bluuebunny/crossref_metadata_2025 huggingface dataset:
Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers
Authors: Loft Anne , Forss Isabel , Siersbæk Majken Storm , Schmidt Søren Fisker , Larsen Ann-Sofie Bøgh , Madsen Jesper Grud Skat , Pisani Didier F. , Nielsen Ronni , Aagaard Mads Malik , Mathison Angela , Neville Matt J. , Urrutia Raul , Karpe Fredrik , Amri Ez-Zoubir , Mandrup Susanne
Published: December 2014

Long-term exposure to peroxisome proliferator-activated receptor γ (PPARγ) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARγ binding, leading to the formation of PPARγ “superenhancers” that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARγ and appears to cooperate with PPARγ in a feed-forward manner to activate and maintain the brite-selective gene program.
Down-Regulation of Kelch Domain-Containing F-Box Protein in Arabidopsis Enhances the Production of (Poly)phenols and Tolerance to Ultraviolet Radiation
Authors: Zhang Xuebin , Gou Mingyue , Guo Chunrong , Yang Huijun , Liu Chang-Jun
Published: December 2014

Phenylpropanoid biosynthesis in plants engenders myriad phenolics with diverse biological functions. Phenylalanine ammonia-lyase (PAL) is the first committed enzyme in the pathway, directing primary metabolic flux into a phenylpropanoid branch. Previously, we demonstrated that the Arabidopsis (Arabidopsis thaliana) Kelch domain-containing F-box proteins, AtKFB01, AtKFB20, and AtKFB50, function as the negative regulators controlling phenylpropanoid biosynthesis via mediating PAL’s ubiquitination and subsequent degradation. Here, we reveal that Arabidopsis KFB39, a close homolog of AtKFB50, also interacts physically with PAL isozymes and modulates PAL stability and activity. Disturbing the expression of KFB39 reciprocally affects the accumulation/deposition of a set of phenylpropanoid end products, suggesting that KFB39 is an additional posttranslational regulator responsible for the turnover of PAL and negatively controlling phenylpropanoid biosynthesis. Furthermore, we discover that exposure of Arabidopsis to ultraviolet (UV)-B radiation suppresses the expression of all four KFB genes while inducing the transcription of PAL isogenes; these data suggest that Arabidopsis consolidates both transcriptional and posttranslational regulation mechanisms to maximize its responses to UV light stress. Simultaneous down-regulation of all four identified KFBs significantly enhances the production of (poly)phenols and the plant’s tolerance to UV irradiation. This study offers a biotechnological approach for engineering the production of useful phenolic chemicals and for increasing a plant’s resistance to environmental stress.
Predicting climate warming effects on green turtle hatchling viability and dispersal performance
Authors: Cavallo Catherine , Dempster Tim , Kearney Michael R. , Kelly Ella , Booth David , Hadden Kate M. , Jessop Tim S.
Published: December 2014

Ectotherms are taxa considered highly sensitive to rapid climate warming. This is because body temperature profoundly governs their performance, fitness and life history. Yet, while several modelling approaches currently predict thermal effects on some aspects of life history and demography, they do not consider how temperature simultaneously affects developmental success and offspring phenotypic performance, two additional key attributes that are needed to comprehensively understand species responses to climate warming.

Here, we developed a stepwise, individual‐level modelling approach linking biophysical and developmental models with empirically derived performance functions to predict the effects of temperature‐induced changes to offspring viability, phenotype and performance, using green sea turtle hatchlings as an ectotherm model. Climate warming is expected to particularly threaten sea turtles, as their life‐history traits may preclude them from rapid adaptation.

Under conservative and extreme warming, our model predicted large effects on performance attributes key to dispersal, as well as a reduction in offspring viability. Forecast sand temperatures produced smaller, weaker hatchlings, which were up to 40% slower than at present, albeit with increased energy stores. Conversely, increases in sea surface temperatures aided swimming performance.

Our exploratory study points to the need for further development of integrative individual‐based modelling frameworks to better understand the complex outcomes of climate change for ectotherm species. Such advances could better serve ecologists to highlight the most vulnerable species and populations, encouraging prioritization of conservation effort to the most threatened systems.
Heat‐induced mortality and expression of heat shock proteins in Colorado potato beetles treated with imidacloprid
Authors: Chen Jie , Kitazumi Ai , Alpuerto Jasper , Alyokhin Andrei , de los Reyes Benildo
Published: December 2014

The Colorado potato beetle is an important pest of solanaceous plants in the Northern Hemisphere. Better understanding of its physiological responses to temperature stress and their interactions with still‐prevalent chemical control has important implications for the management of this insect. We measured mortality and expression of the Hsp70 heat shock proteins in the Colorado potato beetle larvae exposed to sublethal concentration of the commonly used insecticide imidacloprid, and to supraoptimal temperatures. Both turned out to be significant stress factors, although induction of Hsp70 by imidacloprid observed in the present study was low compared to its induction by the heat. The two factors also interacted with each other. At an extreme temperature of 43 °C, exposure to a sublethal dose of imidacloprid resulted in a significant rise in larval mortality, which was not observed at an optimal temperature of 25 °C. Heat‐stressed larvae also failed to respond to imidacloprid by producing more Hsp70. These findings suggest that when field rates of insecticides become insufficient for killing the exposed beetles under optimal temperature conditions due to the evolution of resistance in beetle populations, they may still reduce the probability of resistant beetles surviving the heat shock created by using propane flamers as a rescue treatment.
Putative nicotinic acetylcholine receptor subunits express differentially through the life cycle of codling moth, Cydia pomonella (Lepidoptera: Tortricidae)
Authors: Martin Jessica A. , Garczynski Stephen F.
Published: December 2014

Nicotinic acetylcholine receptors (nAChRs) are the targets of neonicotinoids and spinosads, two insecticides used in orchards to effectively control codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae). Orchardists in Washington State are concerned about the possibility of codling moth field populations developing resistance to these two insecticides. In an effort to help mitigate this issue, we initiated a project to identify and characterize codling moth nAChR subunits expressed in heads. This study had two main goals; (i) identify transcripts from a codling moth head transcriptome that encode for nAChR subunits, and (ii) determine nAChR subunit expression profiles in various life stages of codling moth. From a codling moth head transcriptome, 24 transcripts encoding for 12 putative nAChR subunit classes were identified and verified by PCR amplification, cloning, and sequence determination. Characterization of the deduced protein sequences encoded by putative nAChR transcripts revealed that they share the distinguishing features of the cys‐loop ligand‐gated ion channel superfamily with 9 α‐type subunits and 3 β‐type subunits identified. Phylogenetic analysis comparing these protein sequences to those of other insect nAChR subunits supports the identification of these proteins as nAChR subunits. Stage expression studies determined that there is clear differential expression of many of these subunits throughout the codling moth life cycle. The information from this study will be used in the future to monitor for potential target‐site resistance mechanisms to neonicotinoids and spinosads in tolerant codling moth populations.
De novo assembly of the transcriptome of Acanthaster planci testes
Authors: Stewart Michael James , Stewart Praphaporn , Rivera‐Posada Jairo
Published: December 2014

A key strategy to reduce coral loss is the development of effective control method for the corallivorous crown‐of‐thorns sea star (Acanthaster planci), an omnipresent scourge and threat to the biodiversity of reefs in the Indo‐Pacific region. Limited genetic resources are available for this highly fecund species. In this study, we explored one aspect at the heart of A. planci outbreaks, the male reproductive system. Using high‐throughput sequencing technology, we report for first time the production of a comprehensive transcriptomic data set for the testes of A. placni that can aid in understanding the molecular mechanisms involved in A. planci spermatogenesis and fertilization. Through de novo transcriptome sequencing, we produced 52 965 998 raw reads corresponding to 4.76 Gb clean read data. From this, 243 870 contigs were assembled with Trinity and used to construct 92 792 unigenes. Distinct genes were then annotated with blastx yielding 30 810 unigenes above the cut‐off E‐value set at 10−5, with ESTScan database query analyses yielding up to 5366 unigenes to known hits. The identification of genes directly involved in sperm development (DEAD‐box family proteins), motility, fertilization and signalling (Bindin/Speract receptor) are also discussed.
Estimates from non‐replicated population surveys rely on critical assumptions
Authors: Knape Jonas , Korner‐Nievergelt Fränzi
Published: December 2014

N‐mixture and occupancy models are often used to account for non‐detections in population surveys. The consensus has been that the methods require data that are replicated in space, as well as within a short period of time while the population at each site remains closed, in order for parameters such as detection probabilities and expected abundances to be identifiable. The requirement of replication prohibits the use of N‐mixture and occupancy models for many surveys in practice. Recently, some studies have argued that N‐mixture and occupancy models for surveys with only one visit at each site are identifiable when covariates for both detection probabilities and expected abundances, with at least one distinct covariate for each, are available (Journal of Plant Ecology, 5, 2012, 22; Environmetrics, 23, 2012, 197).

We investigate the reasons for why detection probabilities have traditionally been considered unestimable from non‐replicated counts and how the new methods sidestep these issues. We further use simulations to investigate properties of the new estimators.

We show that detection probabilities of the single‐visit models with covariates are non‐identifiable and that absolute abundances cannot be estimated when particular link functions are employed (log links for both expected abundance and detection probability). Further, assumptions about the range within which detection probabilities vary are necessary to render estimability. The possibility of estimating abundance from single‐visit surveys therefore implicitly hinges on knowledge about the link functions. Simulations show that estimates of abundance can be highly variable and sensitive to the choice of link function. We further show how a reduced parameterization of an N‐mixture model for surveys repeated over time, without replication under closure but where detection probabilities are constant over time, corresponds to a Poisson model.

Non‐robust estimation can result in misleading conclusions about population abundance. When estimating abundance from count data that are not replicated, it is therefore important to be aware of how imprecise estimators may be and how sensitive they are to model assumptions.
The concurrence of subacute cutaneous lupus erythematosus and hand‐foot syndrome in a patient undergoing capecitabine chemotherapy
Authors: Li Zhiming , Jiang Nanyan , Xu Yunsheng
Published: December 2014

We describe an unusual case of subacute cutaneous lupus erythematosus concurrent with hand‐foot syndrome, apparently associated with capecitabine treatment. We hypothesise that subacute cutaneous lupus erythematosus and hand‐foot syndrome may occur in a novel overlap syndrome.
Successful treatment of Dowling‐Degos disease using intense pulsed light
Authors: Gupta Aakriti , Huilgol Shyamala C
Published: December 2014

Dowling‐Degos disease (DDD) is a rare inherited pigmentary disorder characterised by reticulate pigmentation at flexural sites. No treatment modality has yet been established as a definitive method for the effective elimination of lentigines in DDD. We present a case of a 24‐year old woman with DDD treated successfully using intense pulsed light as a novel management strategy.
Vitiligo treatment update
Authors: Daniel Benjamin S , Wittal Richard
Published: December 2014

Vitiligo is a common depigmenting disease that can affect the skin and mucosal surfaces. Various treatments have been used over the years with varying repigmentation rates. This review looks at the evidence of commonly used therapies for vitiligo.
Fractionated microneedle radiofrequency for treatment of primary axillary hyperhidrosis: A sham control study
Authors: Fatemi Naeini Farahnaz , Abtahi‐Naeini Bahareh , Pourazizi Mohsen , Nilforoushzadeh Mohammad Ali , Mirmohammadkhani Majid
Published: December 2014

Background/ Objective

Primary axillary hyperhidrosis (PAH) creates social stress in patients. Although there are several options for treating PAH, only surgical modalities have conferred a permanent solution. This study evaluated the clinical effectiveness of fractionated microneedle radiofrequency (FMR) treatment for PAH.

Methods

This study is based on a single‐blind, sham control comparative design. In all, 25 patients with severe PAH underwent three sessions of FMR at 3‐week intervals. One side was treated with FMR while the other was sham controlled. Efficacy was evaluated using the hyperhidrosis disease severity scale (HDSS), sweating intensity visual analogue scale (VAS) and patient satisfaction at baseline, 3 weeks after each session and at 3 months after the last. Skin biopsies were obtained from two enrolled patients.

Results

The HDSS and VAS demonstrated significant improvement after treatment on the treated side in comparison with the control side. The mean ± SD of the HDSS after 21 weeks were 1.87 ± 0.61 and 3.38 ± 0.49 (P < 0.001) for the treated and the controlled side, respectively. The follow‐up evaluation revealed that 79% of the patients showed a 1 or 2‐score decrease in HDSS. In total, 80% of patients reported more than 50% satisfaction at the end of the study. Histopathological findings showed a decrease of the number of the sweat glands in the treated side, confirming the above findings.

Conclusions

Treatment of PAH with FMR as a non‐invasive modality can be a safe option with positive therapeutic effects on HDSS without any long‐lasting side effects.
Cutaneous non‐tuberculous mycobacterial infection in patients with chronic graft‐versus‐host disease: A case series
Authors: Moreno‐Bonilla Gilberto , Choy Bonita , Fernandez‐Peñas Pablo
Published: December 2014

We report the first case series of allogeneic haematopoietic stem‐cell transplant patients with graft versus host disease who developed cutaneous non‐tuberculous mycobacteria infection. A multidisciplinary approach, reduction of immunosuppressive medications, combination of antibiotics, close skin surveillance and excision of suitable lesions are recommended in this specific subgroup.
Gemcitabine and vinorelbine treatment in cutaneous T‐cell lymphoma in four patients
Authors: Mohd Affandi Azura , Blumetti Tatiana Pinto , Wells Jillian , Hertzberg Mark , Fernandez‐Peñas Pablo
Published: December 2014

Treatment options for advanced stage cutaneous T‐cell lymphoma (CTCL) are limited by the their efficacy and side‐effects profile. Gemcitabine, a pyrimidine analogue, has been reported to be efficacious in CTCL. Most of the studies published used gemcitabine as a single agent in treating advanced CTCL. Our small case series demonstrated that a combination of gemcitabine and vinorelbine induced partial remission in all four patients with refractory or advanced CTCL, although the effects were not sustained for a long duration (2–6 months). Two patients had neutropenia and one had acute hepatitis, requiring discontinuation of treatment.
Think UV, not heat!
Authors: Wong Celestine C , Liu Wenyuan , Gies Peter , Nixon Rosemary
Published: December 2014

Background

Australia has the highest incidence of skin cancer in the world, a preventable disease caused primarily by exposure to ultraviolet radiation (UVR) in sunlight. Health promotion strategies play a significant role in sun protection.

Objectives

To assess the understanding of a population sample as to the time of year that the sun was ‘at its most burning’ in Melbourne, Australia.

Methods

A cross‐sectional study was performed using questionnaires completed at corporate skin checks, conducted on 668 participants during 2011 to 2013.

Results

Only a minority (n = 82, 12%) gave the correct theoretical answer; the summer solstice or 21–22 December, while another 38% (n = 254) correctly named December and January as the times when the UVR is actually highest. In all, 18% (n = 122) said February was the month when the temperature is hottest and 170 (25%) either mentioned the period May–August when UVR is negligible in Melbourne or had no idea, including saying ‘all year round’. There was no significant difference in this knowledge between different age groups.

Conclusion

One‐quarter of participants did not understand that sunburn was related to high levels of UVR, which occur in summer. Almost one‐fifth associated the heat of February with the highest UVR. Understanding these concepts is important for Australians residing in cooler parts of southern Australia, as UVR levels may be high and yet the temperature may be relatively cool. There needs to be more emphasis on UVR in sun awareness campaigns to prompt sun‐protective behaviour.
Evaluation of insulin resistance in idiopathic hirsutism compared with polycystic ovary syndrome patients and healthy individuals
Authors: Bonakdaran Shokoufeh , Kiafar Bita , Barazandeh Ahmadabadi Fatemeh
Published: December 2014

Introduction

Hirsutism is defined as the excessive male‐pattern growth of hair in women. Hirsutism is often idiopathic or the consequence of polycystic ovary syndrome (PCOS). Insulin resistance is common in PCOS (especially in obese patients) but the association between insulin resistance and idiopathic hirsutism (IH) is not clear. The aim of this study was to investigate the rate of insulin resistance in IH, compared with healthy individuals and patients with PCOS.

Methods

The study included three groups, patients with idiopathic hirsutism, PCOS and healthy women. Each group included 30 non‐obese women. Fasting blood sugar (FBS), insulin level and insulin resistance (estimated by the homeostasis model assessment [HOMA‐IRIR]) were compared in the three groups.

Results

There was a significant difference between the age of the women with IH compared with two other groups. There were no significant difference in levels of serum insulin (P = 0.49, HOMA‐IR (P = 0.47) and prevalence of insulin resistance (P = 0.07) in the three groups. The age‐adjusted prevalence of insulin resistance was similar in the three groups.

Conclusion

Insulin resistance was no more frequent in IH patients than in healthy control groups.
Nasal‐type extranodal natural killer/T‐cell lymphoma presenting as a solitary non‐healing lower leg ulcer
Authors: Liaw Tse‐Yuan , Hu Stephen Chu‐Sung
Published: December 2014

Nasal‐type extranodal natural killer/T‐cell lymphoma (ENTCL) is an aggressive form of non‐Hodgkin's lymphoma with a poor prognosis. Primary cutaneous lesions ofENTCLusually present as nodules or infiltrative plaques. The presentation ofENTCLas a solitary ulcer, in the absence of other cutaneous lesions and systemic symptoms and signs, is extremely rare and may be easily misdiagnosed. In this report, we describe an unusual case ofENTCLwith a diagnostically challenging clinical presentation as a solitary non‐healing leg ulcer in an elderly woman.
Negative urodynamic testing in women with stress incontinence
Authors: Liversidge Kylie , Guzmán Rojas Rodrigo , Kamisan Atan Ixora , Dietz Hans Peter
Published: December 2014

Introduction

A minority of women with a subjective complaint of stress urinary incontinence will have negative urodynamic stress incontinence (USI) findings.

Aim

To test clinical and ultrasound measures as predictors of an unexpected absence of USI. We hypothesised that unexpectedly negative USI would be more common in young women with good pelvic floor and urethral function.

Methods

A retrospective study analysing 398 data sets from women attending a urogynaecology clinic for evaluation of lower urinary tract and pelvic floor dysfunction. Clinical, urodynamic and translabial ultrasound data were tested as possible predictors of negative USI findings.

Results

Women with unexpectedly negative USI findings were younger, had less anterior compartment prolapse and had a higher maximum urethral pressure. Measures of pelvic floor muscle function were not predictive.

Conclusions

Women with unexpectedly negative USI are younger and have better urethral function, but voluntary pelvic floor muscle function seems unrelated to this phenomenon.
Heuristic cognitive diagnosis when the Q‐matrix is unknown
Authors: Köhn Hans‐Friedrich , Chiu Chia‐Yi , Brusco Michael J.
Published: December 2014

Cognitive diagnosis models of educational test performance rely on a binary Q‐matrix that specifies the associations between individual test items and the cognitive attributes (skills) required to answer those items correctly. Current methods for fitting cognitive diagnosis models to educational test data and assigning examinees to proficiency classes are based on parametric estimation methods such as expectation maximization (EM) and Markov chain Monte Carlo (MCMC) that frequently encounter difficulties in practical applications. In response to these difficulties, non‐parametric classification techniques (cluster analysis) have been proposed as heuristic alternatives to parametric procedures. These non‐parametric classification techniques first aggregate each examinee's test item scores into a profile of attribute sum scores, which then serve as the basis for clustering examinees into proficiency classes. Like the parametric procedures, the non‐parametric classification techniques require that the Q‐matrix underlying a given test be known. Unfortunately, in practice, the Q‐matrix for most tests is not known and must be estimated to specify the associations between items and attributes, risking a misspecified Q‐matrix that may then result in the incorrect classification of examinees. This paper demonstrates that clustering examinees into proficiency classes based on their item scores rather than on their attribute sum‐score profiles does not require knowledge of the Q‐matrix, and results in a more accurate classification of examinees.
TAZ regulates cell proliferation and epithelial–mesenchymal transition of human hepatocellular carcinoma
Authors: Xiao Heng , Jiang Ning , Zhou Baoyong , Liu Qiang , Du Chengyou
Published: December 2014

The transcriptional coactivator with PDZ binding motif (TAZ) has been reported to be one of the nuclear effectors of Hippo‐related pathways. TAZ is expressed in many primary tumors and could regulate many biological processes. However, little is known about the role of TAZ in hepatocellular carcinoma (HCC). In the current study, we show that TAZ regulates cellular proliferation and epithelial–mesenchymal transition (EMT) of HCC. TAZ is overexpressed in HCC tissues and cell lines and upregulation of TAZ correlates with a lower overall survival rate of HCC patients after hepatic resection. TAZ knockdown results in inhibition of cancer cell proliferation through decreases in expression of stem cell markers (OCT4, Nanog, and SOX2). Reduction in HCC cell migration and invasion is also evident through reversal of EMT by increases E‐cadherin expression, decreases in N‐cadherin, vimentin, Snail, and Slug expression, and suppression of MMP‐2 and MMP‐9 expression. In a xenograft tumorigenicity model, TAZ knockdown could effectively inhibit tumor growth and metastasis through reversal of the EMT pathway. In conclusion, TAZ is associated with the proliferation and invasiveness of HCC cells, and the TAZ gene may contribute to a novel therapeutic approach against HCC.
Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B‐cell lymphoma
Authors: Tateishi Ukihide , Tatsumi Mitsuaki , Terauchi Takashi , Ando Kiyoshi , Niitsu Nozomi , Kim Won Seog , Suh Cheolwon , Ogura Michinori , Tobinai Kensei
Published: December 2014

The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F‐18] fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) treated with bendamustine–rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of 18F‐FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty‐five patients with relapsed or refractory DLBCL were enrolled. The 18F‐FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value–volume histogram was significantly greater in complete response patients than in non‐complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression‐free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression‐free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine–rituximab.
Neonatal hypertonia – a diagnostic challenge
Authors: Hart Anthony R , Sharma Ruchi , Rittey Christopher D , Mordekar Santosh R
Published: December 2014

In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hypertonia is scant, with no suggested diagnostic algorithm easily available to clinicians. Aetiologies include conditions affecting the central nervous system and spine, and rare peripheral neuromuscular disorders leading to hypertonia. Aetiology onset may be antepartum, peripartum with either transient hypertonia or persistent hypertonia which may appear later, or from a postnatal event/disease. This review discusses neonatal hypertonia and a diagnostic approach to neonatal hypertonia is suggested.
Long‐term efficacy and safety of canagliflozin over 104 weeks in patients aged 55–80 years with type 2 diabetes
Authors: Bode B. , Stenlöf K. , Harris S. , Sullivan D. , Fung A. , Usiskin K. , Meininger G.
Published: December 2014

Aims

The long‐term efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, was evaluated over 104 weeks in patients aged 55–80 years with type 2 diabetes mellitus (T2DM) inadequately controlled on a stable antihyperglycaemic agent regimen.

Methods

In this randomized, double‐blind, phase III study, patients received canagliflozin 100 or 300 mg or placebo once daily during a 26‐week core period (N = 714) and a 78‐week extension period (n = 624). Efficacy endpoints at week 104 included change from baseline in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and systolic blood pressure, and percent change from baseline in body weight and fasting plasma lipids. Safety was assessed by adverse event (AE) reports.

Results

At week 104, canagliflozin 100 and 300 mg were associated with reductions in HbA1c versus placebo (−0.32 and −0.43% vs 0.17%, respectively; overall mean baseline, 7.7%) and more patients achieved HbA1c <7.0% with canagliflozin 100 and 300 mg than with placebo (35.8 and 41.9% vs 20.3%, respectively). Reductions in FPG, body weight and systolic blood pressure, and increases in high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) were seen with canagliflozin compared with placebo. The overall incidence rates of AEs over 104 weeks were 88.0, 89.8 and 86.1% with canagliflozin 100 and 300 mg and placebo, respectively; serious AE rates were low across treatment groups. The incidence rates of urinary tract infections, genital mycotic infections and osmotic diuresis– and volume depletion–related AEs were higher with canagliflozin than with placebo.

Conclusion

Canagliflozin improved glycaemic control, reduced body weight and systolic blood pressure, and was generally well tolerated in patients aged 55–80 years with T2DM over 104 weeks.
A Pareto‐improving Minimum Wage
Authors: Danziger Eliav , Danziger Leif
Published: December 2014

This paper shows that a graduated minimum wage, in contrast to a constant minimum wage, can provide a strict Pareto improvement over what can be achieved with an optimal income tax. The reason is that a graduated minimum wage requires high‐productivity workers to work more to earn the same income as low‐productivity workers, which makes it more difficult for the former to mimic the latter. In effect, a graduated minimum wage allows the low‐productivity workers to benefit from second‐degree price discrimination, which increases their income.
Equilibrium Shirking, Access to Credit and Endogenous TFP Fluctuations
Authors: Atolia Manoj , Einarsson Tor , Marquis Milton
Published: December 2014

This paper develops a model in which idea‐rich, cash‐poor entrepreneurs undertake risky investment projects that are subject to future liquidity needs and shirking due to moral hazard. The model suggests that the strength of the entrepreneur's incentive to shirk is countercyclical and that endogenous shirking adds volatility to the economy by increasing the persistence and volatility of TFP. This increase in persistence and volatility is driven by the variation in the number of successfully completed projects, compounded by the effect of the incentive to shirk on access to credit; changes in factor employment play only a minor role.
The Persistent Effect of Colonialism on Corruption
Authors: Angeles Luis , Neanidis Kyriakos C.
Published: December 2014

This paper argues that corruption in developing countries has deep historical roots that go all the way back to their colonial experience. We substantiate our thesis with empirical evidence where the degree of European settlement during colonial times is a powerful explanatory factor of present‐day corruption. Interestingly, our mechanism is different from the prevailing view in the literature on institutions and growth, where European settlement has only positive effects. We argue that European settlement leads to higher levels of corruption for all countries where Europeans remained a minority in the population, i.e. for all developing countries.
Does Law and Order Attenuate the Benefits of Democracy on Economic Growth?
Authors: Assiotis Andreas , Sylwester Kevin
Published: December 2014

Recent studies have reported positive associations between democracy and economic growth. They have also explored how associations could differ across regions or income levels. However, might the effects of democracy on growth also depend on factors such as institutions promoting law and order? Using a panel specification, we employ a democracy–law and order interactive term to examine if the effects of democracy on economic growth depend on these other institutions. We find that positive effects of democracy diminish and might even turn negative in countries where other institutions such as those supporting law and order are strong.
TRADE IN POLARIZED AMERICA: THE BORDER EFFECT BETWEEN RED STATES AND BLUE STATES
Authors: Ishise Hirokazu , Matsuo Miwa
Published: December 2014

Political and cultural polarization in the United States is widely discussed, but does it relate to any economic disconnection among states? We estimate the “border” effect between Red and Blue states using the gravity equation with a nonlinear generalized method of moments estimator to simultaneously overcome the problems associated with endogeneity, cross‐state price differences, and zero‐trade flow. The border effect is robustly confirmed for the 2000s, while not so robustly detected for the 1990s. Notably, in 2007, the border reduces trade between Red and Blue states to approximately 75% of the trade within each set of states. This estimated border effect is much smaller than the United States–Canada national border effect estimated by Anderson and van Wincoop (2003), and by Feenstra (2002), yet is comparable to the border effect that Nitsch and Wolf (2009) find for the former West and East Germanies approximately 10 years after reunification. While the border effect in Germany after reunification is decreasing, the border effect between the Red and Blue states is emerging. We also find the border effect is more significant for consumption, rather than intermediate, goods. The border effect is an important indicator for a potential dismantling of the economic connectivity in the United States. (JEL D72, F10, F15, R1)
NORMS OF PUNISHMENT: EXPERIMENTS WITH STUDENTS AND THE GENERAL POPULATION
Authors: Bortolotti Stefania , Casari Marco , Pancotto Francesca
Published: December 2014

Norms of cooperation and punishment differ across societies, but also within a single society. In an experiment with two subject pools sharing the same geographical and cultural origins, we show that opportunities for peer punishment increase cooperation among students but not in the general population. In previous studies, punishment magnified the differences across societies in people's ability to cooperate. Here, punishment reversed the order: with punishment, students cooperate more than the general population while they cooperate less without it. (JEL C72, C90, Z13)
Statins and the neuromuscular system: a neurologist's perspective
Authors: Argov Z.
Published: December 2014

Statins intolerance is mainly due to their side effects on the neuromuscular system (primarily muscle). It has become an important issue because of the major cardiovascular risk reduction of this class of drugs. However, the facts related to these side effects are sometimes under‐recognized or controversial. A literature review of the recent developments in the field is given. The clinical definition of statin myopathy and its presentation are not suitable for the myology field. Management and prevention are not validated. More genetic risk factors need to be established. Neurologists should become more involved in statin intolerance evaluation and management.
The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist
Authors: Patsalos Philip N.
Published: December 2014

The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5–2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co‐ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2–12 mg); perampanel is 95% protein‐bound to albumin and α1‐acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half‐life is ~105 h, whereas the calculated effective half‐life is 48 h. These half‐life values allow for once‐daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half‐life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4‐inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.
Long‐term seizure outcome in 211 patients with focal cortical dysplasia
Authors: Fauser Susanne , Essang Charles , Altenmüller Dirk‐Matthias , Staack Anke Maren , Steinhoff Bernhard J. , Strobl Karl , Bast Thomas , Schubert‐Bast Susanne , Stephani Ulrich , Wiegand Gert , Prinz Marco , Brandt Armin , Zentner Josef , Schulze‐Bonhage Andreas
Published: December 2014

Objective

Focal cortical dysplasia (FCD) is currently recognized as the most common cause of neocortical pharmacoresistant epilepsy. Epilepsy surgery has become an increasingly successful treatment option. Herein, the largest patient cohort reported to date is analyzed regarding long‐term outcome and factors relevant for long‐term seizure control.

Methods

Two hundred eleven children and adults undergoing epilepsy surgery for histologically proven FCD and a follow‐up period of 2–12 years were analyzed regarding the longitudinal course of seizure control, effects of FCD type, localization, magnetic resonance imaging (MRI), timing of surgery, and postoperative antiepileptic treatment.

Results

After 1 year, Engel class I outcome was achieved in 65% of patients and the percentage of seizure‐free patients remained stable over the following (up to 12) years. Complete resection of the assumed epileptogenic area, lower age at surgery, and unilobar localization were positive prognostic indicators of long‐term seizure freedom. Seizure recurrence was 12% after the first year, whereas 8% achieved late seizure freedom either following additional introduction of antiepileptic drugs (AEDs) (4%), a reoperation (2%), or a running down phenomenon (2%). Thirty‐nine percent of patients had a reduction of AED from polytherapy to monotherapy or a complete cessation of AED treatment. Late seizure relapse was seen in nine patients during reduction of AEDs (i.e., in 12% of all patients with AED tapering); in four of them seizures persisted after reestablishment of antiepileptic medication.

Significance

Postoperative long‐term seizure outcome was favorable in patients with FCD and remained stable in 80% of patients after the first postoperative year. Several preoperative factors revealed to be predictive for the postoperative outcome and may help in the preoperative counseling of patients with FCD and in the selection of ideal candidates for epilepsy surgery.
Diagnostic practice of psychogenic nonepileptic seizures (PNES) in the pediatric setting
Authors: Wichaidit Bianca T. , Østergaard John R. , Rask Charlotte U.
Published: December 2014

Objective

No formal guidelines for diagnosing psychogenic nonepileptic seizures (PNES) in children exist, and little is known about the clinical practice of diagnosing PNES in the pediatric setting. We therefore performed a national survey as a first step to document pediatricians’ current diagnostic practice for PNES.

Methods

A questionnaire was distributed to all pediatricians (n = 64) working in the field of neuropediatrics and/or social pediatrics in the Danish hospital setting to uncover their use of terminology and of the International Classification of Diseases, 10th Revision (ICD‐10) codes as well as their clinical diagnostic approach to pediatric PNES. The questionnaire included questions on 18 history and 24 paroxysmal event characteristics.

Results

The response rate was 95% (61/64). There was no consensus on which terminology and diagnostic codes to use. Five history characteristics (psychosocial stressors/trauma, sexual abuse, paroxysmal events typically occur in stressful situations, no effect of antiepileptic drugs, and physical abuse) and six paroxysmal event characteristics (resisted eyelid opening, avoidance/guarding behavior, paroxysmal events occur in the presence of others, closed eyes, rarely injury related to paroxysmal event, and absence of postictal change) were agreed to be very predictive of PNES by at least 50% of the pediatricians. Supplementary diagnostic tests such as blood chemistry measurements (e.g., blood glucose or acute phase reactants; i.e., white blood cell count and C‐reactive protein) and electrocardiography were inconsistently used. Only 49% of the respondents reported to use video‐electroencephalography (VEEG) frequently as part of their diagnostic procedure.

Significance

To our knowledge, this is the first national survey that offers a systematic insight into the diagnostic practices for children with PNES in the hospital setting. The results demonstrate a need for clinical guidelines to improve and systematize the diagnostic approach for PNES in children.
Muscarinic excitation of parvalbumin‐positive interneurons contributes to the severity of pilocarpine‐induced seizures
Authors: Yi Feng , DeCan Evan , Stoll Kurt , Marceau Eric , Deisseroth Karl , Lawrence J. Josh
Published: December 2014

Objective

A common rodent model in epilepsy research employs the muscarinic acetylcholine receptor (mAChR) agonist pilocarpine, yet the mechanisms underlying the induction of pilocarpine‐induced seizures (PISs) remain unclear. Global M1 mAChR (M1R) knockout mice are resistant to PISs, implying that M1R activation disrupts excitation/inhibition balance. Parvalbumin‐positive (PV) inhibitory neurons express M1Rs, participate in cholinergically induced oscillations, and can enter a state of depolarization block (DB) during epileptiform activity. Here, we test the hypothesis that pilocarpine activation of M1Rs expressed on PV cells contributes to PISs.

Methods

CA1 PV cells in PV‐CRE mice were visualized with a floxed YFP or hM3Dq‐mCherry adeno‐associated virus, or by crossing PV‐CRE mice with the RosaYFP reporter line. To eliminate M1Rs from PV cells, we generated PV‐M1knockout (KO) mice by crossing PV‐CRE and floxed M1 mice. Action potential (AP) frequency was monitored during application of pilocarpine (200 μm). In behavioral experiments, locomotion and seizure symptoms were recorded in wild‐type (WT) or PV‐M1KO mice during PISs.

Results

Pilocarpine significantly increased AP frequency in CA1 PV cells into the gamma range. In the continued presence of pilocarpine, a subset (5/7) of PV cells progressed to DB, which was mimicked by hM3Dq activation of Gq‐receptor signaling. Pilocarpine‐induced depolarization, AP firing at gamma frequency, and progression to DB were prevented in CA1 PV cells of PV‐M1KO mice. Finally, compared to WT mice, PV‐M1KO mice were associated with reduced severity of PISs.

Significance

Pilocarpine can directly depolarize PV+ cells via M1R activation, but a subset of these cells progress to DB. Our electrophysiologic and behavioral results suggest that this mechanism is active during PISs, contributing to a collapse of PV‐mediated γ‐aminobutyric acid (GABA)ergic inhibition, dysregulation of excitation/inhibition balance, and increased susceptibility to PISs.
Abietic acid inhibits UVB‐induced MMP‐1 expression in human dermal fibroblast cells through PPARα/γ dual activation
Authors: Jeon Youngsic , Jung Yujung , Youm Jong‐Kyung , Kang Ki Sung , Kim Yong Kee , Kim Su‐Nam
Published: December 2014

Peroxisome proliferator‐activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand‐activated transcription factors and consist of three isotypes: PPARα, PPARβ/δ and PPARγ. PPARs are expressed in various cell types in the skin, including keratinocytes, fibroblasts and infiltrating immune cells. Thus, these receptors are highly studied in dermato‐endocrine research, and their ligands are targets for the treatment of various skin disorders, such as photoageing and chronological ageing of skin. Intensive studies have revealed that PPARα/γ functions in photoageing and age‐related inflammation by regulating matrix metalloproteinases (MMPs) via nuclear factor‐kappa B (NF‐κB) and activator protein‐1 (AP‐1). However, the detailed mechanism of PPARα/γ's role in photoageing has not yet been elucidated. In this study, we confirmed that abietic acid (AA) is a PPARα/γ dual ligand and significantly decreased UVB‐induced MMP‐1 expression by downregulating UVB‐induced MAPK signalling and downstream transcription factors, subsequently reducing IκBα degradation and blocking NF‐κB p65 nuclear translocation in Hs68 human dermal fibroblast cells. Treatment of cells with AA and GW6471 or bisphenol A diglycidyl ether (BADGE), PPARα or PPARγ antagonists, respectively, reversed the effect on UVB‐induced MMP‐1 expression and inflammatory signalling pathway activation. Taken together, our data suggest that AA acts as a PPARα/γ dual activator to inhibit UVB‐induced MMP‐1 expression and age‐related inflammation by suppressing NF‐κB and the MAPK/AP‐1 pathway and can be a useful agent for improving skin photoageing.