bluuebunny/crossref_metadata_2025 huggingface dataset:
Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells
Authors: Zibetti Cristina , Liu Sheng , Wan Jun , Qian Jiang , Blackshaw Seth
Published: December 2017

Retinal progenitor cells (RPCs) pass through multiple stages of developmental competence, where they successively acquire and lose the ability to generate individual cell subtypes. To identify the transcriptional regulatory networks that control these transitions, we conducted epigenomic and transcriptomic profiling of early and late-stage RPCs and observed a developmentally dynamic landscape of chromatin accessibility. Open chromatin regions that showed stage-specificity, as well as those shared by early and late-stage RPCs, were selectively targeted by the homeodomain factor Lhx2, which is expressed throughout retinal neurogenesis but also regulates many stage-specific processes in RPCs. Stage-specific Lhx2 binding sites were frequently associated with target sites for transcription factors that are preferentially expressed in either early or late-stage RPCs, and which were predicted to possess pioneer activity.Lhx2loss of function in RPCs led to a loss of chromatin accessibility at both direct Lhx2 target sites and more broadly across the genome, as well as a loss of binding by transcription factors associated with stage-specific Lhx2 target sites. These findings demonstrate a central role for Lhx2 in control of chromatin accessibility in RPCs, and identify transcription factors that may guide stage-specific target site selection by Lhx2.

Lhx2 is a central regulator of chromatin accessibility in retinal progenitor cells, and interacts with stage-specific transcription factors to regulate genes that are dynamically expressed during retinal neurogenesis.
The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation
Authors: McKenzie Andrew J. , Hicks Stephanie R. , Svec Kathryn V. , Naughton Hannah , Edmunds Zöe L. , Howe Alan K.
Published: December 2017

There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we investigated the effect of substrate rigidity on various aspects of SKOV3 human EOC cell morphology and migration. Young’s modulus values of normal mouse peritoneum, a principal target tissue for EOC metastasis, were determined by atomic force microscopy (AFM) and hydrogels were fabricated to mimic these values. We find that cell spreading, focal adhesion formation, myosin light chain phosphorylation, and cellular traction forces all increase on stiffer matrices. Substrate rigidity also positively regulates random cell migration and, importantly, directional increases in matrix tension promote SKOV3 cell durotaxis. Matrix rigidity also promotes nuclear translocation of YAP1, an oncogenic transcription factor associated with aggressive metastatic EOC. Furthermore, disaggregation of multicellular EOC spheroids, a behavior associated with dissemination and metastasis, is enhanced by matrix stiffness through a mechanotransduction pathway involving ROCK, actomyosin contractility, and FAK. Finally, this pattern of mechanosensitivity is maintained in highly metastatic SKOV3ip.1 cells. These results establish that the mechanical properties of the tumor microenvironment may play a role in EOC metastasis.
Solution NMR structures of oxidized and reducedEhrlichia chaffeensisthioredoxin: NMR-invisible structure owing to backbone dynamics
Authors: Buchko Garry W. , Hewitt Stephen N. , Van Voorhis Wesley C. , Myler Peter J.
Published: December 2017

Thioredoxins are small ubiquitous proteins that participate in a diverse variety of redox reactionsviathe reversible oxidation of two cysteine thiol groups in a structurally conserved active site. Here, the NMR solution structures of a reduced and oxidized thioredoxin fromEhrlichia chaffeensis(Ec-Trx, ECH_0218), the etiological agent responsible for human monocytic ehrlichiosis, are described. The overall topology of the calculated structures is similar in both redox states and is similar to those of other thioredoxins: a five-stranded, mixed β-sheet (β1–β3–β2–β4–β5) surrounded by four α-helices. Unlike other thioredoxins studied by NMR in both redox states, the1H–15N HSQC spectrum of reducedEc-Trx was missing eight additional amide cross peaks relative to the spectrum of oxidizedEc-Trx. These missing amides correspond to residues Cys35–Glu39 in the active-site-containing helix (α2) and Ser72–Ile75 in a loop near the active site, and suggest a change in backbone dynamics on the millisecond-to-microsecond timescale associated with the breakage of an intramolecular Cys32–Cys35 disulfide bond in a thioredoxin. A consequence of the missing amide resonances is the absence of observable or unambiguous NOEs to provide the distance restraints necessary to define the N-terminal end of the α-helix containing the CPGC active site in the reduced state. This region adopts a well defined α-helical structure in other reported reduced thioredoxin structures, is mostly helical in oxidizedEc-Trx and CD studies ofEc-Trx in both redox states suggests there is no significant difference in the secondary structure of the protein. The NMR solution structure of reducedEc-Trx illustrates that the absence of canonical structure in a region of a protein may be owing to unfavorable dynamics prohibiting NOE observations or unambiguous NOE assignments.
Crystal structure of ethyl 2-cyano-2-(1,3-dithian-2-ylidene)acetate
Authors: Boukhedena Wafia , Fiala Abdelali , Brahim Ladouani Hayet , Lemallem Salah Eddine , Hamdouni Noudjoud , Boudjada Ali
Published: December 2017

The title compound, C9H11NO2S2, contains a 1,3-dithiane ring which has a twist-boat conformation. The dihedral angle between the mean planes of the ethyl acetate group and the dithiane ring is 17.56 (13)°. In the crystal, molecules stack in layers up thea-axis direction, however, there are no significant intermolecular interactions present.
Modeling brand resonance score (BRS) – an application in financial services
Authors: Raja Ambedkar Ande , Murugesan Punniyamoorthy , Thamaraiselvan N.
Published: December 2017

Purpose

The experts in industry and academicians value brand resonance is the prerequisite factor in the firms of financial services. In this regard, the purpose of this paper is to model the brand resonance score (BRS) for modified customer-based brand equity (CBBE) model in mutual fund financial services using structural equation modeling (SEM) and analytic network process (ANP).

Design/methodology/approach

Criteria and sub-criteria relative weights are calculated from the SEM and sub-sub-criteria relative weights are measured through pair-wise comparison matrix for BRS modeling using ANP approach.

Findings

The brand resonance using ANP has been quantified, and BRSs of each brand through brand judgments and brand feelings criteria are calculated using two renowned Indian mutual fund services brands State Bank of India and Hong Kong and Shanghai Banking Corporation.

Research limitations/implications

Interdependency between sub-criteria are not explored. This research study is specific to Indian bank mutual fund services context.

Practical implications

Research findings provide useful guidelines for fund managers/analysts of mutual fund service firms to improve the brand resonance to investors.

Originality/value

The paper explained modeling BRS using ANP technique which helps organizations quantify the brand resonance effectively.
Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial
Authors: Pratley Richard E. , Eldor Roy , Raji Annaswamy , Golm Gregory , Huyck Susan B. , Qiu Yanping , Sunga Sheila , Johnson Jeremy , Terra Steven G. , Mancuso James P. , Engel Samuel S. , Lauring Brett
Published: December 2017

Aim

To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin.

Methods

In this study (Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co‐administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26.

Results

At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (−1.5%) and E15/S100 (−1.5%) than with individual agents (−1.0%, −1.1% and −1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin‐treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups.

Conclusions

In patients with uncontrolled type 2 diabetes while using metformin, co‐administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents.
HMGA2, but not HMGA1, is overexpressed in human larynx carcinomas
Authors: Palumbo Antonio , De Martino Marco , Esposito Francesco , Fraggetta Filippo , Neto Pedro N , Valverde Fernandes Priscila , Santos Izabella C , Dias Fernando L , Nasciutti Luiz E , Meireles Da Costa Nathalia , Fusco Alfredo , Ribeiro Pinto Luís Felipe
Published: December 2017

Aims

Malignant tumours from the upper aerodigestive tract are grouped collectively in the class of head and neck squamous cell carcinoma (HNSCC). The head and neck tumours were responsible for more than 500 000 cancer cases in 2012, accounting for the sixth highest incidence rate and mortality worldwide among all tumour types. Laryngeal squamous cell carcinoma (LSCC) possesses the second highest incidence rate among all HNSCC. Despite significant advances in surgery and radiotherapy during the last few decades, no treatment has been shown to achieve a satisfactory therapeutic outcome and the mortality rate of LSCC is still high, with a 5‐year survival rate of 64%. Therefore, further investigations are required to identify the pathogenesis of LSCC.

Methods and results

In order to search for new LSCC biomarkers, we have analysed the expression of the HMGA family members, HMGA1 and HMGA2, by quantitative reverse transcription–polymerase chain reaction (qRT–PCR) and immunohistochemistry. HMGA proteins are usually absent in the healthy adult tissues. In contrast, their constitutive expression is a feature of several neoplasias, being associated with a highly malignant phenotype and reduced survival. Here, we report HMGA2 overexpression in larynx carcinomas. Conversely, HMGA1 does not show any differences in its expression between normal and carcinoma tissues. Interestingly, HMGA2 overexpression appears associated with that of two HMGA1‐pseudogenes, HMGA1P6 and HMGA1P7, acting as a sponge for HMGA1‐ and HMGA2‐targeting microRNAs and involved in several human cancers.

Conclusions

Therefore, HMGA2 overexpression appears to be a strong feature of larynx carcinoma, supporting its detection as a valid tool for the diagnosis of these malignancies.
Predicting response after infliximab salvage in acute severe ulcerative colitis
Authors: Choy Matthew C , Seah Dean , Gorelik Alexandra , An Yoon‐Kyo , Chen Cheng‐Yu , Macrae Finlay A , Sparrow Miles P , Connell William R , Moore Gregory T , Radford‐Smith Graham , Van Langenberg Daniel R , De Cruz Peter
Published: December 2017

Background and Aim

Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification.

Methods

Fifty‐four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014–May 2015). Follow‐up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared.

Results

Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow‐up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C‐reactive protein (CRP)/albumin ratio cut‐off of 0.37 post‐commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage.

Conclusions

The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms.
Persistent reduction of mucosal‐associated invariant T cells in primary biliary cholangitis
Authors: Setsu Toru , Yamagiwa Satoshi , Tominaga Kentaro , Kimura Naruhiro , Honda Hiroki , Kamimura Hiroteru , Tsuchiya Atsunori , Takamura Masaaki , Terai Shuji
Published: December 2017

Background and Aim

Mucosal‐associated invariant T (MAIT) cells constitute a novel subset of innate‐like T lymphocytes characterized by a semi‐invariant T‐cell receptor repertoire capable of recognizing bacterial products. Considering the abundance of MAIT cells in the liver and the possible association between bacterial infections and primary biliary cholangitis (PBC), we aimed to analyze the involvement of MAIT cells in the immunopathogenesis of PBC.

Methods

Peripheral blood and liver biopsy specimens were collected from 25 patients with PBC and 19 patients with chronic viral hepatitis. Surgically removed liver tissues distant from tumors in patients with metastatic liver tumors were used as controls. Mononuclear cells were separated using Ficoll gradient, and the expression of various markers was investigated by flow cytometry. Cytokine production was investigated using blood MAIT cells after stimulation by anti‐CD3/CD28‐coupled beads with/without interleukin‐7 (IL‐7).

Results

Mucosal‐associated invariant T cells were significantly reduced in both the blood and liver of PBC patients compared with those in controls. MAIT cells in the blood of PBC patients expressed significantly lower levels of activation markers and IL‐7 receptor. Moreover, MAIT cells in the blood of PBC patients showed impaired production of cytokines, especially tumor necrosis factor alpha, after in vitro stimulation with IL‐7. Interestingly, even after biochemical responses were achieved by ursodeoxycholic acid treatment, the frequencies of MAIT cells did not fully recover to normal levels.

Conclusions

These findings suggested that MAIT cells were activated, exhausted, and persistently depleted in PBC patients even after ursodeoxycholic acid treatment, possibly as a consequence of persistent liver inflammation.
Τhe Effect of a Traditional Dance Program on Health-Related Quality of Life as Perceived by Primary School Students
Authors: Georgios Lykesas , Ioannis Giosos , Olga Theocharidou , Dimitris Chatzopoulos , Maria Koutsouba
Published: December 2017

Physical exercise is acknowledged to play a highly significant role in human health and life quality. The concept “Quality of Life” (QoL) refers to many parameters, including the individual's physical condition, psychological status, level of independence, social relationships and interaction with the environment. Participating in dance activities, and more particularly in traditional dances, can significantly increase one’s physical and psychological well-being, and therefore improve their QoL.The aim of the present study was to investigate whether there are differences in the way Health-Related Quality of Life (HRQoL) is perceived by fifth and sixth graders of two public primary schools attending two different programs: a) program focused on traditional dance and b) program implemented within the context of the Physical Education curriculum as provided by the Ministry of Education, Research and Religious Affairs.According to the results of the research, the traditional dance intervention program presented higher perceived HRQoL values in six of the eight dimensions of the Kidscreen-52 Questionnaire, these dimensions being "Health", "Mood", "Self-perception", "Friends", "School-Learning" and "Self & Others". The most highly statistically significant difference was found for the "Health" dimension.In conclusion, traditional dance offers multiple benefits to participants, since it is an enjoyable physical activity contributing to the improvement of many QoL-related factors.
The Transformation of Traditional Dance from Its First to Its Second Existence: The Effectiveness of Music - Movement Education and Creative Dance in the Preservation of Our Cultural Heritage
Authors: Georgios Lykesas
Published: December 2017

Being an indispensable part of our folk tradition, the traditional dance bears elements of our cultural tradition and heritage and passes them down from generation to generation. Therefore, it contributes substantially to the reinforcement of our cultural identity and plays a crucial role in the "cultural development" of our society.Our culture is going through a constant process of mutation. Some traditional elements get lost, while others resist and survive or get transformed and readjust to new emerging circumstances.The aim of the present study is to investigate the learning process of Music/ Movement Education and Creative Dance within the context of the “second existence” of dance, and the way in which this learning process can effectively save and preserve the characteristic cultural traits of the "first existence" of the traditional dance.The experiential way of learning and transmitting dance from one generation to the other, is characterized as “the first existence” of dance. Changes in modern social, political and economic conditions have influenced the Greek traditional dance, which has acquired a more entertaining and tourist-commercial character, while its educational character has transformed going through teacher-centered educational processes. Having undergone this change, the traditional dance is now defined as “the second existence” of folk dance. The conversion of the traditional dance from its "first existence" into its "second existence" is supported and interpreted by the three components of the dancing process, the so-called “communication triangle”: the dancer, the dance and the viewer. The adoption of the particular approach of Music - Movement Education and Creative Dance in teaching Greek traditional dances can preserve and convey a large part of our cultural heritage to the new generation.Only by learning their country’s history and culture will the young generations be able to learn their own identity and make the best of the past in order to live more happily today and create a better future.
Evaluating hearing aid amplification using idiosyncratic consonant errors
Authors: Abavisani Ali , Allen Jont B.
Published: December 2017

The goal of this study is to provide a metric for evaluating a given hearing-aid insertion gain using a consonant recognition based measure. The basic question addressed is how treatment impacts phone recognition at the token level, relative to a flat insertion gain, at the most-comfortable-level (MCL). These tests are directed at fine-tuning a treatment, with the ultimate goal of improving speech perception, and to identify when a hearing level gain-based treatment degrades phone recognition. Eight subjects with hearing loss were tested under two conditions: flat-gain and a treatment insertion gain, based on subject's hearing level. The speech corpus consisted of consonant-vowel tokens at different signal to speech-weighted noise conditions, presented at the subject's MCL. The treatment caused the average score to improve for 31% of the trials and decrease for 12%. An analysis method based on the accumulated error differences was devised to quantify the benefit each individual ear received from the treatment. Using this measure, the effect of the treatment could be evaluated, providing precise characterization of idiosyncratic phone recognition. This analysis directs the audiologist toward the most susceptible subject-dependent tokens, to focus in the process of fine-tuning the insertion gain of the hearing-aid.
History and Current Use of Antimicrobial Drugs in Veterinary Medicine
Authors: Prescott John F.
Published: December 2017

This chapter briefly reviews the history and current use of antimicrobials in animals, with a focus on food animals in the more economically developed countries. It identifies some of the differences between human medical and food animal use, particularly in growth promotional and “subtherapeutic” use of medically-important antibiotics in animals. The public health impact of the extensive use of antibiotics in food animals for these purposes, differences internationally in such usage, and the major changes in current practices now underway in agricultural use are summarized. The emerging framing of the dimensions of antimicrobial resistance within a “One Health” framework is focusing global efforts to address the antimicrobial resistance crisis in a collaborative manner. The rapidly evolving development and application of practices of antimicrobial stewardship in animal is a critical part of the huge global effort to address antimicrobial resistance. The outcome is still uncertain.
Pathways to diagnosis of a second primary cancer: protocol for a mixed-methods systematic review
Authors: Kanguru Lovney , Bikker Annemieke , Cavers Debbie , Barnett Karen , Brewster David H , Weller David , Campbell Christine
Published: December 2017

Introduction

As cancer survivors continue to live longer, the incidence of second primary cancers (SPCs) will also rise. Relatively little is understood about the diagnostic pathway for SPCs, how people appraise, interpret symptoms and seek help for a second different cancer and the experiences (including challenges) of healthcare providers relating to SPCs. This study aims to systematically appraise and synthesise the literature on the pathways to diagnosis of an SPC and the associated patient and healthcare provider experiences.

Methods

The approach taken includes systematic searches of published and unpublished literature without any date or language restrictions. MEDLINE, Embase, CAB Abstracts, MEDLINE In-Process and non-indexed citations, PsycINFO, Epub Ahead of Print, In-Process and other non-indexed citations, Ovid MEDLINE Daily, CINAHL, ASSIA, Sociological Abstracts, Web of Science, PROSPERO and grey literature will be searched to identify observational, systematic reviews, mixed methods and qualitative studies of interest. Titles, abstracts and full texts will be screened against the inclusion–exclusion criteria by at least two reviewers independently. Relevant outcomes of interest and study and population characteristics will be extracted. Synthesis will be used guided by the Pathways to Treatment model and the Olesen model of time intervals.

Ethics and dissemination

Ethical approval is not required. This systematic review will provide a deeper understanding of the complex and heterogeneous diagnostic pathways of SPCs, while identifying common themes across the diagnostic interval, routes to diagnosis and patient and healthcare provider experiences. These findings will help provide a nuanced picture of the diagnostic pathway for SPCs that may inform policy and consistent practice. In particular, approaches to early diagnosis for an SPC; including the timing and reasons behind the decision by the patient to seek care,the challenges faced by healthcare providers, and in the development of future interventions to reduce the delay in patient time-to-presentation.

PROSPERO registration number

CRD42016051692.
Design and rationale of the Cardiovascular Health and Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study: two randomised controlled trials of text messaging to improve secondary prevention for coronary heart disease and diabetes
Authors: Huo Xiqian , Spatz Erica S , Ding Qinglan , Horak Paul , Zheng Xin , Masters Claire , Zhang Haibo , Irwin Melinda L , Yan Xiaofang , Guan Wenchi , Li Jing , Li Xi , Spertus John A , Masoudi Frederick A , Krumholz Harlan M , Jiang Lixin
Published: December 2017

Introduction

Mobile health interventions have the potential to promote risk factor management and lifestyle modification, and are a particularly attractive approach for scaling across healthcare systems with limited resources. We are conducting two randomised trials to evaluate the efficacy of text message-based health messages in improving secondary coronary heart disease (CHD) prevention among patients with or without diabetes.

Methods and analysis

The Cardiovascular Health And Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study are multicentre, single-blind, randomised controlled trials of text messaging versus standard treatment with 6 months of follow-up conducted in 37 hospitals throughout 17 provinces in China. The intervention group receives six text messages per week which target blood pressure control, medication adherence, physical activity, smoking cessation (when appropriate), glucose monitoring and lifestyle recommendations including diet (in CHAT-DM). The text messages were developed based on behavioural change techniques, using models such as the information-motivation-behavioural skills model, goal setting and provision of social support. A total sample size of 800 patients would be adequate for CHAT Study and sample size of 500 patients would be adequate for the CHAT-DM Study. In CHAT, the primary outcome is the change in systolic blood pressure (SBP) at 6 months. Secondary outcomes include a change in proportion of patients achieving a SBP <140 mm Hg, low-density lipoprotein cholesterol (LDL-C), physical activity, medication adherence, body mass index (BMI) and smoking cessation. In CHAT-DM, the primary outcome is the change in glycaemic haemoglobin (HbA1C) at 6 months. Secondary outcomes include a change in the proportion of patients achieving HbA1C<7%, fasting blood glucose, SBP, LDL-C, BMI, physical activity and medication adherence.

Ethics and dissemination

The central ethics committee at the China National Center for Cardiovascular Disease and the Yale University Institutional Review Board approved the CHAT and CHAT-DM studies. Results will be disseminated via usual scientific forums including peer-reviewed publications.

Trial registration number

CHAT (NCT02888769) and CHAT-DM (NCT02883842); Pre-results.
Associations between neighbourhood characteristics and depression: a twin study
Authors: Cohen-Cline Hannah , Beresford Shirley A A , Barrington Wendy Elizabeth , Matsueda Ross L , Wakefield Jon , Duncan Glen E
Published: December 2017

Background

Depression is an important contributor to the global burden of disease. Besides several known individual-level factors that contribute to depression, there is a growing recognition that neighbourhood environment can also profoundly affect mental health. This study assessed associations between three neighbourhood constructs—socioeconomic deprivation, residential instability and income inequality—and depression among adult twin pairs. The twin design is used to examine the association between neighbourhood constructs and depression, controlling for selection factors (ie, genetic and shared environmental factors) that have confounded purported associations.

Methods

We used multilevel random-intercept Poisson regression among 3738 same-sex twin pairs from a community-based twin registry to examine the association between neighbourhood constructs and depression. The within-pair association controls for confounding by genetic and environmental factors shared between twins within a pair, and is the main parameter of interest. Models were adjusted for individual-level income, education and marital status, and further by neighbourhood-level population density.

Results

When twins were analysed as individuals (phenotypic model), all neighbourhood constructs were significantly associated with depression. However, only neighbourhood socioeconomic deprivation showed a significant within-pair association with depression. A 10-unit within-pair difference in neighbourhood socioeconomic deprivation was associated with 6% greater depressive symptoms (1.06, 95% CI 1.01 to 1.11); the association did not substantially change in adjusted models.

Conclusion

This study provides new evidence linking neighbourhood socioeconomic deprivation with greater depression. Future studies should employ longitudinal designs to better test social causation versus social selection.
Opposite regulatory effects of cAMP and cGMP on sugar uptake in rat thymocytes
Authors: Segal J.
Published: December 2017

The present study provides several lines of evidence which indicate that in the rat thymocyte adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5-cyclic monophosphate (cGMP) induce opposing regulatory effects on 2-deoxyglucose (2-DG) uptake; cAMP is stimulatory, whereas cGMP is inhibitory. First, the cyclic nucleotide analogues dibutyryl cAMP (dBcAMP) and dibutyryl cGMP (dBcGMP) produced a dose-related increase and decrease in thymocyte 2-DG uptake, respectively. Second, 3,5,3'-triiodo-L-thyronine (T3) and epinephrine, which increased cellular cAMP concentration but had no effect on cellular cGMP concentration, increased 2-DG uptake in the rat thymocyte. Third, dBcGMP inhibited the stimulatory effects of dBcAMP, T3, and epinephrine on thymocyte 2-DG uptake. Fourth, prostaglandin E1 and the inhibitors of the cyclic nucleotide phosphodiesterases, 3-isobutyl-1-methylxanthine, theophylline, and caffeine, all increased both cellular cAMP and cGMP concentration but had no effect on 2-DG uptake. Insulin did not change cellular cAMP and cGMP concentration, but produced a dose-related increase in 2-DG uptake by the rat thymocyte. From these results I have concluded that in the rat thymocyte cAMP and cGMP produce opposite effects on sugar uptake and that the effect of certain, but not all, agents on thymocyte sugar uptake results from their modulation of cellular cAMP and cGMP concentration.
Epinephrine increases plasma immunoreactive atrial natriuretic hormone levels in humans
Authors: Sanfield J. A. , Shenker Y. , Grekin R. J. , Rosen S. G.
Published: December 2017

Six normal human subjects each underwent sequential 80-min infusions of saline and epinephrine (EPI) at 0.55 and 2.75 micrograms X min-1 X m-2 to determine the role of EPI in the control of atrial natriuretic hormone (ANH) in humans. Plasma immunoreactive-ANH (IR-ANH) levels nearly doubled in response to the infusion of EPI at 0.55 microgram X min-1 X m-2 (P less than 0.05) and then plateaued; heart rate accelerated significantly (P less than 0.01) with increasing plasma EPI levels, whereas systolic blood pressure increased only with higher plasma EPI levels (P less than 0.05). To determine whether beta-adrenergic mechanisms mediate the EPI-induced increase in IR-ANH, six additional subjects each received infusions on two separate days of saline for 240 min and the beta-adrenergic antagonist propranolol followed by propranolol plus EPI at 2.75 micrograms X min-1 X min-2 each for 80 min. Neither saline nor propranolol plus EPI caused a significant increase in plasma IR-ANH. We conclude that EPI increases plasma IR-ANH through beta-adrenergic mechanisms in humans. beta-Adrenergic-mediated increases in plasma IR-ANH levels appear to be unrelated to changes in the heart rate.
Effects of fasting on serum lactogenic hormone concentrations during mid- and late pregnancy in mice
Authors: Fielder P. J. , Ogren L. , Edwards D. , Talamantes F.
Published: December 2017

Hormonal and metabolic responses to fasting were studied in pregnant Swiss Webster mice. Food was removed from pregnant mice 12, 24, 36, or 48 h before death on day 12 or 15 of pregnancy. Serum mouse placental lactogen-II (mPL-II), mouse growth hormone (mGH), mouse prolactin (mPRL), free fatty acids (FFA), and glucose concentrations were determined for each group. In comparing fasted animals with fed controls, there was a significant increase in the serum mPL-II concentration after 24 and 48 h of fasting on day 12 and after 12, 36, and 48 h of fasting on day 15. Fasting significantly decreased the glucose and increased the FFA concentration of the serum at all fasting periods. Fasting had no effect on serum mPRL or mGH concentrations. In the second part of this study, pregnant mice were fasted for 24 h and then refed for an additional 24 h before being killed on day 12 of pregnancy. The changes in serum mPL-II, glucose, and FFA concentrations that occurred after a 24-h fast on day 12 of pregnancy were completely reversed by refeeding the animals for 24 h. Results from both studies indicate the involvement of mPL-II in the maternal response to fasting in pregnant mice.
Thyroid autoregulation: impact on thyroid structure and function in rats
Authors: Penel C. , Rognoni J. B. , Bastiani P.
Published: December 2017

Global response of the thyroid to a 10-fold increase in plasma iodide concentration results only in modifications of basolateral transfer for iodide where, by a balance phenomenon between influx and efflux, a net thyroid intake of 1.2 micrograms I/day is constantly maintained. The other main steps of thyroid iodine metabolism, thyroglobulin (Tg) iodination, endocytosis, and hydrolysis, remain constant. A stationary hormone secretion delivery results. This constant state is not found at a cellular level, where structural changes are observed in correlation with functional regulation of the cell dynamic state. Thus, an increase in plasma iodide concentration results in an increase of the apical membrane area (40%), whereas the basolateral membrane area decreases (18%). The volume of the follicle lumen increases (76%). Nevertheless, neither epithelial cell volume nor the structure of microvilli are modified. Comparison of iodine fluxes through the apical and basolateral membrane of the epithelial cell shows that an increase in plasma iodide concentration is correlated to a decrease of the Tg iodination and endocytotic fluxes (45%). A regulation also appears for basolateral transfer of iodide, whereas the lysosome system does not modulate the hormone secretion mechanism.
Sample site selection for tracer studies applying a unidirectional circulatory approach
Authors: Layman D. K. , Wolfe R. R.
Published: December 2017

The optimal arterial or venous sites for infusion and sampling during isotopic tracer studies have not been established. This study determined the relationship of plasma and tissue enrichment (E) when isotopes were infused in an artery and sampled from a vein (av mode) or infused in a vein and sampled from an artery (va mode). Adult dogs were given primed constant infusions of [3-13C]lactate, [1-13C]leucine, and 14C-labeled bicarbonate. Simultaneous samples were drawn from the vena cava, aortic arch, and breath. Tissue samples were removed from skeletal muscle, liver, kidney, and gut. Breath samples were analyzed for 14CO2 by liquid scintillation counting and plasma isotopic enrichments of [13C]lactate, [13C]leucine, and alpha-[13C]ketoisocaproate (KIC) were determined by gas chromatography-mass spectrometry. By using the va mode, the plasma E for lactate and leucine were 30-40% above tissue E. The av mode provided an accurate reflection of tissue E for lactate, which equilibrates rapidly with tissues, and a reasonable estimate for leucine, which exchanges more slowly. The isotopic enrichment of plasma KIC more directly reflected tissue leucine E than did plasma leucine E, and KIC enrichment was insensitive to sampling site. We also evaluated theoretically a circulatory model that predicts venous isotopic enrichments when the va mode is used. We conclude that the av mode is optimal but that the problems arising from use of the va mode can be overcome by use of a metabolic product (i.e., KIC) or by calculation of venous specific activity with our circulatory mode.
Long-latency growth-promoting activity of EGF when administered to mice at the neonatal stage
Authors: Imada O. , Hayashi N. , Masamoto K. , Kasuga S. , Fuwa T. , Nakagawa S.
Published: December 2017

The effect of biosynthetic human epidermal growth factor (Bh-EGF) as well as mouse EGF on postnatal development of mice of ICR strain was examined. Daily administration of Bh-EGF (0.01, 0.1, and 1.0 microgram X g body wt-1 X day-1) for 30 consecutive days postpartum caused a clearly dose-dependent increase in their body weight. Furthermore, in addition to the well-known premature eyelid opening and early tooth eruption, we have also observed precocious opening of the vagina among treated females. As far as the accelerated growth rate as reflected in their body weight gain was concerned, daily administration for only five consecutive days postpartum was just as effective as the above noted 30 consecutive daily injections. As to the precocious vaginal opening, however, the susceptible 5-day-period was found to be 14-18 days after the parturition. Some of those treated females also entered the estrous cycle precociously, a few days after the precocious opening of their vagina. The microscopic examination of various organs from treated males and females revealed no apparent pathological changes. As far as the above noted effects of EGF were concerned, Bh-EGF, which is xenogenic to mice, was as potent as mouse EGF.
Plasma catecholamine and serum cortisol responses to experimental cardiac arrest in dogs
Authors: Foley P. J. , Tacker W. A. , Wortsman J. , Frank S. , Cryer P. E.
Published: December 2017

The plasma catecholamine and serum cortisol responses to cardiac arrest (ventricular fibrillation), cardiopulmonary resuscitation (CPR), and ventricular defibrillation were examined in 10 intact (sham-operated controls) and 10 bilaterally adrenalectomized dogs. One hour after surgery, the cardiac ventricles were electrically fibrillated, and 30 s later Standard American Heart Association CPR was begun. After 12 min of CPR, the ventricles were defibrillated. Cardiac arrest per se results in a massive increase in plasma epinephrine and norepinephrine concentrations and indicates that the adrenal medullas are the predominant source of this response. Although the epinephrine response was virtually nonexistent in the adrenalectomized dogs, the norepinephrine response was approximately 30% of that in the sham-operated control animals. Thus there is an adrenomedullary, and perhaps a sympathetic neural, component to the sympathochromaffin response to cardiac arrest. Resuscitation from experimental cardiac arrest tended (P greater than 0.05 less than 0.1) to be lower in the adrenalectomized dogs (1 of 10) than in the animals with intact adrenal glands (6 of 10).
Clenbuterol-induced muscle growth: investigation of possible mediation by insulin
Authors: McElligott M. A. , Mulder J. E. , Chaung L. Y. , Barreto A.
Published: December 2017

The role of insulin as a possible mediator of the beta-adrenergic agonist stimulation of muscle growth was investigated. To exclude possible action of the beta-agonist on the pancreatic release of insulin, diabetes was induced in rats by a streptozotocin injection (100 mg/kg). Insulin levels were almost not detectable in these rats. Feeding either normal diet or diet containing the beta-adrenergic agonist clenbuterol (10 parts/million) did not alter plasma insulin concentrations. The effects of clenbuterol on muscle and weight gain were determined in diabetic rats given daily insulin replacement (D + I) and fed either a normal diet or clenbuterol-treated diet. Clenbuterol, fed for 1 wk, increased the wet weight of the gastrocnemius, soleus, and extensor digitorum longus muscles (15-23%) in both normal and D + I rats. Although clenbuterol increased body weight gain, it did not alter feed consumption and, therefore, feed efficiency (g gain/g food) was improved. Activities of cathepsin B and N-acetyl-beta-glucosaminidase, but not cathepsin D, were elevated in the soleus muscles of clenbuterol-treated rats. The clenbuterol-induced increase in muscle growth in the insulin-replaced diabetic rats indicated that this beta-adrenergic agonist effect was not mediated by an alteration of circulating levels of insulin, secondary to beta-agonist action on pancreatic insulin release.
Hyperglycemia stimulates carbohydrate oxidation in humans
Authors: Yki-Jarvinen H. , Bogardus C. , Howard B. V.
Published: December 2017

We examined whether hyperglycemia stimulates carbohydrate oxidation independent of insulin. Rates of total glucose disposal and substrate oxidation (indirect calorimetry) were measured at 4 insulin concentrations and at each level of insulin at 4 glucose concentrations in 88 separate studies in 22 normal volunteers. The insulin sensitivity of carbohydrate and lipid oxidation was independent of glycemia, but glucose, independent of insulin, increased the absolute rate of carbohydrate oxidation and decreased lipid oxidation. To compare the ability of glucose and insulin to stimulate carbohydrate oxidation, oxidation rates were examined at similar rates of total glucose disposal induced by hyperinsulinemia or hyperglycemia. At physiological matched rates of glucose disposal, insulin stimulated carbohydrate oxidation 2.4-fold more than glucose. The free fatty acids (FFA) were significantly lower in the presence of hyperinsulinemia than hyperglycemia. When compared at similar (supraphysiological) rates of total glucose disposal, where the FFA were completely suppressed, the rate of carbohydrate oxidation was related to the total rate of glucose disposal rather than the ambient glucose or insulin concentrations. We conclude that both glucose and insulin can increase carbohydrate oxidation in humans. We propose that the rate of carbohydrate oxidation is determined by FFA availability and by glucose availability independent of the FFA level in glucose-consuming tissues. Although FFA availability is almost solely determined by insulin, both glucose and insulin can increase carbohydrate oxidation by increasing glucose availability.
Effect of superfused insulin on cerebral cortical glucose utilization in awake goats
Authors: Pelligrino D. A. , Miletich D. J. , Albrecht R. F.
Published: December 2017

The effect on cortical cerebral glucose utilization (CMRglu) of intracerebral insulin administration in awake goats was studied. The insulin was superfused in a mock cerebrospinal fluid (CSF) solution employing chronically implanted cranial windows. Two windows were implanted bilaterally: one window over an equivalent portion of each parietal cortex. With one window used to deliver insulin/CSF and the other used to simultaneously deliver CSF alone (control), changes in CMRglu were assessed using a modification of a sequential 2-[3H]- then 2-[14C]deoxy-D-glucose (2DG) technique originally described by Altenau and Agranoff (Brain Res. 153: 375-381, 1978). Initial experiments employing 125I-insulin demonstrated that the superfusion procedure increased insulin levels only in the outer 1 mm of cortical tissue exposed to insulin containing perfusate. Additional preliminary evaluations, using conditions known to alter CMRglu, generally established that present methods were adequate to induce and detect CMRglu changes. However, it was also shown experimentally and using a mathematical model that 2-[3H]DG test/control tissue ratios could be influenced by subsequent changes in CMRglu and the dephosphorylation rate. Thus 3H ratios could not be used to establish preexperimental test/control CMRglu relationships as the originally devised model assumed but could be employed to indicate changes in dephosphorylation. The mathematical model allowed for improved estimates of CMRglu changes from 2-[14C]DG/2-[3H]DG test over control tissue ratios. Even with these corrections, insulin was estimated to cause no more than an 8-15% increase in cortical CMRglu. A very limited role for insulin, at least in cerebral cortical metabolic regulation, is thus indicated.
Effect of somatostatin on glucose homeostasis in conscious long-fasted dogs
Authors: Stevenson R. W. , Steiner K. E. , Hendrick G. K. , Cherrington A. D.
Published: December 2017

The effects of somatostatin plus intraportal insulin and glucagon replacement (pancreatic clamp) on carbohydrate metabolism were studied in conscious dogs fasted for 7 days so that gluconeogenesis was a major contributor to total glucose production. By use of [3-3H]glucose, glucose production (Ra) and utilization (Rd) and glucose clearance were assessed before and after implementation of the pancreatic clamp. After an initial control period, somatostatin (0.8 microgram . kg-1 . min-1) was infused with intraportal replacement amounts of glucagon (0.42 ng . kg-1 . min-1) and insulin. The insulin infusion rate was varied to maintain euglycemia and then kept constant (68 +/- 16 microU . kg-1 . min-1) for 250 min. Plasma glucagon was similar (84 +/- 14 and 89 +/- 19 pg/ml) before and during somatostatin infusion, while plasma insulin was lower (9.3 +/- 0.9 and 6.6 +/- 0.5 microU/ml, P less than 0.05). Plasma glucose levels remained similar (89 +/- 2 and 96 +/- 9 mg/dl), while Ra and Rd and the ratio of glucose clearance to plasma insulin were significantly (P less than 0.05) increased (from 2.18 +/- 0.12 to 3.21 +/- 0.35 and 2.30 +/- 0.09 to 3.26 +/- 0.38 mg . kg-1 . min-1, and 0.30 +/- 0.03 to 0.59 +/- 0.11, respectively). Net hepatic lactate uptake and [14C]alanine plus [14C]lactate conversion to [14C]glucose increased (P greater than 0.05) (from 9.32 +/- 0.47 to 16.54 +/- 2.97 mumol . kg-1 . min-1 and 100 to 263 +/- 37%, respectively). In conclusion, somatostatin alters glucose clearance in 7-day fasted dogs, resulting in changes in several indices of carbohydrate metabolism.