognitively normal patients (P = 0.038). Indeed, expedited immunotherapy (P = 0.031) and normal cognition (P = 0.0014) also predicted reduced disability at 24 months. Furthermore, of 80 patients with faciobrachial dystonic seizures as their initial feature, 56% developed cognitive impairment after 90 days of active faciobrachial dystonic seizures. Whereas only one patient developed cognitive impairment after cessation of faciobrachial dystonic seizures (P < 0.0001). All patients had IgG4-LGI1 antibodies, but those with cognitive impairment had higher proportions of complement-fixing IgG1 antibodies (P = 0.03). Both subclasses caused LGI1-ADAM22 complex internalization, a potential non-inflammatory epileptogenic mechanism. In summary, faciobrachial dystonic seizures show striking time-sensitive responses to immunotherapy, and their cessation can prevent the development of cognitive impairment.awx323media15681705685001

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Evaluation of the noradrenergic system in Parkinson’s disease: an 11C-MeNER PET and neuromelanin MRI study

Abstract

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson’s disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson’s disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while ¹¹C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson’s disease with loss of noradrenergic function. Thirty non-demented Parkinson’s disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with ¹¹C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson’s disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of ¹¹C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson’s disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced ¹¹C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson’s disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson’s disease, and may be of relevance when treating these conditions in Parkinson’s disease.

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Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer’s disease: preclinical proof of concept

Abstract

Microglia significantly contribute to the pathophysiology of Alzheimer’s disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels K_v1.3 and K_ir2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the ‘M1-like pro-inflammatory’ or ‘M2-like anti-inflammatory’ state of microglia, respectively. We here found that amyloid-β oligomer-induced expression of K_v1.3 and K_ir2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer’s model 5xFAD mice co-expressed K_v1.3 and K_ir2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-β oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule K_v1.3 blocker PAP-1 as a tool, we showed that pro-inflammatory and neurotoxic microglial responses induced by amyloid-β oligomer required K_v1.3 activity in vitro and in hippocampal slices. Since we further observed that K_v1.3 was highly expressed in microglia of transgenic Alzheimer’s mouse models and human Alzheimer’s disease brains, we hypothesized that pharmacological K_v1.3 inhibition could mitigate the pathology induced by amyloid-β aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-β uptake by microglia. Collectively, these results provide proof-of-concept data to advance K_v1.3 blockers to Alzheimer’s disease clinical trials.

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IJMS, Vol. 19, Pages 400: Altered Circadian Timing System-Mediated Non-Dipping Pattern of Blood Pressure and Associated Cardiovascular Disorders in Metabolic and Kidney Diseases

IJMS, Vol. 19, Pages 400: Altered Circadian Timing System-Mediated Non-Dipping Pattern of Blood Pressure and Associated Cardiovascular Disorders in Metabolic and Kidney Diseases

International Journal of Molecular Sciences doi: 10.3390/ijms19020400

Authors: Asadur Rahman Arif Hasan Akira Nishiyama Hiroyuki Kobori

The morning surge in blood pressure (BP) coincides with increased cardiovascular (CV) events. This strongly suggests that an altered circadian rhythm of BP plays a crucial role in the development of CV disease (CVD). A disrupted circadian rhythm of BP, such as the non-dipping type of hypertension (i.e., absence of nocturnal BP decline), is frequently observed in metabolic disorders and chronic kidney disease (CKD). The circadian timing system, controlled by the central clock in the suprachiasmatic nucleus of the hypothalamus and/or by peripheral clocks in the heart, vasculature, and kidneys, modulates the 24 h oscillation of BP. However, little information is available regarding the molecular and cellular mechanisms of an altered circadian timing system-mediated disrupted dipping pattern of BP in metabolic disorders and CKD that can lead to the development of CV events. A more thorough understanding of this pathogenesis could provide novel therapeutic strategies for the management of CVD. This short review will address our and others’ recent findings on the molecular mechanisms that may affect the dipping pattern of BP in metabolic dysfunction and kidney disease and its association with CV disorders.

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IJMS, Vol. 19, Pages 401: Discovery of Cryoprotective Activity in Human Genome-Derived Intrinsically Disordered Proteins

IJMS, Vol. 19, Pages 401: Discovery of Cryoprotective Activity in Human Genome-Derived Intrinsically Disordered Proteins

International Journal of Molecular Sciences doi: 10.3390/ijms19020401

Authors: Naoki Matsuo Natsuko Goda Kana Shimizu Satoshi Fukuchi Motonori Ota Hidekazu Hiroaki

Intrinsically disordered proteins (IDPs) are an emerging phenomenon. They may have a high degree of flexibility in their polypeptide chains, which lack a stable 3D structure. Although several biological functions of IDPs have been proposed, their general function is not known. The only finding related to their function is the genetically conserved YSK2 motif present in plant dehydrins. These proteins were shown to be IDPs with the YSK2 motif serving as a core region for the dehydrins’ cryoprotective activity. Here we examined the cryoprotective activity of randomly selected IDPs toward the model enzyme lactate dehydrogenase (LDH). All five IDPs that were examined were in the range of 35–45 amino acid residues in length and were equally potent at a concentration of 50 μg/mL, whereas folded proteins, the PSD-95/Dlg/ZO-1 (PDZ) domain, and lysozymes had no potency. We further examined their cryoprotective activity toward glutathione S-transferase as an example of the other enzyme, and toward enhanced green fluorescent protein as a non-enzyme protein example. We further examined the lyophilization protective activity of the peptides toward LDH, which revealed that some IDPs showed a higher activity than that of bovine serum albumin (BSA). Based on these observations, we propose that cryoprotection is a general feature of IDPs. Our findings may become a clue to various industrial applications of IDPs in the future.

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IJMS, Vol. 19, Pages 399: Sex Hormone Receptors in Benign and Malignant Salivary Gland Tumors: Prognostic and Predictive Role

IJMS, Vol. 19, Pages 399: Sex Hormone Receptors in Benign and Malignant Salivary Gland Tumors: Prognostic and Predictive Role

International Journal of Molecular Sciences doi: 10.3390/ijms19020399

Authors: Gabriella Aquino Francesca Collina Rocco Sabatino Margherita Cerrone Francesco Longo Franco Ionna Nunzia Losito Rossella De Cecio Monica Cantile Giuseppe Pannone Gerardo Botti

The role of sex hormone receptors in human cancer development and progression has been well documented in numerous studies, as has the success of sex hormone antagonists in the biological therapy of many human tumors. In salivary gland tumors (SGTs), little and conflicting information about the role of the estrogen receptor alpha (ERα), progesterone receptor (PgR) and androgen receptor (AR) has been described and in most cases the use of sex hormone antagonists is not contemplated in clinical practice. In this study, we analyzed a panel of sex hormone receptors that have not been widely investigated in SGTs—ERα, PgR, AR, but also ERβ and GPR30—to define their expression pattern and their prognostic and predictive value in a case series of 69 benign and malignant SGTs. We showed the aberrant expression of AR in mucoepidermoid and oncocytic carcinoma, a strong relation between cytoplasmic ERβ expression and tumor grade, and a strong correlation between nuclear GPR30 expression and disease-free survival (DFS) of SGT patients.

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Biosensors, Vol. 8, Pages 12: Glucose Sensing Using Capacitive Biosensor Based on Polyvinylidene Fluoride Thin Film

Biosensors, Vol. 8, Pages 12: Glucose Sensing Using Capacitive Biosensor Based on Polyvinylidene Fluoride Thin Film

Biosensors doi: 10.3390/bios8010012

Authors: Ambran Hartono Edi Sanjaya Ramli Ramli

A polyvinylidene fluoride (PVDF) film-based capacitive biosensor was developed for glucose sensing. This device consists of a PVDF film sandwiched between two electrodes. A capacitive biosensor measures the dielectric properties of the dielectric layers at the interface between the electrolyte and the electrode. A glucose oxidase (GOx) enzyme was immobilized onto the electrode to oxidize glucose. In practice, the biochemical reaction of glucose with the GOx enzyme generates free electron carriers. Consequently, the potential difference between the electrodes is increased, resulting in a measurable voltage output of the biosensor. The device was tested for various glucose concentrations in the range of 0.013 to 5.85 M, and various GOx enzyme concentrations between 4882.8 and 2.5 million units/L. We found that the sensor output increased with increasing glucose concentration up to 5.85 M. These results indicate that the PVDF film-based capacitive biosensors can be properly applied to glucose sensing and provide opportunities for the low-cost fabrication of glucose-based biosensors based on PVDF materials.

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Viruses, Vol. 10, Pages 55: CRISPR–Cas9 Genetic Analysis of Virus–Host Interactions

Viruses, Vol. 10, Pages 55: CRISPR–Cas9 Genetic Analysis of Virus–Host Interactions

Viruses doi: 10.3390/v10020055

Authors: Makda Gebre Jason Nomburg Benjamin Gewurz

Clustered regularly interspaced short palindromic repeats (CRISPR) has greatly expanded the ability to genetically probe virus–host interactions. CRISPR systems enable focused or systematic, genomewide studies of nearly all aspects of a virus lifecycle. Combined with its relative ease of use and high reproducibility, CRISPR is becoming an essential tool in studies of the host factors important for viral pathogenesis. Here, we review the use of CRISPR–Cas9 for the loss-of-function analysis of host dependency factors. We focus on the use of CRISPR-pooled screens for the systematic identification of host dependency factors, particularly in Epstein–Barr virus-transformed B cells. We also discuss the use of CRISPR interference (CRISPRi) and gain-of-function CRISPR activation (CRISPRa) approaches to probe virus–host interactions. Finally, we comment on the future directions enabled by combinatorial CRISPR screens.

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Negative Regulation of PTEN by MicroRNA-221 and Its Association with Drug Resistance and Cellular Senescence in Lung Cancer Cells

Objective. Chemotherapy is the routine method for treating many cancers, but long-term treatment may result in developing resistance to the drugs. The aim of this study was to identify whether noncoding RNAs play a role in drug resistance and how they affect drug resistance. Materials and Methods. The expression levels of miR-221 in different lung cancer cell lines H226, H1299, and A549 were measured. H1299 and A549 cell lines were transfected to overexpress and downexpress miR-221, and cell viability and cell senescence were determined. The PTEN/Akt pathway was then examined by real-time polymerase chain reaction and Western blot analysis. Results. MiR-221 together with proteins MDR1 and ABCG2 was upregulated in Cisplatin-resistant A549 lung cancer cells. Anti-miR-221 inhibits proliferation and induces senescence in lung cancer cells. PTEN/Akt pathway axis was identified as a target of drug resistance induced by miR-221. Conclusion. Our results revealed that miR-221 is an important regulator for chemotherapy sensitivity and showed miR-221 as a potential target for drug sensitization.

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Onychophagia Induced Melanonychia, Splinter Hemorrhages, Leukonychia, and Pterygium Inversum Unguis Concurrently

Onychophagia, which refers to compulsive nail-biting behavior, is common among children and young adults. Onychophagia can cause destruction to the cuticle and nail plate, leading to shortening of nails, chronic paronychia, and secondary infections. Relatively uncommon effects include pigmentary changes, such as longitudinal melanonychia and splinter hemorrhages. We report a case of a young adult with longitudinal melanonychia, splinter hemorrhages, punctate leukonychia, and pterygium inversum unguis, concurrently induced by onychophagia. Importantly, patients usually do not report this behavior when asked about nail-related changes. Even upon questioning, they may deny nail-biting behavior. As in many other dermatological disorders, dermoscopy can be helpful in the diagnosis of nail disorders.

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Applications of Steel Slag Powder and Steel Slag Aggregate in Ultra-High Performance Concrete

The applications of steel slag powder and steel slag aggregate in ultra-high performance concrete (UHPC) were investigated by determining the fluidity, nonevaporable water content, and pore structure of paste and the compressive strength of concrete and by observing the morphologies of hardened paste and the concrete fracture surface. The results show that the fluidity of the paste containing steel slag is higher. The nonevaporable water content of the hardened paste containing steel slag powder is close to that of the control sample at late ages. Both steel slag powder and steel slag aggregate react and connect tightly to gels and hardened paste, respectively. When the cement replacement ratio is no more than 10%, the proportion of pores larger than 50 nm in the hardened paste containing steel slag powder is close to that of the control sample, and the UHPC containing steel slag powder can display satisfactory compressive strengths. The UHPC containing steel slag aggregate demonstrates higher compressive strengths.

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Predicting Hidden Links in Supply Networks

Manufacturing companies often lack visibility of the procurement interdependencies between the suppliers within their supply network. However, knowledge of these interdependencies is useful to plan for potential operational disruptions. In this paper, we develop the Supply Network Link Predictor (SNLP) method to infer supplier interdependencies using the manufacturer’s incomplete knowledge of the network. SNLP uses topological data to extract relational features from the known network to train a classifier for predicting potential links. Using a test case from the automotive industry, four features are extracted: (i) number of existing supplier links, (ii) overlaps between supplier product portfolios, (iii) product outsourcing associations, and (iv) likelihood of buyers purchasing from two suppliers together. Naïve Bayes and Logistic Regression are then employed to predict whether these features can help predict interdependencies between two suppliers. Our results show that these features can indeed be used to predict interdependencies in the network and that predictive accuracy is maximised by (i) and (iii). The findings give rise to the exciting possibility of using data analytics for improving supply chain visibility. We then proceed to discuss to what extent such approaches can be adopted and their limitations, highlighting next steps for future work in this area.

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Role of luxS in Stress Tolerance and Adhesion Ability in Lactobacillus plantarum KLDS1.0391

Lactobacillus plantarum, a probiotic, has a high survival rate and high colonization ability in the gastrointestinal tract. Tolerance to the gastrointestinal environment and adhesion to intestinal epithelial cells by some Lactobacillus species (excluding L. plantarum) are related to luxS/AI-2. Here, the role of luxS in tolerance to simulated digestive juice (SDJ) and adhesion to Caco-2 cells by L. plantarum KLDS1.0391 (hereafter, KLDS1.0391) was investigated. The KLDS1.0391 luxS mutant strain was constructed by homologous recombination. When luxS was deleted, acid and bile salt tolerance and survival rates in SDJ significantly decreased ( for all). The ability of the luxS deletion strain to adhere to Caco-2 cells was markedly lower than that of the wild-type strain (). The ability of the luxS mutant strain to adhere (competition, exclusion, and displacement) to Escherichia coli ATCC 25922 was significantly lower than that of the wild-type strain ( for all). A significant decrease was noted only in the exclusion adhesion inhibition of the luxS mutant strain to Salmonella typhimurium ATCC 14028 (). These results indicate that the luxS gene plays an important role in the gastrointestinal environment tolerance and adhesion ability of KLDS1.0391.

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Alleviating the Intestinal Absorption of Rhein in Rhubarb through Herb Compatibility in Tiaowei Chengqi Tang in Caco-2 Cells

Tiaowei Chengqi Tang (TWCQT) is composed of rhubarb, processed liquorice, and Natrii Sulfas, which is used as a purgative in traditional Chinese medicine (TCM). This study focused on the intestinal absorption of rhein in disassembly of the TWCQT extracts through the Caco-2 cell monolayer model to explicate the possible detoxification mechanism of herb-herb compatibility in TWCQT. The results showed that the intestinal absorption of rhein occurred through active diffusion, and rhein might be composed of breast cancer resistance protein (BCRP) substrates. The extract of processed liquorice increased the exclusion rate and reduced intracellular uptake of rhein. The consistent results observed in TWCQT further implied that processed liquorice in TWCQT could suppress the absorption of rhein across the Caco-2 cell monolayer. It has therefore been concluded that the active ingredients of processed liquorice may play a critical role in reducing the intestinal absorption of rhein to alleviate the toxicity of rhubarb in TWCQT. Because of BCRP’s involvement in rhein transport, we conjectured that some components in processed liquorice could inhibit the transport of rhein, possibly by mediating BCRP. These results would provide new insight into this ancient drug combination in toxicity reduction and clinical use.

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Needle-Knife Fistulotomy for the Rescue: An Unusual Cause of Iatrogenic Extrahepatic Biliary Obstruction

A 71-year-old male presented to our institution with cholestatic hepatitis after having recently undergone upper endoscopy for treatment of gastrointestinal bleeding. Further investigation with endoscopic retrograde cholangiopancreatography revealed a hemostatic clip on the ampulla of Vater. After initial attempts at cannulation of the common bile duct were unsuccessful, biliary decompression was achieved by use of needle-knife fistulotomy. A common bile duct stent was placed and the liver function tests improved prior to discharge.

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Parameter Identification and Hybrid Synchronization in an Array of Coupled Chaotic Systems with Ring Connection: An Adaptive Integral Sliding Mode Approach

This article presents an adaptive integral sliding mode control (SMC) design method for parameter identification and hybrid synchronization of chaotic systems connected in ring topology. To employ the adaptive integral sliding mode control, the error system is transformed into a special structure containing nominal part and some unknown terms. The unknown terms are computed adaptively. Then the error system is stabilized using integral sliding mode control. The controller of the error system is created that contains both the nominal control and the compensator control. The adapted laws and compensator controller are derived using Lyapunov stability theory. The effectiveness of the proposed technique is validated through numerical examples.

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A Coupled Lattice Boltzmann-Volume Penalization for Flows Past Fixed Solid Obstacles with Local Mesh Refinement

A coupled Lattice Boltzmann-Volume Penalization (LBM-VP) with local mesh refinement is presented to simulate flows past obstacles in this article. Based on the finite-difference LBM, the local mesh refinement is incorporated into the LBM to improve computing efficiency. The volume penalization method is introduced into the LBM by an external forcing term. In the LBM-VP method, the processes of interpolating velocities on the boundaries points and distributing the force density to the Eulerian points near the boundaries are unnecessary. Performing the LBM-VP on a certain point, only the variables of this point are needed, which means the whole procedure can be conducted parallelly. As a consequence, the whole computing efficiency can be improved. To verify the presented method, flows past a single circular cylinder, a pair of cylinders in tandem arrangement, and a NACA-0012 are investigated. A good agreement between the present results and the data in the previous literatures is achieved, which demonstrates the accuracy and effectiveness of the present method to solve the flows past obstacle problems.

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Positive Association of Metabolic Syndrome with a Single Nucleotide Polymorphism of Syndecan-3 (rs2282440) in the Taiwanese Population

Background/Purpose. Metabolic syndrome (MetS) poses a major public health burden on the general population worldwide. Syndecan-3 (SDC3), a heparin sulfate proteoglycan, had been found by previous studies to be linked with energy balance and obesity, but its association with MetS is not known. The objective of this study is to investigate whether SDC3 polymorphism (rs2282440) is associated with MetS in the Taiwanese population. Methods. Genotypes of SDC3 polymorphism (rs2282440) were analyzed in 545 Taiwanese adult subjects, of which 154 subjects had MetS. Results. Subjects with SDC3 rs2282440 TT homozygote had higher frequency of MetS than those with CC or CT genotype (). SDC3 rs2282440 TT homozygote had a 1.96-fold risk of being obese and 1.8-fold risk of having MetS (with CC genotype as reference). As for the individual components of MetS, subjects with SDC3 rs2282440 TT homozygote were more likely to have large waist circumference and low high-density lipoprotein cholesterol (OR = 1.75 and OR = 1.84, resp.). Conclusion. SDC3 rs2282440 polymorphism is positively associated with MetS in the Taiwanese population. Further investigation is needed to see if this association is mediated by mere adiposity or SDC3 polymorphism is also linked with other components of MetS such as lipid metabolism.

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