bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamin‐like protein 1 cleavage by calpain in Alzheimer’s disease
Authors: Jiang Sirui , Shao Changjuan , Tang Fangqiang , Wang Wenzhang , Zhu Xiongwei
Published: February 2019

Abnormal mitochondrial dynamics contributes to mitochondrial dysfunction in Alzheimer's disease (AD), yet the underlying mechanism remains elusive. In the current study, we reported that DLP1, the key mitochondrial fission GTPase, is a substrate of calpain which produced specific N‐terminal DLP1 cleavage fragments. In addition, various AD‐related insults such as exposure to glutamate, soluble amyloid‐β oligomers, or reagents inducing tau hyperphosphorylation (i.e., okadaic acid) led to calpain‐dependent cleavage of DLP1 in primary cortical neurons. DLP1 cleavage fragments were found in cortical neurons of CRND8 APP transgenic mice which can be inhibited by calpeptin, a potent small molecule inhibitor of calpain. Importantly, these N‐terminal DLP1 fragments were also present in the human brains, and the levels of both full‐length and N‐terminal fragments of DLP1 and the full‐length and calpain‐specific cleavage product of spectrin were significantly reduced in AD brains along with significantly increased calpain. These results suggest that calpain‐dependent cleavage is at least one of the posttranscriptional mechanisms that contribute to the dysregulation of mitochondrial dynamics in AD.
The crowding out effect of booming real estate markets on corporate TFP: evidence from China
Authors: Lu Bing , Tan Xiaofen , Zhang Jinhui
Published: February 2019

This paper explores the impact of housing price appreciation on corporate total factor productivity (TFP) in Chinese A‐share listed corporations. Results show that increasing real estate prices negatively affect corporate TFP. Meanwhile, we find that the deterring effect is especially significant for state‐owned enterprises (SOEs), large corporations and manufacturing corporations. This research further provides suggestive evidence that managerial myopia may be one potential explanation for the crowding out effect of increasing housing prices. When home purchase is under restriction, however, the negative impact of rising housing prices on corporate TFP declines sharply. This study illustrates the efficiency cost of China's booming real estate market.
Combination lenalidomide‐rituximab immunotherapy activates anti‐tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma
Authors: Chiu Hsiling , Trisal Preeti , Bjorklund Chad , Carrancio Soraya , Toraño Estela G. , Guarinos Carla , Papazoglou Despoina , Hagner Patrick R. , Beldi‐Ferchiou Asma , Tarte Karin , Delfau‐Larue Marie‐Hélène , Morschhauser Franck , Ramsay Alan G. , Gandhi Anita K.
Published: February 2019

Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2) has shown clinical synergy in front‐line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T‐ and NK‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2 versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.
Immune off‐target effects of Brentuximab Vedotin in relapsed/refractory Hodgkin Lymphoma
Authors: Romano Alessandra , Parrinello Nunziatina L. , Chiarenza Annalisa , Motta Giovanna , Tibullo Daniele , Giallongo Cesarina , La Cava Piera , Camiolo Giuseppina , Puglisi Fabrizio , Palumbo Giuseppe A. , Di Raimondo Francesco
Published: February 2019

Hodgkin Lymphoma (HL) is associated with deep microenvironment re‐shaping and myeloid dysfunction. Given that only limited data are available regarding the role of Brentuximab Vedotin (BV) as single agent in transplant‐naive relapsed/refractory (R/R) patients and its off‐target effects on immune system, we evaluated the amount of regulatory T‐cells (T‐regs), myeloid‐derived suppressor cells (MDSC) subpopulations, and their functional marker, serum arginase‐1 (s‐Arg‐1), in peripheral blood of 15 consecutive R/R HL patients. After a median of four BV cycles, the overall response rate (complete response + partial response) was 47%, with 4 (27%) complete metabolic remissions. BV reduced the absolute number of three MDSC subtypes and s‐Arg‐1 levels. Patients with baseline s‐Arg‐1 ≥200 ng/ml had inferior progression‐free survival at 36 months compared to those with low s‐Arg‐1. T‐regs dysfunction was recovered by BV: absolute T‐regs count was increased after treatment with BV, independently of metabolic response achieved, with a significant reduction of CD30+T‐regs. Our data disclose off‐target effects of BV in the microenvironment that could explain its deep and durable clinical efficacy.
Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post‐BCRinhibitor setting: aUKwide analysis
Authors: Eyre Toby A. , Kirkwood Amy A. , Gohill Sat , Follows George , Walewska Renata , Walter Harriet , Cross Matthew , Forconi Francesco , Shah Nimish , Chasty Richard , Hart Alistair , Broom Angus , Marr Helen , Patten Piers E. M. , Dann Andy , Arumainathan Arvind , Munir Tal , Shankara Paneesha , Bloor Adrian , Johnston Rosalynd , Orchard Kim , Schuh Anna H. , Fox Christopher P. ,   the UK CLL Forum
Published: February 2019

Venetoclax is aBCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi‐centre retrospective analysis of 105 R/RCLLpatients who received venetoclax pre‐National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1–15). 48% hadTP53disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3‐kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no priorBTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR23%) inBTKi‐exposed patients, 92% (CR38%) in Pi3Ki‐exposed patients and 80% (CR20%) in both (P = 0·59). With a median follow‐up of 15·6 months, 1‐year progression‐free survival was 65·0% and 1‐year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression‐free or discontinuation‐free survival. Risk of progression or death after stopping a priorBCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01P = 0·05). Venetoclax is active and well tolerated in R/RCLLpost ≥1BCRi. Reason(s) for stoppingBCRi influences venetoclax outcomes.
Induction of C‐C motif chemokine ligand 2 through Toll‐like receptor 3 signaling in human cerebral microvascular endothelial cell/D3 cells: possible regulation by nuclear factor‐κB
Authors: Sassa Naoko , Hirono Koji , Shiratori Toshihiro , Kawaguchi Shogo , Matsumiya Tomoh , Yoshida Hidemi , Seya Kazuhiko , Tanaka Hiroshi , Imaizumi Tadaatsu
Published: February 2019

Objective

C‐C motif chemokine ligand 2 (CCL2) is a potent chemokine that plays an important role in host defense and inflammatory diseases in the central nervous system. Toll‐like receptor 3 (TLR3) is a pattern recognition receptor that recognizes viral double‐stranded RNAs. In the present study, we examined whether a TLR3 agonist induces CCL2 expression in brain microvascular endothelial cells, and investigated the mechanism underlying upregulation of CCL2 expression through TLR3 signaling.

Methods

A human brain microvascular endothelial cell line, human cerebral microvascular endothelial cell (hCMEC)/D3 was treated with a TLR3 agonist, polyinosinic‐polycytidylic acid (poly IC). The mRNA and protein expression of CCL2 were evaluated using real‐time reverse transcription polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively. The role of TLR3 and nuclear factor‐κB (NF‐κB) were examined with RNA interference. We also examined the effect of pretreatment with an NF‐κB inhibitor, SN50, an interferon regulatory factor 3 inhibitor MR67307 and human type I interferon neutralizing antibody mixture on poly IC‐induced CCL2 expression.

Results

Expression of CCL2 was induced by poly IC. Poly IC‐induced CCL2 expression was decreased by knockdown of TLR3 or NF‐κB p65 and by pretreatment with SN50. Neither MR67307 nor human type I interferon neutralizing antibody mixture affected the CCL2 expression induced by poly IC.

Conclusions

CCL2 expression was induced by poly IC through TLR3 signaling, and NF‐κB is involved in this reaction. CCL2 produced by human brain endothelial cells might induce the infiltration of monocytes followed by immune and inflammatory reactions in the brain, and could be involved in the pathogenesis of viral encephalitis.
‘They Cry, Cry, They Want to go to School’: the Micro‐Politics of Asylum‐Seeking Children's Articulated Emotions and Belonging in Relation to the Swedish School
Authors: Karlsson Sandra
Published: February 2019

This study illustrates how asylum‐seeking children, through articulated emotions, respond to being affected by experiences that enhance or restrict their sense of belonging. The findings show that, owing to power structures and relations, the children's sense of belonging was made uncertain by temporal, situational and relational boundaries of belonging. However, through their articulations, the children also contested these boundaries. The study argues that the children were moved by their structural situatedness and that their articulated emotions demonstrated their micro‐politics. The study also visualises how children may be affected when their rights are not realised in their lived forms.
The Diabetes Unmet Need with Basal Insulin Evaluation (DUNE) study in type 2 diabetes: Achieving HbA1c targets with basal insulin in a real‐world setting
Authors: Meneghini Luigi F. , Mauricio Didac , Orsi Emanuela , Lalic Nebojsa M. , Cali Anna M.G. , Westerbacka Jukka , Stella Peter , Candelas, DEA Christophe , Pilorget Valerie , Perfetti Riccardo , Khunti Kamlesh ,   on behalf of the DUNE investigators
Published: February 2019

Aims

To describe in a real‐world setting the achievement of physician‐selected individualized HbA1c targets in individuals with type 2 diabetes, newly or recently initiated with basal insulin, and the association of hypoglycaemia with target achievement.

Materials and methods

A 12‐week, prospective, single‐arm, observational study of adults with type 2 diabetes, either newly initiated with any basal insulin or start on basal insulin within the preceding 12 months. At enrollment, eligible participants from 28 countries were treated with or without oral antihyperglycaemic drugs and/or GLP‐1 receptor agonists.

Results

Individualized targets for almost all of the 3139 evaluable participants (99.7%) had been set by their physicians, with 57% of participants having HbA1c targets between 7.0% and <7.5% (53 and <58 mmol/mol). By week 12, 28% and 27% of newly and previously initiated participants, respectively, achieved individualized HbA1c targets with modest average increases in daily insulin dose of 9 and 5 U (0.10 and 0.06 U/kg), respectively, from baseline (14 and 23 U [0.17 and 0.29 U/kg], respectively). Overall, 16% of participants experienced at least one episode of hypoglycaemia. Both the incidence and frequency of hypoglycaemia, but not the severity, were positively associated with a higher likelihood of achieving individualized HbA1c targets (P < 0.05).

Conclusions

In this prospective real‐world study, most participants using basal insulin did not achieve the individualized HbA1c targets set by their physicians. Participants who experienced symptomatic hypoglycaemia were more likely to achieve HbA1c targets than those who did not.
Msc6p is required for mitochondrial translation initiation in the absence of formylated Met‐tRNAfMet
Authors: Franco Leticia Veloso Ribeiro , Moda Bruno S. , Soares Maria A. K. M. , Barros Mario H.
Published: February 2019

Mitochondrial translation normally requires formylation of the initiator tRNA‐met, a reaction catalyzed by the enzyme formyltransferase, Fmt1p and MTFMT in Saccharomyces cerevisiae and human mitochondria, respectively. Yeast fmt1 mutants devoid of Fmt1p, however, can synthesize all mitochondrial gene products by initiating translation with a non‐formylated methionyl‐tRNA. Yeast synthetic respiratory‐deficient fmt1 mutants have uncovered several factors suggested to play a role in translation initiation with non‐formylated methionyl‐tRNA. Here, we present evidence that Msc6p, a member of the pentatricopeptide repeat (PPR) motif family, is another essential factor for mitochondrial translation in fmt1 mutants. The PPR motif is characteristic of RNA‐binding proteins found in chloroplasts and plant and fungal mitochondria, and is generally involved in RNA stability and transport. Moreover, in the present study, we show that the respiratory deficiency of fmt1msc6 double mutants can be rescued by overexpression of the yeast mitochondrial initiation factor mIF‐2, encoded by IFM1. The role of Msc6p in translational initiation is further supported by pull‐down assays showing that it transiently interacts with mIF‐2. Altogether, our data indicate that Msc6p is an important factor in mitochondrial translation with an auxiliary function related to the mIF‐2‐dependent formation of the initiation complex.
Congenital myopathy‐related mutations in tropomyosin disrupt regulatory function through altered actin affinity and tropomodulin binding
Authors: Moraczewska Joanna , Robaszkiewicz Katarzyna , Śliwinska Małgorzata , Czajkowska Marta , Ly Thu , Kostyukova Alla , Wen Han , Zheng Wenjun
Published: February 2019

Tropomyosin (Tpm) binds along actin filaments and regulates myosin binding to control muscle contraction. Tropomodulin binds to the pointed end of a filament and regulates actin dynamics, which maintains the length of a thin filament. To define the structural determinants of these Tpm functions, we examined the effects of two congenital myopathy mutations, A4V and R91C, in the Tpm gene, TPM3, which encodes the Tpm3.12 isoform, specific for slow‐twitch muscle fibers. Mutation A4V is located in the tropomodulin‐binding, N‐terminal region of Tpm3.12. R91C is located in the actin‐binding period 3 and directly interacts with actin. The A4V and R91C mutations resulted in a 2.5‐fold reduced affinity of Tpm3.12 homodimers for F‐actin in the absence and presence of troponin, and a two‐fold decrease in actomyosin ATPase activation in the presence of Ca2+. Actomyosin ATPase inhibition in the absence of Ca2+ was not affected. The Ca2+ sensitivity of ATPase activity was decreased by R91C, but not by A4V. In vitro, R91C altered the ability of tropomodulin 1 (Tmod1) to inhibit actin polymerization at the pointed end of the filaments, which correlated with the reduced affinity of Tpm3.12‐R91C for Tmod1. Molecular dynamics simulations of Tpm3.12 in complex with F‐actin suggested that both mutations reduce the affinity of Tpm3.12 for F‐actin binding by perturbing the van der Waals energy, which may be attributable to two different molecular mechanisms—a reduced flexibility of Tpm3.12‐R91C and an increased flexibility of Tpm3.12‐A4V.
Global temporal patterns in plant nutrient resorption plasticity
Authors: Drenovsky Rebecca E. , Pietrasiak Nicole , Short Thomas H.
Published: February 2019

Aim

Leaf nutrient resorption is a key nutrient conservation trait, which also influences nutrient cycling rates and pools. Most global biogeochemical models assume that resorption is non‐varying at a temporal scale. However, this trait can differ substantially within populations among years. We assessed the commonality of attaining proficient resorption, the factors associated with proficient resorption, as well as the variability of this trait and the factors controlling trait variability.

Location

Global.

Time period

1965–2009.

Major taxa studied

Plants.

Methods

We compiled multi‐year nutrient resorption data from the literature, representing 50 studies, 94 unique study locations, and 141 species from 53 families and 29 orders. We used multiple linear regression to relate resorption data, as well as the variability in this trait, expressed as the coefficient of variation, to environmental factors.

Results

Resource availability was a key driver of resorption, with nutrient‐poor soils associated with more complete resorption and lower resorption plasticity. Nitrogen and phosphorus resorption differentially responded to some drivers, such as leaf habit, soil order and mycorrhizal status.

Main conclusions

Overall, environmental and biological factors representing a strong selective force for nutrient conservation, such as nutrient‐poor soil orders, semi‐arid soil moisture regimes, or lack of plant mutualists, were associated with complete resorption, whereas incomplete resorption was associated with weak selective forces, such as nutrient‐rich soil orders, or factors impeding this physiological process (e.g., drought). Inter‐annual variability in resorption was common, particularly for phosphorus. This plasticity has implications for ecosystem nutrient cycling and plant productivity, and accounting for this plasticity in dynamic models of nutrient cycling will improve predictions of nutrient limitations and productivity under future climate conditions.
Determinants of audit report lag: A meta‐analysis
Authors: Habib Ahsan , Bhuiyan Md. Borhan Uddin , Huang Hedy Jiaying , Miah Muhammad Shahin
Published: February 2019

This paper provides a meta‐analysis of the determinants of audit report lag, defined as the period between a company's fiscal year end and the audit report date. We group the meta‐analyzed studies into three categories: (a) audit and audit‐related determinants, (b) corporate governance‐related determinants, and (c) firm‐specific determinants. We find that audit opinion and audit season variables increase audit report lag, whereas Big 4 affiliation, nonaudit services, and auditor tenure decrease audit report lag. Among the corporate governance determinants, the existence of a financial expert member on an audit committee, and ownership concentration, reduce audit report lag. Finally, an examination of firm‐level characteristics reveals that firm complexity increases audit report lag, whereas profitability reduces it. We employ a meta‐regression technique and identify publication bias. Although we find some evidence of journal quality as a contributor to publication bias, the extent of publication bias from this source is small.
Spontaneous, anecdotal, retrospective, open-label study on the efficacy, safety and tolerability of cannabis galenical preparation (Bedrocan)
Authors: Palmieri Beniamino , Laurino Carmen , Vadalà Maria
Published: February 2019

Objectives

Our main aim was to investigate the short-term therapeutic effects, safety/tolerability and potential side effects of the cannabis galenical preparation (Bedrocan) in patients with a range of chronic conditions unresponsive to other treatments.

Methods

In this retrospective, ‘compassionate use’, observational, open-label study, 20 patients (age 18–80 years) who had appealed to our ‘Second Opinion Medical Consulting Network’ (Modena, Italy), were instructed to take sublingually the galenical oil twice a day for 3 months of treatment. The usual starting dose was low (0.5 ml/day) and gradually titrated upward to the highest recommended dose (1 ml/day). Tolerability and adverse effects were assessed at baseline and monthly thereafter during the treatment period through direct contact (email or telephone) or visit if required. Patients’ quality of life was evaluated at baseline and 3 months using the medical outcome short-form health survey questionnaire (SF-36).

Key findings

From baseline to 6 months post-treatment, SF-36 scores showed: reductions in total pain (P < 0.03); improvements in the physical component (P < 0.02); vitality (P < 0.03); social role functioning (P < 0.02); and general health state (P < 0.02). No changes in role limitations (P = 0.02) due to emotional state (e.g. panic, depression, mood alteration) were reported. Monthly reports of psychoactive adverse effects showed significant insomnia reduction (P < 0.03) and improvement in mood (P < 0.03) and concentration (P < 0.01).

Conclusions

These data suggest that a cannabis galenical preparation may be therapeutically effective and safe for the symptomatic treatment of some chronic diseases. Further studies on the efficacy of cannabis as well as cannabinoid system involvement in the pathophysiology are warranted.
Pentraxin‐3: A new parameter in predicting the severity of diabetic foot infection?
Authors: Ozer Balin Safak , Sagmak Tartar Ayse , Uğur Kader , Kilinç Faruk , Telo Selda , Bal Ali , Balin Mehmet , Akbulut Ayhan
Published: February 2019

This study was undertaken to evaluate the diagnostic and prognostic values of pentraxin‐3 (PTX‐3) in patients with infected diabetic foot ulcers (IDFU) as well as to assess the association between PTX‐3 levels and IDFU severity. This study included 60 IDFU patients (Group 1), 45 diabetic patients without DFU (Group 2), and 45 healthy controls. Patients with IDFU were divided into mild, moderate, and severe subgroups based on classification of clinical severity. Patients who underwent amputation were also documented. Blood samples were collected to determine PTX‐3 levels. PTX‐3 levels in healthy controls, Group 1, and Group 2 were 5.83 (3.41‐20) ng/mL, 1.47 (0.61‐15.13) ng/mL, and 3.26 (0.67‐20) ng/mL, respectively. A negative correlation between plasma PTX‐3 and glucose levels was found. There were significant differences in terms of procalcitonin (PCT) and PTX‐3 levels in the subgroup analysis of Group 1. The PTX‐3 level in patients who did or did not undergo amputation was 4.1 (0.8‐13.7) and 1 (0.6‐15.1) ng/mL, respectively. Results suggest that PTX‐3 is a particularly effective marker in patients with IDFU, both in terms of predicting disease severity and assisting in the decision to perform amputation.
A left common pulmonary vein: Anatomical variant predicting good outcomes of repeat catheter ablation for atrial fibrillation
Authors: Xu Buyun , Xing Yangbo , Xu Chao , Peng Fang , Sun Yong , Wang Shengkai , Guo Hangyuan
Published: February 2019

Introduction

A left common pulmonary vein (LCPV) is a common anatomical variant in atrial fibrillation (AF) patients. Whether an LCPV influences outcomes of repeated radiofrequency catheter ablation (RFCA) for AF has not been elucidated.

Methods

From a prospectively collected database, we enrolled 154 patients who received repeated RFCA for recurrent AF after the initial RFCA (56 ± 9 years, 72% paroxysmal AF, 32 patients with an LCPV, and 122 patients with typical left‐sided pulmonary veins [PVs]). Median postprocedural follow‐up was 26 months. The primary outcome was an episode of AF, atrial tachyarrhythmia, or atrial flutter lasting for more than 30 seconds, after the 3 months blanking period following the repeated procedure.

Results

After the follow‐up period, 75 patients suffered recurrence after repeated ablation. In the Kaplan‐Meier analysis, an LCPV was significantly associated with less recurrence (hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.28‐0.79; P = 0.005). In subgroup analysis, the significant association persisted in paroxysmal AF patients. Regarding persistent AF patients, an LCPV tended to be associated with less recurrence with no statistical significance (HR: 0.40; 95% CI: 0.20‐1.03;
P = 0.067). In multivariate analyses, an LCPV still independently predicted freedom from recurrence (HR: 0.44; 95% CI: 0.22‐0.88;
P = 0.02).

Conclusion

Compared with typical left‐sided PVs, an LCPV was independently associated with better outcomes after repeated RFCA of AF, particularly in patients with paroxysmal AF.
The clinical impact of the left atrial posterior wall lesion formation by the cryoballoon application for persistent atrial fibrillation: Feasibility and clinical implications
Authors: Nishimura Takuro , Yamauchi Yasuteru , Aoyagi Hideshi , Tsuchiya Yusuke , Shigeta Takatoshi , Nakamura Rena , Yamashita Mitsumi , Asano Mitsutoshi , Nakamura Tomofumi , Suzuki Hidetoshi , Shimura Tsukasa , Kurabayashi Manabu , Keida Takehiko , Sasano Tetsuo , Hirao Kenzo , Okishige Kaoru
Published: February 2019

Introduction

The left atrial (LA) posterior wall (LAPW) has been targeted to improve the clinical outcomes in patients with persistent atrial fibrillation (PersAF). This study aimed to investigate the feasibility, safety, and clinical implications of cryoballoon (CB) applications on the LAPW to accomplish electrical isolation (EI) of the LAPW with CB.

Methods

A total of 100 patients (males, 84; mean age, 64 ± 10 years) with PersAF were enrolled. The first 50 patients underwent only pulmonary vein isolation (PVI) (PVI‐only group) and the remaining 50 patients underwent PVI and EI of the LAPW with CB (EI‐LAPW group).

Results

One‐year sinus rhythm maintenance probability was significantly higher in the EI‐LAPW group than in PVI‐only group (80.0% vs 55.1%, P = 0.01). The success rate of constructing an LA roof block line (LA‐RB), bottom block line, and EI of the LAPW was 92%, 60%, and 58%, respectively. The nadir CB temperature (−45°C ± 4°C vs −39°C ± 5°C,
P = 0.005) and anatomical angle of the left atrial roof (106°C ± 30°C vs 144°C ± 17°C,
P < 0.001) significantly predicted the successful LA‐RB construction. The left ventricular ejection fraction was significantly higher in unsuccessful cases than in successful cases of an EI of the LAPW (64% ± 8% vs 58% ± 11%,
P = 0.041). Even though the EI of the LAPW was unsuccessful, CB freezing in LAPW significantly debulked the nonscar area (≥0.1 mV) in LAPW (18.1 ± 5.6 vs 2.2 ± 3.1 cm
2,
P < 0.001) and provided the equivalent 1‐year outcome of successful cases (79.3% vs 81.0%,
P = 0.90).

Conclusion

The combination of PVI and EI of the LAPW with CB provided better clinical outcomes than conventional PVI procedure for patients with PersAF.
Periodontal health: A national cross‐sectional study of knowledge, attitudes and practices for the public oral health strategy in China
Authors: Zhao Qian , Wang Shi‐Bin , Xu Guodong , Song Yiqing , Han Xiaozhe , Liu Zhiqiang , Zhou Xuan , Zhang Tianyi , Huang Kewu , Yang Ting , Lin Yingxiang , Wu Sinan , Wang Zuomin , Wang Chen
Published: February 2019

Aim

To assess the status of periodontal health knowledge, attitudes and practices (KAP) among Chinese adults.

Materials and Methods

A cross‐sectional study was conducted in a nationally representative sample of adults (N = 50,991) aged 20 years or older from ten provinces, autonomous regions, and municipalities. Percentages of Chinese adults with correct periodontal knowledge, positive periodontal attitudes, and practices were estimated. Multiple logistic regression analyses were used to examine the related factors.

Results

Less than 20% of Chinese adults were knowledgeable about periodontal disease. Very few (2.6%) of Chinese adults use dental floss ≥once a day and undergo scaling ≥once a year and visit a dentist (6.4%) in the case of gingival bleeding. Periodontal health KAP was associated with gender, age, body mass index, marital status, place of residence, education level, income, smoking status, and history of periodontal disease.

Conclusions

Periodontal health KAP are generally poor among the Chinese adult population. Community‐based health strategies to improve periodontal health KAP need to be implemented. Increasing knowledge of periodontal disease, the cultivation of correct practices in response to gingival bleeding, and the development of good habits concerning the use of dental floss and regular scaling should be public oral health priorities.
Psoriasis and skin pain: real‐life effectiveness of calcipotriol plus betamethasone dipropionate in aerosol foam formulation
Authors: Gallo L. , Megna M. , Cirillo T. , Caterino P. , Lodi G. , Mozzillo R. , Dente V. , Balato A.
Published: February 2019

Background/objective

Although 40% of psoriasis patients reported skin pain, this symptom is often underestimated. A new formula of calcipotriol plus betamethasone dipropionate (Cal/BD) has been recently approved for psoriasis treatment. Therefore, we aimed to evaluate the efficacy of Cal/BD aerosol foam on skin pain of patients with plaque psoriasis.

Methods

A real‐life 4‐week prospective, open study on Cal/BD aerosol foam (not compared to vehicle or emollient cream) was performed in adult psoriasis patients attending three Dermatology units located in Campania region, Italy, between March and October 2018. Inclusion criteria were a history of skin pain over the last week and psoriatic involvement of the palmar area. Before (t0) and after a course of once daily application of Cal/BD aerosol foam for 4 weeks (t1), the following items were evaluated: Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA) index of target plaque on palmar region, subjective skin pain features through Pain Qualities Assessment Scale questionnaire and skin pain threshold measured by pressure digital algometer at palmar psoriatic plaques.

Results

Seventy‐five patients (43 male, mean age of 43.2 years) were enrolled. After 4 weeks of therapy with Cal/BD aerosol foam, a significant improvement in both PASI (mean: 6.5 ± 2.1 at t0 vs. 2.3 ± 1.6 at t1) and palmar plaques PGA (mean: 3.6 at t0 vs. 1.7 at t1) was observed (P < 0.001). The mean intensity score of skin pain decreased from 7.6 to 1.3 (P < 0.001); among skin pain qualities, intense, sensible, aching and unpleasant showed the highest rate of reduction (t0–t1: 6.3, 6.3, 6.1 and 5.8, respectively). Pain threshold of palmar skin lesions increased at t1.

Conclusions

Our real‐life study suggested that Cal/BD aerosol foam may represent a valid topical anti‐psoriatic treatment, not only improving skin lesions, but also relieving cutaneous pain, thus contributing to ameliorate patients' quality of life.
Investigation of the utility of Curcuma caesia in the treatment of diabetic neuropathy
Authors: Grover Madhuri , Shah Karan , Khullar Gaurav , Gupta Jyoti , Behl Tapan
Published: February 2019

Objectives

Curcuma caesia has shown positive results in treating number of diseases, but till date no work was reported on its activity in diabetic neuropathy. So, the present review aims at exploring several hypothesis which can be proposed to explain further its utility in diabetic neuropathy by its antioxidant property, anti-inflammatory, CNS depressant effect, antibacterial and antifungal property. For finding the accurate and exact detail, a thorough review of all the available research and review article was done. A number of book chapters and encyclopaedias were taken into consideration to find out the origin, botany and genetics. The databases were searched using different keywords like antioxidant, inflammation, turmeric, diabetic neuropathy.

Key findings

After getting data on pathogenesis of diabetic neuropathy, it has been found out that its role as antioxidant will reduce the level of oxidative stress which is the main reason for the occurrence of the present complication. Apart this, the anti-inflammatory activity will further prevent the inflammation of neurons and antibacterial effect will inhibit the spread of infection. Combining all the factors together, the plant can be utilized in the treatment of diabetic neuropathy.

Curcuma caesia can be proved as a useful approach in the treatment of diabetic neuropathy.
Adolescents' Agentic Work on Developing Personal Pedagogies on Social Media
Authors: Tan Lynde , Kim Beaumie
Published: February 2019

While current research points out that young people are developing emerging culture of learning in informal spaces, less is known about such digital literacy practices in the Asian contexts where the notion of literacy tends to refer to school literacy. Research on young people's online participatory culture continues to suggest that social media offer affinity spaces where extensive knowledge is acquired, constructed and produced outside of schools. In this paper, we use two case studies on social media as illustrative examples to understand how adolescents shape their learning online. We aim to contribute to the ongoing dialectics on social media and learning by examining how adolescents exhibit agency online. We argue that social media such as Facebook offer high learner agency environments for adolescents to participate in self‐initiated enterprise and allow them to develop personal trajectories for learning. The case studies presented in this paper suggested that the adolescents' pursuit of their passions on online affinity spaces gave rise to intellectual friendships and the development of personal pedagogies.
Global Ambitions: Evidence, Scale, and Child Well‐being in El Salvador
Authors: Matza Tomas
Published: February 2019

Experimental design and metrics have become increasingly common in international assistance, as donor agencies have demanded rigorous forms of evaluation and monitoring. This article contributes to debates about the effects of an “evidence‐based turn” on interventions and recipients by exploring two questions: What constitutes evidence when it comes to everyday practices of aid at global scales? How are the goals of assistance affected? The article draws on collaborative research with an NGO and a group of social scientists who seek to improve child well‐being in El Salvador. It shows how evidence‐making was polysemic and costly, ultimately impacting the NGO's planned intervention. This outcome, I argue, was not a matter of poor planning, but reflects structural, evidence‐making demands placed on global assistance at this historical conjuncture. Discussions among stakeholders about the trade‐offs between evidence‐making and assistance is a possible future route through the challenges described in this article.
Ecotypic divergence in Crepis tectorum (Asteraceae): inferring trait lability and correlational constraints from hormonally manipulated phenotypes
Authors: Andersson Stefan
Published: February 2019

Despite long‐standing interest in the evolutionary role of plant hormones, relatively few studies have used hormonally manipulated phenotypes to address questions about phenotypic evolution in plants. In the present investigation, I subjected plants of Crepis tectorum subsp. pumila to simple gibberellin (GA) treatments under both field and greenhouse conditions to assess developmental lability and correlational constraints of phenotypic traits that distinguish this dwarf ecotype from conspecific populations of the much taller weed ecotype (subsp. tectorum). The hormonally manipulated plants largely phenocopied the weed ecotype in leaf shape, plant stature and branching habit, indicative of both high lability and tight integration of traits reflecting gross morphology. Floral size traits sometimes declined after GA application, especially under field conditions. The latter result conflicts with the positive correlations between floral and vegetative size traits seen in previous comparative analyses and point to a tradeoff that could act as a constraint on ecotype divergence. The response to GA was consistent in direction for most traits, as opposed to the magnitude of response, which varied depending on the trait, the population, the growing environment and the timing and level of hormone application. Taken together, the results highlight the potential for simple hormonal changes to cause large, plastic shifts in phenotype, but also illustrate the constrained nature of such influences.
Conflicting selection on floral scent emission in the orchid Gymnadenia conopsea
Authors: Chapurlat Elodie , Ågren Jon , Anderson Joseph , Friberg Magne , Sletvold Nina
Published: February 2019

Floral scent is a crucial trait for pollinator attraction. Yet only a handful of studies have estimated selection on scent in natural populations and no study has quantified the relative importance of pollinators and other agents of selection.

In the fragrant orchid Gymnadenia conopsea, we used electroantennographic data to identify floral scent compounds detected by local pollinators and quantified pollinator‐mediated selection on emission rates of 10 target compounds as well as on flowering start, visual display and spur length.

Nocturnal pollinators contributed more to reproductive success than diurnal pollinators, but there was significant pollinator‐mediated selection on both diurnal and nocturnal scent emission. Pollinators selected for increased emission of two compounds and reduced emission of two other compounds, none of which were major constituents of the total bouquet. In three cases, pollinator‐mediated selection was opposed by nonpollinator‐mediated selection, leading to weaker or no detectable net selection.

Our study demonstrates that minor scent compounds can be targets of selection, that pollinators do not necessarily favour stronger scent signalling, and that some scent compounds are subject to conflicting selection from pollinators and other agents of selection. Hence, including floral scent traits into selection analysis is important for understanding the mechanisms behind floral evolution.
Metabolic responses to potassium availability and waterlogging reshape respiration and carbon use efficiency in oil palm
Authors: Cui Jing , Davanture Marlène , Zivy Michel , Lamade Emmanuelle , Tcherkez Guillaume
Published: February 2019

Oil palm is by far the major oil‐producing crop on the global scale, with c. 62 Mt oil produced each year. This species is a strong potassium (K)‐demanding species cultivated in regions where soil K availability is generally low and waterlogging due to tropical heavy rains can limit further nutrient absorption. However, the metabolic effects of K and waterlogging have never been assessed precisely.

Here, we examined the metabolic response of oil palm saplings in the glasshouse under controlled conditions (nutrient composition with low or high K availability, with or without waterlogging), using gas exchange, metabolomics and proteomics analyses.

Our results showed that both low K and waterlogging have a detrimental effect on photosynthesis but stimulate leaf respiration, with differential accumulation of typical metabolic intermediates and enzymes of Krebs cycle and alternative catabolic pathways. In addition, we found a strong relationship between metabolic composition, the rate of leaf dark respiration, and cumulated respiratory loss.

Advert environmental conditions (here, low K and waterlogging) therefore have an enormous effect on respiration in oil palm. Leaf metabolome and proteome appear to be good predictors of carbon balance, and open avenues for cultivation biomonitoring using functional genomics technologies.
Isoprene is more affected by climate drivers than monoterpenes: A meta‐analytic review on plant isoprenoid emissions
Authors: Feng Zhaozhong , Yuan Xiangyang , Fares Silvano , Loreto Francesco , Li Pin , Hoshika Yasutomo , Paoletti Elena
Published: February 2019

Isoprene and monoterpenes (MTs) are among the most abundant and reactive volatile organic compounds produced by plants (biogenic volatile organic compounds). We conducted a meta‐analysis to quantify the mean effect of environmental factors associated to climate change (warming, drought, elevated CO2, and O3) on the emission of isoprene and MTs. Results indicated that all single factors except warming inhibited isoprene emission. When subsets of data collected in experiments run under similar change of a given environmental factor were compared, isoprene and photosynthesis responded negatively to elevated O3 (−8% and −10%, respectively) and drought (−15% and −42%), and in opposite ways to elevated CO2 (−23% and +55%) and warming (+53% and −23%, respectively). Effects on MTs emission were usually not significant, with the exceptions of a significant stimulation caused by warming (+39%) and by elevated O3 (limited to O3‐insensitive plants, and evergreen species with storage organs). Our results clearly highlight individual effects of environmental factors on isoprene and MT emissions, and an overall uncoupling between these secondary metabolites produced by the same methylerythritol 4‐phosphate pathway. Future results from manipulative experiments and long‐term observations may help untangling the interactive effects of these factors and filling gaps featured in the current meta‐analysis.
Low temperature‐induced aberrations in male and female reproductive organ development cause flower abortion in chickpea
Authors: Kiran Asha , Kumar Sanjeev , Nayyar Harsh , Sharma Kamal Dev
Published: February 2019

Chickpea (Cicer arietinum L.) is susceptible to low temperature (LT) at reproductive stage. LT causes flower abortion and delays pod set in chickpea until terminal drought becomes an issue, thereby decreasing yield potential. In chickpea, flower and anther/pollen development as well as LT‐induced abnormalities on anther and pollen development are described inadequately. In the present manuscript, we report flower development stages, anther development stages, and aberrations in male gamete formation in chickpea under LT. Flower length was linearly correlated to flower and anther stages and can be used to predict these stages in chickpea. LT affected male gamete development in a flower/anther age‐dependent manner where outcome ranged from no pollen formation to pollen sterility or no anther dehiscence to delayed dehiscence. In anthers, LT inhibited microsporogenesis, microgametogenesis, tapetum degeneration, breakage of septum and stomium, and induced pollen sterility. Whereas disruption of male function was the prime cause of abortion in flowers below vacuolated pollen stage, flower abortion was due to a combination of male and female reproductive functions in flowers with mature pollen. The study will help in elucidating mechanisms governing flower development, anther and pollen development, and tolerance/susceptibility to LT.
Mechanism of action of 4‐substituted phenols to induce vitiligo and antimelanoma immunity
Authors: Kammeyer Arthur , Willemsen Karin J. , Ouwerkerk Wouter , Bakker Walbert J. , Ratsma Danielle , Pronk Sebas D. , Smit Nico P. M. , Luiten Rosalie M.
Published: February 2019

Monobenzone is a 4‐substituted phenol that can induce vitiligo and antimelanoma immunity. We investigated the influence of the chemical structure on the biological activity of a series of structurally related 4‐substituted phenols. All phenols inhibited cellular melanin synthesis, and eight of ten phenols inhibited tyrosinase activity, using the MBTH assay. These phenols also induced glutathione (GSH) depletion, indicative of quinone formation and protein thiol binding, which can increase the immunogenicity of melanosomal proteins. Specific T‐cell activation was found upon stimulation with phenol‐exposed pigmented cells, which also reacted with unexposed cells. In contrast, 4‐tertbutylphenol induced immune activation was not restricted to pigment cells, analogous to contact sensitization. We conclude that 4‐substituted phenols can induce specific T‐cell responses against melanocytes and melanoma cells, also acting at distant, unexposed body sites, and may confer a risk of chemical vitiligo. Conversely, these phenols may be applicable to induce specific antimelanoma immunity.
Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti‐PD‐1 antibodies
Authors: Pires da Silva Ines , Glitza Isabella C. , Haydu Lauren E. , Johnpulle Romany , Banks Patricia D. , Grass George D. , Goldinger Simone M. A. , Smith Jessica L. , Everett Ashlyn S. , Koelblinger Peter , Roberts‐Thomson Rachel , Millward Michael , Atkinson Victoria G. , Guminski Alexander , Kapoor Rony , Conry Robert M. , Carlino Matteo S. , Wang Wei , Shackleton Mark J. , Eroglu Zeynep , Lo Serigne , Hong Angela M. , Long Georgina V. , Johnson Douglas B. , Menzies Alexander M.
Published: February 2019

Background

Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti‐PD‐1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer‐term survivors with MBM treated with this combination.

Methods

Patients with MBM treated with radiotherapy and anti‐PD‐1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148).

Results

From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery.

Conclusions

Radionecrosis is a significant toxicity in longer‐term melanoma survivors with MBM treated with anti‐PD‐1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.
Ferrochelatase Deficiency Abrogated the Enhancement of Aminolevulinic Acid‐mediated Protoporphyrin IX by Iron Chelator Deferoxamine
Authors: Palasuberniam Pratheeba , Kraus Daniel , Mansi Matthew , Braun Alexander , Howley Richard , Myers Kenneth A. , Chen Bin
Published: February 2019

Aminolevulinic acid (ALA) is a prodrug that is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX) for tumor fluorescence detection and photodynamic therapy (PDT). The iron chelator deferoxamine (DFO) has been widely used to enhance PpIX accumulation by inhibiting the iron‐dependent bioconversion of PpIX to heme, a reaction catalyzed by ferrochelatase (FECH). Tumor response to DFO treatment is known to be highly variable, and some tumors even show no response. Given the fact that tumors often exhibit reduced FECH expression/enzymatic activity, we examined how reducing FECH level affected the DFO enhancement effect. Our results showed that reducing FECH level by silencing FECH in SkBr3 breast cancer cells completely abrogated the enhancement effect of DFO. Although DFO enhanced ALA‐PpIX fluorescence and PDT response in SkBr3 vector control cells, it caused a similar increase in MCF10A breast epithelial cells, resulting in no net gain in the selectivity toward tumor cells. We also found that DFO treatment induced less increase in ALA‐PpIX fluorescence in tumor cells with lower FECH activity (MDA‐MB‐231, Hs 578T) than in tumor cells with higher FECH activity (MDA‐MB‐453). Our study demonstrates that FECH activity is an important determinant of tumor response to DFO treatment.