bluuebunny/crossref_metadata_2025 huggingface dataset:
Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D2 receptor activation using multi‐biomarker pharmacokinetic/pharmacodynamic modelling
Authors: van den Brink Willem J , van den Berg Dirk‐Jan , Bonsel Floor E M , Hartman Robin , Wong Yin‐Cheong , van der Graaf Piet H , de Lange Elizabeth C M
Published: July 2018

Background and Purpose

Because biological systems behave as networks, multi‐biomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint was identified using multi‐biomarker pharmacokinetic/pharmacodynamic (PK/PD) modelling. Short‐ and long‐term D2 receptor activation was evaluated using quinpirole as a paradigm compound.

Experimental Approach

Rats received 0, 0.17 or 0.86 mg·kg−1 of the D2 agonist quinpirole i.v. Quinpirole concentrations in plasma and brain extracellular fluid (brainECF), as well as plasma concentrations of 13 hormones and neuropeptides, were measured. Experiments were performed at day 1 and repeated after 7‐day s.c. drug administration. PK/PD modelling was applied to identify the in vivo concentration–effect relations and neuroendocrine dynamics.

Key Results

The quinpirole pharmacokinetics were adequately described by a two‐compartment model with an unbound brainECF‐to‐plasma concentration ratio of 5. The release of adenocorticotropic hormone (ACTH), growth hormone, prolactin and thyroid‐stimulating hormone (TSH) from the pituitary was influenced. Except for ACTH, D2 receptor expression levels on the pituitary hormone‐releasing cells predicted the concentration–effect relationship differences. Baseline levels (ACTH, prolactin, TSH), hormone release (ACTH) and potency (TSH) changed with treatment duration.

Conclusions and Implications

The integrated multi‐biomarker PK/PD approach revealed a fingerprint reflecting D2 receptor activation. This forms the conceptual basis for in vivo evaluation of on‐ and off‐target CNS drug effects. The effect of treatment duration is highly relevant given the long‐term use of D2 agonists in clinical practice. Further development towards quantitative systems pharmacology models will eventually facilitate mechanistic drug development.
DS‐70, a novel and potent α4 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs
Authors: Dattoli Samantha Deianira , Baiula Monica , De Marco Rossella , Bedini Andrea , Anselmi Michele , Gentilucci Luca , Spampinato Santi
Published: July 2018

Background and Purpose

Allergic conjunctivitis is an eye inflammation that involves the infiltration of immune cells into the conjunctiva via cell surface‐adhesion receptors, such as integrin α4β1. These receptors interact with adhesion molecules expressed on the conjunctival endothelium and may be a target to treat this disease. We synthesized DS‐70, a novel α/β‐peptidomimetic α4 integrin antagonist, to prevent the conjunctival infiltration of immune cells and clinical symptoms in a model of allergic conjunctivitis.

Experimental Approach

In vitro, DS‐70 was pharmacologically characterized using a scintillation proximity procedure to measure its affinity for α4β1 integrin, and its effect on cell adhesion mediated by different integrins was also evaluated. The effects of DS‐70 on vascular cell adhesion molecule‐1 (VCAM‐1)‐mediated degranulation of a human mast cell line and an eosinophilic cell line, which both express α4β1, and on VCAM‐1‐mediated phosphorylation of ERK 1/2 in Jurkat E6.1 cells were investigated. Effects of DS‐70 administered in the conjunctival fornix of ovalbumin‐sensitized guinea pigs were evaluated.

Key Results

DS‐70 bound to integrin α4β1 with nanomolar affinity, prevented the adhesion of α4 integrin‐expressing cells, antagonized VCAM‐1‐mediated degranulation of mast cells and eosinophils and ERK 1/2 phosphorylation. Only 20% was degraded after an 8 h incubation with serum. DS‐70 dose‐dependently reduced the clinical symptoms of allergic conjunctivitis, conjunctival α4 integrin expression and conjunctival levels of chemokines and cytokines in ovalbumin‐sensitized guinea pigs.

Conclusions and Implications

These findings highlight the role of α4 integrin in allergic conjunctivitis and suggest that DS‐70 is a potential treatment for this condition.
Association between thyroid hormone levels, body composition and insulin resistance in euthyroid subjects with normal thyroid ultrasound: The Kangbuk Samsung Health Study
Authors: Kwon Hyemi , Cho Jung‐Hwan , Lee Da Young , Park Se Eun , Park Cheol‐Young , Lee Won‐Young , Oh Ki‐Won , Park Sung‐Woo , Rhee Eun‐Jung
Published: July 2018

Objective

Thyroid hormones play crucial roles in the control of energy homoeostasis and can influence body composition. In contrast, the changes in body composition might influence thyroid hormone levels. We evaluated associations between thyroid hormone levels, body composition and insulin resistance in euthyroid subjects with normal thyroid ultrasound (US) findings.

Design and Patients

This retrospective cross‐sectional study included 36 655 euthyroid subjects who joined the medical health check‐up programme at our institution. Serum thyroid hormone levels were analysed in association with body fat percentage (BFP), skeletal muscle mass index (SMI) and homoeostatic model assessment of insulin resistance (HOMA‐IR). Linear regression analyses were performed to evaluate relationships between thyroid hormone levels and anthropometric parameters.

Results

Mean age was 36.4 years, and 49% of subjects were female. In multiple linear regression analysis, serum‐free triiodothyronine (FT3) levels exhibited positive associations with waist circumference (WC) and HOMA‐IR and a negative association with body weight, body mass index (BMI) and SMI among both men and women. The association between serum‐free thyroxine (FT4) levels and anthropometric markers showed inconsistent results in men and women. Serum thyroid‐stimulating hormone (TSH) levels showed a positive association with HOMA‐IR in both men and women.

Conclusions

Lower SMI was significantly associated with higher serum FT3 levels, the active form of thyroid hormone, in both men and women. Higher insulin resistance was positively associated with serum FT3 levels and inversely associated with serum TSH levels in euthyroid subjects with normal thyroid US findings.
Examining fostering readiness in treatment parents
Authors: Strickler Amy , Mihalo Jennifer R. , Celedonia Karen L. , Kaelin Michael S.
Published: July 2018

Preservice trainings have the potential to improve treatment parent and youth outcomes, yet researchers have noted the lack of empirical research on the effectiveness of these trainings. Preservice outcomes are typically collected immediately after training completion, with little to no follow‐up assessments at other time points. This study aimed to examine the longitudinal changes treatment parents experience throughout preservice training and after a youth is placed in their home. Secondary data analyses were performed on an archival data set (N = 57) that included demographic information and training participant scores from two standardized measurements that examined their fostering readiness before and after preservice trainings as well as after a youth was placed in the home: Personal Dedication to Fostering Scale and Willingness to Foster Scale. Analyses revealed significant changes for treatment parents' personal dedication to fostering, but no significant changes for their willingness to foster. Treatment parents' fostering readiness scores were compared to a normed sample of foster parents and were found to be significantly higher for their personal dedication scores but not for their willingness to foster. The findings suggest certain treatment parent outcomes may change as a result of preservice training and experience with youth, but additional measurements and outcomes should be examined.
A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia
Authors: Uchiyama Yuri , Yanagisawa Kunio , Kunishima Shinji , Shiina Masaaki , Ogawa Yoshiyuki , Nakashima Mitsuko , Hirato Junko , Imagawa Eri , Fujita Atsushi , Hamanaka Kohei , Miyatake Satoko , Mitsuhashi Satomi , Takata Atsushi , Miyake Noriko , Ogata Kazuhiro , Handa Hiroshi , Matsumoto Naomichi , Mizuguchi Takeshi
Published: July 2018

We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α‐helix of the cytochrome c (CYCS) C‐terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in‐frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss‐of‐function variants.
Weight gain after kidney donation: Association with increased risks of type 2 diabetes and hypertension
Authors: Issa Naim , Sánchez Otto A. , Kukla Aleksandra , Riad Samy M. , Berglund Danielle M. , Ibrahim Hassan N. , Matas Arthur J.
Published: July 2018

In the general population, obesity is associated with an increased risk of developing hypertension (HTN), type 2 diabetes mellitus (DM), and end‐stage renal disease (ESRD). Therefore, most transplant centers have a body mass index (BMI) threshold for accepting living kidney donors. But there have been no studies of postdonation weight gain trends and any associated risks. We tracked serial BMIs in 940 donors for a median (IQ range) follow‐up of 22.3 (15.4‐35.8) years. We studied the impact of postdonation weight gain in a model adjusted for family history of HTN or DM. Donor characteristics included age, sex, smoking, fasting blood glucose, eGFR, systolic and diastolic BP, and BMI at time of donation and time postdonation. Postdonation weight gain was associated with a significant increase in the relative risk of developing HTN RR 1.93 (95% CI 1.51‐2.46) (P < 0.001) and/or DM RR 4.18 (95% CI 2.05‐8.5) (P < 0.0001), but not (to date) cardiovascular disease (CVD), reduced eGFR or death. Like the general population, donors gained weight as they aged; a higher BMI was associated with higher incidence of DM and HTN. Postdonation care should include ongoing counseling on the risks of substantial weight gain.
Meeting report: Consensus recommendations for a research agenda to address immunosuppressant nonadherence in organ transplantation
Authors: Maldonado Angela Q. , West‐Thielke Patricia , Dew Mary Amanda , Peipert John Devin , Heldenbrand Seth , Kaiser Tiffany E. , Chisholm‐Burns Marie , Potter Lisa M. ,   the AST Transplant Pharmacy Adherence Consortium (AST TPAC)
Published: July 2018

Despite advances in the field of transplantation, immunosuppressant medication nonadherence (NA) remains a primary contributor to suboptimal long‐term outcomes. Due to the multidimensional and multifactorial causes of medication NA, studies to date have focused on individual differing facets or single point barriers of NA with relative success. However, these successes have not proven to be sustainable, partly due to the intense resources needed for continued viability. This article provides a summary of a 2‐day meeting held in April 2017 (Chicago, IL) prior to the American Transplant Congress in which a multidisciplinary group convened to identify the unmet research needs related to medication NA in transplantation. Thought leaders in the field presented the past, present, and future directions of medication NA with the primary outcome of designing, developing, and ranking targeted interventions into a dynamic research agenda to identify which interventions maintained effects over time. Break‐out sessions were created based on the five World Health Organization (WHO) dimensions of adherence. Participants were then organized into the newly formed AST Transplant Pharmacy Adherence Consortium (AST TPAC) research group. This meeting report summarizes the content of the symposium, and the development, background, and future directions of the AST TPAC.
Assessment of Dermal Absorption of Aluminum from a Representative Antiperspirant Formulation Using a 26Al Microtracer Approach
Authors: de Ligt Rianne , van Duijn Esther , Grossouw Dimitri , Bosgra Sieto , Burggraaf Jacobus , Windhorst Albert , Peeters Pierre A.M. , van der Luijt Gerrit A. , Alexander‐White Camilla , Vaes Wouter H.J.
Published: July 2018

A clinical pharmacokinetic study was performed in 12 healthy women to evaluate systemic exposure to aluminum following topical application of a representative antiperspirant formulation under real‐life use conditions. A simple roll‐on formulation containing an extremely rare isotope of aluminum (26Al) chlorohydrate (ACH) was prepared to commercial specifications. A 26Al radio‐microtracer was used to distinguish dosed aluminum from natural background, using accelerated mass spectroscopy. The 26Al citrate was administered intravenously (i.v.) to estimate fraction absorbed (Fabs) following topical delivery. In blood samples after i.v. administration, 26Al was readily detected (mean area under the curve (AUC) = 1,273 ± 466 hours×fg/mL). Conversely, all blood samples following topical application were below the lower limit of quantitation (LLOQ; 0.12 fg/mL), except two samples (0.13 and 0.14 fg/mL); a maximal AUC was based on LLOQs. The aluminum was above the LLOQ (61 ag/mL) in 31% of urine samples. From the urinary excretion data, a conservative estimated range for dermal Fabs of 0.002–0.06% was calculated, with a mean estimate of 0.0094%.
Leptin concentration and oxidative stress in diabetic ketoacidosis
Authors: Li Juan , Shen Xingping
Published: July 2018

Background

Diabetes is a common metabolic state during ageing, and one in five elderly individuals suffers from diabetes. However, few studies have been performed in elderly diabetic patients, and large randomized clinical trials in this population are rare. The purpose of this study was to investigate changes in serum leptin levels in elderly patients with diabetic ketoacidosis (DKA) before and after treatment and assess its relationship with oxidative stress parameters.

Materials and methods

Serum leptin levels, plasma superoxide dismutase (SOD) activity, plasma malondialdehyde (MDA) levels, plasma total antioxidant capacity (TAC) and plasma 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α) levels were measured in elderly patients aged 81.76 ± 9.42 years with DKA before and after treatment.

Results

Plasma SOD activity, TAC and serum leptins before treatment were significantly lower in elderly patients with DKA compared with the control group (P < 0.05), whereas plasma MDA and 8‐iso‐PGF2α levels before treatment were significantly higher in elderly patients with DKA (P < 0.05). Plasma SOD activity, TAC and serum leptin levels in elderly patients with DKA were significantly elevated after treatment, whereas their plasma MDA and 8‐iso‐PGF2α levels were significantly reduced (P < 0.05). Leptin levels negatively correlated with plasma 8‐iso‐PGF2α after treatment in elderly DKA patients (r = −0.36, P < 0.05). Stepwise multiple regression analysis showed that 8‐iso‐PGF2α was a significant factor affecting serum leptin levels.

Conclusions

Serum leptin levels in the elderly patients with DKA were significantly reduced after treatment, which was associated with oxidative stress.
Dental trauma in social media—Analysis of Facebook content and public engagement
Authors: Abu‐Ghazaleh Suha , Hassona Yazan , Hattar Susan
Published: July 2018

Background/Aim

Social media sites such as Facebook are increasingly used to obtain healthcare‐related information. The aim of this study was to examine Facebook content on dental trauma and to assess public engagement with this content.

Materials and Methods

An anonymous account was created to search Facebook for information on dental trauma using the key words “dental trauma,” “broken tooth,” “tooth fracture,” and “tooth trauma” over a period of 1 year (from February 27, 2017, to February 27, 2018). The content was analyzed with regard to demographic characteristics, topic domains, and public engagement.

Results

A total of 395 Facebook pages and 149 groups were identified, but only one page and two groups met the inclusion criteria. There were 329 posts on dental trauma during the study period. More than half of the posts were event advertisements and personal highlights (56.2%), followed by posts mentioning articles in academia (17.9%). The average yearly engagement rate was 0.25%; news posts generated the highest engagement rate (0.76%), while academic posts generated the lowest engagement rate (0.16%). The singular post that generated the highest engagement rate (2.2%) was a news post referring to a dental trauma incident suffered by a professional football player. Only 14 posts (4.3%) contained information on prevention and immediate management of dental trauma.

Conclusions

Facebook information on dental trauma is limited in quantity and quality. More emphasis should be placed on posting information suitable for the layperson and concerned with the basics of prevention and immediate management of dental trauma.
Dental caries and externalizing behaviour problems in a high‐risk child population
Authors: de Jong‐Lenters Maddelon , Duijster Denise , Schuller Annemarie , van Loveren Cor , Verrips Erik
Published: July 2018

The aim of this study was to assess the association between externalizing behaviour problems and dental caries in children. A further objective was to explore direct and indirect pathways between sociodemographic factors, family functioning and parenting factors, oral health behaviours, externalizing behaviour problems, and dental caries using structural equation modelling. Cross‐sectional data were collected on 251, 5‐ to 8‐yr‐old children from a paediatric dental practice in the Netherlands. Children's decayed, missing, and filled primary teeth (dmft) scores were obtained from their dental records. Validated self‐report questionnaires were used to collect sociodemographic, behavioural, and family‐related data. Externalizing problem behaviour was significantly associated with a higher dmft score [incidence risk ratio (IRR) = 1.19; 95% CI: 1.06–1.34], but this association did not remain significant after adjustment for sociodemographic factors (IRR = 1.11; 95% CI: 0.99–1.26). A valid path model was presented after applying some modifications. Findings from the model suggest that it is plausible that child behaviour problems are directly associated with dental caries via toothbrushing behaviour. The model also provided support that maternal education level, the restrictiveness and warmth of parenting, and the communication of the family, play an indirect role in the association between children's externalizing behavioural problems and dental caries experience.
Dose‐ and time‐dependent effects of triethylene glycol dimethacrylate on the proteome of human THP‐1 monocytes
Authors: Nilsen Bo W. , Simon‐Santamaria Jaione , Örtengren Ulf , Jensen Einar , Bruun Jack‐Ansgar , Michelsen Vibeke B. , Sørensen Karen K.
Published: July 2018

Triethylene glycol dimethacrylate (TEGDMA) is commonly used in polymer resin‐based dental materials. This study investigated the molecular mechanisms of TEGDMA toxicity by identifying its time‐ and dose‐dependent effects on the proteome of human THP‐1 monocytes. The effects of different concentrations (0.07–5 mM) and exposure times (0–72 h) of TEGDMA on cell viability, proliferation, and morphology were determined using a real‐time viability assay, automated cell counting, and electron microscopy, and laid the fundament for choice of exposure scenarios in the proteomic experiments. Solvents were not used, as TEGDMA is soluble in cell culture medium (determined by photon correlation spectroscopy). Cells were metabolically labeled [using the stable isotope labeled amino acids in cell culture (SILAC) strategy], and exposed to 0, 0.3 or 2.5 mM TEGDMA for 6 or 16 h before liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) analyses. Regulated proteins were analyzed in the STRING database. Cells exposed to 0.3 mM TEGDMA showed increased viability and time‐dependent upregulation of proteins associated with stress/oxidative stress, autophagy, and cytoprotective functions. Cells exposed to 2.5 mM TEGDMA showed diminished viability and a protein expression profile associated with oxidative stress, DNA damage, mitochondrial dysfunction, and cell cycle inhibition. Altered expression of immune genes was observed in both groups. The study provides novel knowledge about TEGDMA toxicity at the proteomic level. Of note, even low doses of TEGDMA induced a substantial cellular response.
Continental‐scale nitrogen pollution is shifting forest mycorrhizal associations and soil carbon stocks
Authors: Averill Colin , Dietze Michael C. , Bhatnagar Jennifer M.
Published: July 2018

Most tree roots on Earth form a symbiosis with either ecto‐ or arbuscular mycorrhizal fungi. Nitrogen fertilization is hypothesized to favor arbuscular mycorrhizal tree species at the expense of ectomycorrhizal species due to differences in fungal nitrogen acquisition strategies, and this may alter soil carbon balance, as differences in forest mycorrhizal associations are linked to differences in soil carbon pools. Combining nitrogen deposition data with continental‐scaleUSforest data, we show that nitrogen pollution is spatially associated with a decline in ectomycorrhizal vs. arbuscular mycorrhizal trees. Furthermore, nitrogen deposition has contrasting effects on arbuscular vs. ectomycorrhizal demographic processes, favoring arbuscular mycorrhizal trees at the expense of ectomycorrhizal trees, and is spatially correlated with reduced soil carbon stocks. This implies future changes in nitrogen deposition may alter the capacity of forests to sequester carbon and offset climate change via interactions with the forest microbiome.
Assessing environmental impacts and change in Myanmar's mangrove ecosystem service value due to deforestation (2000–2014)
Authors: Estoque Ronald C. , Myint Soe W. , Wang Chuyuan , Ishtiaque Asif , Aung Toe T. , Emerton Lucy , Ooba Makoto , Hijioka Yasuaki , Mon Myat S. , Wang Zhe , Fan Chao
Published: July 2018

Myanmar is one of the mangrove‐richest countries in the world, providing valuable ecosystem services to people. However, due to deforestation driven primarily by agricultural expansion, Myanmar's mangrove forest cover has declined dramatically over the past few decades, while what remains is still under pressure. To support management planning, accurate quantification of mangrove forest cover changes on a national scale is needed. In this study, we quantified Myanmar's mangrove forest cover changes between 2000 and 2014 using remotely sensed data, examined the environmental impacts of such changes, and estimated the changes in the economic values of mangrove ecosystem services in the country. Results indicate that Myanmar had a net mangrove loss of 191,122 ha over the study period. Since 2000, Myanmar has been losing mangrove forest cover at an alarming rate of 14,619 ha/year (2.2%/year). The loss was predominant in Rakhine and Ayeyarwady. The observed mangrove forest cover loss has resulted in decreased evapotranspiration, carbon stock, and tree cover percentage. Due to deforestation, Myanmar also suffered a net loss of 2,397 million US$/year in its mangrove ecosystem service value (i.e. 28.7% decrease from 2000), in which maintenance of fisheries nursery populations and habitat and coastal protection were among those services that were greatly affected. We suggest that intensive reforestation and mangrove protection programs be implemented immediately. Agroforestry and community forestry programs are encouraged in areas that are under immense pressure from paddy field expansion, fuelwood extraction, charcoal production, and fish and shrimp farming activities. Potential alternative sustainable solutions should include intensive government‐led private forest plantations or community‐owned forest plantations to be developed with care by local farmers, nongovernmental organizations, and business owners.
Dental status in the Polish senior population and its correlates—Results of the national survey PolSenior
Authors: Mehr Katarzyna , Olszanecka‐Glinianowicz Magdalena , Chudek Jerzy , Szybalska Aleksandra , Mossakowska Małgorzata , Zejda Jan , Wieczorowska‐Tobis Katarzyna , Grodzicki Tomasz , Piotrowski Paweł
Published: July 2018

Objective

The aim of the study was to assess dental status of Polish seniors having and wearing dentures in relation to demographic, socioeconomic and lifestyle factors.

Background

Tooth loss is associated with deterioration of general health status. The epidemiological data on dental status in Poland, including Polish seniors, are fragmented.

Materials and methods

The study cohort consisted of 4524 randomly selected participants, aged 65 years and over, representative for Polish seniors. Demographic, socioeconomic, lifestyle factors and dental status were collected using standardised questionnaires.

Results

The prevalence of partial and complete edentulism in the Polish senior population was estimated at 45.7% and 47.1%, respectively. Fourteen point four per cent (14.4%) of complete edentulous participants and 31.1% with partial edentulism (1‐19 natural teeth) did not have dentures, and one‐twelfth of respondents having dentures were not wearing them. The independent correlates of complete edentulism were: female sex, advanced age, rural dwelling, lower education level, physical work in the past, smoking and diabetes. Male sex, age 90+, rural dwelling, type of work, dependence in activities of daily living and partial edentulism were independent correlates of not having dentures and denture disuse. Lower than average personal income was only significant for not having dentures.

Conclusions

Complete edentulism is frequent among older Poles and affects almost 50% of them. It is associated with female sex, age, rural dwelling, poor economic status, smoking and diabetes. Rural dwelling and dependence of daily living are significant correlates of not having dentures and denture disuse.
Inflating profits and industry competitiveness
Authors: Beladi Hamid , Marjit Sugata , Oladi Reza
Published: July 2018

We provide a theoretical model in which managers inflate actual profits to attract capital and shareholders cannot monitor such actions. We focus on the role of market competition in cross‐industry difference in financial performance overstatement. We show that the degree of competition negatively affects the extent of overstatement.
Intranasal immunization with recombinant chlamydial protease‐like activity factor attenuates atherosclerotic pathology following Chlamydia pneumoniae infection in mice
Authors: Li Weidang , Gudipaty Pareesha , Li Chuxi , Henderson Kyle K , Ramsey Kyle H , Murthy Ashlesh K
Published: July 2018

We have shown previously that intranasal vaccination with recombinant chlamydial protease‐like activity factor (rCPAF: antigen) and interleukin‐12 (IL‐12) as an adjuvant induces robust protection against pathological consequences of female genital tract infection with Chlamydia muridarum, a closely related species and a rodent model for the human pathogen Chlamydia trachomatis. Another related species Chlamydia pneumoniae, a human respiratory pathogen, has been associated with exacerbation of atherosclerotic pathology. CPAF is highly conserved among Chlamydia spp. leading us to hypothesize that immunization with rCPAF with IL‐12 will protect against high‐fat diet (HFD) and C. pneumoniae‐induced acceleration of atherosclerosis. rCPAF ± IL‐12 immunization induced robust splenic antigen (Ag)‐specific IFN‐γ and TNF‐α production and significantly elevated serum total anti‐CPAF Ab, IgG2c, and IgG1 antibody levels compared to mock or IL‐12 alone groups. The addition of IL‐12 to rCPAF significantly elevated splenic Ag‐specific IFN‐γ production and IgG2c/IgG1 anti‐CPAF antibody ratio. Following intranasal C. pneumoniae challenge and HFD feeding, rCPAF ± IL‐12‐immunized mice displayed significantly enhanced splenic IFN‐γ, not TNF‐α, response on days 6 and 9 after challenge, and significantly reduced lung chlamydial burden on day 9 post‐challenge compared to mock‐ or IL‐12‐immunized mice. Importantly, rCPAF ± IL‐12‐immunized mice displayed significantly reduced atherosclerotic pathology in the aortas after C. pneumoniae challenge. Serum cholesterol levels were comparable between the groups suggesting that the observed differences in pathology were due to protective immunity against the infection. Together, these results confirm and extend our previous observations that CPAF is a promising candidate antigen for a multisubunit vaccine regimen to protect against Chlamydia‐induced pathologies, including atherosclerosis.
Seasonality and clinical impact of human parainfluenza viruses
Authors: Maykowski Philip , Smithgall Marie , Zachariah Philip , Oberhardt Matthew , Vargas Celibell , Reed Carrie , Demmer Ryan T. , Stockwell Melissa S. , Saiman Lisa
Published: July 2018

Background

Widespread availability of rapid diagnostic testing for respiratory viruses allows more in‐depth studies of human parainfluenza viruses (HPIV).

Objectives

This study aimed to assess seasonality of HPIV types 1‐4, clinical outcomes by HPIV type, and risk factors for illness severity.

Patients/Methods

This retrospective study was performed from January 2013 to December 2015 in children and adults with HPIV, detected by multiplex reverse transcription polymerase chain reaction, participating in a community surveillance study of acute respiratory infections (ARIs) in New York City and patients admitted to a tertiary care center in the same neighborhood. Seasonality trends by HPIV type were compared between the community and hospital groups. The associations between HPIV type, demographics, clinical characteristics, and illness severity were assessed.

Results

HPIV was detected in 69 (4%) of 1753 community surveillance participants (median age 9.2 years) and 680 hospitalized patients (median age 6.8 years). Seasonality for HPIV types 1‐3 agreed with previously described patterns; HPIV‐4 occurred annually in late summer and fall. In the community cohort, 22 (32%) participants sought medical care, 9 (13%) reported antibiotic use, and 20 (29%) reported ≥1 day of missed work or school. Among hospitalized patients, 24% had ≥4 chronic conditions. Multivariable ordinal logistic regression demonstrated that increased severity of illness was significantly associated with HPIV‐4 and chronic cardiovascular and respiratory conditions in children and with age ≥65 years and chronic respiratory conditions in adults.

Conclusions

HPIV‐4 presented late summer and early fall annually and was associated with increased severity of illness in hospitalized children.
Outpatient influenza antivirals in a distributed data network for influenza surveillance
Authors: Cocoros Noelle M. , Panucci Genna , Haug Nicole , Maher Carmen , Reichman Marsha , Toh Sengwee
Published: July 2018

Electronic data collected from routine health care can be used for public health surveillance. To examine the Sentinel System, a distributed data network of health plans, as a source for influenza surveillance, we compared trends in outpatient prescription dispensings of influenza antivirals in Sentinel to trends in CDC's ILINet and NREVSS systems over five seasons. There were 2 102 885 dispensed prescriptions of oseltamivir capsules, 494 188 of oseltamivir powder, and 7955 of zanamivir. Across all seasons, the magnitude and timing of peaks in drug utilization were highly comparable to those in ILINet and NREVSS. Oseltamivir capsules and powder were well correlated with ILINet and NREVSS. This lays the foundation for further exploration of Sentinel's utility for influenza surveillance.
Do parenting behaviors modify the way sensation seeking influences antisocial behaviors?
Authors: Okuda Mayumi , Martins Silvia S. , Wall Melanie M. , Chen Chen , Santaella‐Tenorio Julian , Ramos‐Olazagasti Maria , Wei Chiaying , Canino Glorisa , Bird Hector R. , Duarte Cristiane S.
Published: July 2018

Background

Parenting behaviors have been shown to moderate the association between sensation seeking and antisocial behaviors.

Methods

Data were obtained from the Boricua Youth Study, a longitudinal study of 2,491 Puerto Rican youth living in the South Bronx, New York, and the metropolitan area of San Juan, Puerto Rico. First, we examined the prospective relationship between sensation seeking and antisocial behaviors across 3 yearly waves and whether this relationship varied by sociodemographic factors. Second, we examined the moderating role of parenting behaviors—including parental monitoring, warmth, and coercive discipline—on the prospective relationship between sensation seeking and antisocial behaviors.

Results

Sensation seeking was a strong predictor of antisocial behaviors for youth across two different sociocultural contexts. High parental monitoring buffered the association between sensation seeking and antisocial behaviors, protecting individuals with this trait. Low parental warmth was associated with high levels of antisocial behaviors, regardless of the sensation seeking level. Among those with high parental warmth, sensation seeking predicted antisocial behaviors, but the levels of antisocial behaviors were never as high as those of youth with low parental warmth.

Conclusions

Study findings underscore the relevance of person–family context interactions in the development of antisocial behaviors. Future interventions should focus on the interplay between individual vulnerabilities and family context to prevent the unhealthy expression of a trait that is present in many individuals.
Rethinking disease in psychiatry: Disease models and the medical imaginary
Authors: Radden Jennifer
Published: July 2018

The first decades of the 21st century have seen increasing dissatisfaction with the diagnostic psychiatry of the American Psychiatric Association's Diagnostic and Statistical Manuals (DSMs). The aim of the present discussion is to identify one source of these problems within the history of medicine, using melancholy and syphilis as examples. Coinciding with the 19th‐century beginnings of scientific psychiatry, advances that proved transformative and valuable for much of the rest of medicine arguably engendered, and served to entrench, mistaken, and misleading conceptions of psychiatric disorder. Powerful analogical reasoning based on what is assumed, projected, and expected (and thus occupying the realm of the medical imaginary), fostered inappropriate models for psychiatry. Dissatisfaction with DSM systems have given rise to alternative models, exemplified here in (i) network models of disorder calling for revision of ideas about causal explanation, and (ii) the critiques of categorical analyses associated with recently revised domain criteria for research. Such alternatives reflect welcome, if belated, revisions.
Population dynamics of a poorly known serranid, the duskytail grouper Epinephelus bleekeri in the Arabian Sea
Authors: Richu Avinipully , Dahanukar Neelesh , Ali Anvar , Ranjeet Kutty , Raghavan Rajeev
Published: July 2018

A demographic study on Epinephelus bleekeri based on a sample of 1,003 individuals caught in commercial fisheries along the Arabian Sea coast of southern India considerably extends the maximum recorded standard length for this species to 870 mm, indicates a high natural mortality rate and an exploitation level (E) greater than the Emax.
Multilocus sequence typing reveals clonality in Saprolegnia parasitica outbreaks
Authors: Ravasi Damiana , De Respinis Sophie , Wahli Thomas
Published: July 2018

The molecular epidemiology of fish pathogen Saprolegnia parasitica is still largely unknown. We developed a multilocus sequence typing scheme based on seven housekeeping genes to characterize 77 S. parasitica strains isolated from different fish host species at different times and from different geographic areas in Switzerland between 2015 and 2017. Ten different diploid sequence types (DSTs) were identified. The majority (52%) of outbreaks in Switzerland seemed to be caused by one genotype, namely DST3, which was recovered from farm‐raised and wild‐caught fish in all the geographic areas and river basins included in the study. DST3 was also recovered from the rivers Bienne (eastern France) and Doubs, where the episodes of massive mortality due to saprolegniosis started in 2009. Another genotype (DST7) showed, to a lesser extent, a distribution across different river basins, while eight DSTs were unique to a defined geographic area or river basin. The occurrence of sporadic DSTs indicates a certain degree of diversity within S. parasitica in the environment. The wide distribution of DST3 suggests that a clonal population may have spread in eastern France and Switzerland across geographic barriers, with strong implications for the management of both captive and wild fish populations.
The effect of β‐1,3‐glucan derived from Euglena gracilis (Algamune™) on the innate immunological responses of Nile tilapia (Oreochromis niloticus L.)
Authors: Yamamoto Fernando Y. , Sutili Fernando J. , Hume Michael , Gatlin Delbert M.
Published: July 2018

Algamune™ is a commercial additive produced from Euglena gracilis, providing a rich source of the β‐1,3‐glucan paramylon. Isolated kidney phagocytes of Nile tilapia were incubated with graded doses (0, 8, 16, 32, 64 and 128 μg/ml) of Algamune™ and purified paramylon to gauge their ability to elicit the production of reactive oxygen species. A linear response was observed for extracellular superoxide anion for both sources but only Algamune™ for intracellular superoxide anion. After corroborating the immunostimulant properties ex vivo, a feeding trial was conducted to evaluate the dietary supplementation of Algamune™ (0, 100, 200, 400 and 800 mg/kg of diet) for Nile tilapia. Fish were fed for 3 weeks, after which, fish were sampled for blood and head kidney phagocytes. The remaining fish were challenged with Streptococcus iniae. Macrophage extracellular superoxide anion production was significantly elevated in fish fed diets with 200 mg of Algamune™ kg−1 when compared to fish fed the basal diet. Even though the disease challenge did not show statistical differences, it is worth mentioning that fish fed intermediate doses of Algamune™ had lowest numerical mortality values. Therefore, Algamune™ was demonstrated to enhance some immunological responses of tilapia both in ex vivo and in vivo.
pirA‐ and pirB‐like gene identification in Micrococcus luteus strains in Mexico
Authors: Durán‐Avelar Ma. de Jesús , Vázquez‐Reyes Alejandro , González‐Mercado Ana Lourdes , Zambrano‐Zaragoza José Francisco , Ayón‐Pérez Miriam Fabiola , Agraz‐Cibrián Juan Manuel , Gutiérrez‐Franco Jorge , Vibanco‐Pérez Norberto
Published: July 2018

Acute hepatopancreatic necrosis disease (AHPND) was first reported in China in 2009 and afterwards in Mexico in 2013. AHPND is caused by Vibrio parahaemolyticus and affects Penaeus monodon and Litopenaeus vannamei shrimp cultures. The bacterium contains the pirA‐ and pirB‐like genes in 69‐ to 70‐Kb plasmids, which encode the toxins that produce the disease. The aim of this study was to determine whether pirA‐ and pirB‐like genes existed in bacterial genera distinct from Vibrio before the first cases of AHPND were documented in Mexico. Two bacterial isolates were selected from shrimp farms in Nayarit in 2006 and analysed by nested‐PCR to determine the presence of pirA‐ and pirB‐like genes. The two isolates chosen did indeed show the presence of these genes, and those findings were confirmed by sequencing. Both strains matched to the bacterial species Micrococcus luteus. Results revealed two important situations: (a) the pirA‐ and pirB‐like genes were present in a bacterial species that has not been reported previously (Micrococcus luteus); and (b) pirA‐ and pirB‐like bacterial genes were present in Mexico before the first AHPND outbreak was reported in China.
Biomarkers for Alzheimer's disease: current status and prospects for the future
Authors: Blennow K. , Zetterberg H.
Published: July 2018

Accumulating data from the clinical research support that the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid‐β (Aβ42), total tau (T‐tau), and phosphorylated tau (P‐tau) reflect key elements of AD pathophysiology. Importantly, a large number of clinical studies very consistently show that these biomarkers contribute with diagnostically relevant information, also in the early disease stages. Recent technical developments have made it possible to measure these biomarkers using fully automated assays with high precision and stability. Standardization efforts have given certified reference materials for CSF Aβ42, with the aim to harmonize results between assay formats that would allow for uniform global reference limits and cut‐off values. These encouraging developments have led to that the core AD CSF biomarkers have a central position in the novel diagnostic criteria for the disease and in the recent National Institute on Aging and Alzheimer's Association biological definition of AD. Taken together, this progress will likely serve as the basis for a more general introduction of these diagnostic tests in clinical routine practice. However, the heterogeneity of pathology in late‐onset AD calls for an expansion of the AD CSF biomarker toolbox with additional biomarkers reflecting additional aspects of AD pathophysiology. One promising candidate is the synaptic protein neurogranin that seems specific for AD and predicts future rate of cognitive deterioration. Further, recent studies bring hope for easily accessible and cost‐effective screening tools in the early diagnostic evaluation of patients with cognitive problems (and suspected AD) in primary care. In this respect, technical developments with ultrasensitive immunoassays and novel mass spectrometry techniques give promise of biomarkers to monitor brain amyloidosis (the Aβ42/40 or APP669‐711/Aβ42 ratios) and neurodegeneration (tau and neurofilament light proteins) in plasma samples, but future studies are warranted to validate these promising results further.
RNA interference of long noncoding RNA HOTAIR suppresses autophagy and promotes apoptosis and sensitivity to cisplatin in oral squamous cell carcinoma
Authors: Wang Xia , Liu Wei , Wang Peiyuan , Li Shu
Published: July 2018

Background

Long noncoding RNA HOX transcript antisense RNA (lncRNA HOTAIR) is overexpressed in many types of human cancers and is correlated with clinical stage and lymph node metastasis in oral squamous cell carcinoma (OSCC). Autophagy, an important mechanism of self‐protection, plays vital roles in adapting to hypoxia, tolerating external stimulation, and inducing chemotherapy resistance in OSCC cells. This study aims to investigate the effect of HOTAIR on autophagy, apoptosis, and invasion of OSCC cells.

Methods

HOTAIR expression in OSCC cells was knocked down by small RNA interference. Transmission electron microscope, Western blot, and flow cytometry assay were used to detect the level of autophagy and apoptosis. OSCC cells were medicated with cisplatin, and median lethal dose (LD50) was performed to evaluate the effect on chemosensitivity of HOTAIR.

Results

After HOTAIR silence, autophagy was inhibited with the downregulated expression of MAP1LC3B (microtubule‐associated protein 1 light chain 3B), beclin1, and autophagy‐related gene (ATG) 3 and ATG7. The expressions of mTOR increased. Proliferation, migration, and invasion of OSCC cells were suppressed. Furthermore, apoptosis rate was enhanced, and the sensitivity to cisplatin was promoted when compared with the negative control group.

Conclusion

HOTAIR acts as an oncogene in OSCC cells, and HOTAIR silence may be a potential therapeutic target for OSCC.
Lacosamide in children with drug‐resistant epilepsy
Authors: Rüegger Andrea D , Freeman Jeremy L , Harvey A Simon
Published: July 2018

Aim

To assess the effectiveness and tolerability of lacosamide in paediatric clinical practice.

Methods

A search of our hospital's pharmacy database yielded all children <16 years old dispensed lacosamide for drug‐resistant epilepsy between January 2011 and June 2016. Medical records were reviewed for clinical and drug details. Continued treatment for ≥12 months was considered an indicator of effectiveness and tolerability.

Results

A total of 107 children (61 boys) satisfied inclusion criteria. Median age at lacosamide commencement was 9.9 years (interquartile range 6.7–13.7). Of those children, 57 (53%) children had focal epilepsy, with focal motor or impaired awareness seizures most commonly reported; 50 (47%) children had generalised epilepsy, most with tonic–clonic seizures, tonic seizures or epileptic spasms; 83 (78%) children had an intellectual disability, 24 (22%) had a physical disability and 22 (21%) had an autism spectrum disorder; 69 (65%) children continued lacosamide for ≥12 months. Reasons for discontinuation before 12 months in 38 (35%) children included ineffectiveness in 25 (66%), adverse events in 7 (18%) and worsening of seizures in 2 (5%). The most common adverse events were drowsiness, behavioural changes, unsteadiness, nausea and vomiting. Epilepsy type and comorbidities were not associated with continuation or reasons for discontinuation.

Conclusions

Most children continued treatment with lacosamide, suggesting effectiveness and tolerability. Lacosamide may prove to be a useful, ‘broad‐spectrum’ antiepileptic medication in children for focal and generalised epilepsies and in association with comorbidities.