bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary patterns and retinal vascular calibre in children and adolescents with type 1 diabetes
Authors: Keel Stuart , Itsiopoulos Catherine , Koklanis Konstandina , Vukicevic Meri , Cameron Fergus , Gilbertson Heather , Brazionis Laima
Published: January 2016

Purpose

To examine the association between dietary patterns and retinal vascular calibre in children and adolescents with type 1 diabetes.

Methods

A hospital‐based cross‐sectional study of 83 children and adolescents with type 1 diabetes was conducted over an 8‐month period. Dietary patterns were extracted using principal components analysis from completed food frequency questionnaires. Retinal vascular calibre was measured by a trained grader using a standardized protocol and later summarized as central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) using a semi‐automated computer program.

Results

Three major dietary patterns were identified as follows: (1) processed foods, (2) plant‐based foods and (3) vegetable/fish avoidance pattern. The processed pattern had high component loadings for processed meats and high fat takeaway foods. The plant‐based pattern had high component loadings for a number of fruits including, but not limited to, pineapple, grapes oranges and mangos as well as a smaller number of vegetables, including beans and leeks. The vegetable and fish avoidance pattern had high inverse component loadings for canned and fresh fish as well as a number of vegetables including, but not limited to, pumpkin, green beans, broccoli, sweet potato and cabbage. Adjusted regression analysis revealed the ‘vegetable/fish avoidance’ dietary pattern was associated with a wider CRVE (ExpB = 3.67, 95% CI = 0.11/7.24, p = 0.039). After multivariable adjustments, a vascular risk profile that included: older age, higher BMI, higher systolic blood pressure, greater gestational age, longer screen viewing time, lower maternal education level, lower physical activity levels and lower high‐density lipoproteins concentrations were more likely to display narrower CRAE (ExpB = −2.43, 95% CI = −4.92/0.06, p = 0.041).

Conclusions

This study provides the first evidence for a diet–calibre relationship in children and adolescents with type 1 diabetes. This outcome has potential public health implications, as promotion of healthy eating patterns in children and adolescents might attenuate changes in microvasculature that have been related to an increased risk of microvascular disease, such as retinopathy, in adulthood. Additional studies are warranted to explore and validate this novel finding.
Does cataract surgery reduce the long‐term risk of glaucoma in eyes with pseudoexfoliation syndrome?
Authors: Kristianslund Olav , Østern Atle E. , Råen Marianne , Sandvik Gunhild F. , Drolsum Liv
Published: January 2016

Purpose

To compare glaucoma development and intraocular pressure (IOP) in the longer term following phacoemulsification cataract surgery in eyes with and without pseudoexfoliation syndrome (PEX).

Methods

Fifty‐one patients with PEX were compared with 102 age‐ and gender‐matched controls without PEX. Patients were re‐examined a mean of 76 (SD 5.4) months after cataract surgery, recording IOP, glaucoma diagnosis, glaucoma treatment and LogMAR. Data from the preoperative visit (baseline) and IOP on the first postoperative day were obtained from medical records. A glaucoma parameter was predefined as patients developing glaucoma or needing increased glaucoma treatment during the postoperative time period.

Results

One new glaucoma case in each group was diagnosed postoperatively, yielding glaucoma incidences of 0.47 cases per 100 person‐years [95% confidence interval (CI) 0.006–2.61] and 0.17 cases per 100 person‐years (CI 0.002–0.95) in the PEX and control groups respectively (p = 0.53). IOP declined by 2.6 (SD 4.0) mmHg in the PEX group (p < 0.001) and 1.9 (SD 3.5) mmHg in the control group (p < 0.001) from baseline to the re‐examination, with a non‐significant group difference (p = 0.310). IOP spike (≥6 mmHg increase) was significantly associated with the glaucoma parameter, both within the PEX (p = 0.034) and the control group (p = 0.044).

Conclusion

The number of newly diagnosed glaucoma cases was lower than expected 6–7 years following cataract extraction, especially in the PEX group, which indicates that PEX eyes benefit particularly from cataract surgery in terms of IOP and glaucoma development.
Effect of selective laser trabeculoplasty on corneal biomechanics
Authors: Pillunat Karin R. , Spoerl Eberhard , Terai Naim , Pillunat Lutz E.
Published: January 2016

Purpose

To evaluate the effect of selective laser trabeculoplasty (SLT) on ocular biomechanics as measured with the ocular response analyzer (ORA, AMETEK Inc. and Reichert Inc.).

Methods

In a prospective case series, 52 eyes of 52 patients (aged 66.6 ± 9.6 years) with insufficient intraocular pressure (IOP) control despite maximum tolerated medical therapy underwent SLT (Solo™ SLT, Ellex Inc.) for further IOP reduction. Goldmann‐correlated IOP (IOPg), corneal‐compensated IOP (IOPcc), corneal hysteresis (CH) and the corneal resistance factor (CRF) were measured with the ORA prior to and at least 4 weeks following SLT.

Results

IOPg decreased statistically significantly from 18.0 ± 6.4 to 14.8 ± 3.8 mmHg and IOPcc from 20.2 ± 6.5 to 16.7 ± 3.4 mmHg (p < 0.001). CH increased from 8.53 ± 2.03 to 9.12 ± 1.83 mmHg (p = 0.028) and CRF decreased from 9.58 ± 2.18 to 9.1 ± 2.1 mmHg (p = 0.037), which was statistically significant. Correcting the CH and CRF data for the influence of IOP reduction with a covariance analysis, however, resulted in an unchanged CH (IOPg adjusted: p = 0.318; IOPcc adjusted: p = 0.468) and CRF (IOPg adjusted: p = 0.320; IOPcc adjusted: p = 0.464) after SLT.

Conclusion

Selective laser trabeculoplasty does not change corneal biomechanical properties as measured with the ORA in already pretreated patients with glaucoma. The measured increase in CH and decrease in CRF can be solely explained by IOP reduction.
Thyroid hormone reduces inflammatory cytokines improving glycaemia control in alloxan‐induced diabetic wistar rats
Authors: Panveloski‐Costa A. C. , Silva Teixeira S. , Ribeiro I. M. R. , Serrano‐Nascimento C. , das Neves R. X. , Favaro R. R. , Seelaender M. , Antunes V. R. , Nunes M. T.
Published: January 2016

Aim

This study aimed at evaluating whether thyroid hormone treatment could improve glycaemia and insulin response in alloxan‐induced diabetic rats by altering cytokine expression in the skeletal muscle and epididymal white adipose tissue (eWAT) as well as altering inflammatory cell infiltration in eWAT.

Methods

Diabetes mellitus (DM) was induced in male Wistar rats by alloxan injection, and a subset of the diabetic rats was treated with T3 (1.5 μg per 100 g body weight) for a 28‐day period (DT3). Cytokines were measured in serum (MILIplex assay kit) as well as in soleus and EDL skeletal muscles and eWAT by Western blotting. Thyroid function was evaluated by morphological, molecular and biochemical parameters. Cardiac function was assessed by measuring heart rate, blood pressure, maximal rate of pressure development (dp/dtmax) and decline (dp/dtmin) as well as the contractility index (CI). Sixty rats were used in the study.

Results

Diabetic rats exhibited decreased thyroid function and increased inflammatory cytokines in serum, soleus muscle and eWAT. T3 treatment decreased glycaemia and improved insulin sensitivity in diabetic animals. These alterations were accompanied by decreased TNF‐alpha and IL‐6 content in soleus muscle and eWAT, and inflammatory cell infiltration in eWAT. T3 treatment did not affect cardiac function of diabetic rats.

Conclusions

The present data provide evidence that T3 treatment reduces glycaemia and improves insulin sensitivity in diabetic rats, and that at least part of this effect could result from its negative modulation of inflammatory cytokine expression.
Emerging role of thyroid hormone metabolites
Authors: Gnocchi D. , Steffensen K. R. , Bruscalupi G. , Parini P.
Published: January 2016

Thyroid hormones (THs) are essential for the regulation of development and metabolism in key organs. THs produce biological effects both by directly affecting gene expression through the interaction with nuclear receptors (genomic effects) and by activating protein kinases and/or ion channels (short‐term effects). Such activations can be either direct, in the case of ion channels, or mediated by membrane or cytoplasmic receptors. Short‐term‐activated signalling pathways often play a role in the regulation of genomic effects. Several TH intermediate metabolites, which were previously considered without biological activity, have now been associated with a broad range of actions, mostly attributable to short‐term effects. Here, we give an overview of the physiological roles and mechanisms of action of THs, focusing on the emerging position that TH metabolites are acquiring as important regulators of physiology and metabolism.
Systematic review with meta‐analysis: the adverse effects of tobacco smoking on the natural history of Crohn's disease
Authors: To N. , Gracie D. J. , Ford A. C.
Published: January 2016

Background

Tobacco smoking is a well‐established risk factor for the development of Crohn's disease, and this may lead to a more complicated disease course. However, recent evidence suggests that many patients with Crohn's disease are unaware of this fact.

Aim

To perform a systematic review and meta‐analysis of the effects of smoking on disease course in Crohn's disease.

Methods

A search of MEDLINE, EMBASE and EMBASE classic was carried out (up to July 2015) to identify observational studies reporting data on smoking and rates of surgery or flares of disease activity in patients with Crohn's disease. Dichotomous data were pooled to obtain odds ratios (ORs) for flares of disease activity or need for surgery, with 95% confidence intervals (CIs).

Results

The search identified 33 eligible studies. Compared with nonsmokers, smokers had increased odds of flare of disease activity (OR, 1.56; 95% CI, 1.21–2.01), flare after surgery (OR, 1.97; 95% CI, 1.36–2.85), need for first surgery (OR, 1.68; 95% CI, 1.33–2.12) and need for second surgery (OR, 2.17; 95% CI, 1.63–2.89). The odds of these outcomes among ex‐smokers diminished upon smoking cessation, with ORs comparable to those among nonsmokers and, in the case of flare or second surgery, significantly lower than smokers.

Conclusions

Smokers with Crohn's disease have a more complicated disease course than nonsmokers, and quitting smoking may ameliorate this. Patients should be reminded of the detrimental effects of smoking on the course of their disease, and smoking cessation advice should be provided to reduce disease burden and costs in these patients.
Patients with large‐duct primary sclerosing cholangitis and Crohn's disease have a better outcome than those with ulcerative colitis, or without IBD
Authors: Fevery J. , Van Steenbergen W. , Van Pelt J. , Laleman W. , Hoffman I. , Geboes K. , Vermeire S. , Nevens F.
Published: January 2016

Background

Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD).

Aim

To compare PSC/CD with other PSC patients.

Methods

Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow‐up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver‐related death were endpoints.

Results

Sixty‐three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu.

Small‐duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small‐duct PSC had a markedly better survival than large‐duct PSC: no patient developed cholangiocarcinoma or liver‐related death, but colorectal cancer occurred in three patients. In large‐duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver‐related deaths were absent compared to 7% in the other PSC groups.

Conclusions

The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one‐fourth has small‐duct PSC. In large‐duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.
The Exploration of Sr Isotopic Analysis Applied to Chinese Glazes: Part Two
Authors: Ma H. , Henderson J. , Evans J.
Published: January 2016

To continue the enquiry into strontium isotope compositions in southern Chinese glazes, this study determines the strontium isotope compositions of porcelain glazes of Dehua ‘Blanc De Chine’ porcelain and blue‐and‐white porcelain, and Tai Po blue‐and‐white porcelain. Mixing lines are displayed in the strontium isotope compositions of the Dehua glazes, suggesting that raw materials of different natures were used to make the two glazes. By referring to the historical resources, a high‐calcium plant ash and a mixture of limestone and high‐silica ash can be suggested as the fluxes used in the recipes for ‘Blanc De Chine’ glaze and blue‐and‐white glaze respectively. The strontium isotope compositions of Tai Po blue‐and‐white porcelain glazes separate into two groups, suggesting that different recipes were used to make the same glaze. The group A includes too few samples to allow an identification of the raw materials used, while the strontium isotope compositions of group B samples suggest that a high‐calcium plant ash was added as the flux.
Consistent functional response of meadow species and communities to land‐use changes across productivity and soil moisture gradients
Authors: Májeková Maria , Janeček Štěpán , Mudrák Ondřej , Horník Jan , Janečková Petra , Bartoš Michael , Fajmon Karel , Jiráská Šárka , Götzenberger Lars , Šmilauer Petr , Lepš Jan , de Bello Francesco
Published: January 2016

Questions

Wet meadows have traditionally been managed at low intensity, promoting the co‐existence of a variety of plant species. The remaining fragments of these meadows are now being degraded by either mowing abandonment or by agricultural intensification, such as increased fertilization. We tested the theoretical expectation that certain functional traits can explain vegetation changes along gradients of productivity and soil moisture in response to these land‐use changes.

Location

Železné hory Mts., Czech Republic, Central Europe.

Methods

We set up a long‐term experiment where we applied a full factorial design of fertilization and abandonment to 17 traditionally mown wet meadows covering a broad range of productivity and soil moisture conditions found within the region. Plant functional traits that cover different aspects of plant ecological strategies – plant height, specific leaf area (SLA), leaf dry matter content (LDMC), seed mass and clonality – were used to explain both species and whole community response to land‐use change. We employed linear mixed effect models to test for the consistency of functional changes across different productivity and soil moisture conditions.

Results

We found that the functional response of species and whole communities to land‐use change was consistent across meadows differing substantially in their productivity and soil moisture. Specifically, irrespective of the local conditions, both fertilization and abandonment selected for tall species within communities, highlighting the effect of increased competition for light. Traits related to a more exploitative strategy in species (higher SLA, more prominent clonal growth and smaller seeds) were consistently favoured with increased fertilization.

Conclusions

We show that within a given region with a common land‐use history, certain functional traits consistently explain and can help to predict changes in plant communities caused by land‐use change, irrespective of different productivity and soil moisture conditions. Our results demonstrate a simple way to use functional traits in applied nature conservation. We hope this will encourage practitioners to use functional traits to complement existing knowledge on composition and productivity of considered habitats to enhance the planning of management practices. We encourage practitioners to build regional trait databases to actively use trait information for the purpose of habitat management.
Ten‐year updated meta‐analysis of the clinical characteristics of pediatric mania and hypomania
Authors: Van Meter Anna R , Burke Coty , Kowatch Robert A , Findling Robert L , Youngstrom Eric A
Published: January 2016

Objectives

The phenomenology and diagnosis of pediatric bipolar disorder has been controversial. We aimed to update a 2005 meta analysis of the prevalence of manic symptoms in youth, in order to determine whether the picture of pediatric mania has changed as research on pediatric bipolar disorder has grown.

Methods

We conducted literature reviews in PsycINFO and PubMed; studies with the prevalence of manic symptoms in youth were included. Two raters coded each study; kappa was 0.86–1.0.

Results

Twenty studies were meta‐analyzed (N = 2,226 youths). The most common symptoms across bipolar subtypes, using a random‐effects model, were: increased energy 79%, irritability 77%, mood lability 76%, distractibility 74%, goal‐directed activity 72%, euphoric/elated mood 64%, pressured speech 63%, hyperactive 62%, racing thoughts 61%, poor judgment 61%, grandiosity 57%, inappropriate laughter 57%, decreased need for sleep 56%, and flight of ideas 54%. Symptom rates were heterogeneous across samples; potential predictors were explored but no clear patterns were found.

Conclusions

Debate continues about the definitions of pediatric bipolar disorder; the results of this meta‐analysis suggest that there is significant heterogeneity of symptom prevalence between studies, and that symptoms vary widely across individuals. Understanding the roots of this heterogeneity could broaden understanding of the complex clinical presentation of pediatric mania, and aid in diagnosis.
Effect of lie labelling on children's evaluation of selfish, polite, and altruistic lies
Authors: Cheung Him , Chan Yawen , Tsui Wan Chi Gigi
Published: January 2016

This study investigates how 5‐ and 6‐year‐olds' evaluations of selfish, polite, and altruistic lies change as a result of whether these false statements are explicitly labelled as lies. We are also interested in how interpretive theory of mind may correlate with such evaluations with and without a lie label. Our results showed that labelling lowered children's evaluations for the polite and altruistic lies, but not for the selfish lies. Interpretive theory of mind correlated positively with the evaluation difference between the polite and altruistic lies and that between the selfish and altruistic lies in the label, but not in the non‐label condition. Correlation between the selfish and altruistic lies and that between the polite and altruistic lies were stronger with than without labelling, after controlling for age, and verbal and non‐verbal intelligence. We conclude that lie labelling biases children towards more negative evaluations for non‐selfish lies and makes them see lies of different motives as more similar. If a lie label is applied, whether lies of different motives are still evaluated differently depends on interpretive theory of mind, which reflects the child's ability to represent and allow different interpretations of an ambiguous reality.
Altered Expression of Growth Associated Protein‐43 and Rho Kinase in Human Patients with Parkinson's Disease
Authors: Saal Kim‐Ann , Galter Dagmar , Roeber Sigrun , Bähr Mathias , Tönges Lars , Lingor Paul
Published: January 2016

Causative treatment strategies for Parkinson's disease (PD) will have to address multiple underlying pathomechanisms to attenuate neurodegeneration. Additionally, the intrinsic regenerative capacity of the central nervous system is also an important factor contributing to restoration. Extracellular cues can limit sprouting and regrowth of adult neurons, but even aged neurons have a low intrinsic regeneration capacity. Whether this capacity has been lost or if growth inhibitory cues are increased during PD progression has not been resolved yet. In this study, we assessed the regenerative potential in the nigrostriatal system in post‐mortem brain sections of PD patients compared to age‐matched and young controls. Investigation of the expression pattern of the regeneration‐associated protein GAP‐43 suggested a lower regenerative capacity in nigral dopaminergic neurons of PD patients. Furthermore, the increase in protein expression of the growth‐inhibitory protein ROCK2 in astrocytes and a similar trend in microglia, suggests an important role for ROCK2 in glial PD pathology, which is initiated already in normal aging. Considering the role of astro‐ and microglia in PD pathogenesis as well as beneficial effects of ROCK inhibition on neuronal survival and regeneration in neurodegenerative disease models, our data strengthens the importance of the ROCK pathway as a therapeutic target in PD.
Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Frontal Lobe Epilepsy: A New Clinico‐Pathological Entity
Authors: Schurr Johannes , Coras Roland , Rössler Karl , Pieper Tom , Kudernatsch Manfred , Holthausen Hans , Winkler Peter , Woermann Friedrich , Bien Christian G. , Polster Tilman , Schulz Reinhard , Kalbhenn Thilo , Urbach Horst , Becker Albert , Grunwald Thomas , Huppertz Hans‐Juergen , Gil‐Nagel Antonio , Toledano Rafael , Feucht Martha , Mühlebner Angelika , Czech Thomas , Blümcke Ingmar
Published: January 2016

The histopathological spectrum of human epileptogenic brain lesions is widespread including common and rare variants of cortical malformations. However, 2–26% of epilepsy surgery specimens are histopathologically classified as nonlesional. We hypothesized that these specimens include also new diagnostic entities, in particular when presurgical magnetic resonance imaging (MRI) can identify abnormal signal intensities within the anatomical region of seizure onset. In our series of 1381 en bloc resected epilepsy surgery brain specimens, 52 cases could not be histopathologically classified and were considered nonlesional (3.7%). An increase of Olig2‐, and PDGFR‐alpha‐immunoreactive oligodendroglia was observed in white matter and deep cortical layers in 22 of these patients (42%). Increased proliferation activity as well as heterotopic neurons in white matter were additional histopathological hallmarks. All patients suffered from frontal lobe epilepsy (FLE) with a median age of epilepsy onset at 4 years and 16 years at epilepsy surgery. Presurgical MRI suggested focal cortical dysplasia (FCD) in all patients. We suggest to classify this characteristic histopathology pattern as “mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE).” Further insights into pathomechanisms of MOGHE may help to bridge the diagnostic gap in children and young adults with difficult‐to‐treat FLE.
Association of Ant Predators and Edaphic Conditions with Termite Diversity in an Amazonian Rain Forest
Authors: Dambros Cristian S. , Morais José W. , Vasconcellos Alexandre , Souza Jorge L. P. , Franklin Elizabeth , Gotelli Nicholas J.
Published: January 2016

Predation is a key determinant of prey community structure, but few studies have measured the effect of multiple predators on a highly diverse prey community. In this study, we asked whether the abundance, species richness, and species composition of a species‐rich assemblage of termites in an Amazonian rain forest is more strongly associated with the density of predatory ants or with measures of vegetation, and soil texture and chemistry. We sampled termite assemblages with standardized hand‐collecting in 30 transects arranged in a 5 km × 6 km grid in aterra firmeAmazonian rain forest. For each transect, we also measured vegetation structure, soil texture, and soil phosphorus, and estimated the density of predatory ants from baits, pitfall traps, and Winkler samples. Seventy‐nine termite species were recorded, and the total density of predatory ants was the strongest single predictor of local termite abundance (r = −0.66) and termite species richness (r = −0.44). In contrast, termite abundance and species richness were not strongly correlated with edaphic conditions (¦r¦ < 0.01), or with the density of non‐predatory ants (rabund = −0.27;rs = −0.06). Termite species composition was correlated with soil phosphorus content (r = 0.79), clay content (r = −0.75), and tree density (r = −0.42). Assemblage patterns were consistent with the hypothesis that ants collectively behaved as generalist predators, reducing total termite abundance, and species richness. There was no evidence that ants behaved as keystone predators, or that any single termite species benefited from the reduction in the abundance of potential competitors.
Nature, cities, people: An exploration of Aboriginal perspectives
Authors: Smith Jenna , Smith Derek , Sioui Miguel
Published: January 2016

Key Messages

A large body of scholarship focuses on relationships between Aboriginal peoples and the natural environment, but almost no research explores the importance of nature for Aboriginal people living in cities.

Interviews with Aboriginal people in Ottawa reveal that nature plays an important role in their lives, that their relationship with nature is conceived of as reciprocal, and that this relationship is practiced in a variety of specific ways.

While the city in general is seen as an artificial, human‐created environment, there are certain ways of experiencing nature directly in the urban setting.
Feasibility study of chemoradiotherapy followed by amrubicin and cisplatin for limited‐disease small cell lung cancer
Authors: Sekine Ikuo , Sumi Minako , Satouchi Miyako , Tsujino Kayoko , Nishio Makoto , Kozuka Takuyo , Niho Seiji , Nihei Keiji , Yamamoto Nobuyuki , Harada Hideyuki , Ishikura Satoshi , Tamura Tomohide
Published: January 2016

To evaluate the feasibility of amrubicin plus cisplatin (AP) following chemoradiotherapy for limited‐disease small‐cell lung cancer, chemo‐naïve patients aged 20–70 years with a performance status of 0 or 1 and normal organ functions were treated with etoposide 100 mg/m2 on days 1–3, cisplatin 80 mg/m2 on day 1 and concurrent thoracic radiotherapy at 45 Gy/30 fractions (EP‐TRT), followed by three cycles of amrubicin 40 mg/m2 on days 1–3 and cisplatin 60 mg/m2 on day 1 every 3 weeks. The EP‐TRT could be completed in 21 patients (15 male and 6 female patients with a median age of 62 years). Of these, 2, 1 and 18 (86%) patients received one, two and three cycles of AP, respectively. Sixteen (76%) patients required granulocyte‐colony stimulating factor (G‐CSF) support. Grade 3/4 neutropenia occurred in all patients. Grade 3 febrile neutropenia was observed in 9 patients, lasting for 1 day in 5 patients. The incidences of grade 3/4 thrombocytopenia and anemia were 43 and 24%, respectively. Grade 3 infection and anorexia occurred in 2 and 3 patients, respectively. The response rate was 95%. The median (95% confidence interval [CI]) progression‐free survival (PFS) was 41.9 (0–102) months, and the 5‐year PFS rate (CI) was 41.9% (20.4–63.4%). The median overall survival (OS) has not been reached yet, and the 5‐year OS rate (CI) was 57.8% (35.2–80.4%). In conclusion, EP‐TRT followed by AP therapy was well‐tolerated, although a large number of patients required G‐CSF support.
Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma
Authors: Saito Yuichi , Nagae Genta , Motoi Noriko , Miyauchi Eisaku , Ninomiya Hironori , Uehara Hirofumi , Mun Mingyon , Okumura Sakae , Ohyanagi Fumiyoshi , Nishio Makoto , Satoh Yukitoshi , Aburatani Hiroyuki , Ishikawa Yuichi
Published: January 2016

Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome‐wide methylation profile of SCLC. We investigated the genome‐wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non‐negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non‐CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis‐related chemotherapeutic agents for treatment of the aggressive tumor.
RAP80 regulates epithelial–mesenchymal transition related with metastasis and malignancy of cancer
Authors: Park Song Yi , Korm Sovannarith , Chung Hee Jin , Choi Su jin , Jang Jin‐Ju , Cho Sunhee , Lim Yong Taik , Kim Hongtae , Lee Joo‐Yong
Published: January 2016

Epithelial–mesenchymal transition (EMT) has been closely related with invasive and metastatic properties of cancer. Recently, the convergence of DNA damage response and EMT in cancer development has received a great amount of scientific attention. Here, we showed that EMT is induced by the downregulation of RAP80, a well‐known regulator for DNA damage response. The knockdown of RAP80 leads to EMT‐like morphological changes and the increase of tumor sphere formation in non‐adhesive culture. Mechanistically, RAP80 controls a reciprocal regulatory axis of ZEB1 (for EMT activation) and miR200c (for EMT inhibition). The downregulation of RAP80 increases ZEB1 protein and decreases miR200c expression to activate EMT signaling in the form of drastic inhibitions of E‐cadherin, p16 and p21 expression. Using in vivo metastasis analysis, RAP80 knockdown cells are shown to dramatically metastasize into the lung and generate more malignant phenotype compared to controls. Interestingly, the expression level of RAP80 was positively correlated with the survival rate in lung adenocarcinoma and breast cancer patients. These findings indicate that RAP80 is a critical gatekeeper in impeding EMT‐induced metastasis and malignant phenotypes of cancer as well as preserving DNA integrity.
Specific transport of 3‐fluoro‐l‐α‐methyl‐tyrosine by LAT1 explains its specificity to malignant tumors in imaging
Authors: Wei Ling , Tominaga Hideyuki , Ohgaki Ryuichi , Wiriyasermkul Pattama , Hagiwara Kohei , Okuda Suguru , Kaira Kyoichi , Oriuchi Noboru , Nagamori Shushi , Kanai Yoshikatsu
Published: January 2016

3‐18F‐l‐α‐methyl‐tyrosine ([18F]FAMT), a PET probe for tumor imaging, has advantages of high cancer‐specificity and lower physiologic background. FAMT‐PET has been proved useful in clinical studies for the prediction of prognosis, the assessment of therapy response and the differentiation of malignant tumors from inflammation and benign lesions. The tumor uptake of [18F]FAMT in PET is strongly correlated with the expression of L‐type amino acid transporter 1 (LAT1), an isoform of system L upregulated in cancers. In this study, to assess the transporter‐mediated mechanisms in FAMT uptake by tumors, we examined amino acid transporters for FAMT transport. We synthesized [14C]FAMT and measured its transport by human amino acid transporters expressed in Xenopus oocytes. The transport of FAMT was compared with that of l‐methionine, a well‐studied amino acid PET probe. The significance of LAT1 in FAMT uptake by tumor cells was confirmed by siRNA knockdown. Among amino acid transporters, [14C]FAMT was specifically transported by LAT1, whereas l‐[14C]methionine was taken up by most of the transporters. Km of LAT1‐mediated [14C]FAMT transport was 72.7 μM, similar to that for endogenous substrates. Knockdown of LAT1 resulted in the marked reduction of [14C]FAMT transport in HeLa S3 cells, confirming the contribution of LAT1 in FAMT uptake by tumor cells. FAMT is highly specific to cancer‐type amino acid transporter LAT1, which explains the cancer‐specific accumulation of [18F]FAMT in PET. This, vice versa, further supports the cancer‐specific expression of LAT1. This study has established FAMT as a LAT1‐specific molecular probe to monitor the expression of a potential tumor biomarker LAT1.
Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor‐β signaling
Authors: Tian Yao , Yu Yue , Hou Li‐Kun , Chi Jiang‐Rui , Mao Jie‐Fei , Xia Li , Wang Xin , Wang Ping , Cao Xu‐Chen
Published: January 2016

Serum deprivation response (SDPR), a key substrate for protein kinase C, play a critical role in inducing membrane curvature and participate in the formation of caveolae. However, the function of SDPR in cancer development and progression is still not clear. Here, we found that SDPR is downregulated in human breast cancer. Overexpression of SDPR suppresses cell proliferation and invasion in MDA‐MB‐231 cells, while depletion of SDPR promotes cell proliferation and invasion in MCF10A cells. Subsequently, SDPR depletion induces epithelial–mesenchymal transition (EMT)‐like phenotype. Finally, knockdown of SDPR activates transforming growth factor‐β (TGF‐β) signaling by upregulation of TGF‐β1 expression. In conclusion, our results showed that SDPR inhibits breast cancer progression by blocking TGF‐β signaling.

Serum deprivation response suppresses cell proliferation and invasion in breast cancer cells. SDPR depletion induces epithelial–mesenchymal transition by activation of TGF‐β signaling.
Antibody‐dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells
Authors: Mise Naoko , Takami Mariko , Suzuki Akane , Kamata Toshiko , Harada Kazuaki , Hishiki Tomoro , Saito Takeshi , Terui Keita , Mitsunaga Tetsuya , Nakata Mitsuyuki , Ikeuchi Takayuki , Nakayama Toshinori , Yoshida Hideo , Motohashi Shinichiro
Published: January 2016

Anti‐ganglioside GD2 antibodies mainly work through antibody‐dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high‐risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti‐GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti‐tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti‐GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co‐cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti‐GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK‐NKT cell contact or NK cell‐dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell‐based immunotherapy could be an appropriate candidate for anti‐GD2 antibody therapy for neuroblastoma.
Rapid weight gain during early childhood is associated with overweight in preadolescence: a longitudinal study in Japan
Authors: Nanri H. , Shirasawa T. , Ochiai H. , Ohtsu T. , Hoshino H. , Kokaze A.
Published: January 2016

Background

The objective of this study was to examine the relationship between rapid weight gain during early childhood and overweight in preadolescence by sex.

Method

Study subjects were 676 boys and 620 girls in fourth grade (aged 9 or 10 years) from elementary schools in Ina‐town, Japan, during 2010–2012. Height and weight of subjects at birth, age 1.5 and 3 years, were collected from the Maternal and Child Health Handbook, while values at 9–10 years were measured. Rapid weight gain was defined as a change in weight‐for‐age standard deviation score greater than 0.67 from birth to age 1.5 years (0–1.5 years) or from age 1.5 to 3 years (1.5–3 years).

Results

After adjustment for confounding factors, compared with no rapid weight gain, rapid weight gain during 0–1.5 years and 1.5–3 years or rapid weight gain during 1.5–3 years but not during 0–1.5 years significantly increased the odds ratio (OR) for overweight at age 9–10 years in boys (OR, 6.21; 95% confidence interval [CI], 2.84–13.58 and OR, 3.31; 95% CI, 1.67–6.54, respectively) and girls (OR, 7.55; 95% CI, 2.99–19.07 and OR, 3.42; 95% CI, 1.38–8.49, respectively).

Conclusion

The present study suggests that rapid weight gain during early childhood was associated with being overweight in preadolescence, regardless of sex.
The Development of Body Structure Knowledge in Infancy
Authors: Bhatt Ramesh S. , Hock Alyson , White Hannah , Jubran Rachel , Galati Ashley
Published: January 2016

Although we know much about the development of face processing, we know considerably less about the development of body knowledge—despite bodies also being significant sources of social information. One set of studies indicated that body structure knowledge is poor during the 1st year of life and spawned a model that posits that, unlike the development of face knowledge, which benefits from innate propensities and dedicated learning mechanisms, the development of body knowledge relies on general learning mechanisms and develops slowly. In this article, we review studies on infants' knowledge about the structure of bodies and their processing of gender and emotion that paint a different picture. Although questions remain, a general social cognition system likely engenders similar trajectories of development of knowledge about faces and bodies, and may equip developing infants with the capacity to obtain socially critical information from many sources.
IL‐33 is related to innate immune activation and sensitization to HDM in mild steroid‐free asthma
Authors: Porsbjerg C. , Baines K. , Gibson P. , Bergqvist A. , Erjefält J. S. , Sverrild A. , Backer V.
Published: January 2016

Background

IL‐33 represents a potential link between the airway epithelium and induction of a Th2‐type inflammatory response in asthma. However, the association with markers of eosinophilic airway inflammation has not previously been reported in patients with steroid‐free asthma.

Aim

To describe the relationship between airway IL‐33 and markers of eosinophilic airway inflammation, as well potential triggers of IL‐33, in mild, steroid‐free asthma.

Methods

IL‐33 mRNA expression and IL‐33 immunoreactivity were measured in bronchial biopsies from patients with asthma untreated with inhaled steroids and healthy individuals. Furthermore, fractional exhaled nitric oxide (FeNO) and eosinophils in sputum and BAL were measured, as well as airway hyperresponsiveness to mannitol and methacholine. Epithelial integrity was assessed by computerized image analysis on haematoxylin‐stained sections, and TLR mRNA expression by PCR.

Results

A total of 23 patients with asthma and 10 healthy individuals were examined (age: 24 years (20–40); females: 53%). The level of IL‐33 mRNA expression was significantly higher in patients with asthma compared to healthy individuals (Median (IQR) 1.12 (0.78) vs. 0.86, P = 0.04). There was a positive correlation between IL‐33 mRNA expression and the level of FeNO (r = 0.56, P = 0.01), whereas there was no association with airway or blood eosinophils. IL‐33 expression was unrelated to loss of epithelial integrity, but correlated with an increased expression of TLR2 and TLR4 (TLR2: r = 0.47, P = 0.04; TLR4: 0.68, P < 0.001), as well allergy to house dust mites (HDMs).

Conclusion

In mild untreated asthma, the expression of IL‐33 mRNA in bronchial mucosa is related to innate immune activation and allergic sensitization to HDM, rather than epithelial damage, and correlates with FeNO. These findings suggest that in mild allergic asthma, IL‐33 may represent a link between innate immune activation and FeNO production.
Helicobacter pylori infection in patients with selective immunoglobulin a deficiency
Authors: Magen E , Waitman D-A , Goldstein N , Schlesinger M , Dickstein Y , Kahan N R
Published: January 2016

Selective immunoglobulin A (IgA) deficiency (IgAD) is the most common primary immunodeficiency in the western world. The aim of the study was to investigate the prevalence and clinical characteristics of Helicobacter pylori-infected dyspeptic patients with IgAD. Case samples were drawn from all subjects ≥ 12 years of age (n = 104729) who had undergone serum total IgA measurements during 2004–14 for any reason at Leumit Healthcare Services (Israel) and had serum total IgA < 0·07 g/l. The control group was comprised of a random sample of remaining patients with a case–control ratio of 10 controls for each case. The dyspeptic diseases were identified and retrieved from Leumit Health Care Services electronic database using specific ICD-9-CM diagnostic codes. The case group included 347 subjects and the control group 3470 subjects. There were no significant differences in the prevalence of patients with dyspepsia [84 (24·2%) versus 821 (23·6%) for cases and controls, respectively]. Additionally, there was no difference in a proportion of dyspeptic H. pylori-positive subjects [59 (17·1%) versus 524 (15·1%)] between the case and control groups. Only 59 (17%) among the 347 IgAD patients underwent gastroscopy. A significantly larger proportion of case subjects experienced several forms of gastritis [13 (61·9%) versus 38 (21·6%), P < 0·001), duodenal ulcers [seven (33·3%) versus 19 (10·8%); P = 0·01] and nodular lymphoid hyperplasia (NLH) [two (9·5%) versus none; P = 0·011]. IgAD is not associated with increased prevalence of H. pylori-associated dyspepsia; nevertheless, H. pylori-infected dyspeptic IgAD subjects experience more EGD-proved gastritis, duodenal ulcers and NLH.
Pneumolysin activates neutrophil extracellular trap formation
Authors: Nel J G , Theron A J , Durandt C , Tintinger G R , Pool R , Mitchell T J , Feldman C , Anderson R
Published: January 2016

The primary objective of the current study was to investigate the potential of the pneumococcal toxin, pneumolysin (Ply), to activate neutrophil extracellular trap (NET) formation in vitro. Isolated human blood neutrophils were exposed to recombinant Ply (5-20 ng ml−1) for 30–90 min at 37°C and NET formation measured using the following procedures to detect extracellular DNA: (i) flow cytometry using Vybrant® DyeCycle™ Ruby; (ii) spectrofluorimetry using the fluorophore, Sytox® Orange (5 μM); and (iii) NanoDrop® technology. These procedures were complemented by fluorescence microscopy using 4′, 6-diamino-2-phenylindole (DAPI) (nuclear stain) in combination with anti-citrullinated histone monoclonal antibodies to visualize nets. Exposure of neutrophils to Ply resulted in relatively rapid (detected within 30–60 min), statistically significant (P < 0·05) dose- and time-related increases in the release of cellular DNA impregnated with both citrullinated histone and myeloperoxidase. Microscopy revealed that NETosis appeared to be restricted to a subpopulation of neutrophils, the numbers of NET-forming cells in the control and Ply-treated systems (10 and 20 ng ml−1) were 4·3 (4·2), 14.3 (9·9) and 16·5 (7·5), respectively (n = 4, P < 0·0001 for comparison of the control with both Ply-treated systems). Ply-induced NETosis occurred in the setting of retention of cell viability, and apparent lack of involvement of reactive oxygen species and Toll-like receptor 4. In conclusion, Ply induces vital NETosis in human neutrophils, a process which may either contribute to host defence or worsen disease severity, depending on the intensity of the inflammatory response during pneumococcal infection.
Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy
Authors: Bahia El Idrissi N , Hakobyan S , Ramaglia V , Geluk A , Morgan B Paul , Das P Kumar , Baas F
Published: January 2016

Mycobacterium leprae infection gives rise to the immunologically and histopathologically classified spectrum of leprosy. At present, several tools for the stratification of patients are based on acquired immunity markers. However, the role of innate immunity, particularly the complement system, is largely unexplored. The present retrospective study was undertaken to explore whether the systemic levels of complement activation components and regulators can stratify leprosy patients, particularly in reference to the reactional state of the disease. Serum samples from two cohorts were analysed. The cohort from Bangladesh included multi-bacillary (MB) patients with (n = 12) or without (n = 46) reaction (R) at intake and endemic controls (n = 20). The cohort from Ethiopia included pauci-bacillary (PB) (n = 7) and MB (n = 23) patients without reaction and MB (n = 15) patients with reaction. The results showed that the activation products terminal complement complex (TCC) (P ≤ 0·01), C4d (P ≤ 0·05) and iC3b (P ≤ 0·05) were specifically elevated in Bangladeshi patients with reaction at intake compared to endemic controls. In addition, levels of the regulator clusterin (P ≤ 0·001 without R; P < 0·05 with R) were also elevated in MB patients, irrespective of a reaction. Similar analysis of the Ethiopian cohort confirmed that, irrespective of a reaction, serum TCC levels were increased significantly in patients with reactions compared to patients without reactions (P ≤ 0·05). Our findings suggests that serum TCC levels may prove to be a valuable tool in diagnosing patients at risk of developing reactions.