bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of perampanel on pharmacokinetics of concomitant antiepileptics in patients with partial‐onset seizures: pooled analysis of clinical trials
Authors: Majid Oneeb , Laurenza Antonio , Ferry Jim , Hussein Ziad
Published: April 2016

Aims

To evaluate the impact of perampanel and demographics on clearance of concomitant antiepileptic drugs (AEDs), in patients with refractory partial‐onset seizures.

Methods

Pooled data from three Phase III clinical studies with adjunctive perampanel were used. Blood samples for evaluation of 11 concomitant AEDs were taken during baseline (before perampanel initiation), and at weeks 10, 14, and 19 during the maintenance phase of perampanel treatment (2–12 mg/day, once daily at bedtime). Models estimating apparent clearance of each concomitant AED were fitted to the data, and the effects of perampanel and demographic variables on clearance were determined. Final models were assessed with goodness of fit plots including population predictions and individual predictions against observations.

Results

No significant impact of perampanel on clearance was found for clonazepam (n = 81), levetiracetam (n = 330), phenobarbital (n = 54), phenytoin (n = 90), topiramate (n = 226) or zonisamide (n = 93). Statistically significant, but small and not clinically relevant increases in model‐predicted clearance were detected for carbamazepine (+4.3% with 12 mg perampanel; n = 379), clobazam (+3.4% males, +7.7% females, 12 mg; n = 114), lamotrigine (+9.3%, 12 mg; n = 356), and valproic acid (+5.0%, 12 mg; n = 349). Oxcarbazepine clearance was reduced (26%; n = 200), but the clinical relevance is unclear as levels of the active metabolite (the monohydroxy derivative of oxcarbazepine) were not measured.

Conclusions

Population PK data show that perampanel (2–12 mg/day, once daily at bedtime) has no relevant impact on the clearance of the most commonly used concomitant AEDs.
Acute p‐synephrine ingestion increases fat oxidation rate during exercise
Authors: Gutiérrez‐Hellín Jorge , Del Coso Juan
Published: April 2016

Aims

p‐Synephrine is a protoalkaloid widely used in dietary supplements for weight management because of its purported thermogenic effects. However, there is a lack of scientific information about its effectiveness to increase fat metabolism during exercise. The purpose of this investigation was to determine the effects of an acute ingestion of p‐synephrine on fat oxidation at rest and during exercise.

Methods

In a double‐blind, randomized and counterbalanced experimental design, 18 healthy subjects performed two acute experimental trials after the ingestion of p‐synephrine (3 mg kg−1) or after the ingestion of a placebo (cellulose). Energy expenditure and fat oxidation rates were measured by indirect calorimetry at rest and during a cycle ergometer ramp exercise test (increases of 25 W every 3 min) until volitional fatigue.

Results

In comparison with the placebo, the ingestion of p‐synephrine did not change energy consumption (1.6 ± 0.3 vs. 1.6 ± 0.3 kcal min−1; P = 0.69) or fat oxidation rate at rest (0.08 ± 0.02 vs. 0.10 ± 0.04 g min−1; P = 0.15). However, the intake of p‐synephrine moved the fat oxidation–exercise intensity curve upwards during the incremental exercise (P < 0.05) without affecting energy expenditure. Moreover, p‐synephrine increased maximal fat oxidation rate (0.29 ± 0.15 vs. 0.40 ± 0.18 g min−1; P = 0.01) during exercise although it did not affect the intensity at which maximal fat oxidation was achieved (55.8 ± 7.7 vs. 56.7 ± 8.2% VO2peak; P = 0.51).

Conclusions

The acute ingestion of p‐synephrine increased the fat oxidation rate while it reduced the carbohydrate oxidation rate when exercising at low‐to‐moderate exercise intensities.
The determinants of antimicrobial prescribing among hospital doctors in England: a framework to inform tailored stewardship interventions
Authors: Parker Hazel M. , Mattick Karen
Published: April 2016

Aim

Little is known about the determinants of antimicrobial prescribing behaviour (APB), how they vary between hospital prescribers or the mechanism by which interventions are effective. Yet, interventions based on a sound theoretical understanding of APB are more likely to be successful in changing outcomes. This study sought to quantify the potential determinants of APB among hospital doctors in south‐west England.

Methods

This multicentre, quantitative study employed a closed answer questionnaire to garner hospital doctors' views on factors influencing their APB. Underlying constructs within the data were identified using exploratory factor analysis and subsequent pairwise comparisons assessed for variance between groups of prescribers.

Results

The questionnaire was completed by 301 doctors across four centres (response rate ≥ 74%) and three key factors were identified: autonomy, guidelines adherence and antibiotic awareness. The internal consistency for the questionnaire scale and for each factor subscale was good (α ≥ 0.7). Subgroup analysis identified significant differences between groups of prescribers: autonomy scores increased with grade until at the specialist trainee level (P ≤ 0.009), foundation doctors scored higher for guidelines adherence than consultants (P = 0.004) and specialist trainees (P = 0.003) and United Kingdom trained doctors scored higher than those trained abroad for antibiotic awareness (P < 0.0005). Scores did not vary significantly between doctors from different centres.

Conclusion

Autonomy, guidelines adherence and antibiotic awareness were identified as important factors relevant to APB, which vary with experience and training. A theoretical framework is offered to facilitate development of more effective, tailored interventions to change APBs.
Dietary Pyridoxine Protects against Stress and Maintains Immunohaematological Status in Chanos chanos Exposed to Endosulfan
Authors: Kumar Neeraj , Ambasankar Kondusamy , Krishnani Kishore Kumar , Bhushan Shashi , Minhas Paramjit Singh
Published: April 2016

The amelioration effect of water‐soluble vitamin pyridoxine against stress was evaluated in milkfish, Chanos chanos exposed to endosulfan. Two hundred and twenty‐five fish were distributed randomly into five treatments, each with three replicates. Four isocaloric and isonitrogenous diets with graded levels of pyridoxine feed were as follows: normal water and fed with control diet (En0/PY0); endosulfan‐treated water and fed with control diet (En/PY0); and endosulfan‐treated water and fed with 50 (En/PY 50 mg/kg), 75 (En/PY 75 mg/kg) and 100 mg/kg (En/PY 100 mg/kg) pyridoxine‐supplemented feed. The endosulfan in treated water was maintained at a level of 1/40th of LC50 (0.52 ppb). The effect of dietary pyridoxine supplementation was studied in terms of antioxidative enzymes (catalase, superoxide dismutase, glutathione‐S‐transferase), stress markers [heat‐shock protein 70, caspase‐3, cortisol, acetylcholine esterase (AChE), blood glucose], immunohaematological parameters (total protein, albumin, globulin and A/G ratio, nitroblue tetrazolium, RBC, WBC, Hb), gill histopathology and a subsequent challenge study with Vibrio parahaemolyticus. The antioxidative enzymes, stress markers, albumin and A/G ratio were significantly (p < 0.01) elevated, brain AChE and immunohaematological parameters were significantly (p < 0.01) decreased, and chromosome aberration and gill histopathology were also altered due to endosulfan exposure. The relative survival % was reduced due to the combined effect of endosulfan stress and bacterial challenge. Fish fed the diet supplemented with pyridoxine at 75 and 100 mg/kg was found to restore the studied parameter towards normal compared with control and indicated protection against endosulfan‐induced stress significantly (p < 0.01). Results obtained in the present study indicate that the supplementation of 75 and 100 mg/kg of pyridoxine in the diet has a definitive role in the mitigation of the endosulfan‐induced stress in milkfish, C. chanos fingerlings.
High Frequency of CYP2D6 Ultrarapid Metabolizer Genotype in the Finnish Population
Authors: Pietarinen Paavo , Tornio Aleksi , Niemi Mikko
Published: April 2016

CYP2D6 participates in the biotransformation of many commonly used drugs. Large genetic variability in CYP2D6 results in a wide interindividual variability in the response to CYP2D6 substrate drugs. Previous studies have assessed the phenotype and genotype distributions of CYP2D6 in relatively small Finnish population samples. The aim of our study was to investigate the frequencies of CYP2D6 genotypes in a larger Finnish population cohort of 857 healthy volunteers. The volunteers were genotyped for 10 CYP2D6 genetic variants (*2, *3, *4, *5, *6, *9, *10, *17, *39, *41) and copy number variation performed with TaqMan genotyping assays and copy number assay targeting exon 9. CYP2D6 phenotypes were inferred from the genotype data with the classical and activity score methods. According to the classical method, a large majority of the study cases were extensive metabolizers (EM; 87.3%; 95% confidence interval 84.9–89.3) and the second largest group was ultrarapid metabolizers (UM; 7.2%; 5.7–9.2%). Intermediate (IM) and poor metabolizers (PM) were in clear minority (3.0%; 2.1–4.4% and 2.3%; 1.5–3.6%, respectively). The activity score method yielded similar phenotype predictions. These results show that the frequency of UM genotype is higher and that of PM and IM genotype is lower in the Finnish population than in other North European populations. Accordingly, CYP2D6 genetic profile of the Finnish population differs from its geographically close neighbours, which has implications for the effective and safe use of drugs metabolized by CYP2D6.
Robust Risk Prediction with Biomarkers Under Two-Phase Stratified Cohort Design
Authors: Payne Rebecca , Yang Ming , Zheng Yingye , Jensen Majken K. , Cai Tianxi
Published: April 2016

Identification of novel biomarkers for risk prediction is important for disease prevention and optimal treatment selection. However, studies aiming to discover which biomarkers are useful for risk prediction often require the use of stored biological samples from large assembled cohorts, and thus the depletion of a finite and precious resource. To make efficient use of such stored samples, two-phase sampling designs are often adopted as resource-efficient sampling strategies, especially when the outcome of interest is rare. Existing methods for analyzing data from two-phase studies focus primarily on single marker analysis or fitting the Cox regression model to combine information from multiple markers. However, the Cox model may not fit the data well. Under model misspecification, the composite score derived from the Cox model may not perform well in predicting the outcome. Under a general two-phase stratified cohort sampling design, we present a novel approach to combining multiple markers to optimize prediction by fitting a flexible nonparametric transformation model. Using inverse probability weighting to account for the outcome-dependent sampling, we propose to estimate the model parameters by maximizing an objective function which can be interpreted as a weighted C-statistic for survival outcomes. Regardless of model adequacy, the proposed procedure yields a sensible composite risk score for prediction. A major obstacle for making inference under two phase studies is due to the correlation induced by the finite population sampling, which prevents standard inference procedures such as the bootstrap from being used for variance estimation. We propose a resampling procedure to derive valid confidence intervals for the model parameters and the C-statistic accuracy measure. We illustrate the new methods with simulation studies and an analysis of a two-phase study of high-density lipoprotein cholesterol (HDL-C) subtypes for predicting the risk of coronary heart disease.
PCAN: Probabilistic Correlation Analysis of Two Non-Normal Data Sets
Authors: Zoh Roger S. , Mallick Bani , Ivanov Ivan , Baladandayuthapani Veera , Manyam Ganiraju , Chapkin Robert S. , Lampe Johanna W. , Carroll Raymond J.
Published: April 2016

Most cancer research now involves one or more assays profiling various biological molecules, e.g., messenger RNA and micro RNA, in samples collected on the same individuals. The main interest with these genomic data sets lies in the identification of a subset of features that are active in explaining the dependence between platforms. To quantify the strength of the dependency between two variables, correlation is often preferred. However, expression data obtained from next-generation sequencing platforms are integer with very low counts for some important features. In this case, the sample Pearson correlation is not a valid estimate of the true correlation matrix, because the sample correlation estimate between two features/variables with low counts will often be close to zero, even when the natural parameters of the Poisson distribution are, in actuality, highly correlated. We propose a model-based approach to correlation estimation between two non-normal data sets, via a method we call Probabilistic Correlations ANalysis, or PCAN. PCAN takes into consideration the distributional assumption about both data sets and suggests that correlations estimated at the model natural parameter level are more appropriate than correlations estimated directly on the observed data. We demonstrate through a simulation study that PCAN outperforms other standard approaches in estimating the true correlation between the natural parameters. We then apply PCAN to the joint analysis of a microRNA (miRNA) and a messenger RNA (mRNA) expression data set from a squamous cell lung cancer study, finding a large number of negative correlation pairs when compared to the standard approaches.
Chromogranin A and neurone‐specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration‐resistant prostate cancer undergoing abiraterone therapy
Authors: Heck Matthias M. , Thaler Markus A. , Schmid Sebastian C. , Seitz Anna‐Katharina , Tauber Robert , Kübler Hubert , Maurer Tobias , Thalgott Mark , Hatzichristodoulou Georgios , Höppner Michael , Nawroth Roman , Luppa Peter B. , Gschwend Jürgen E. , Retz Margitta
Published: April 2016

Objective

To determine the impact of elevated neuroendocrine serum markers on treatment outcome in patients with metastatic castration‐resistant prostate cancer (mCRPC) undergoing treatment with abiraterone in a post‐chemotherapy setting.

Patients and Method

Chromogranin A (CGa) and neurone‐specific enolase (NSE) were determined in serum drawn before treatment with abiraterone from 45 patients with mCRPC. Outcome measures were overall survival (OS), prostate‐specific antigen (PSA) response defined by a PSA level decline of ≥50%, PSA progression‐free survival (PSA‐PFS), and clinical or radiographic PFS.

Results

The CGa and NSE serum levels did not correlate (P = 0.6). Patients were stratified in to low‐ (nine patients), intermediate‐ (18) or high‐risk (18) groups according to elevation of none, one, or both neuroendocrine markers, respectively. The risk groups correlated with decreasing median OS (median OS not reached vs 15.3 vs 6.6 months; P < 0.001), decreasing median clinical or radiographic PFS (8.3 vs 4.4 vs 2.7 months; P = 0.001) and decreasing median PSA‐PFS (12.0 vs 3.2 vs 2.7 months; P = 0.012). In multivariate Cox regression analysis the combination of CGa and NSE (≥1 marker positive vs both markers negative) remained significant predictors of OS, clinical or radiographic PFS, and PSA‐PFS. We did not observe a correlation with PSA response (63% vs 35% vs 31%; P = 0.2).

Conclusion

Chromogranin A and NSE did not predict PSA response in patients with mCRPC treated with abiraterone. However, we observed a correlation with shorter PSA‐PFS, clinical or radiographic PFS, and OS. This might be due to an elevated risk of developing resistance under abiraterone treatment related to neuroendocrine differentiation.
Guideline of guidelines: thromboprophylaxis for urological surgery
Authors: Violette Philippe D. , Cartwright Rufus , Briel Matthias , Tikkinen Kari A.O. , Guyatt Gordon H.
Published: April 2016

Decisions regarding thromboprophylaxis in urologic surgery involve a trade‐off between decreased risk of venous thromboembolism (VTE) and increased risk of bleeding. Both patient‐ and procedure‐specific factors are critical in making an informed decision on the use of thromboprophylaxis. Our systematic review of the literature revealed that existing guidelines in urology are limited. Recommendations from national and international guidelines often conflict and are largely based on indirect as opposed to procedure‐specific evidence. These issues have likely contributed to large variation in the use of VTE prophylaxis within and between countries. The majority of existing guidelines typically suggest prolonged thromboprophylaxis for high‐risk abdominal or pelvic surgery, without clear clarification of what these procedures are, for up to 4 weeks post‐discharge. Existing guidance may result in the under‐treatment of procedures with low risk of bleeding and the over‐treatment of oncological procedures with low risk of VTE. Guidance for patients who are already anticoagulated are not specific to urological procedures but generally involve evaluating patient and surgical risks when deciding on bridging therapy. The European Association of Urology Guidelines Office has commissioned an ad hoc guideline panel that will present a formal thromboprophylaxis guideline for specific urological procedures and patient risk factors.
Tree Height Reduction After Selective Logging in a Tropical Forest
Authors: Rutishauser Ervan , Hérault Bruno , Petronelli Pascal , Sist Plinio
Published: April 2016

By harvesting scattered large trees, selective logging increases light availability and thereby stimulates growth and crown expansion at early‐life stage among remnant trees. We assessed the effects of logging on total and merchantable bole (i.e., lowest branch at crown base) heights on 952 tropical canopy trees in French Guiana. We observed reductions in both total (mean, −2.3 m) and bole (mean, −2.0 m) heights more than a decade after selective logging. Depending on local logging intensity, height reductions resulted in 2–13 percent decreases in aboveground tree biomass and 3–17 percent decreases in bole volume. These results highlight the adverse effects of logging at both tree and stand levels. This decrease in height is a further threat to future provision of key environmental services, such as timber production and carbon sequestration.
Readability of clinical letters sent from a young people's department
Authors: McAndie Elena , Gilchrist Anne , Ahamat Boolang
Published: April 2016

Background

Writing directly to patients or copying letters to them is common practice in Child and Adolescent Mental Health Services (CAMHS). If the intention is to increase young people's understanding and collaboration in their health care, then the readability of such letters is important. The aim of this study was to reassess the readability of letters sent to patients from the Young People's Department at Royal Cornhill Hospital since it adopted the choice and partnership approach (CAPA).

Method

Readability of clinical letters was measured using indices available in Microsoft Word. Results were compared to readability thresholds.

Results

Most letters sent to patients were still not easily readable.

Conclusions

Awareness of easily accessible readability formulae has not led to acceptable levels of readability in letters. More needs to be done to investigate patients’ views and improve communication.
Pituitary apoplexy – bespoke patient management allows good clinical outcome
Authors: Giritharan Sumithra , Gnanalingham Kanna , Kearney Tara
Published: April 2016

Objective

To describe the clinical presentation, management and outcome of pituitary apoplexy from a single centre and retrospectively apply the Pituitary Apoplexy Score (PAS).

Design

Retrospective review of patients presenting with classical pituitary apoplexy to a single neurosurgical centre in the Greater Manchester region.

Results

A total of 31 cases with classical pituitary apoplexy were identified between 2005 and 2014. The mean age at presentation was 55 years, and there were 19 men. In only one patient was there prior knowledge of a pituitary adenoma. Eleven (35%) patients were managed conservatively and 20 (65%) patients managed surgically. Emergency surgery was carried out in 11 patients. At presentation, visual symptoms were present in a higher proportion of patients in the surgical group (90%) compared to the conservatively managed group (64%). At final follow‐up, visual recovery was apparent in most patients in both the surgical (100%) and conservatively (86%) managed groups. The proportion of patients with hypopituitarism was high in both the surgical (86%) and conservative (73%) groups at presentation, and this failed to improve at final follow‐up (90% vs 73%, respectively). The median PAS scores were higher in the surgical (PAS 2), compared to the conservatively managed group (PAS 0).

Conclusion

In pituitary apoplexy patients managed conservatively or surgically, there is good recovery of visual symptoms but not endocrine function. Patients should be managed on a case‐by‐case basis based on the severity of symptoms at presentation, progression of disease and surgical expertise available. Further prospective studies using the PAS are required to determine its usefulness in clinical practice.
Formation of the circle of Willis during human embryonic development
Authors: Takakuwa Tetsuya , Koike Teppei , Muranaka Taiga , Uwabe Chigako , Yamada Shigehito
Published: April 2016

The circle of Willis (CW) is a circulatory anastomosis that supplies blood to the brain and adjacent structures. We examined the timing of formation of CW in 20 Japanese human embryo samples by using 3‐dimensional reconstruction of serial histological sections. The CW was closed in 1 (n = 6), 2 (n = 8), 2 (n = 3) and 2 (n = 3) samples at Carnegie stages 20, 21, 22, and 23, respectively. The CW was unclosed in 13 samples (unclosed at ACOM alone, 6 samples; ACOM and bilateral P1, 4; left PCOM and right P1, 1; right PCOM and right P1, 1; ACOM and left PCOM, 1). It was difficult to predict whether the circle would close during further development, as such variations frequently exist in adults.
A Survey of Cardiac 4D PC‐MRI Data Processing
Authors: Köhler Benjamin , Born Silvia , van Pelt Roy F. P. , Hennemuth Anja , Preim Uta , Preim Bernhard
Published: April 2016

Cardiac four‐dimensional phase‐contrast magnetic resonance imaging (4D PC‐MRI) acquisitions have gained increasing clinical interest in recent years. They allow to non‐invasively obtain extensive information about patient‐specific hemodynamics, and thus have a great potential to improve the diagnosis, prognosis and therapy planning of cardiovascular diseases. A dataset contains time‐resolved, three‐dimensional blood flow directions and strengths, making comprehensive qualitative and quantitative data analysis possible. Quantitative measures, such as stroke volumes, help to assess the cardiac function and to monitor disease progression. Qualitative analysis allows to investigate abnormal flow characteristics, such as vortices, which are correlated to different pathologies. Processing the data comprises complex image processing methods, as well as flow analysis and visualization. In this work, we mainly focus on the aorta. We provide an overview of data measurement and pre‐processing, as well as current visualization and quantification methods. This allows other researchers to quickly catch up with the topic and take on new challenges to further investigate the potential of 4D PC‐MRI data.
Protective benefit of predominant breastfeeding against otitis media may be limited to early childhood: results from a prospective birth cohort study
Authors: Brennan‐Jones C.G. , Eikelboom R.H. , Jacques A. , Swanepoel D. , Atlas M.D. , Whitehouse A.J.O. , Jamieson S.E. , Oddy W.H.
Published: April 2016

Objectives

To examine the long‐term effects of predominant breastfeeding on incidence of otitis media.

Design

Prospective birth cohort study.

Setting

The West Australian Pregnancy Cohort (Raine) Study recruited 2900 mothers through antenatal clinics at the major tertiary obstetric hospital in Perth, Western Australia, between 1989 and 1992.

Participants

In total, 2237 children participated in a 6‐year cohort follow‐up, and a subset of 1344 were given ear and hearing assessments.

Main outcome measures

OM diagnosis at 6 years of age (diagnosed by low‐compliance tympanograms, 0–0.1 mmho). This was compared to OM diagnosed at the 3‐year cohort follow‐up using parent‐report measures. Main exposure measures were duration of predominant breastfeeding (defined as the age other milk was introduced) and duration of partial (any) breastfeeding (defined as the age breastfeeding was stopped).

Results

There was a significant, independent association between predominant breastfeeding (OR = 1.33 [1.04, 1.69]; P = 0.02) and OM, and breastfeeding duration (OR = 1.35 [1.08, 1.68]; P = 0.01) with OM at 3 years of age. However, at 6 years of age, this relationship was no longer statistically significant (predominant breastfeeding OR = 0.78 [0.48, 1.06]; P = 0.09; duration of breastfeeding, OR = 1.34 [0.81, 2.23]; P = 0.25).

Conclusions

Our findings are in line with a number of epidemiological studies which show a positive association between breastfeeding and OM in early childhood. However, the long‐term follow‐up of these children revealed that by 6 years of age, there was no significant influence of breastfeeding on presence of OM. These results suggest that the protective effect of predominant breastfeeding for at least 6 months does not extend to school‐age children, where other social and environmental factors may be stronger predictors of OM.
The clinical diagnostic value of target biopsy using narrow‐band imaging endoscopy and accurate laryngeal carcinoma pathologic specimen acquisition
Authors: Yang Y. , Liu J. , Song F. , Zhang S.
Published: April 2016

Objective

To estimate the clinical significance of target biopsy for clinical diagnosis and determine accurate laryngeal lesion pathologic specimen acquisition via narrow‐band imaging (NBI) endoscopy.

Methods

A total of 138 samples from patients with laryngeal lesions (carcinoma, 118; hyperplasia, 3; mild dysplasia, 2; moderate dysplasia, 5; severe dysplasia, 5; vocal cord polyp, 1; and inflammatory lesion, 4) were collected from the Department of Otolaryngology Head and Neck Surgery of Tianjin Union Medical Center from 1 January 2013 to 1 February 2015. All patients were divided into the regular biopsy and NBI target biopsy groups; the imaging data were recorded and patient samples were biopsied. Pathologic diagnoses were used to evaluate the accuracies of regular and target biopsy.

Results

Based on the pathologic diagnosis, NBI target pathology yielded an accurate laryngeal lesion pathologic specimen acquisition rate of 95.6% (65/68), significantly higher than that yielded by regular biopsy (75.7%, 53/70; χ2 = 10.99, P = 0.001). In the NBI target pathology group, the correct accurate pathologic specimen acquisition rates at laryngeal cancer diagnostic stages 0 (Tis), I and II were 100%, 100% and 85.71%, respectively, which were higher than the corresponding rates in the regular biopsy group (0%, χ2 = 10.000, P = 0.002; 25%, χ2 = 5.625, P = 0.018; and 38.46%, χ2 = 6.454, P = 0.011, respectively).

Conclusions

In cases of laryngeal carcinoma, NBI endoscopy plays an important role in clinical diagnosis and accurate pathologic specimen acquisition and could be a regular clinical method for laryngeal lesion detection.
GAMDB: a web resource to connect microRNAs with autophagy in gerontology
Authors: Zhang Lan , Xie Tao , Tian Mao , Li Jingjing , Song Sicheng , Ouyang Liang , Liu Bo , Cai Haoyang
Published: April 2016

Objectives

MicroRNAs (miRNAs) are endogenous ~23 nucleotides (nt) RNAs, regulating gene expression by pairing to the mRNAs of protein‐coding genes to direct their post‐transcriptional repression. Both in normal and aberrant activities, miRNAs contribute to a recurring paradigm of cellular behaviors in pathological settings, especially in gerontology. Autophagy, a multi‐step lysosomal degradation process with function to degrade long‐lived proteins and damaged organelles, has significant impact on gerontology. Thus, elucidating how miRNAs participate in autophagy may enlarge the scope of miRNA in autophagy and facilitate researches in gerontology.

Materials and methods

Herein, based upon the published studies, predicted targets and gerontology‐related diseases, we constructed a web resource named Gerontology‐Autophagic‐MicroRNA Database (GAMDB) (http://gamdb.liu-lab.com/index.php), which contained 836 autophagy‐related miRNAs, 197 targeted genes/proteins and 56 aging‐related diseases such as Parkinson' disease, Alzheimer's disease and Huntington's disease.

Results and Conclusion

We made use of large amounts of data to elucidate the intricate relationships between microRNA‐regulated autophagic mechanisms and gerontology. This database will facilitate better understanding of autophagy regulation network in gerontology and thus promoting gerontology‐related therapy in the future.
Hormone resuscitation therapy for brain‐dead donors – is insulin beneficial or detrimental?
Authors: Novitzky Dimitri , Mi Zhibao , Videla Luis A. , Collins Joseph F. , Cooper David K. C.
Published: April 2016

Hormonal replacement therapy to brain‐dead potential organ donors remains controversial. A retrospective study was carried out of hormonal therapy on procurement of organs in 63 593 donors in whom information on thyroid hormone therapy (triiodothyronine or levothyroxine [T3/T4]) was available. In 40 124 donors, T3/T4 and all other hormonal therapy were recorded. The percentage of all organs procured, except livers, was greater when T3/T4 had been administered. An independent beneficial effect of antidiuretic hormone (ADH) was also clear. Corticosteroids were less consistently beneficial (most frequently when T3/T4 had not been administered), although never detrimental. Insulin was almost never beneficial and at times was associated with a reduced yield of organs, particularly of the pancreas and intestine, an observation that does not appear to have been reported previously. In addition, there was reduced survival at 12 months of recipients of pancreases from T3/T4‐treated donors, but not of pancreas grafts. The possibly detrimental effect observed following insulin therapy is discussed.
Climate change sentinel or false prophet? The case of Aloe dichotoma
Authors: Jack S. L. , Hoffman M. T. , Rohde R. F. , Durbach I.
Published: April 2016

Aim

Previous research suggests that equatorward populations of the iconic arborescent succulent Aloe dichotoma Masson are contracting in response to recent anthropogenic climate change (ACC) in southern Africa. However, previous studies did not account for small‐scale spatial heterogeneity, latitudinal climatic disjunctions or when mortality occurred. We reassess A. dichotoma's suitability as an indicator species and comment on pitfalls in the selection of species with similar life history characteristics.

Location

South‐western Africa.

Methods

A 15,000 km distribution‐wide roadside visual survey was conducted to capture demographic patterns and provide the means for extracting tightly coupled climate profiles for the species. Rainfall and temperature gradients were assessed for latitudinal discontinuities indicating distinct equatorward‐poleward climate zones. Repeat photographs and reference individuals were used to develop an index for dating the approximate time‐since‐death of dead trees at 14 latitudinally spaced populations.

Results

The proportion of dead individuals was greatest within the southern third of the latitudinal distribution rather than at the equatorward range limit. The equatorward summer rainfall zone (SRZ) was significantly drier, rainfall more variable and temperatures hotter compared to the poleward winter rainfall zone (WRZ). This difference was associated with a generally greater proportion of dead individuals in the SRZ and greater proportion of juveniles in the WRZ. Furthermore, juveniles appeared more sensitive to drought stress while adults were more resilient. Most mortality occurred several decades ago, was not more recent at the equatorward limit and was drawn from the more drought resilient adult stage class.

Main conclusions

Aloe dichotoma mortality (and recruitment) patterns reflect prevailing differences in the SRZ and WRZ climate, while differing juvenile and adult drought stress tolerances and windthrow‐mediated mortality reinforces this pattern. This and strong indications of non‐recent death suggest that ACC is not responsible for observed mortality. An alternative hypothesis for current demographic patterns, which incorporates palaeoclimatic evidence and A. dichotoma life history characteristics is proposed. Long‐term climate trends, recruitment‐mortality dynamics and potential climatic discontinuities should be considered before advancing species as indicators of ACC.
Intelligence quotient in paediatric sickle cell disease: a systematic review and meta‐analysis
Authors: Kawadler Jamie M , Clayden Jonathan D , Clark Chris A , Kirkham Fenella J
Published: April 2016

Aim

Sickle cell disease (SCD) is the commonest cause of childhood stroke worldwide. Magnetic resonance imaging (MRI) is routinely used to detect additional silent cerebral infarction (SCI), as IQ is lower in SCI as well as stroke. This review assesses the effect of infarction on IQ, and specifically whether, compared to healthy controls, IQ differences are seen in children with SCI with no apparent MRI abnormality.

Method

A systematic review was conducted to include articles with an SCD paediatric population, MRI information, and Wechsler IQ. A meta‐analysis of 19 articles was performed to compare IQ in three groups: stroke vs SCI; SCI vs no SCI; and no SCI vs healthy controls.

Results

Mean differences in IQ between all three groups were significant: stroke patients had lower IQ than patients with SCI by 10 points (six studies); patients with SCI had lower IQ than no patients with SCI by 6 points (17 studies); and no patients with SCI had lower IQ than healthy controls by 7 points (seven studies).

Interpretation

Children with SCD and no apparent MRI abnormality have significantly lower IQ than healthy controls. In this chronic condition, other biological, socioeconomic, and environmental factors must play a significant role in cognition.
The ICF as a measure of effectiveness: structure, function, and contextual factors
Authors: Murphy Nancy
Published: April 2016

This commentary is on the original article by Smith et al. on pages 979–988 of this issue.
Transthoracic Echocardiography‐Guided Percutaneous Patent Ductus Arteriosus Occlusion: A New Strategy for Interventional Treatment
Authors: Pan Xiang‐Bin , Ouyang Wen‐Bin , Wang Shou‐Zheng , Liu Yao , Zhang Da‐Wei , Zhang Feng‐Wen , Pang Kun‐Jing , Zhang Zhe , Hu Sheng‐Shou
Published: April 2016

Introduction

Percutaneous patent ductus arteriosus (PDA) occlusion has become the preferred therapeutic option, which uses fluoroscopy as the guidance. To reduce the x‐ray exposure, PDA occlusion using the Amplatzer Duct Occluder II (ADO II) under guidance of transthoracic echocardiography only was conducted. This single center study aims to access the safety and efficiency of this new strategy.

Methods and Results

From June 2013 to May 2015, 63 consecutive PDA patients underwent transthoracic echocardiography‐guided PDA occlusion through the femoral artery. Outpatient follow‐up was conducted at 1, 3, and 6 months, and yearly. Sixty‐two patients successfully underwent echocardiography‐guided percutaneous PDA occlusion. One patient was converted to minimally invasive transthoracic occlusion due to failure of delivery sheath passage through tortuous PDA. Mean procedure duration was 24.3 ± 7.0 minutes; ADO II diameter averaged 4.6 ± 0.9 mm; 8 cases showed traces of residual shunt immediately after operation which resolved after 24 hours; and mean hospital stay was 3.4 ± 0.5 days. There was no occluder migration, hemolysis, pericardial effusion, pulmonary branch or aortic stenosis at mean 13.5 ± 4.8 months follow‐up.

Conclusions

This study demonstrated that percutaneous PDA occlusion can be successfully performed under guidance of transthoracic echocardiography only and appears safe and effective while avoiding radiation and contrast agent use.
IDENTIFYING THE LOCAL ECONOMIC DEVELOPMENT EFFECTS OF MILLION DOLLAR FACILITIES
Authors: Patrick Carlianne
Published: April 2016

Using incentives to attract firms is the primary economic development policy for many local governments. Yet, relatively little is known about the local economic development outcomes induced by successful attraction of new establishments. The empirical challenge lies in correctly identifying the counterfactual outcome. This article tests for induced economic development in winning counties using a set of highly incentivized large plants. The article makes a methodological contribution by comparing difference‐in‐differences results from a natural experiment (in which counterfactuals are losers reported bySite Selectionmagazine) with a geographically proximate matching control by design strategy. Estimates are sensitive to identification strategy, with distributional and placebo tests suggesting geographically proximate matching as preferable to the natural experiment. The preferred estimates indicate successful attraction of a large new plant induces modest increases in new economic activity that does not generate fiscal surplus for winning counties. (JELR11, R31, H71, O18)
Influence of platelet and white blood cell counts on major thrombosis – analysis from a patient registry in essential thrombocythemia
Authors: Buxhofer‐Ausch Veronika , Steurer Michael , Sormann Siegfried , Schloegl Ernst , Schimetta Wolfgang , Gisslinger Bettina , Ruckser Reinhard , Gastl Günther , Gisslinger Heinz
Published: April 2016

Objectives

Although guidelines recommend normalization of platelet counts as an appropriate endpoint for treatment in high‐risk essential thrombocythemia (ET), retrospective studies could not prove a correlation of diagnostic platelet counts with an increased thrombotic rate. There is, however, an increasing evidence that leukocytosis is an important risk factor for arterial thrombosis in myeloproliferative neoplasms.

Methods

This study considers the Austrian cohort of a European registry regarding the platelet‐lowering therapeutic anagrelide. Influence of platelet and white blood cell (WBC) counts on thrombotic risk was assessed.

Results

Using the calculated cutoffs of 574.5 G/L for platelets and 8.48 G/L for WBC counts, respectively, the Cox regression analysis revealed a clear influence of elevated platelets (P = 0.008) and WBC counts (P = 0.011) on the occurrence of major thrombotic events. The time to a major thrombotic event was shortest (P < 0.001) and the frequency related to 100 patient‐years was highest (P = <0.001) when both platelet and WBC counts ranged above the calculated cutoffs.

Conclusion

Our data add evidence to the impact of platelet and WBC counts on thrombosis in ET. We suspect a particular interaction between platelets and WBC which might be based on a biological interplay depending on particular cell counts.
Lack of mGluR6‐related cascade elements leads to retrograde trans‐synaptic effects on rod photoreceptor synapses via matrix‐associated proteins
Authors: Tummala Shanti R. , Dhingra Anuradha , Fina Marie E. , Li Jian J. , Ramakrishnan Hariharasubramanian , Vardi Noga
Published: April 2016

Heterotrimeric G‐proteins couple metabotropic receptors to downstream effectors. In retinal ON bipolar cells, Go couples the metabotropic receptor mGluR6 to the TRPM1 channel and closes it in the dark, thus hyperpolarizing the cell. Light, via GTPase‐activating proteins, deactivates Go, opens TRPM1 and depolarizes the cell. Go comprises Gαo1, Gβ3 and Gγ13; all are necessary for efficient coupling. In addition, Gβ3 contributes to trafficking of certain cascade proteins and to maintaining the synaptic structure. The goal of this study was to determine the role of Gαo1 in maintaining the cascade and synaptic integrity. Using mice lacking Gαo1, we quantified the immunostaining of certain mGluR6‐related components. Deleting Gαo1 greatly reduced staining for Gβ3, Gγ13, Gβ5, RGS11, RGS7 and R9AP. Deletion of Gαo1 did not affect mGluR6, TRPM1 or PCP2. In addition, deleting Gαo1 reduced the number of rod bipolar dendrites that invaginate the rod terminal, similar to the effect seen in the absence of mGluR6, Gβ3 or the matrix‐associated proteins, pikachurin, dystroglycan and dystrophin, which are localized presynaptically to the rod bipolar cell. We therefore tested mice lacking mGluR6, Gαo1 and Gβ3 for expression of these matrix‐associated proteins. In all three genotypes, staining intensity for these proteins was lower than in wild type, suggesting a retrograde trans‐synaptic effect. We propose that the mGluR6 macromolecular complex is connected to the presynaptic rod terminal via a protein chain that includes the matrix‐associated proteins. When a component of the macromolecular chain is missing, the chain may fall apart and loosen the dendritic tip adherence within the invagination.
Echo‐level compensation and delay tuning in the auditory cortex of the mustached bat
Authors: Macías Silvio , Mora Emanuel C. , Hechavarría Julio C. , Kössl Manfred
Published: April 2016

During echolocation, bats continuously perform audio‐motor adjustments to optimize detection efficiency. It has been demonstrated that bats adjust the amplitude of their biosonar vocalizations (known as ‘pulses’) to stabilize the amplitude of the returning echo. Here, we investigated this echo‐level compensation behaviour by swinging mustached bats on a pendulum towards a reflective surface. In such a situation, the bats lower the amplitude of their emitted pulses to maintain the amplitude of incoming echoes at a constant level as they approach a target. We report that cortical auditory neurons that encode target distance have receptive fields that are optimized for dealing with echo‐level compensation. In most cortical delay‐tuned neurons, the echo amplitude eliciting the maximum response matches the echo amplitudes measured from the bats’ biosonar vocalizations while they are swung in a pendulum. In addition, neurons tuned to short target distances are maximally responsive to low pulse amplitudes while neurons tuned to long target distances respond maximally to high pulse amplitudes. Our results suggest that bats dynamically adjust biosonar pulse amplitude to match the encoding of target range and to keep the amplitude of the returning echo within the bounds of the cortical map of echo delays.
Amphetamine elevates nucleus accumbens dopamine via an action potential‐dependent mechanism that is modulated by endocannabinoids
Authors: Covey Dan P. , Bunner Kendra D. , Schuweiler Douglas R. , Cheer Joseph F. , Garris Paul A.
Published: April 2016

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential‐independent, non‐exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests thatAMPHalso acts by an action potential‐dependent mechanism. Indeed, fast‐scan cyclic voltammetry demonstrates thatAMPHactivates dopamine transients, reward‐related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established forAMPHbut indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast‐scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence ofAMPH‐induced elevations in nucleus accumbens dopamine.AMPHincreased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished allAMPH‐induced dopamine elevations, identifying an action potential‐dependent origin. Blocking cannabinoid type 1 receptors preventedAMPHfrom increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus,AMPHelevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider byAMPH. Collectively, these findings are inconsistent withAMPHeliciting action potential‐independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement.
Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models
Authors: van der Pijl Elizabeth M. , van Putten Maaike , Niks Erik H. , Verschuuren Jan J. G. M. , Aartsma‐Rus Annemieke , Plomp Jaap J.
Published: April 2016

Duchenne muscular dystrophy (DMD) is an X‐linked myopathy caused by dystrophin deficiency. Dystrophin is present intracellularly at the sarcolemma, connecting actin to the dystrophin‐associated glycoprotein complex. Interestingly, it is enriched postsynaptically at the neuromuscular junction (NMJ), but its synaptic function is largely unknown. Utrophin, a dystrophin homologue, is also concentrated at the NMJ, and upregulated in DMD. It is possible that the absence of dystrophin at NMJs in DMD causes neuromuscular transmission defects that aggravate muscle weakness. We studied NMJ function in mdx mice (lacking dystrophin) and wild type mice. In addition, mdx/utrn+/− and mdx/utrn−/− mice (lacking utrophin) were used to investigate influences of utrophin levels. The three Duchenne mouse models showed muscle weakness when comparatively tested in vivo, with mdx/utrn−/− mice being weakest. Ex vivo muscle contraction and electrophysiological studies showed a reduced safety factor of neuromuscular transmission in all models. NMJs had ~ 40% smaller miniature endplate potential amplitudes compared with wild type, indicating postsynaptic sensitivity loss for the neurotransmitter acetylcholine. However, nerve stimulation‐evoked endplate potential amplitudes were unchanged. Consequently, quantal content (i.e. the number of acetylcholine quanta released per nerve impulse) was considerably increased. Such a homeostatic compensatory increase in neurotransmitter release is also found at NMJs in myasthenia gravis, where autoantibodies reduce acetylcholine receptors. However, high‐rate nerve stimulation induced exaggerated endplate potential rundown. Study of NMJ morphology showed that fragmentation of acetylcholine receptor clusters occurred in all models, being most severe in mdx/utrn−/− mice. Overall, we showed mild ‘myasthenia‐like’ neuromuscular synaptic dysfunction in several Duchenne mouse models, which possibly affects muscle weakness and degeneration.
Two drugs are better than one … for a while. Duration of dual‐antiplatelet therapy following stroke or transient ischaemic attack
Authors: Klaas J. P.
Published: April 2016

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