bluuebunny/crossref_metadata_2025 huggingface dataset:
The changes in, and relationship between, plasma nitric oxide and corticotropin‐releasing hormone in patients with major depressive disorder
Authors: Lu Yun‐Rong , Zhang Yan , Rao Ying‐Bo , Chen Xi , Lou Han‐Fen , Zhang Yu , Xie Hai‐Yan , Fang Ping , Hu Li‐Wei
Published: July 2017

There is strong evidence of roles of the hypothalamus‐pituitary‐adrenal axis and nitric oxide (NO) synthase‐NO system in depression, but the relationship between them is unknown. The aim of this study, therefore, was to elucidate whether there is any correlation between NO and corticotropin‐releasing hormone (CRH) in major depressive disorder (MDD) patients. In 16 outpatients with MDD and 18 healthy controls, the plasma amino acids citrulline (Cit) and arginine (Arg) were determined by high‐performance liquid chromatography, and CRH levels was measured by radioimmunoassay. The Cit/Arg ratio was calculated as an index of NO synthesis. Correlations between NO and CRH were examined with the Spearman test. Before treatment, no significant correlation was observed between the plasma NO level and CRH levels in MDD patients. The plasma NO levels were significantly higher in MDD patients. A significant correlation was found between NO levels and Hamilton Depression Rating Scale (HAMD) scores in MDD patients. The plasma CRH levels were significantly higher in MDD patients than in controls. After monotherapy for 2 months, the NO levels had dramatically declined but were also higher than those in the controls. This study is the first report of the absence of a significant correlation between plasma NO and CRH levels, although both levels are elevated in MDD patients. Furthermore, the strong links between the plasma NO levels and the HAMD scores, as well as the increased NO reduction after remission, suggest that NO plays a key role in depression and may be an indicator of therapeutic success.
Defining definitions: a Delphi study to develop a core outcome set for conditions of severe maternal morbidity
Authors: Schaap T , Bloemenkamp K , Deneux‐Tharaux C , Knight M , Langhoff‐Roos J , Sullivan E , van den Akker T ,   INOSS
Published: July 2017

Objective

Develop a core outcome set of international consensus definitions for severe maternal morbidities.

Design

Electronic Delphi study.

Setting

International.

Population

Eight expert panels.

Methods

All 13 high‐income countries represented in the International Network of Obstetric Surveillance Systems (INOSS) nominated five experts per condition of morbidity, who submitted possible definitions. From these suggestions, a steering committee distilled critical components: eclampsia: 23, amniotic fluid embolism: 15, pregnancy‐related hysterectomy: 11, severe primary postpartum haemorrhage: 19, uterine rupture: 20, abnormally invasive placentation: 12, spontaneous haemoperitoneum in pregnancy: 16, and cardiac arrest in pregnancy: 10. These components were assessed by the expert panel using a 5‐point Likert scale, following which a framework for an encompassing definition was constructed. Possible definitions were evaluated in rounds until a rate of agreement of more than 70% was reached. Expert commentaries were used in each round to improve definitions.

Main outcome measures

Definitions with a rate of agreement of more than 70%.

Results

The invitation to participate in one or more of eight Delphi processes was accepted by 103 experts from 13 high‐income countries. Consensus definitions were developed for all of the conditions.

Conclusion

Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process. These should be used in national registrations and international studies, and should be taken up by the Core Outcomes in Women's and Newborn Health initiative.

Tweetable abstract

Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process.
Diagnostic accuracy of haptoglobin within ovarian cyst fluid as a potential point‐of‐care test for epithelial ovarian cancer: an observational study
Authors: Mahyuddin AP , Liu L , Zhao C , Kothandaraman N , Salto‐Tellez M , Pang BNK , Lim DGS , Annalamai L , Chan JKY , Lim TYK , Biswas A , Rice G , Razvi K , Choolani M
Published: July 2017

Objective

To investigate haptoglobin within ovarian cyst fluid (OCF) as a diagnostic biomarker for epithelial ovarian cancer (EOC) and develop an in vitro diagnostic point‐of‐care device test (IVDPCT) for use in the operating theatre.

Design

Retrospective and prospective cohort study.

Setting

South‐East Asia.

Population

Women with suspicious ovarian cysts.

Methods

Proteomic, immunohistochemical and ELISA methods measured haptoglobin in OCF to differentiate benign and EOCs. Diagnostic performance of haptoglobin was compared with CA125, risk malignancy indices (RMI) and frozen section. Blinded validation of the IVDPCT was performed.

Main outcome measures

Prediction of malignancy.

Results

Haptoglobin concentration measured by ELISA was 0.70 ± 0.09 mg/ml in patients with benign cysts (n = 87), 6.22 ± 0.53 mg/ml in early stage‐EOC (n = 17), and 6.57 ± 0.65 mg/ml in late stage‐EOC (n = 20). Haptoglobin in EOCs was significantly higher than in benign cysts (P < 0.0001). Haptoglobin using rapid colorimetric assay (RCA) on a training set had a sensitivity of 97.3% and a specificity 92.0%, comparable to ELISA and frozen sections. The haptoglobin AUROC curve was 0.999 (95% CI 0.997–1.000) compared with 0.895 (95% CI 0.814–0.977, P < 0.05) for CA125. Haptoglobin performed significantly better than all the RMIs (P < 0.01). Blinded validation studies showed a minor drop in average diagnostic performance (sensitivity 85.2% and specificity 90.5%) compared with the training set. However, when compared with frozen section, haptoglobin was no worse in diagnostic accuracy for malignancy.

Conclusion

Haptoglobin was identified as a biomarker for the detection of EOC with potential as a point‐of‐care diagnostic tool.

Tweetable abstract

Haptoglobin within ovarian cyst fluid: a biomarker for epithelial ovarian cancer and point‐of‐care diagnostics.
Diagnosis and management of endometriosis: a systematic review of international and national guidelines
Authors: Hirsch M , Begum MR , Paniz É , Barker C , Davis CJ , Duffy JMN
Published: July 2017

Background

The development of clinical guidelines requires standardised methods informed by robust evidence synthesis.

Objectives

We evaluated the methodological quality of endometriosis guidelines, mapped their recommendations, and explored the relationships between recommendations and research evidence.

Search strategy

We searched EMBASE, MEDLINE, and PubMed from inception to February 2016.

Selection criteria

We included guidelines related to the diagnosis and management of endometriosis.

Data collection and analysis

The search strategy identified 879 titles and abstracts. We include two international and five national guidelines. Four independent authors assessed the methodological quality of the included guidelines, using the Appraisal of Guidelines for Research & Evaluation (AGREE‐II) instrument, and systematically extracted the guideline recommendations and supporting research evidence.

Main results

One hundred and fifty‐two different recommendations were made. Ten recommendations (7%) were comparable across guidelines. The European Society of Human Reproduction and Embryology was objectively evaluated as the highest quality guideline (methodological quality score: 88/100). There was substantial variation between the supporting evidence presented by individual guidelines for comparable recommendations. Forty‐two recommendations (28%) were not supported by research evidence. No guideline followed the standardised guideline development methods (AGREE‐II).

Conclusions

There is substantial variation in the recommendations and methodological quality of endometriosis guidelines. Future guidelines should be developed with reference to high‐quality methods in consultation with key stakeholders, including women with endometriosis, ensuring that their scope can truly inform clinical practice and eliminate unwarranted and unjustified variations in clinical practice.

Tweetable abstract

#Endometriosis guidelines vary in recommendations and quality. @EndometriosisUK
The effectiveness of surgical interventions for women with FGM/C: a systematic review
Authors: Berg RC , Taraldsen S , Said MA , Sørbye IK , Vangen S
Published: July 2017

Background

Female genital mutilation/cutting (FGM/C) changes normal genital functionality and can cause complications. There is an increasing demand for treatment of FGM/C‐related complications.

Objectives

We conducted a systematic review of empirical quantitative research on the outcomes of interventions for women with FGM/C‐related complications.

Search strategy

A search specialist searched 16 electronic databases.

Selection criteria

Selection was performed independently by two researchers. We accepted quantitative studies that examined the outcome of an intervention for an FGM/C‐related concern.

Data collection and analysis

We extracted data into a pre‐designed form, calculated effect estimates, and performed meta‐analyses.

Main results

We included 62 studies (5829 women), which investigated the effect of defibulation, excision of cysts, and clitoral reconstruction. Meta‐analyses of defibulation versus no defibulation showed a significantly lower risk of caesarean section (relative risk, RR: 0.33; 95% confidence interval, 95% CI: 0.25–0.45) and perineal tears with defibulation: second‐degree tear (RR: 0.44, 95% CI: 0.24–0.79), third‐degree tear (RR: 0.21, 95% CI: 0.05–0.94), fourth‐degree tear (RR: 0.06, 95% CI: 0.01–0.41). The meta‐analyses detected no significant differences in obstetric outcomes of antenatal versus intrapartum defibulation. Except for one study, none of the studies on the excision of cysts indicated any complications, and the results were deemed favourable. Reconstructive surgery resulted in a visible clitoris in about 77% of women. Most women self‐reported improvements in their sexual life, but up to 22% experienced a worsening in sexuality‐related outcomes after reconstruction.

Conclusions

Women with FGM/C who seek therapeutic surgery should be informed about the scarcity of evidence for benefits and the potential harms of the available procedures.

Tweetable abstract

Systematic review shows defibulation after FGM/C has obstetric benefits; effect of reconstruction is uncertain.
Do Managers of U.S. Defined Benefit Pension Plan Sponsors Use Regulatory Freedom Strategically?
Authors: KISSER MICHAEL , KIFF JOHN , SOTO MAURICIO
Published: July 2017

We use historical particularities of pension funding law to investigate whether managers of U.S. corporate defined benefit pension plan sponsors strategically use regulatory freedom to lower the reported value of pension liabilities, and hence required cash contributions. For some years, pension plans were required to estimate two liabilities—one with mandated discount rates and mortality assumptions, and another where these could be chosen freely. Using a sample of 11,963 plans, we find that the regulated liability exceeds the unregulated measure by 10% and the difference further increases for underfunded pension plans. Underfunded plans tend to assume substantially higher discount rates and lower life expectancy. The effect persists both in the cross‐section of plans and over time and it serves to reduce cash contributions. We further show that plan sponsor managers use the freed‐up cash for corporate investment and that credit risk is unlikely to explain the finding.
Short term in vivo precision of whole body composition measurements on the Horizon A densitometer
Authors: Nowitz Michael , Monahan Paula
Published: July 2017

Introduction

Dual‐energy X‐ray absorptiometry (DXA) is increasingly being used to assess abnormalities in body composition associated with a wide variety of conditions including obesity, sarcopenia, diabetes, anorexia, human immunodeficiency virus lipodystrophy, malabsorption and neuromuscular disorders. The objective of this study was to determine the short‐term in vivo precision and least significant change in serial body composition measurements provided by the Hologic Horizon A densitometer as there is no published, peer reviewed body composition precision data on Horizon scanners in the medical literature.

Methods

After acquiring two new Hologic Horizon A densitometers, short term precision scanning was performed on the two scanners using different groups of 30 volunteers, who had duplicate scans with all scans performed by the same operator. Using the International Society of Clinical Densitometry's advanced precision tool, the scan data were recorded and the coefficient of variation (CV) and least significant change (LSC) determined for total fat, lean and bone mineral content (BMC) and bone mineral density (BMD).

Results

Coefficients of variation of 0.78% and 0.77% were achieved for total fat (LSC at 95% confidence 2.15%) and 0.52% and 0.40% for total lean (LSC at 95% confidence 1.45% and 1.11%).

Conclusions

These results indicate that the two Horizon A scanners in this study exceeded the minimum acceptable precision values by roughly a factor of four and are therefore capable of detecting small differences in lean and fat mass of 1–2% between two measurements at 95% confidence.
Epac1, PDE4, and PKC protein expression and their association with AKAP95, Cx43, and cyclinD2/E1 in breast cancer tissues
Authors: Huang Ping , Sun Qian , Zhuang Wenxin , Peng Kuan , Wang Dai , Yao Youliang , Guo Dongbei , Zhang Lu , Shen Chuhan , Sun Mengyun , Tang Chaoying , Teng Bogang , Zhang Yongxing
Published: July 2017

Background

This study was conducted to investigate the exchange protein directly activated by cAMP (Epac1), PDE4, and PKC expression in breast cancer tissues, and the correlation between these proteins and AKAP95, Cx43, cyclin D2, and cyclin E1.

Methods

PV‐9000 two‐step immunohistochemistry was used to analyze protein expression.

Results

The positive rate of Epac1 protein expression in breast cancer tissues (58%) was higher than in para‐carcinoma tissues (10%) (P < 0.05). There were no significant differences in the positive rates of PDE4 and PKC expression between breast cancer and para‐carcinoma tissues (P > 0.05). The positive expression rate of PDE4 was higher in the P53 protein positive group compared to the P53 negative group (P < 0.05). Correlations between Epac1 and cyclin D2, PDE4 and cyclin D2, AKAP95 and PKC, Cx43 and PKC, and cyclin D2 and PKC proteins were observed (P < 0.05).

Conclusion

Epac1 expression in breast cancer tissues was increased, suggesting that the protein may be involved in the development of breast cancer. Correlations between Epac1 and cyclin D2, PDE4 and cyclin D2, AKAP95 and PKC, Cx43 and PKC, and cyclin D2 and PKC proteins suggested synergistic effects among these proteins in the development of breast cancer.
Blood and nasal epigenetics correlate with allergic rhinitis symptom development in the environmental exposure unit
Authors: North M. L. , Jones M. J. , MacIsaac J. L. , Morin A. M. , Steacy L. M. , Gregor A. , Kobor M. S. , Ellis A. K.
Published: July 2017

Background

Epigenetic alterations may represent new therapeutic targets and/or biomarkers of allergic rhinitis (AR). Our aim was to examine genome‐wide epigenetic changes induced by controlled pollen exposure in the environmental exposure unit (EEU).

Methods

38 AR sufferers and eight nonallergic controls were exposed to grass pollen for 3 hours on two consecutive days. We interrogated DNA methylation at baseline and 3 hours in peripheral blood mononuclear cells (PBMCs) using the Infinium Methylation 450K array. We corrected for demographics, cell composition, and multiple testing (Benjamini‐Hochberg) and verified hits using bisulfite PCR pyrosequencing and qPCR. To extend these findings to a clinically relevant tissue, we investigated DNA methylation and gene expression of mucin 4 (MUC4), in nasal brushings from a separate validation cohort exposed to birch pollen.

Results

In PBMCs of allergic rhinitis participants, 42 sites showed significant DNA methylation changes of 2% or greater. DNA methylation changes in tryptase gamma 1 (TPSG1), schlafen 12 (SLFN12), and MUC4 in response to exposure were validated by pyrosequencing. SLFN12 DNA methylation significantly correlated with symptoms (P < 0.05), and baseline DNA methylation pattern was found to be predictive of symptom severity upon grass allergen exposure (P = 0.029). Changes in MUC4 DNA methylation in nasal brushings in the validation cohort correlated with drop in peak nasal inspiratory flow (Spearman's r = 0.314, P = 0.034), and MUC4 gene expression was significantly increased (P < 0.0001).

Conclusion

This study revealed novel and rapid epigenetic changes upon exposure in a controlled allergen challenge facility, and identified baseline epigenetic status as a predictor of symptom severity.
Antibiotic‐induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice
Authors: Caputi Valentina , Marsilio Ilaria , Filpa Viviana , Cerantola Silvia , Orso Genny , Bistoletti Michela , Paccagnella Nicola , De Martin Sara , Montopoli Monica , Dall'Acqua Stefano , Crema Francesca , Di Gangi Iole‐Maria , Galuppini Francesca , Lante Isabella , Bogialli Sara , Rugge Massimo , Debetto Patrizia , Giaroni Cristina , Giron Maria Cecilia
Published: July 2017

Background and Purpose

Gut microbiota is essential for the development of the gastrointestinal system, including the enteric nervous system (ENS). Perturbations of gut microbiota in early life have the potential to alter neurodevelopment leading to functional bowel disorders later in life. We examined the hypothesis that gut dysbiosis impairs the structural and functional integrity of the ENS, leading to gut dysmotility in juvenile mice.

Experimental Approach

To induce gut dysbiosis, broad‐spectrum antibiotics were administered by gavage to juvenile (3weeks old) male C57Bl/6 mice for 14 days. Bile acid composition in the intestinal lumen was analysed by liquid chromatography‐mass spectrometry. Changes in intestinal motility were evaluated by stool frequency, transit of a fluorescent‐labelled marker and isometric muscle responses of ileal full‐thickness preparations to receptor and non‐receptor‐mediated stimuli. Alterations in ENS integrity were assessed by immunohistochemistry and Western blot analysis.

Key Results

Antibiotic treatment altered gastrointestinal transit, luminal bile acid metabolism and bowel architecture. Gut dysbiosis resulted in distorted glial network, loss of myenteric plexus neurons, altered cholinergic, tachykininergic and nitrergic neurotransmission associated with reduced number of nNOS neurons and different ileal distribution of the toll‐like receptor TLR2. Functional defects were partly reversed by activation of TLR2 signalling.

Conclusions and Implications

Gut dysbiosis caused complex morpho‐functional neuromuscular rearrangements, characterized by structural defects of the ENS and increased tachykininergic neurotransmission. Altogether, our findings support the beneficial role of enteric microbiota for ENS homeostasis instrumental in ensuring proper gut neuromuscular function during critical stages of development.
Raising awareness of Graves' orbitopathy with early warning cards
Authors: Mitchell Anna L. , Hickey Janis , Vaidya Bijay , Mason Rhianne , Ajjan Ramzi , Zammitt Nicola , Perros Petros , Dayan Colin ,   TEAMeD
Published: July 2017

Background

Clinically significant Graves' orbitopathy (GO) develops in about 25% of those with Graves' disease (GD); most cases of GD in the UK are managed by endocrinologists. Despite this, patients report significant delays before a diagnosis of GO is made. Measures to increase awareness of the early signs of GO and establishing a fast‐track referral pathway to specialist care should overcome these delays and potentially improve outcomes.

Aims

We aimed to determine whether issuing a “GO early warning card” to all GD patients raises awareness of GO and facilitates early diagnosis, what percentage of cards result in a telephone contact, the number of “false reports” from card carriers and patient perceptions of the cards.

Methods

We designed cards, detailing common GO symptoms and a telephone number for patients developing symptoms. Cards were distributed to 160 GD patients, without known GO, attending four endocrine clinics in the UK (December 2015‐March 2016). We recorded telephone contacts over twelve months from when the last card was distributed and gathered patient feedback.

Results

The early warning cards were well received by patients in general. Over twelve months, ten telephone contacts from nine patients, all related to ocular symptoms, were received (6% of cards issued). Nine calls resulted in an additional clinic review (for eight patients), and four diagnoses of GO were made.

Conclusions

This pilot study demonstrates that it is feasible to distribute GO early warning cards in clinic, and that they can be used to facilitate an early diagnosis of GO.
Mechanisms of Mendelian dominance
Authors: Veitia R.A. , Caburet S. , Birchler J.A.
Published: July 2017

Genetic dominance has long been considered as a qualitative reflection of interallelic interactions. Dominance arises from many multiple sources whose unifying theme is the existence of non‐linear relationships between the genotypic and phenotypic values. One of the clearest examples are dominant negative mutations (DNMs) in which a defective subunit poisons a macromolecular complex. Dominance can also be due to the presence of a heterozygous null allele, as is the case of haploinsufficiency. Dominance can also be influenced by epistatic (interloci) interactions. For instance, a pre‐existing genetic variant can make possible the expression of a pathogenic variant in a seemingly “dominant” fashion. Such interactions, which can make an individual more or less sensitive to a particular pathogenic variant, will also be discussed here.
Thioredoxin‐interacting protein induced α‐synuclein accumulation via inhibition of autophagic flux: Implications for Parkinson's disease
Authors: Su Cun‐Jin , Feng Yu , Liu Teng‐Teng , Liu Xu , Bao Jun‐Jie , Shi Ai‐Ming , Hu Duan‐Min , Liu Tong , Yu Yun‐Li
Published: July 2017

Aims

Thioredoxin‐interacting protein (TXNIP) is associated with activation of oxidative stress through inhibition of thioredoxin (Trx). However, some evidences point out that TXNIP acts as a scaffolding protein in signaling complex independent of cellular redox regulation. The autophagy‐lysosomal pathway plays important roles in the clearance of misfolded proteins and dysfunctional organelles. Lysosomal dysfunction has been involved in several neurodegenerative disorders including Parkinson's disease (PD). Although researchers have reported that TXNIP inhibited autophagic flux, the specific mechanism is rarely studied.

Methods

In this study, we investigated the effects of TXNIP on autophagic flux and α‐synuclein accumulation by Western blot in HEK293 cells transfected with TXNIP plasmid. Further, we explored the influence of TXNIP on DA neuron survival in substantia nigra by IHC.

Results

We found that TXNIP induced LC3‐II expression, but failed to degrade p62, a substrate of autophagy. Also, TXNIP aggravated α‐synuclein accumulation. We also found that TXNIP inhibited the expression of ATP13A2, a lysosomal membrane protein. Moreover, we found that overexpression of ATP13A2 attenuated the impairment of autophagic flux and α‐synuclein accumulation induced by TXNIP. Furthermore, overexpression of TXNIP in substantia nigra resulted in loss of DA neuron.

Conclusion

Our data suggested that TXNIP blocked autophagic flux and induced α‐synuclein accumulation through inhibition of ATP13A2, indicating TXNIP was a disease‐causing protein in PD.
The effect of a multidisciplinary regional educational programme on the quality of colon cancer resection
Authors: Sheehan‐Dare G. E. , Marks K. M. , Tinkler‐Hundal E. , Ingeholm P. , Bertelsen C. A. , Quirke P. , West N. P.
Published: July 2017

Aim

Mesocolic plane surgery with central vascular ligation produces an oncologically superior specimen following colon cancer resection and appears to be related to optimal outcomes. We aimed to assess whether a regional educational programme in optimal mesocolic surgery led to an improvement in the quality of specimens.

Method

Following an educational programme in the Capital and Zealand areas of Denmark, 686 cases of primary colon cancer resected across six hospitals were assessed by grading the plane of surgery and undertaking tissue morphometry. These were compared to 263 specimens resected prior to the educational programme.

Results

Across the region, the mesocolic plane rate improved from 58% to 77% (P < 0.001). One hospital had previously implemented optimal surgery as standard prior to the educational programme and continued to produce a high rate of mesocolic plane specimens (68%) with a greater distance between the tumour and the high tie (median for all fresh cases: 113 vs 82 mm) and lymph node yield (33 vs 18) compared to the other hospitals. Three of the other hospitals showed a significant improvement in the plane of surgical resection.

Conclusion

A multidisciplinary regional educational programme in optimal mesocolic surgery improved the oncological quality of colon cancer specimens as assessed by mesocolic planes; however, there was no significant effect on the amount of tissue resected centrally. Surgeons who attempt central vascular ligation continue to produce more radical specimens suggesting that such educational programmes alone are not sufficient to increase the amount of tissue resected around the tumour.
Characteristics of people with high visit‐to‐visit glycaemic variability in Type 2 diabetes
Authors: Noyes J. D. , Soto‐Pedre E. , Donnelly L. A. , Pearson E. R.
Published: July 2017

Aims

Increased visit‐to‐visit glycaemic variability is independently associated with adverse outcomes in Type 2 diabetes. Our aim was to identify the patient characteristics associated with raised visit‐to‐visit glycaemic variability in people with Type 2 diabetes.

Methods

A case–control study was conducted to establish associations between HbA1c variability and clinical covariates in 10 130 people with Type 2 diabetes. Variability was calculated by two metrics [sd and coefficient of variation (CV)] from a minimum of four HbA1c readings obtained over a 4‐year period. High and low variability groups were defined as the top and bottom tertile of the sd or CV, and used in logistic regression analyses including a number of clinical and biochemical covariates. The analyses were stratified into low mean (< 53 mmol/mol; 7%) and high mean (≥ 53 mmol/mol; 7%) HbA1c groups.

Results

Findings were consistent across both HbA1c groups and variability metrics. Treatment, independent of other factors, was the most strongly associated covariate for the risk of high HbA1c variability. A six‐fold increased risk was observed in the low HbA1c group, between the most and least intense treatment regimens (P < 0.001). Similar findings were present in the high HbA1c group with a three‐fold increase in risk (P < 0.001). In addition, male gender, younger age, reduced HDL‐cholesterol and increased BMI were all found to be independently associated with raised visit‐to‐visit glycaemic variability.

Conclusions

Intensive treatment resulting in low mean HbA1c was associated with marked increase in HbA1c variability. Irrespective of diabetes control, the greatest visit‐to‐visit variability was observed in young, insulin resistant men.
Decline‐associated Phaeoacremonium species occurring on forest trees in the north of Iran
Authors: Kazemzadeh Chakusary M. , Mohammadi H. , Khodaparast S. A.
Published: July 2017

Between 2013 and 2015, several surveys were conducted throughout forest areas in the north of Iran with the aim of isolating and identifying fungi present on trees showing decline symptoms. Fungal species, isolated from symptomatic wood tissues of various tree genera, including Zelkova, Acer, Parrotia, Quercus, Diospyros, Fagus, Fraxinus, Populus, Pinus, Pterocarya, Gleditsia, Carpinus, Ulmus, Crataegus, Alnus, Mespilus, Punica, Cydonia, Cupressus and Prunus, were morphologically identified and characterized. A molecular identification based on comparisons of DNA sequences of the β‐tubulin gene allowed us to identify seven species belonging to Phaeoacremonium; namely, Phaeoacremonium parasiticum, Pm. alvesii, Pm. minimum, Pm. iranianum, Pm. scolyti, Pm. fraxinopennsylvanicum and Pm. croatiense were isolated and identified. Phaeoacremonium minimum was the most common species and isolated from Gleditsia caspica, Parrotia persica, Cydonia oblonga and Alnus glutinosa. Pathogenicity on selected plants using a mycelium plug inoculation method revealed that most of these species are pathogenic to all the tested trees, with Pm. parasiticum and Pm. minimum being the most pathogenic species. According to host plant species and geographical distribution, the majority of Phaeoacremonium species found represent new records. This is also the first report of Pm. croatiense in Iran and outside Croatia.
Morphological features of congenital dyserythropoietic anemia type I: The role of electron microscopy in diagnosis
Authors: Resnitzky Peretz , Shaft Dina , Shalev Hanna , Kapelushnik Joseph , Dgany Orly , Krasnov Tanya , Tamary Hannah
Published: July 2017

Introduction

Congenital dyserythropoietic anemias are rare blood disorders characterized by congenital anemia and a wide range of morphological and functional abnormalities of erythroid precursors.

Objectives

To analyze the relative frequency of both light microscopic (LM) and electron microscopic (EM) morphological features of erythroblasts in a large group of patients with molecular proven congenital dyserythropoietic anemia type I (CDAI).

Methods

We retrospectively evaluated the LM and EM of bone marrow (BM) erythroblasts in 35 patients with CDAI. Thirty‐four patients carried the CDAN1 Arg1042Trp founder mutation and one the p.Pro1130Leu mutation. BM slides of 24 patients were available for LM examination. EM studies were performed in all 35 patients.

Results

On LM, marked erythroid hyperplasia, binuclear erythroblasts, and various non‐specific dyserythropoietic features were documented in every case; internuclear chromatin bridges were detected in 19 patients (79%). In all, EM of erythroblasts revealed a spongy appearance of heterochromatin, a widening of nuclear pores, and invagination of cytoplasm into the nuclear region.

Conclusions

EM studies revealed high morphological frequency of specific ultrastructural changes in erythroblasts which facilitate prompt diagnosis of CDAI. Due to low specificity of BM LM findings, when BM EM is unavailable diagnostic approach should also include other inherited anemias.
Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity
Authors: Pellock John M. , Arzimanoglou Alexis , D'Cruz O'Neill , Holmes Gregory L. , Nordli Douglas , Shinnar Shlomo ,   the Pediatric Epilepsy Academic Consortium for Extrapolation
Published: July 2017

Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long‐term follow‐up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.
Bufalin, a bufanolide steroid from the parotoid glands of the Chinese toad, suppresses hERG K+ currents expressed in HEK293 cells
Authors: Song Tao , Zhang Yuanyuan , Song Qiongtao , Han Xue , Guan Shengjiang , Zhang Xuan , Chu Xi , Zhang Fenghua , Zhang Jianping , Chu Li
Published: July 2017

In this study, we investigated the effect of bufalin on the human ether‐à‐go‐go‐related gene (hERG) K+ channels using the perforated patch recording technique. We measured a half‐maximal inhibitory concentration (IC50) of 24.83 μM and maximal inhibitory effect of 39.45 ± 1.14% with bufalin. These findings suggest that bufalin is a potent hERG K+ channel blocker and may provide a new way for understanding Chan Su‐induced arrhythmia.
Hierarchical role for transcription factors and chromatin structure in genome organization along adipogenesis
Authors: Sarusi Portuguez Avital , Schwartz Michal , Siersbaek Rasmus , Nielsen Ronni , Sung Myong‐Hee , Mandrup Susanne , Kaplan Tommy , Hakim Ofir
Published: July 2017

The three dimensional folding of mammalian genomes is cell type specific and difficult to alter suggesting that it is an important component of gene regulation. However, given the multitude of chromatin‐associating factors, the mechanisms driving the colocalization of active chromosomal domains and the role of this organization in regulating the transcription program in adipocytes are not clear. Analysis of genome‐wide chromosomal associations revealed cell type‐specific spatial clustering of adipogenic genes in 3T3‐L1 cells. Time course analysis demonstrated that the adipogenic ‘hub’, sampled by PPARγ and Lpin1, undergoes orchestrated reorganization during adipogenesis. Coupling the dynamics of genome architecture with multiple chromatin datasets indicated that among all the transcription factors (TFs) tested, RXR is central to genome reorganization at the beginning of adipogenesis. Interestingly, at the end of differentiation, the adipogenic hub was shifted to an H3K27me3‐repressive environment in conjunction with attenuation of gene transcription. We propose a stage‐specific hierarchy for the activity of TFs contributing to the establishment of an adipogenic genome architecture that brings together the adipogenic genetic program. In addition, the repositioning of this network in a H3K27me3‐rich environment at the end of differentiation may contribute to the stabilization of gene transcription levels and reduce the developmental plasticity of these specialized cells.

Database

All sequence data reported in this paper have been deposited at GEO (http://www.ncbi.nlm.nih.gov/geo/) (GSE92475)
Bax, Bak and beyond — mitochondrial performance in apoptosis
Authors: Peña‐Blanco Aida , García‐Sáez Ana J.
Published: July 2017

Bax and Bak are members of the Bcl‐2 family and core regulators of the intrinsic pathway of apoptosis. Upon apoptotic stimuli, they are activated and oligomerize at the mitochondrial outer membrane (MOM) to mediate its permeabilization, which is considered a key step in apoptosis. However, the molecular mechanism underlying Bax and Bak function has remained a key question in the field. Here, we review recent structural and biophysical evidence that has changed our understanding of how Bax and Bak promote MOM permeabilization. We also discuss how the spatial regulation of Bcl‐2 family preference for binding partners contributes to regulate Bax and Bak activation. Finally, we consider the contribution of mitochondrial composition, dynamics and interaction with other organelles to apoptosis commitment. A new perspective is emerging, in which the control of apoptosis by Bax and Bak goes beyond them and is highly influenced by additional mitochondrial components.
The Impact of Government Intervention on Corporate Investment Allocations and Efficiency: Evidence from China
Authors: Hao Ying , Lu Jing
Published: July 2017

We examine whether government intervention plays an important role in determining corporate investment allocations and efficiency in China. We find the government tends to intervene to promote corporate investment in fixed assets, equity in other state‐owned enterprises (SOEs), and natural resources including oil, natural gas, and mines, but reduces research and development (R&D) investment. However, the effects of government intervention on these investment allocations are primarily found in local SOEs rather than in central SOEs or in private enterprise. Government intervention also induces a crowding‐out effect in natural resource investments of private firms, suggesting that government intervention distorts investment allocations and reduces investment efficiency.
The Seal of Biliteracy: Variations in Policy and Outcomes
Authors: Davin Kristin J. , Heineke Amy J.
Published: July 2017

The Seal of Biliteracy is an award that recognizes students who have demonstrated proficiency in English and one or more other world languages. In participating school districts in states that have adopted the Seal of Biliteracy, students who demonstrate proficiency in both English and a world language are eligible to earn a seal that is affixed to their high school diploma or transcript. With scant research conducted to date on the Seal of Biliteracy, this study aimed to understand the variation in policies across participating states. Documentation and interview data were collected and analyzed from each state offering the Seal of Biliteracy. Findings revealed that substantial variation existed across states regarding minimum required levels of proficiency, world language proficiency requirements, and English language proficiency requirements. These variations in policy influenced the types of schools offering the award and the percentage of students earning it. This article offers implications for those in the process of policy adoption or revision and for those who are interested in researching efforts to increase equity and access to the Seal of Biliteracy.
BDNF genotype is associated with hippocampal volume in mild traumatic brain injury
Authors: Hayes J. P. , Reagan A. , Logue M. W. , Hayes S. M. , Sadeh N. , Miller D. R. , Verfaellie M. , Wolf E. J. , McGlinchey R. E. , Milberg W. P. , Stone A. , Schichman S. A. , Miller M. W.
Published: July 2017

The negative long‐term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative‐type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain‐derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single‐nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non‐Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.
Impact of winter roads on boreal peatland carbon exchange
Authors: Strack Maria , Softa Divya , Bird Melanie , Xu Bin
Published: July 2017

Across Canada's boreal forest, linear disturbances, including cutlines such as seismic lines and roads, crisscross the landscape to facilitate resource exploration and extraction; many of these linear disturbances cross peatland ecosystems. Changes in tree canopy cover and the compression of the peat by heavy equipment alter local thermal, hydrological, and ecological conditions, likely changing carbon exchange on the disturbance, and possibly in the adjacent peatland. We measured bulk density, water table, soil temperature, plant cover, and CO2 and CH4 flux along triplicate transects crossing a winter road through a wooded fen near Peace River, Alberta, Canada. Sample plots were located 1, 5, and 10 m from the road on both sides with an additional three plots on the road. Productivity of the overstory trees, when present, was also determined. The winter road had higher bulk density, shallower water table, higher graminoid cover, and thawed earlier than the adjacent peatland. Tree productivity and CO2 flux varied between the plots, and there was no clear pattern in relation to distance from the road. The plots on the winter road acted as a greater CO2 sink and greater CH4 source compared to the adjacent peatland with plots on the winter road emitting on average (standard error) 479 (138) compared to 41 (10) mg CH4 m−2 day−1 in the adjacent peatland. Considering both gases, global warming potential increased from 70 to 250 g CO2e m−2 year−1 in the undisturbed area to 2100 g CO2e m−2 year−1 on the winter road. Although carbon fluxes on any given cutline through peatland will vary depending on level of compaction, line width and vegetation community shifts, the large number of linear disturbances in Canada's boreal forest and slow recovery on peatland ecosites suggest they could represent an important anthropogenic greenhouse gas source.
Identifying keystone habitats with a mosaic approach can improve biodiversity conservation in disturbed ecosystems
Authors: Hitchman Sean M. , Mather Martha E. , Smith Joseph M. , Fencl Jane S.
Published: July 2017

Conserving native biodiversity in the face of human‐ and climate‐related impacts is a challenging and globally important ecological problem that requires an understanding of spatially connected, organismal‐habitat relationships. Globally, a suite of disturbances (e.g., agriculture, urbanization, climate change) degrades habitats and threatens biodiversity. A mosaic approach (in which connected, interacting collections of juxtaposed habitat patches are examined) provides a scientific foundation for addressing many disturbance‐related, ecologically based conservation problems. For example, if specific habitat types disproportionately increase biodiversity, these keystones should be incorporated into research and management plans. Our sampling of fish biodiversity and aquatic habitat along ten 3‐km sites within the Upper Neosho River subdrainage, KS, from June‐August 2013 yielded three generalizable ecological insights. First, specific types of mesohabitat patches (i.e., pool, riffle, run, and glide) were physically distinct and created unique mosaics of mesohabitats that varied across sites. Second, species richness was higher in riffle mesohabitats when mesohabitat size reflected field availability. Furthermore, habitat mosaics that included more riffles had greater habitat diversity and more fish species. Thus, riffles (<5% of sampled area) acted as keystone habitats. Third, additional conceptual development, which we initiate here, can broaden the identification of keystone habitats across ecosystems and further operationalize this concept for research and conservation. Thus, adopting a mosaic approach can increase scientific understanding of organismal‐habitat relationships, maintain natural biodiversity, advance spatial ecology, and facilitate effective conservation of native biodiversity in human‐altered ecosystems.
How disturbance, competition, and dispersal interact to prevent tree range boundaries from keeping pace with climate change
Authors: Liang Yu , Duveneck Matthew J. , Gustafson Eric J. , Serra‐Diaz Josep M. , Thompson Jonathan R.
Published: July 2017

Climate change is expected to cause geographic shifts in tree species' ranges, but such shifts may not keep pace with climate changes because seed dispersal distances are often limited and competition‐induced changes in community composition can be relatively slow. Disturbances may speed changes in community composition, but the interactions among climate change, disturbance and competitive interactions to produce range shifts are poorly understood. We used a physiologically based mechanistic landscape model to study these interactions in the northeastern United States. We designed a series of disturbance scenarios to represent varied disturbance regimes in terms of both disturbance extent and intensity. We simulated forest succession by incorporating climate change under a high‐emissions future, disturbances, seed dispersal, and competition using the landscape model parameterized with forest inventory data. Tree species range boundary shifts in the next century were quantified as the change in the location of the 5th (the trailing edge) and 95th (the leading edge) percentiles of the spatial distribution of simulated species. Simulated tree species range boundary shifts in New England over the next century were far below (usually <20 km) that required to track the velocity of temperature change (usually more than 110 km over 100 years) under a high‐emissions scenario. Simulated species` ranges shifted northward at both the leading edge (northern boundary) and trailing edge (southern boundary). Disturbances may expedite species' recruitment into new sites, but they had little effect on the velocity of simulated range boundary shifts. Range shifts at the trailing edge tended to be associated with photosynthetic capacity, competitive ability for light and seed dispersal ability, whereas shifts at the leading edge were associated only with photosynthetic capacity and competition for light. This study underscores the importance of understanding the role of interspecific competition and disturbance when studying tree range shifts.