bluuebunny/crossref_metadata_2025 huggingface dataset:
ADCK3 mutations with epilepsy, stroke‐like episodes and ataxia: a POLG mimic?
Authors: Hikmat O. , Tzoulis C. , Knappskog P. M. , Johansson S. , Boman H. , Sztromwasser P. , Lien E. , Brodtkorb E. , Ghezzi D. , Bindoff L. A.
Published: April 2016

Background and purpose

Defects of coenzyme Q10 (CoQ10) metabolism cause a variety of disorders ranging from isolated myopathy to multisystem involvement. ADCK3 is one of several genes associated with CoQ10 deficiency that presents with progressive cerebellar ataxia, epilepsy, migraine and psychiatric disorders. Diagnosis is challenging due to the wide clinical spectrum and overlap with other mitochondrial disorders.

Methods

A detailed description of three new patients and one previously reported patient from three Norwegian families with novel and known ADCK3 mutations is provided focusing on the epileptic semiology and response to treatment. Mutations were identified by whole exome sequencing and in two measurement of skeletal muscle CoQ10 was performed.

Results

All four patients presented with childhood‐onset epilepsy and progressive cerebellar ataxia. Three patients had epilepsia partialis continua and stroke‐like episodes affecting the posterior brain. Electroencephalography showed focal epileptic activity in the occipital and temporal lobes. Genetic investigation revealed ADCK3 mutations in all patients including a novel change in exon 15: c.T1732G, p.F578V. There was no apparent genotype−phenotype correlation.

Conclusion

ADCK3 mutations can cause a combination of progressive ataxia and acute epileptic encephalopathy with stroke‐like episodes. The clinical, radiological and electrophysiological features of this disorder mimic the phenotype of polymerase gamma (POLG) related encephalopathy and it is therefore suggested that ADCK3 mutations be considered in the differential diagnosis of mitochondrial encephalopathy with POLG‐like features.
Long‐term prognosis of epilepsy, prognostic patterns and drug resistance: a population‐based study
Authors: Giussani G. , Canelli V. , Bianchi E. , Erba G. , Franchi C. , Nobili A. , Sander J. W. , Beghi E. ,   the EPIRES Group
Published: April 2016

Background and purpose

Seizures in most people with epilepsy remit but prognostic markers are poorly understood. There is also little information on the long‐term outcome of people who fail to achieve seizure control despite the use of two antiepileptic drugs (drug resistance).

Methods

People with a validated diagnosis of epilepsy in whom two antiepileptic drugs had failed were identified from primary care records. All were registered with one of 123 family physicians in an area of northern Italy. Remission (uninterrupted seizure freedom lasting 2 years or longer) and prognostic patterns (early remission, late remission, remission followed by relapse, no remission) were determined.

Results

In all, 747 individuals (381 men), aged 11 months to 94 years, were followed for 11 045.5 person‐years. 428 (59%) were seizure‐free. The probability of achieving 2‐year remission was 18% at treatment start, 34% at 2 years, 45% at 5, 52% at 10 and 67% at 20 years (terminal remission, 60%). Epilepsy syndrome and drug resistance were the only independent predictors of 2‐ and 5‐year remission. Early remission was seen in 101 people (19%), late remission in 175 (33%), remission followed by relapse in 85 (16%) and no remission in 166 (32%). Treatment response was the only variable associated with differing prognostic patterns.

Conclusion

The long‐term prognosis of epilepsy is favourable in most cases. Early seizure remission is not invariably followed by terminal remission and seizure outcome varies according to well‐defined patterns. Prolonged seizure remission and prognostic patterns can be predicted by broad syndromic categories and the failure of two antiepileptic drugs.
The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis mimicking an acute stroke
Authors: Guillan M. , DeFelipe‐Mimbrera A. , Alonso‐Canovas A. , Matute M. C. , Vera R. , Cruz‐Culebras A. , Garcia‐Barragan N. , Masjuan J.
Published: April 2016

Background and purpose

The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) can present as sudden onset of focal neurological deficits which are clinically and radiologically indistinguishable from an ischaemic stroke. Its diagnosis requires a lumbar puncture (LP), which contraindicates intravenous thrombolytic therapy (IV‐tPA).

Methods

All patients referred to our stroke centre as a stroke code resulting in a final diagnosis of HaNDL syndrome from June 2005 to June 2015 were retrospectively analysed.

Results

Nine cases were identified: seven women and two men (mean age 27.6 years, range 15–51). Clinical onset consisted of isolated aphasia (two) and aphasia with right hemiparesis/hemiparaesthesia (seven). All patients had headache in the acute setting, lasting 2–12 h. Cranial computed tomography (CT) and CT angiography (CTA) were normal in all patients. Perfusion CT was performed in seven patients, showing left hemispheric focal hypoperfusion in five cases; the remaining two were normal. Five patients were initially diagnosed as stroke and treated uneventfully with IV‐tPA. Cranial magnetic resonance imaging within 48 h was normal in all cases. LP performed in all patients showed pleocytosis (range 17–351 cells/mm3), high protein levels (range 0.4–1.6 g/l) and normal glucose levels. All cases recovered within 12 h and suffered a second episode within 72 h. Patients were asymptomatic between episodes and after remission.

Conclusions

The decision to thrombolyse or perform an LP in HaNDL patients mimicking a stroke is difficult in the acute setting. Perfusion CT can provide misleading results and CTA may be useful in ruling out occlusion of a cerebral vessel.
Fibulin‐5: a novel biomarker for evaluating severity and predicting prognosis in patients with acute intracerebral haemorrhage
Authors: Hu L. , Dong M.‐X. , Zhao H. , Xu G.‐H. , Qin X.‐Y.
Published: April 2016

Background and purpose

The aim was to investigate relationships between serum fibulin‐5 concentration and the severity or prognosis in patients with acute intracerebral haemorrhage (ICH).

Methods

Consecutive ICH patients and healthy controls were included and clinical data were collected. National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) were assessed at admission time within 3 days after bleeding. Cerebral haemorrhage volume was calculated and serum fibulin‐5 concentration was measured at the same time. Multivariate linear regression analyses were performed to determine risk factors for serum fibulin‐5 concentration and Spearman correlation coefficients were obtained to explore the relationships between fibulin‐5 concentration and NIHSS or GCS scores. Patients were followed up for 3 months and the modified Rankin Scale was evaluated for all survivors. Receiver operating characteristic (ROC) curves were obtained to explore fibulin‐5 concentration in predicting prognosis.

Results

Serum fibulin‐5 concentration had increased in ICH patients compared with healthy controls (65.86 ± 26.39 μg/l vs. 40.66 ± 5.03 μg/l, P = 0.00) and was mainly influenced by haemorrhage volume (β = 0.905, P = 0.000) and extension to ventricles (β = 10.173, P = 0.097). Serum fibulin‐5 concentration was positively correlated with NIHSS score (r = 0.511, P = 0.000) but inversely correlated with GCS score (r = −0.585, P = 0.000). Based on the ROC curves, the optimal cut‐off point was 80.68 μg/l for death, and the sensitivity and specificity values of serum fibulin‐5 were 77.8% and 93.2%, whilst the optimal cut‐off point was 48.45 μg/l for poor prognosis and the sensitivity and specificity values were 86.4% and 54.1%, respectively.

Conclusions

Serum fibulin‐5 concentration can be regarded as a biomarker for evaluating disease severity and predicting prognosis in ICH patients.
Managing anti‐epileptic drug treatment in adult patients with intellectual disability: a serious conundrum
Authors: Doran Z. , Shankar R. , Keezer M. R. , Dale C. , McLean B. , Kerr M. P. , Devapriam J. , Craig J. , Sander J. W.
Published: April 2016

Background and purpose

About a quarter of people with epilepsy have intellectual disability (ID). This group has communication issues, premature mortality, more treatment resistance, difficulties in making informed choices and greater risks of physical and mental health comorbidities. There is no specific prescribing guidance for this large and vulnerable group. The literature on prescribing for epilepsy in this group was reviewed, in particular examining how antiepileptic drugs (AEDs) work regarding their side effect profiles, effects on specific epilepsy syndromes associated with ID and their individual strengths and weaknesses based on the nature and degree of ID.

Method

This is a narrative review for which a comprehensive search was conducted to identify evidence for prescribing commonly used AEDs to people with ID including genetic syndromes specifically associated with epilepsy.

Results

A detailed analysis of the results has highlighted the urgent requirement for suitable and reliable evidence in AED prescribing amongst adults with epilepsy and ID as no studies taking account of the response to AEDs of the ID populations based on the WHO Diagnostic and Statistical Manual of Mental Disorders criteria of clinical severity of ID were identified.

Conclusion

There is a significant shortfall in suitably powered studies to provide sufficient evidence for safe prescribing of AEDs to people with ID.
Is treatment in adults with intellectual and developmental disability also suffering from epilepsy different from adults with uncomplicated epilepsy?
Authors: Kothare S. , Kaleyias J.
Published: April 2016

Click here to view the accompanying paper in this issue.
Anti–tumor necrosis factor alpha therapy (adalimumab) in Rasmussen's encephalitis: An open pilot study
Authors: Lagarde Stanislas , Villeneuve Nathalie , Trébuchon Agnès , Kaphan Elsa , Lepine Anne , McGonigal Aileen , Roubertie Agathe , Barthez Marie‐Anne J. , Trommsdorff Valérie , Lefranc Jérémie , Wehbi Samer , des Portes Vincent , Laguitton Virginie , Quartier Pierre , Scavarda Didier , Giusiano Bernard , Milh Mathieu , Bulteau Christine , Bartolomei Fabrice
Published: April 2016

Objective

Rasmussen's encephalitis (RE) is a severe chronic inflammatory brain disease affecting one cerebral hemisphere and leading to drug‐resistant epilepsy, progressive neurologic deficit, and unilateral brain atrophy. Hemispherotomy remains the gold standard treatment but causes permanent functional impairment. No standardized medical treatment protocol currently exists for patients prior to indication of hemispherotomy, although some immunotherapies have shown partial efficacy with functional preservation but poor antiseizure effect. Some studies suggest a role for tumor necrosis factor alpha (TNF‐α) in RE pathophysiology.

Methods

We report an open‐label study evaluating the efficacy and the safety of anti‐TNF‐α therapy (adalimumab) in 11 patients with RE. The primary outcome criterion was the decrease of seizure frequency. The secondary outcome criteria were neurologic and cognitive outcomes and existence of side effects.

Results

Adalimumab was introduced with a median delay of 31 months after seizure onset (range 1 month to 16 years), and follow‐up was for a median period of 18 months (range 9–54 months). There was a significant seizure frequency decrease after adalimumab administration (from a median of 360 to a median of 32 seizures per quarter, p ≤ 0.01). Statistical analysis showed that adalimumab had a significant intrinsic effect (p < 0.005) independent from disease fluctuations. Five patients (45%) were found to have sustained improvement over consecutive quarters in seizure frequency (decrease of 50%) on adalimumab. Three of these five patients also had no further neurocognitive deterioration. Adalimumab was well tolerated.

Significance

Our study reports efficacy of adalimumab in terms of seizure frequency control. In addition, stabilization of functional decline occurred in three patients. This efficacy might be particularly relevant for atypical slowly progressive forms of RE, in which hemispherotomy is not clearly indicated. Due to our study limitations, further studies are mandatory to confirm these preliminary results.
Susceptible and protective associations ofHLA DRB1*/DQB1* alleles and haplotypes with ischaemic stroke
Authors: Murali V. , Rathika C. , Ramgopal S. , Padma Malini R. , Arun Kumar M. J. , Neethi Arasu V. , Jeyaram Illiayaraja K. , Balakrishnan K.
Published: April 2016

Stroke has emerged as the second commonest cause of mortality worldwide and is a major public health problem. For the first time, we present here the association of human leucocyte antigen (HLA)‐DRB1*/DQB1* alleles and haplotypes with ischaemic stroke in South Indian patients. Ischaemic stroke (IS) cases and controls were genotyped forHLA‐DRB1*/DQB1* alleles by polymerase chain reaction sequence‐specific primers (PCR‐SSP) method. The frequencies ofHLAclassIIalleles such asDRB1*04,DRB1*07,DRB1*11,DRB1*12,DRB1*13,DQB1*02 andDQB1*07 were high inISpatients than in the age‐ and gender‐matched controls, suggesting that the individuals with these alleles are susceptible to ischaemic stroke in South India. The frequencies of alleles such asDRB1*03,DRB1*10,DRB1*14,DQB1*04 andDQB1*05 were less inIScases than in the controls, suggesting a protective association. HaplotypesDRB1*04‐DQB1*0301,DRB1*07‐DQB1*02,DRB1*07‐DQB1*0301,DRB1*11‐DQB1*0301 andDRB1*13‐DQB1*06 were found to be high inISpatients conferring susceptibility. The frequency of haplotypeDRB1*10‐DQB1*05 was high in controls conferring protection.IS‐LVDand gender‐stratified analysis too confirmed these susceptible and protective associations.Thus, HLA‐DRB1*/DQB1* alleles and haplotypes strongly predispose South Indian population to ischaemic stroke. Further studies in different populations with large sample size or the meta‐analysis are needed to explain the exact mechanism of associations ofHLAgene(s) withIS.
Genetic and paleomodelling evidence of the population expansion of the cattle egretBubulcus ibisin Africa during the climatic oscillations of the Late Pleistocene
Authors: Congrains Carlos , Carvalho Antônio F. , Miranda Elder A. , Cumming Graeme S. , Henry Dominic A. W. , Manu Shiiwua A. , Abalaka Jacinta , Rocha Cristiano D. , Diop Moussa S. , Sá Joãozinho , Monteiro Hamilton , Holbech Lars H. , Gbogbo Francis , Lama Silvia N. Del
Published: April 2016

Increasing aridity during glacial periods produced the retraction of forests and the expansion of arid and semi‐arid environments in Africa, with consequences for birds. Cattle egretBubulcus ibisis a dispersive species that prefers semi‐arid environments and requires proximity to bodies of water. We expected that climatic oscillations led to the expansion of the range of the cattle egret during arid periods, such as the Last Maximum Glacial (LGM) and contraction of distribution during the Last Interglacial (LIG) period, resulting in contact of populations previously isolated. We investigated this hypothesis by evaluating the genetic structure and population history of 15 cattle egret breeding colonies located in west and South Africa using the mitochondrial DNA (mtDNA) control region, mtDNA ATPase 8 and 6, and an intron of nuclear gene transforming growth factor‐beta 2. Occurrence data and bioclimatic information were used to generate ecological niche models of three periods (present, LGM and LIG). We used the genetic and paleomodelling data to assess the responses of the cattle egret from Africa to the climatic oscillations during the late Pleistocene. Genetic data revealed low levels of genetic differentiation, signs of isolation‐by‐distance, as well as recent increases in effective population size that started during the LGM. The observed low genetic structure may be explained by recent colonization events due to the demographic expansion following the last glacial period and by dispersal capacity of this species. The paleomodels corroborated the expansion during the LGM, and a more restricted potential distribution during the LIG. Our findinds supports the hypothesis that the species range of the cattle egret expanded during arid periods and contracted during wet periods.
Tumour‐associated macrophages correlate with microvascular bed extension in colorectal cancer patients
Authors: Marech Ilaria , Ammendola Michele , Sacco Rosario , Sammarco Giuseppe , Zuccalà Valeria , Zizzo Nicola , Leporini Christian , Luposella Maria , Patruno Rosa , Filippelli Gianfranco , Russo Emilio , Porcelli Mariangela , Gadaleta Cosmo Damiano , De Sarro Giovambattista , Ranieri Girolamo
Published: April 2016

Tumour‐associated macrophages (TAMs) represent pivotal components of tumour microenvironment promoting angiogenesis, tumour progression and invasion. In colorectal cancer (CRC), there are no conclusive data about the role of TAMs in angiogenesis‐mediated tumour progression. In this study, we aimed to evaluate a correlation between TAMs, TAM immunostained area (TAMIA) microvascular density (MVD), endothelial area (EA) and cancer cells positive to VEGF‐A (CCP‐VEGF‐A) in primary tumour tissue of locally advanced CRC patients undergone to radical surgery. A series of 76 patients with CRC were selected and evaluated by immunohistochemistry and image analysis. An anti‐CD68 antibody was employed to assess TAMs and TAMIA expression, an anti‐CD34 antibody was utilized to detect MVD and EA expression, whereas an anti‐VEGF‐A antibody was used to detect CCP‐VEGF‐A; then, tumour sections were evaluated by image analysis methods. The mean ± S.D. of TAMs, MVD and CCP‐VEGF‐A was 65.58 ± 21.14, 28.53 ± 7.75 and 63% ± 37%, respectively; the mean ± S.D. of TAMIA and EA was 438.37 ± 124.14μ2 and 186.73 ± 67.22μ2, respectively. A significant correlation was found between TAMs, TAMIA, MVD and EA each other (r ranging from 0.69 to 0.84; P ranging from 0.000 to 0.004). The high level of expression of TAMs and TAMIA in tumour tissue and the significant correlation with both MVD and EA illustrate that TAMs could represent a marker that plays an important role in promoting angiogenesis‐mediated CRC. In this context, novel agents killing TAMs might be evaluated in clinical trials as a new anti‐angiogenic approach.
Manual versus sonic powered toothbrushing in patients with intellectual disability: a cluster‐randomized clinical trial
Authors: García‐Carrillo Ana , Jover Antonio , Plá Rafael , Martorell Almudena , Sota Cristina , Gómez‐Moreno Gerardo , Figuero Elena , Sanz Mariano , Herrera David
Published: April 2016

Objectives

To compare the use of sonic powered or manual toothbrush in patients with intellectual disability (ID) in terms of plaque (PlI) and gingival (GI) indices and adverse effects.

Material and Methods

Subjects with ID were recruited for this cluster‐randomized, single blinded (examiner), 6‐month clinical trial, comparing powered versus manual toothbrushing. Outcome variables included PlI and GI, evaluated at baseline and 3 months after supervised toothbrushing and after 3 additional months of unsupervised used. Clinical outcome variables were analysed by repeated measures ANCOVA considering time and group as factors and respective baseline values as covariates (generalized linear model).

Results

Sixty‐four patients (34 male, mean age 34.5) in six clusters were included in the study. No statistically significant effect of toothbrushing group was observed for PlI or GI. A significant effect of time was identified (p < 0.001) with mean reductions ranging 0.44–0.45 for PlI and 0.30–0.36 for GI from baseline to 3–6 months. No relevant adverse effect or technical problems were observed.

Conclusion

The tested sonic powered toothbrush was as effective and safe as the manual toothbrush. The use of powered or manual toothbrushes, together with fluoride toothpaste, may improve plaque and gingivitis levels, in patients with mild to limit ID.
A pilot study of active enzyme levels in gingival crevicular fluid of patients with chronic periodontal disease
Authors: Gul Sarhang S. , Douglas Charles W. I. , Griffiths Gareth S. , Rawlinson Andrew
Published: April 2016

Aim

To determine whether combinations of enzymes in gingival crevicular fluid (GCF) can act as improved biomarkers compared with single enzymes for predicting the outcome of treatment and also for diagnosing the clinical status of sites.

Methods

Thirty subjects with chronic periodontitis were recruited to a 12‐month longitudinal pilot study. GCF samples from three representative sites: healthy (≤3 mm), deep non‐bleeding (NB) (≥6 mm) and deep bleeding (DB) (≥6 mm) sites and clinical data were collected at baseline, 3 months, 6 months and 12 months following periodontal treatment. Active enzyme levels (MMP‐8, cathepsin G, elastase, trypsin‐like activity and sialidase) in GCF samples were assessed. The enzyme profiles and clinical data of each site were analysed for correlation and logistic regression was performed to find the predictive value of the active enzyme levels regarding the outcome of treatment.

Results

Twenty‐two individuals completed the study. All active enzyme levels were significantly higher in diseased sites than healthy sites. Logistic regression showed that the combination of MMP8, elastase and sialidase provided accurate predictions of treatment outcome (88% for NB and 86% for DB), which was significantly better than each enzyme alone (61%).

Conclusion

This pilot has suggested that combined active enzyme profiling could provide significant prediction of outcome of treatment.
‘Who Knows What?’ in New Venture Teams: Transactive Memory Systems as a Micro‐Foundation of Entrepreneurial Orientation
Authors: Dai Ye , Roundy Philip T. , Chok Jay I. , Ding Fangsheng , Byun Gukdo
Published: April 2016

The increasing importance of entrepreneurial behaviour has led scholars to embrace the idea that an entrepreneurial orientation (EO) is an important predictor of firm performance. While EO occupies a central position in strategic entrepreneurship research, scholars have yet to explore its origins in new ventures. Drawing on the knowledge‐based and cognitive views, we theorize that a new venture team's transactive memory system is a cognitive mechanism that spurs the development of an EO. In a field study of high‐tech new ventures in China, we examined the relationship between venture teams’ transactive memory systems (representing the distribution, integration, and utilization of the teams’ knowledge) and EO and the moderating influence of team‐, firm‐, and environment‐level factors. We found that the transactive memory system of a new venture team enhanced their EO and that this relationship was positively influenced by intra‐team trust, the structural organicity of a venture, and environmental dynamism. Our findings provide novel insights into the micro‐foundations of TMS in developing an EO in new ventures.
Multiparametric magnetic resonance imaging in patients with chronic liver disease: are we there yet?
Authors: Ronot Maxime , Vilgrain Valérie
Published: April 2016

See Article on Page 659
Admixture mapping identifies introgressed genomic regions in North American canids
Authors: vonHoldt Bridgett M. , Kays Roland , Pollinger John P. , Wayne Robert K.
Published: April 2016

Hybrid zones typically contain novel gene combinations that can be tested by natural selection in a unique genetic context. Parental haplotypes that increase fitness can introgress beyond the hybrid zone, into the range of parental species. We used the Affymetrix canine SNP genotyping array to identify genomic regions tagged by multiple ancestry informative markers that are more frequent in an admixed population than expected. We surveyed a hybrid zone formed in the last 100 years as coyotes expanded their range into eastern North America. Concomitant with expansion, coyotes hybridized with wolves and some populations became more wolflike, such that coyotes in the northeast have the largest body size of any coyote population. Using a set of 3102 ancestry informative markers, we identified 60 differentially introgressed regions in 44 canines across this admixture zone. These regions are characterized by an excess of exogenous ancestry and, in northeastern coyotes, are enriched for genes affecting body size and skeletal proportions. Further, introgressed wolf‐derived alleles have penetrated into Southern US coyote populations. Because no wolves currently exist in this area, these alleles are unlikely to have originated from recent hybridization. Instead, they probably originated from intraspecific gene flow or ancient admixture. We show that grey wolf and coyote admixture has far‐reaching effects and, in addition to phenotypically transforming admixed populations, allows for the differential movement of alleles from different parental species to be tested in new genomic backgrounds.
To recycle or steal? Nutrient resorption in Australian and Brazilian mistletoes from three low‐phosphorus sites
Authors: Scalon Marina C. , Wright Ian J. , Franco Augusto C.
Published: April 2016

Resorption is the process by which nutrients are withdrawn from leaves prior to leaf fall. Mistletoes are generally thought not to rely on nutrient resorption; being xylem‐tapping parasites, they instead derive the nutrients required for new growth from their host plant, at little or no cost. We measured nutrient (N, P, K, Ca, Mg) resorption in 18 parasitic mistletoe–host species pairs distributed across three sites with notably low‐P soil, also quantifying relationships with leaf lifespan (LL) and specific leaf area (SLA). There was little or no evidence of N, Ca or Mg resorption. By contrast, on average ∼30% of P and ∼20% of K were resorbed prior to leaf fall. Longer LL in mistletoes was associated with lower N and P concentrations in mistletoes and in host leaves. We provide evidence that, even though mistletoes are relatively inefficient in terms of nutrient resorption compared to non‐parasite species, on low‐P soils their ecological and evolutionary strategies for conserving phosphorous involve modulation of both leaf lifespan and P concentration in senesced leaves.
Dutch Pain Specialists’ Adherence to the Multidisciplinary Guideline on Treating Pain in Patients with Cancer: A Case Vignette Study
Authors: Besse Kees , Steegers Monique , Vernooij‐Dassen Myrra , Vissers Kris , Engels Yvonne
Published: April 2016

Background

Many patients with cancer suffer from pain, which is often not optimally treated. In 2008, the evidence‐based, multidisciplinary Dutch guideline on the diagnosis and treatment of pain in this patient group was published. We assessed knowledge about and adherence to the guideline by pain specialists.

Methods

A cross‐sectional case vignette survey describing a palliative patient with intractable pancreatic cancer and pain was sent to all 350 Dutch anesthesiologists registered as pain specialists at the Netherlands Association of Anesthesiology. Descriptive statistics were conducted.

Results

Ninety‐three pain specialists completed the questionnaire (27%). The majority appeared to follow the guideline recommendations on pharmacological (99%) and invasive treatment (95%) in the diverse stages of the disease. However, the recommendation to use a one‐dimensional pain scale to evaluate the effect of pain treatment and the recommendation to perform a multidimensional pain assessment if the patient in pain is in a deteriorating stage were only followed by a minority of the respondents (23% and 15%, respectively).

Conclusions

Regarding most recommendations, Dutch pain specialists know and intend to follow the national multidisciplinary cancer pain guideline. Yet, only a minority of them perform structural pain assessment of the patient with cancer pain. However, as the response rate was low (27%), the results should be interpreted with caution and cannot be generalized to the entire population of pain specialists in the Netherlands. We recommend that, in the guideline update and implementation programs, more attention be given to thorough assessment of the patient with pain and cancer.
QTL‐seq for rapid identification of candidate genes for 100‐seed weight and root/total plant dry weight ratio under rainfed conditions in chickpea
Authors: Singh Vikas K. , Khan Aamir W. , Jaganathan Deepa , Thudi Mahendar , Roorkiwal Manish , Takagi Hiroki , Garg Vanika , Kumar Vinay , Chitikineni Annapurna , Gaur Pooran M. , Sutton Tim , Terauchi Ryohei , Varshney Rajeev K.
Published: April 2016

Terminal drought is a major constraint to chickpea productivity. Two component traits responsible for reduction in yield under drought stress include reduction in seeds size and root length/root density. QTL‐seq approach, therefore, was used to identify candidate genomic regions for 100‐seed weight (100SDW) and total dry root weight to total plant dry weight ratio (RTR) under rainfed conditions. Genomewide SNP profiling of extreme phenotypic bulks from the ICC 4958 × ICC 1882 population identified two significant genomic regions, one on CaLG01 (1.08 Mb) and another on CaLG04 (2.7 Mb) linkage groups for 100SDW. Similarly, one significant genomic region on CaLG04 (1.10 Mb) was identified for RTR. Comprehensive analysis revealed four and five putative candidate genes associated with 100SDW and RTR, respectively. Subsequently, two genes (Ca_04364 and Ca_04607) for 100SDW and one gene (Ca_04586) for RTR were validated using CAPS/dCAPS markers. Identified candidate genomic regions and genes may be useful for molecular breeding for chickpea improvement.
The OsmiR396c‐OsGRF4‐OsGIF1 regulatory module determines grain size and yield in rice
Authors: Li Shuangcheng , Gao Fengyan , Xie Kailong , Zeng Xiuhong , Cao Ye , Zeng Jing , He Zhongshan , Ren Yun , Li Wenbo , Deng Qiming , Wang Shiquan , Zheng Aiping , Zhu Jun , Liu Huainian , Wang Lingxia , Li Ping
Published: April 2016

Grain weight is the most important component of rice yield and is mainly determined by grain size, which is generally controlled by quantitative trait loci (QTLs). Although numerous QTLs that regulate grain weight have been identified, the genetic network that controls grain size remains unclear. Herein, we report the cloning and functional analysis of a dominant QTL, grain length and width 2 (GLW2), which positively regulates grain weight by simultaneously increasing grain length and width. The GLW2 locus encodes OsGRF4 (growth‐regulating factor 4) and is regulated by the microRNA miR396c in vivo. The mutation in OsGRF4 perturbs the OsmiR396 target regulation of OsGRF4, generating a larger grain size and enhanced grain yield. We also demonstrate that OsGIF1 (GRF‐interacting factors 1) directly interacts with OsGRF4, and increasing its expression improves grain size. Our results suggest that the miR396c‐OsGRF4‐OsGIF1 regulatory module plays an important role in grain size determination and holds implications for rice yield improvement.
TGF‐β induces SOX2 expression in a time‐dependent manner in human melanoma cells
Authors: Weina Kasia , Wu Huizi , Knappe Nathalie , Orouji Elias , Novak Daniel , Bernhardt Mathias , Hüser Laura , Larribère Lionel , Umansky Viktor , Gebhardt Christoffer , Utikal Jochen
Published: April 2016

The sry‐related high‐mobility box (SOX)‐2 protein has recently been proven to play a significant role in progression, metastasis, and clinical prognosis spanning several cancer types. Research on the role of SOX2 in melanoma is limited and currently little is known about the mechanistic function of this gene in this context. Here, we observed high expression of SOX2 in both human melanoma cell lines and primary melanomas in contrast to melanocytic nevi. This overexpression in melanoma can, in part, be explained by extra gene copy numbers of SOX2 in primary samples. Interestingly, we were able to induce SOX2 expression, mediated by SOX4, via TGF‐β1 stimulation in a time‐dependent manner. Moreover, the knockdown of SOX2 impaired TGF‐β‐induced invasiveness. This phenotype switch can be explained by SOX2‐mediated cross talk between TGF‐β and non‐canonical Wnt signaling. Thus, we propose that SOX2 is involved in the critical TGF‐β signaling pathway, which has been shown to correlate with melanoma aggressiveness and metastasis. In conclusion, we have identified a novel downstream factor of TGF‐β signaling in melanoma, which may have further implications in the clinic.
Resolution of Graves’ disease after renal transplantation
Authors: Lee Yvonne , Butani Lavjay , Glaser Nicole , Nguyen Stephanie
Published: April 2016

We report a case of an adolescent boy with Down's syndrome and ESRD on hemodialysis who developed mild Graves’ disease that was not amenable to radioablation, surgery, or ATDs. After 14 months of observation without resolution of Graves’ disease, he successfully received a DDRT with a steroid minimization protocol. Thymoglobulin and a three‐day course of steroids were used for induction and he was started on tacrolimus, MMF, and pravastatin for maintenance transplant immunosuppression. One month after transplantation, all biochemical markers and antibody profiling for Graves’ disease had resolved and remain normal one yr later.
Salicylic acid differently impacts ethylene and polyamine synthesis in the glycophyte Solanum lycopersicum and the wild‐related halophyte Solanum chilense exposed to mild salt stress
Authors: Gharbi Emna , Martínez Juan‐Pablo , Benahmed Hela , Fauconnier Marie‐Laure , Lutts Stanley , Quinet Muriel
Published: April 2016

This study aimed to determine the effects of exogenous application of salicylic acid (SA) on the toxic effects of salt in relation to ethylene and polyamine synthesis, and to correlate these traits with the expression of genes involved in ethylene and polyamine metabolism in two tomato species differing in their sensitivity to salt stress, Solanum lycopersicum cv Ailsa Craig and its wild salt‐resistant relative Solanum chilense. In S. chilense, treatment with 125 mM NaCl improved plant growth, increased production of ethylene, endogenous salicylic acid and spermine. The production was related to a modification of expression of genes involved in ethylene and polyamine metabolism. In contrast, salinity decreased plant growth in S. lycopersicum without affecting endogenous ethylene, salicylic or polyamine concentrations. Exogenous application of salicylic acid at 0.01 mM enhanced shoot growth in both species and affected ethylene and polyamine production in S. chilense. Concomitant application of NaCl and salicylic acid improved osmotic adjustment, thus suggesting that salt and SA may act in synergy on osmolyte synthesis. However, the beneficial impact of exogenous application of salicylic acid was mitigated by salt stress since NaCl impaired endogenous SA accumulation in the shoot and salicylic acid did not improve plant growth in salt‐treated plants. Our results thus revealed that both species respond differently to salinity and that salicylic acid, ethylene and polyamine metabolisms are involved in salt resistance in S. chilense.
Theoretical Guarantees for Approximate Sampling from Smooth and Log-Concave Densities
Authors: Dalalyan Arnak S.
Published: April 2016

Sampling from various kinds of distribution is an issue of paramount importance in statistics since it is often the key ingredient for constructing estimators, test procedures or confidence intervals. In many situations, exact sampling from a given distribution is impossible or computationally expensive and, therefore, one needs to resort to approximate sampling strategies. However, there is no well-developed theory providing meaningful non-asymptotic guarantees for the approximate sampling procedures, especially in high dimensional problems. The paper makes some progress in this direction by considering the problem of sampling from a distribution having a smooth and log-concave density defined on Rp, for some integer p > 0. We establish non-asymptotic bounds for the error of approximating the target distribution by the distribution obtained by the Langevin Monte Carlo method and its variants. We illustrate the effectiveness of the established guarantees with various experiments. Underlying our analysis are insights from the theory of continuous time diffusion processes, which may be of interest beyond the framework of log-concave densities that are considered in the present work.
No association between donor age and recipient outcomes: transfusion of plasma in patients undergoing coronary artery bypass grafting surgery
Authors: Guinn Nicole R. , Waldron Nathan H. , Cooter Mary L. , Goldberg Corinne L. , Kertai Miklos D. , Raghunathan Karthik , Bandarenko Nicholas , Hoffman Maureane , Bennett‐Guerrero Elliott
Published: April 2016

BACKGROUND

Recent animal studies suggest that transfusion of plasma from young donors reverses age‐related neurologic and cardiac changes in older recipients. Associations between age of blood product donors and corresponding outcomes in recipients have not been studied in humans. Therefore, our primary objective was to examine this relationship between donor age and recipient outcomes among patients that received plasma during and after coronary artery bypass grafting (CABG) surgery.

STUDY DESIGN AND METHODS

This retrospective cohort included patients undergoing CABG surgery who received plasma during or after surgery. All plasma units transfused were evenly divided into tertiles based on the plasma donor age (17‐37, 38‐50, and 51‐86 years), and CABG patients receiving all perioperative plasma within a single donor tertile were studied. Patient demographics and outcomes including mortality, length of stay (LOS), and acute kidney injury (AKI) were measured.

RESULTS

Overall, 1306 patients (24% of 5339) received American Red Cross plasma perioperatively, with a median dose of 2 units. In a multivariate model of 1‐year mortality, transfusion of a greater number of plasma units (p = 0.0007) and EuroSCORE (p < 0.0001) were significantly associated with patient mortality while donor age was not. There was no difference in mortality between patients receiving plasma from donors in the youngest, middle, or oldest age tertile (10.2 and 8.1% vs. 7.8%, respectively, p = 0.76). Other outcomes, including rates of AKI or LOS, were also independent of plasma donor age.

CONCLUSIONS

We did not observe an association between donor age and recipient outcomes among patients who received plasma perioperatively while undergoing CABG surgery.
Phrenic motor outputs in response to bronchopulmonary C‐fibre activation following chronic cervical spinal cord injury
Authors: Lee Kun‐Ze
Published: April 2016

Key points

Activation of bronchopulmonary C‐fibres, the main chemosensitive afferents in the lung, can induce pulmonary chemoreflexes to modulate respiratory activity.

Following chronic cervical spinal cord injury, bronchopulmonary C‐fibre activation‐induced inhibition of phrenic activity was exaggerated.

Supersensitivity of phrenic motor outputs to the inhibitory effect of bronchopulmonary C‐fibre activation is due to a shift of phrenic motoneuron types and slow recovery of phrenic motoneuron discharge in cervical spinal cord‐injured animals.

These data suggest that activation of bronchopulmonary C‐fibres may retard phrenic output recovery following cervical spinal cord injury.

The alteration of phenotype and discharge pattern of phrenic motoneuron enables us to understand the impact of spinal cord injury on spinal respiratory activity.

Cervical spinal injury interrupts bulbospinal pathways and results in cessation of phrenic bursting ipsilateral to the lesion. The ipsilateral phrenic activity can partially recover over weeks to months following injury due to the activation of latent crossed spinal pathways and exhibits a greater capacity to increase activity during respiratory challenges than the contralateral phrenic nerve. However, whether the bilateral phrenic nerves demonstrate differential responses to respiratory inhibitory inputs is unclear. Accordingly, the present study examined bilateral phrenic bursting in response to capsaicin‐induced pulmonary chemoreflexes, a robust respiratory inhibitory stimulus. Bilateral phrenic nerve activity was recorded in anaesthetized and mechanically ventilated adult rats at 8–9 weeks after C2 hemisection (C2Hx) or C2 laminectomy. Intra‐jugular capsaicin (1.5 μg kg−1) injection was performed to activate the bronchopulmonary C‐fibres to evoke pulmonary chemoreflexes. The present results indicate that capsaicin‐induced prolongation of expiratory duration was significantly attenuated in C2Hx animals. However, ipsilateral phrenic activity was robustly reduced after capsaicin treatment compared to uninjured animals. Single phrenic fibre recording experiments demonstrated that C2Hx animals had a higher proportion of late‐inspiratory phrenic motoneurons that were relatively sensitive to capsaicin treatment compared to early‐inspiratory phrenic motoneurons. Moreover, late‐inspiratory phrenic motoneurons in C2Hx animals had a weaker discharge frequency and slower recovery time than uninjured animals. These results suggest bilateral phrenic nerves differentially respond to bronchopulmonary C‐fibre activation following unilateral cervical hemisection, and the severe inhibition of phrenic bursting is due to a shift in the discharge pattern of phrenic motoneurons.
Are coral reefs victims of their own past success?
Authors: Renema Willem , Pandolfi John M. , Kiessling Wolfgang , Bosellini Francesca R. , Klaus James S. , Korpanty Chelsea , Rosen Brian R. , Santodomingo Nadiezhda , Wallace Carden C. , Webster Jody M. , Johnson Kenneth G.
Published: April 2016

Pleistocene sea-level change transformed staghorn corals into prolific reef builders that are sensitive to anthropogenic stressors.
Identification of catalytic sites for oxygen reduction and oxygen evolution in N-doped graphene materials: Development of highly efficient metal-free bifunctional electrocatalyst
Authors: Yang Hong Bin , Miao Jianwei , Hung Sung-Fu , Chen Jiazang , Tao Hua Bing , Wang Xizu , Zhang Liping , Chen Rong , Gao Jiajian , Chen Hao Ming , Dai Liming , Liu Bin
Published: April 2016

Doping of graphene with nitrogen imparted bifunctional electrocatalytic activities for efficient energy conversion and storage.
Cavity-enhanced coherent light scattering from a quantum dot
Authors: Bennett Anthony J. , Lee James P. , Ellis David J. P. , Meany Thomas , Murray Eoin , Floether Frederik F. , Griffths Jonathan P. , Farrer Ian , Ritchie David A. , Shields Andrew J.
Published: April 2016

A microcavity enhances the efficiency of resonant photon scattering, generating pure indistinguishable single photons.
Actin kinetics shapes cortical network structure and mechanics
Authors: Fritzsche Marco , Erlenkämper Christoph , Moeendarbary Emad , Charras Guillaume , Kruse Karsten
Published: April 2016

Cells adjust their macroscopic mechanical properties by tuning the actin protomer concentration and activity of actin nucleators.
Spatial models reveal the microclimatic buffering capacity of old-growth forests
Authors: Frey Sarah J. K. , Hadley Adam S. , Johnson Sherri L. , Schulze Mark , Jones Julia A. , Betts Matthew G.
Published: April 2016

Spatial models of under-canopy temperature show that old-growth forests are cooler in spring months than mature forest plantations.
A broadband chip-scale optical frequency synthesizer at 2.7 × 10
−16
relative uncertainty
Authors: Huang Shu-Wei , Yang Jinghui , Yu Mingbin , McGuyer Bart H. , Kwong Dim-Lee , Zelevinsky Tanya , Wong Chee Wei
Published: April 2016

Frequency stabilization to 0.3 parts per quadrillion is demonstrated on chip, opening new frontiers in precision metrology.
The evolving interaction of low-frequency earthquakes during transient slip
Authors: Frank William B. , Shapiro Nikolaï M. , Husker Allen L. , Kostoglodov Vladimir , Gusev Alexander A. , Campillo Michel
Published: April 2016

The clustering of repeating low-frequency earthquakes through interaction reveals the state of the tectonic plate boundary.
Ice-nucleating bacteria control the order and dynamics of interfacial water
Authors: Pandey Ravindra , Usui Kota , Livingstone Ruth A. , Fischer Sean A. , Pfaendtner Jim , Backus Ellen H. G. , Nagata Yuki , Fröhlich-Nowoisky Janine , Schmüser Lars , Mauri Sergio , Scheel Jan F. , Knopf Daniel A. , Pöschl Ulrich , Bonn Mischa , Weidner Tobias
Published: April 2016

Specialized bacteria trigger ice formation by controlling the molecular structure and energy transfer in interfacial water.
Complete characterization of the stability of cluster synchronization in complex dynamical networks
Authors: Sorrentino Francesco , Pecora Louis M. , Hagerstrom Aaron M. , Murphy Thomas E. , Roy Rajarshi
Published: April 2016

Group theory and optics predict and test how and when clusters synchronize, merge, and persist in balanced dynamical networks.
Van der Waals metal-semiconductor junction: Weak Fermi level pinning enables effective tuning of Schottky barrier
Authors: Liu Yuanyue , Stradins Paul , Wei Su-Huai
Published: April 2016

The Schottky barrier for carrier injection into 2D semiconductors can be effectively tuned by using 2D metals.
Enumeration of Parasitic Chytrid Zoospores in the Columbia River via Quantitative PCR
Authors: Maier Michelle A. , Peterson Tawnya D.
Published: April 2016

Through lethal infection, fungal parasites of phytoplankton (“chytrids”) repackage organic material from the large, effectively inedible, colonial diatoms they infect into much smaller zoospores, which are easier for zooplankton to consume. However, their small size and lack of distinguishing morphological features render it difficult to distinguish zoospores from other small flagellates in mixed assemblages in the natural environment. In this study, we developed and tested a method to quantify chytrid zoospores in field studies using quantitative PCR (qPCR) targeting the internal transcribed spacer 2 (ITS2) region within the rRNA gene cluster. To achieve accurate quantification, the assay was designed to be highly specific for a parasite (
Rhizophydium planktonicum
) of the diatom
Asterionella formosa
; however, the approach is applicable to additional host-parasite systems. Parasitic zoospores were detected and quantified in the freshwater reaches of the lower Columbia River, as well as in the salt-influenced estuary and river plume. The coincidence between zoospore abundances and a prevalence of small zooplankton during blooms of large, colonial diatoms in the spring suggests that Columbia River zooplankton may be poised to benefit nutritionally from chytrid zoospores, thus providing a mechanism to retain organic carbon within the system and reduce losses to downstream export. We estimate that ∼15% of the carbon biomass tied up in blooms of the dominant diatom species is transformed into zoospores through the parasitic shunt during spring.

IMPORTANCE
The small size of the parasitic fungi that infect phytoplankton makes it difficult to identify and quantify them in natural systems. We developed and tested a method to quantify these organisms (chytrid zoospores) using a molecular technique that targets the internal transcribed spacer region within the rRNA gene cluster. Using this method, we quantified the abundance of the motile stage of a specific parasite in the freshwater and saltwater-influenced regions of the Columbia River in the U.S. Pacific Northwest. Parasitic chytrid zoospores were found to be present throughout the year and at higher abundances during the spring, when phytoplankton blooms occur. The presence of these organisms indicates not only that they may be responsible for the death of host phytoplankton cells but that they may also provide a readily available food source to small consumers (zooplankton) in the food web of the Columbia River.