bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary processing of CRISPR RNA by the endonuclease Cas6 inStaphylococcus epidermidis
Authors: Wakefield Noelle , Rajan Rakhi , Sontheimer Erik J.
Published: September 2015

In many bacteria and archaea, an adaptive immune system (CRISPR–Cas) provides immunity against foreign genetic elements. This system uses CRISPR RNAs (crRNAs) derived from the CRISPR array, along with CRISPR‐associated (Cas) proteins, to target foreign nucleic acids. In most CRISPR systems, endonucleolytic processing of crRNA precursors (pre‐crRNAs) is essential for the pathway. Here we study the Cas6 endonuclease responsible for crRNA processing in the Type III‐A CRISPR–Cas system fromStaphylococcus epidermidis RP62a, a model for Type III‐A CRISPR–Cas systems, and define substrate requirements for SeCas6 activity. We find that SeCas6 is necessary and sufficient for full‐length crRNA biogenesis in vitro, and that it relies on both sequence and stem‐loop structure in the 3′ half of the CRISPR repeat for recognition and processing.
Flocculation inSaccharomyces cerevisiae is regulated by RNA/DNA helicase Sen1p
Authors: Singh Vikash , Azad Gajendra Kumar , Sariki Santhosh Kumar , Tomar Raghuvir S.
Published: September 2015

The Nrd1–Nab3–Sen1 (NNS) complex terminates transcription of non‐coding RNA genes and mediates degradation of the produced transcript by the nuclear exosome. The NNS complex also represses some stress response genes, by stimulating premature termination. A well‐characterized stress response in yeast is flocculation, where cells aggregate to form flocs under expression of lectin‐encoding genes designated as FLOs. In this study, we demonstrated the role of the NNS complex and Rrp6p in the expression of flocculation genes:FLO1,FLO5,FLO9, andFLO10. Furthermore, a deletion mutant of the RNA processing machinery (RNT1), andSEN1 mutants that are unable to interact with Rnt1p, exhibit a flocculation phenotype. In summary, we have identified a cooperative role of Rnt1p, Rrp6p and the NNS complex in the repression ofFLO genes.
Performance and complications of lumbar puncture in memory clinics: Results of the multicenter lumbar puncture feasibility study
Authors: Duits Flora H. , Martinez‐Lage Pablo , Paquet Claire , Engelborghs Sebastiaan , Lleó Alberto , Hausner Lucrezia , Molinuevo José L. , Stomrud Erik , Farotti Lucia , Ramakers Inez H.G.B. , Tsolaki Magda , Skarsgård Constance , Åstrand Ragnar , Wallin Anders , Vyhnalek Martin , Holmber‐Clausen Marie , Forlenza Orestes V. , Ghezzi Laura , Ingelsson Martin , Hoff Erik I. , Roks Gerwin , de Mendonça Alexandre , Papma Janne M. , Izagirre Andrea , Taga Mariko , Struyfs Hanne , Alcolea Daniel A. , Frölich Lutz , Balasa Mircea , Minthon Lennart , Twisk Jos W.R. , Persson Staffan , Zetterberg Henrik , van der Flier Wiesje M. , Teunissen Charlotte E. , Scheltens Philip , Blennow Kaj
Published: September 2015

Introduction

Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient‐acceptance of LP, incidence of and risk factors for post‐LP complications in memory clinic populations.

Methods

We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post‐LP complications, such as typical postlumbar puncture headache (PLPH) and back pain.

Results

A total of 1065 patients (31%) reported post‐LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect.

Discussions

The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
Acanthopanax trifoliatus inhibits lipopolysaccharide‐induced inflammatory response in vitro and in vivo
Authors: Chien Tzu‐Mei , Hsieh Po‐Chow , Huang Shyh‐Shyun , Deng Jeng‐Shyan , Ho Yu‐Ling , Chang Yuan‐Shiun , Huang Guan‐Jhong
Published: September 2015

Acanthopanax trifoliatus is a well‐known herb that is used for the treatment of bruising, neuralgia, impotence, and gout in Taiwan. This herb exhibits multifunctional activities, including anticancer, anti‐inflammation, and antioxidant effects. This paper investigated the in vitro and in vivo anti‐inflammatory effect of A. trifoliatus. High‐performance liquid chromatography analysis established the fingerprint chromatogram of the ethyl acetate fraction of A. trifoliatus (EAAT). The anti‐inflammatory effect of EAAT was detected using lipopolysaccharide (LPS) stimulation of the mouse macrophage cell line RAW264.7 in vitro and LPS‐induced lung injury in vivo. The effects of EAAT on LPS‐induced production of inflammatory mediators in RAW264.7 murine macrophages and the mouse model were measured using enzyme‐linked immunosorbent assay and Western blot. EAAT attenuated the production of LPS‐induced nitric oxide (NO), tumor necrosis factor‐alpha, interleukin‐1β (IL‐1β), and IL‐6 in vitro and in vivo. Pretreatment with EAAT markedly reduced LPS‐induced histological alterations in lung tissues. Furthermore, EAAT significantly reduced the number of total cells and protein concentration levels in the bronchoalveolar lavage fluid. Western blotting test results revealed that EAAT blocked protein expression of inducible NO synthase, cyclooxygenase‐2, phosphorylation of Nuclear factor‐kappa‐B Inhibitor alpha (IκB‐α) protein, and mitogen‐activated protein kinases in LPS‐stimulated RAW264.7 cells as well as LPS‐induced lung injury. This study suggests that A. trifoliatus may be a potential therapeutic candidate for the treatment of inflammatory diseases.
Varner Receives 2015 Sulzman Award for Excellence in Education and Mentoring
Authors:   AGU
Published: September 2015

Ruth Varner will receive the 2015 Sulzman Award for Excellence in Education and Mentoring at the 2015 American Geophysical Union Fall Meeting, to be held 14–18 December in San Francisco, Calif. The award is given for "significant contributions by a mid-career female scientist as a role model and mentor for the next generation of biogeoscientists."
Regulation of the human ether-a-go-go-related gene (hERG) potassium channel by Nedd4 family interacting proteins (Ndfips)
Authors: Kang Yudi , Guo Jun , Yang Tonghua , Li Wentao , Zhang Shetuan
Published: September 2015

The cardiac electrical disorder long QT syndrome (LQTS) pre-disposes affected individuals to ventricular arrhythmias and sudden death. Dysfunction of the human ether-a-go-go-related gene (hERG)-encoded rapidly activating delayed rectifier K+ channel (IKr) is a major cause of LQTS. The expression of hERG channels is controlled by anterograde trafficking of newly synthesized channels to and retrograde degradation of existing channels from the plasma membrane. We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels. In the present study, we demonstrate that Nedd4-2 is directed to specific cellular compartments by the Nedd4 family interacting proteins, Nedd4 family-interacting protein 1 (Ndfip1) and Ndfip2. Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. These findings extend our understanding of hERG channel regulation and provide information which may be useful for the rescue of impaired hERG function in LQTS.
Improving Preschool Educators' Interactive Shared Book Reading: Effects of Coaching in Professional Development
Authors: Rezzonico Stefano , Hipfner-Boucher Kathleen , Milburn Trelani , Weitzman Elaine , Greenberg Janice , Pelletier Janette , Girolametto Luigi
Published: September 2015

Purpose

The objective of this study was to examine the effects of coaching by speech-language pathologists on educators' interactive shared book reading, children's participation in shared reading, and children's language development.

Method

Thirty-two educators and small groups of preschoolers were randomly assigned to experimental and comparison groups. The experimental group (n= 15) received 4 in-service workshops plus 5 individualized coaching sessions. The comparison group received only the 4 workshops. Participants were video-recorded during a shared book reading activity with a small group of children at pretest and posttest. The video recordings were transcribed and coded to yield measures of conversations, educators' questions, and children's responses. The mean length of utterances of the children's responses was also calculated.

Results

There were no significant Time × Group interaction effects for the number and length of shared reading conversations or for the number of participants in these conversations. However, significant Time × Group interactions were observed for the use of educators' experiential reasoning questions, children's experiential reasoning responses, and the mean length of utterances of children's responses.

Conclusion

These results suggest that coaching increases educators' use of inferential questions, enhancing an interactive shared-reading strategy that had a direct impact on the children's quality and complexity of language.
The Visualization of Shaykh Ṣafī al-Dīn Isḥaq Ardabilī: A Unique Illustrated Copy of the Ṣafvat al-Ṣafā at the Aga Khan Museum Collection and Its Illustrations
Authors: Erkmen Aslıhan
Published: September 2015

This paper is a monographic study of the illustrated copy of Ṣafvat al-Ṣafā, the life of Shaykh Ṣafī al-Dīn, by Ismāʿil bin Bazzāz, completed in Shaʿbān 990/September 1582 in Shirāz. It begins by giving information on the original text and its sources; then examines the unique illustrated copy. The features of the illustrated Ṣafvat al-Ṣafā are discussed while each of the fourteen images are explored in terms of the text-image relationship. The themes are also briefly analyzed according to a stylistic and iconographical approach in order to further exhibit the manuscript's uniqueness. The article concludes by emphasizing the significance of this copy at the Aga Khan Museum collection regarding its general condition, the illustration cycle and its records.
An efficient resampling method for calibrating single and gene-based rare variant association analysis in case–control studies
Authors: Lee Seunggeun , Fuchsberger Christian , Kim Sehee , Scott Laura
Published: September 2015

For aggregation tests of genes or regions, the set of included variants often have small total minor allele counts (MACs), and this is particularly true when the most deleterious sets of variants are considered. When MAC is low, commonly used asymptotic tests are not well calibrated for binary phenotypes and can have conservative or anti-conservative results and potential power loss. Empirical $p$-values obtained via resampling methods are computationally costly for highly significant $p$-values and the results can be conservative due to the discrete nature of resampling tests. Based on the observation that only the individuals containing minor alleles contribute to the score statistics, we develop an efficient resampling method for single and multiple variant score-based tests that can adjust for covariates. Our method can improve computational efficiency $>$1000-fold over conventional resampling for low MAC variant sets. We ameliorate the conservativeness of results through the use of mid-$p$-values. Using the estimated minimum achievable $p$-value for each test, we calibrate QQ plots and provide an effective number of tests. In analysis of a case–control study with deep exome sequence, we demonstrate that our methods are both well calibrated and also reduce computation time significantly compared with resampling methods.
The interpretation of traces found on adhesive tapes
Authors: Wieten Remi , De Zoete Jacob , Blankers Bart , Kokshoorn Bas
Published: September 2015

In violent crimes, adhesive tapes such as duct tape are often used by perpetrators e.g. to tie up a victim. In the forensic examination of such tapes many different types of traces can be found, such as finger marks and human biological traces. These traces are first interpreted at source level. However, even when it is certain that a trace was donated by the suspect this does not necessarily mean that he donated the trace while taping the victim, as he could have e.g. used the tape roll from which the pieces came previous to the crime. Therefore, the trace can also be interpreted at activity level. For this, factors such as transfer, persistence and recovery, as well as the position of the trace as it would have been on the original roll have to be taken into consideration. In this study, we have developed a Bayesian network which can aid the forensic practitioner in his interpretation. From a sensitivity analysis, we have concluded that it would be most desirable to set up further studies to determine the most likely positions of DNA on tape rolls if there has only been innocent contact.
When the East meets the West: the future of traditional Chinese medicine in the 21st century
Authors: Qiu Jane
Published: September 2015

Traditional Chinese medicine (TCM) has been practiced in China for thousands of years. In the past decade, there have been intensive debates in China about the nature of this ancient practice and its future development. Some critics argue that TCM theories are inaccurate descriptions of the human body that verge on imagination, and so have no place in modern healthcare systems. Other, however, say that TCM has a lot to offer to Western science and medicine and that emerging analytical tools hold great potentials in bridging the gap between the two worlds with contrasting philosophy and approaches.

In a forum chaired by National Science Review's Executive Associate Editor Mu-ming Poo, five panelists from diverse backgrounds discussed the differences between TCM and Western science and medicine, recent progress in TCM research, and key challenges in modernizing this ancient practice.

Hongxin Cao

Director of Science and Technology Bureau, State Administration of Traditional Chinese Medicine of the People's Republic of China

Aiping Lu

Dean of the School of Chinese Medicine at Hong Kong Baptist University

Yiling Wu

President of Hebei Academy of Integrative Chinese and Western Medicine

Boli Zhang

President of Tianjin University of Traditional Chinese Medicine and President of the Chinese Academy of Traditional Chinese Medicine

Liping Zhao

Professor and former deputy director of the Shanghai Center for System Biology at Shanghai Jiao Tong University

Mu-ming Poo (Chair)

Neuroscientist and Director of Chinese Academy of Sciences’ Institute of Neurosciences in Shanghai
Plate-assisted Lengthening of the Femur and Tibia in Pediatric Patients
Authors: Georgiadis Andrew G. , Rossow Jeffrey K. , Laine Jennifer C. , Iobst Christopher A. , Dahl Mark T.
Published: September 2015

Background

Limb lengthening over a percutaneous plate can be used during pediatric distraction osteogenesis to decrease the time of external fixation.

Methods:

A retrospective, consecutive 2-surgeon experience of pediatric femoral and tibial lengthenings with a plate-assisted lengthening (PAL) technique was performed. The plate was placed at the time of index corticotomy. The primary outcome measures of external fixation index, consolidation index, and complications were assessed for each lengthening.

Results:

From 2005 to 2012, 38 lengthenings (23 femur, 15 tibia) in 30 patients were performed by a PAL technique. All patients experienced successful distraction and consolidation. The average achieved lengthening was 3.80±0.98 cm (range, 2.2 to 6.4) with an average consolidation index of 27 days/cm and a mean external fixation index of 13.1±4.29 days/cm (range, 7.8 to 30). Patients returned to full weight-bearing activity after an average of 98.3±28.5 days. There were an average of 1.08±1.05 total complications and 0.39±0.75 severe complications per lengthening. Complications were encountered most commonly during femoral lengthening, including procurvatum and varus deformity through the regenerate. These deformities were usually corrected by frame adjustment before removal.

Conclusions:

PAL is a safe technique that minimizes time of external fixation, accelerates rehabilitation and weight-bearing, and can be successfully used on the femur or tibia. The most common complications are angular deformities of the regenerate that can be treated with adjustment before or at the time of plate locking.

Level of Evidence:

Level IV—retrospective case series.
Use of the Impella 5.0 Device as a Bridge to Recovery in Adult Fulminant Viral Myocarditis
Authors: Burns Daniel J.P. , Quantz Mackenzie A.
Published: September 2015

We present a case of a 48-year-old female patient successfully bridged to recovery with the Impella 5.0 microaxial pump (Abiomed, Danvers, MA USA) after presenting with cardiogenic shock secondary to acute fulminant viral myocarditis. After 1 week of flu-like symptoms, the patient presented to her community emergency department with chest pain and hypotension. A diagnosis of inferior ST elevation myocardial infarction was made; subsequent angiography demonstrated normal coronary arteries and a left ventricular ejection fraction of 10%. A provisional diagnosis of viral myocarditis was made. As her condition deteriorated further, she underwent insertion of an Impella 5.0 after failure of supportive medical therapy. Myocardial recovery occurred, and the Impella was removed after 1 week. After a prolonged cardiac intensive care unit stay requiring temporary hemodialysis, the patient recovered sufficiently to tolerate device explant, transfer to the recovery ward, and ultimate discharge home. This case report highlights the benefit of mechanical circulatory support in a patient with cardiogenic shock from viral myocarditis as well as some of the complications that can occur in this critically ill subset of patients.
Standard melanoma-associated markers do not identify the MM127 metastatic melanoma cell line
Authors: Haridas Parvathi , McGovern Jacqui A. , Kashyap Ahishek S. , McElwain D.L. Sean , Simpson Matthew
Published: September 2015

Reliable identification of different melanoma cell lines is important for many aspects of melanoma research. Common markers used to identify melanoma cell lines include: S100; HMB-45; and Melan-A. We explore the expression of these three markers in four different melanoma cell lines: WM35; WM793; SK-MEL-28; and MM127. The expression of these markers is examined at both the mRNA and protein level. Our results show that the metastatic cell line, MM127, cannot be detected using any of the commonly used melanoma-associated markers. This implies that it would be very difficult to identify this particular cell line in a heterogeneous sample, and as a result this cell line should be used with care.
Eosinophilic pustular folliculitis associated with hematological disorders: A report of two cases and review of Japanese literature
Authors: Takamura Saori , Teraki Yuichi
Published: September 2015

Eosinophilic pustular folliculitis (EPF) occurs in patients with hematological disorders. However, clinical information about hematological disorder‐associated EPF is scarce. We report two cases of EPF associated with mantle cell lymphoma and reviewed the available published work on Japanese cases. We identified a total of 23 Japanese cases, including the two cases reported here, who had hematological disorder‐associated EPF. Fourteen cases were associated with treatment for hematological malignancies (transplantation‐related EPF) and nine cases were associated with hematological malignancies themselves (hematological malignancy‐related EPF). Although the skin eruption was clinically indistinguishable between the two subtypes, transplantation‐related EPF occurred on the face and trunk of young and middle‐aged men and women, whereas hematological malignancy‐related EPF occurred mostly on the face of older men. Peripheral blood eosinophilia was more frequently observed in transplantation‐related EPF. These observations suggest variations among patients with EPF associated with hematological disorders.
Discussion of “Corporate Political Connections and Tax Aggressiveness”
Authors: Faccio Mara
Published: September 2015

Kim and Zhang (2015) study the relation between corporate political connections and tax aggressiveness. In this discussion, I identify and evaluate three main limitations of their paper: the measurement of political connections, the empirical design, and the possible reasons behind the documented results. I build on these small shortcomings to provide suggestions for further contributions in this area of research.
Review of the role of sentinel node biopsy in cutaneous head and neck melanoma
Authors: Roy Jennifer M. , Whitfield Robert J. , Gill P. Grantley
Published: September 2015

Sentinel node biopsy (SNB) is recommended for selected melanoma patients in many parts of the world. This review examines the evidence surrounding the accuracy and prognostic value of SNB and completion neck dissection in head and neck melanoma. Sentinel nodes were identified in an average of 94.7% of head and neck cases compared with 95.3–100% in all melanoma cases. More false‐negative sentinel nodes were found in head and neck cases. A positive sentinel node was associated with both lower disease‐free survival (53.4 versus 83.2%) and overall survival (40 versus 84%). We conclude that SNB should be offered to all patients with intermediate and high‐risk melanomas in the head and neck area. To date, evidence does not exist to demonstrate the safety of avoiding completion lymph node dissection in sentinel node‐positive patients with head and neck melanoma.
Atopic dermatitis is associated with Caesarean sections in Korean adolescents, but asthma is not
Authors: Yu Mi , Han Kyungdo , Kim Do Hoon , Nam Ga Eun
Published: September 2015

Aim

Studies on the associations between mode of delivery and allergic diseases have produced different results, and research has rarely been conducted in Asian countries such as South Korea. This study assessed the relationship between mode of delivery and atopic dermatitis and asthma in Korean adolescents.

Methods

Data collected from the Korea National Health and Nutrition Examination Survey between 2010 and 2011 were used. We included 1302 adolescents aged from 12 to 18 years, and multivariable logistic regression analysis was performed.

Results

The odds ratio (OR) of having atopic dermatitis in adolescents born by Caesarean section compared with vaginal delivery was 1.50, with a 95% confidence interval (95% CI) of 1.01–2.22, after adjusting for age and sex. The association remained significant after further adjustments for body mass index, breastfeeding and serum 25‐hydroxyvitamin D level (OR = 1.61, 95% CI = 1.05–2.47) and when fat intake was added to those variables (OR = 1.80, 95% CI = 1.14–2.85). However, asthma was not associated with mode of delivery in any of the models.

Conclusions

Atopic dermatitis in adolescents was associated with Caesarean delivery, which is common in South Korea. The findings suggest that the frequency of this practice should be reconsidered and that further research with longitudinal evaluation of relevant mechanisms is needed.
Protective effect of the multitarget compound DPH‐4 on human SSAO/VAP‐1‐expressing hCMEC/D3 cells under oxygen–glucose deprivation conditions: an in vitro experimental model of cerebral ischaemia
Authors: Sun P , Esteban G , Inokuchi T , Marco‐Contelles J , Weksler B B , Romero I A , Couraud P O , Unzeta M , Solé M
Published: September 2015

Background and Purpose

Stroke and Alzheimer's disease (AD) are related pathologies in which the cerebrovascular system is involved. Plasma levels of semicarbazide‐sensitive amine oxidase/vascular adhesion protein 1 (SSAO/VAP‐1, also known as Primary Amine Oxidase ‐PrAO) are increased in both stroke and AD patients and contribute to the vascular damage. During inflammation, its enzymatic activity mediates leukocyte recruitment to the injured tissue, inducing damage in the blood‐brain barrier (BBB) and neuronal tissue. We hypothesized that by altering cerebrovascular function, SSAO/VAP‐1 might play a role in the stroke–AD transition. Therefore, we evaluated the protective effect of the novel multitarget‐directed ligand DPH‐4, initially designed for AD therapy, on the BBB.

Experimental Approach

A human microvascular brain endothelial cell line expressing human SSAO/VAP‐1 was generated, as the expression of SSAO/VAP‐1 is lost in cultured cells. To simulate ischaemic damage, these cells were subjected to oxygen and glucose deprivation (OGD) and re‐oxygenation conditions. The protective role of DPH‐4 was then evaluated in the presence of methylamine, an SSAO substrate, and/or β‐amyloid (Aβ).

Key Results

Under our conditions, DPH‐4 protected brain endothelial cells from OGD and re‐oxygenation‐induced damage, and also decreased SSAO‐dependent leukocyte adhesion. DPH‐4 was also effective at preventing the damage induced by OGD and re‐oxygenation in the presence of Aβ as a model of AD pathology.

Conclusions and Implications

From these results, we concluded that the multitarget compound DPH‐4 might be of therapeutic benefit to delay the onset and/or progression of the neurological pathologies associated with stroke and AD, which appear to be linked.
Novel Inhibitors of Ornithine Decarboxylase of Leishmania Parasite (LdODC): The Parasite Resists LdODC Inhibition by Overexpression of Spermidine Synthase
Authors: Das Mousumi , Singh Shalini , Dubey Vikash Kumar
Published: September 2015

Ornithine decarboxylase (LdODC), a key enzyme in polyamine biosynthesis in Leishmania donovani, catalyzes the conversion of ornithine to putrescine that is finally used for synthesis of spermidine and other polyamines. Inhibition of ornithine decarboxylase is likely to deplete the parasite trypanothione and may result in increased reactive oxygen species (ROS). Sequence as well as structure of LdODC and human ODC shows significant difference; therefore, we have identified novel specific inhibitors of LdODC. These inhibitors are able to inhibit recombinant LdODC and decrease intracellular putrescine concentration showing target specificity. The Ki values of LdODC inhibition do not correlate with IC50 values in Leishmania promastigote possibly due to different stability/pharmacokinetics. These inhibitors, except compound M‐5, have only minor effect on Leishmania promastigotes, and IC50 values are several folds higher as compared to Ki values. In case of compound M‐5, IC50 value is less than Ki value indicating that the compound may have additional targets. Our studies suggest that the parasite resists these LdODC inhibitors by overexpression of spermidine synthase mRNA.
Exposure to a farm environment is associated with T helper 1 and regulatory cytokines at age 4.5 years
Authors: Kääriö H. , Huttunen K. , Karvonen A. M. , Schaub B. , von Mutius E. , Pekkanen J. , Hirvonen M.‐R. , Roponen M.
Published: September 2015

Background

Farm exposure has been shown to protect from childhood asthma and allergic diseases, but underlying immunological mechanisms are not clear yet.

Objective

To explore whether farming lifestyle determines cytokine profile of peripheral blood mononuclear cells (PBMCs) of 4.5‐year‐old children (n = 88) from the Finnish PASTURE birth cohort study.

Methods

We analysed regulatory (IL‐10, IL‐2), T helper 1 (Th1)‐associated (IL‐12, IFN‐γ), inflammatory (IL‐1β, TNF, CXCL8) and Th2‐associated (IL‐13) cytokines in unstimulated PBMCs and after a short‐term (5 h) stimulation with lipopolysaccharide (LPS). Specific farm exposures (stables, hay barn, farm milk) at age 4 years were assessed from questionnaires.

Results

The unstimulated PBMCs of farm children produced more IL‐10 (GMR 1.22, P = 0.032), IL‐12 (GMR 1.24, P = 0.012) and IFN‐γ (GMR 1.24, P = 0.024) than those of non‐farm children. Also, specific farm exposures were associated with higher spontaneous production of cytokines. The number of specific farm exposures tended to be dose dependently associated with higher spontaneous production of IFN‐γ (test for trends, P = 0.013) and lower LPS‐induced production of TNF (test for trends, P = 0.025).

Conclusion and Clinical Relevance

Farming lifestyle seemed to be associated with increased spontaneous production of Th1 and regulatory cytokines. Decreased TNF responses to short‐term LPS stimulation in farm‐exposed children may imply tolerogenic immune mechanisms. These novel findings might contribute to the asthma and allergy protection in farm environment.
High nodal positivity rates even in good clinical responders after chemoradiation of rectal cancer: is organ preservation feasible?
Authors: Vallam K. C. , Engineer R. , Desouza A. , Patil P. , Saklani A.
Published: September 2015

Aim

Local excision (LE) is emerging as a treatment option for rectal cancer responding well to chemoradiation. However, it does not address the mesorectal nodal burden. We aimed to identify the factors influencing nodal positivity and subsequently defined a low‐risk group by including only patients at low risk.

Method

A single‐centre, retrospective database analysis was carried out of patients with radically resected rectal cancer after neoadjuvant chemoradiation.

Results

This study included 524 patients with predominantly low rectal tumours. Nodal positivity among ypT0, T1 and T2 groups was 14.7%, 28% and 30%, respectively. Multivariate analysis with stepwise logistic regression identified the following low‐risk features: age ≥ 40 years, nonsignet ring cell carcinoma (SRCC) histology and pathological complete response (pCR). Sixty‐nine patients fulfilling all three criteria were analysed and the nodal positivity was found to be 10.1%, which implies that, if these patients had been selected for LE, one in 10 would have had positive mesorectal nodes.

Conclusion

Even in patients with low‐risk criteria (pCR, non‐SRCC histology and age ≥ 40 years), the residual positive nodal disease burden is 10%. Whether this high incidence of residual nodal disease translates into a similar risk of locoregional recurrence if an organ‐preservation strategy is adopted is unclear.
Prophylactic levofloxacin in pediatric neutropenic patients during autologous hematopoietic stem cell transplantation
Authors: Hafez Hanafy Ahmed , Yousif Dalia , Abbassi Maggie , Elborai Yasser , Elhaddad Alaa
Published: September 2015

Background

Using fluoroquinolone prophylaxis in pediatric neutropenic patients is a controversial issue due to the concern about emergence of resistant strains in addition to the lack of pediatric studies. This study was performed to assess the effectiveness of levofloxacin prophylaxis in pediatric patients during autologous stem cell transplantation.

Methods

This was an observational study of pediatric patients who underwent autologous stem cell transplantation, comparing patients who received levofloxacin prophylaxis to historical controls.

Results

A total of 96 patients were included (46 patients in the control group and 50 patients received levofloxacin). The median duration till onset of first fever was 11 d in the control group as compared to 15 d in patients who received levofloxacin (p ≤ 0.001). The incidence of infectious complications was higher in patients without levofloxacin (4/46) than those with levofloxacin (1/50). The median duration of empirical antibiotic use was 10 d in the levofloxacin group compared with 14 d in the control group (p < 0.001).

Conclusion

Levofloxacin prophylaxis delayed first spike of fever, decreased the incidence of septic complications, and shortened the duration of empiric antibiotic use, but its impact on emergence of resistant organisms should be closely monitored.
Pathogenesis of osteochondrosis dissecans: How does this translate to management of the clinical case?
Authors: van Weeren P. R. , Olstad K.
Published: September 2015

Osteochondrosis (OC) is the most prevalent developmental orthopaedic disease in the horse. It is a complex disorder because of the interplay of factors that influence the formation of lesions and the ensuing natural healing process, the end result of which determines clinical outcome. The early pathogenetic mechanism ofOChas long remained elusive, but recent research has provided compelling evidence for vascular disturbances leading to areas of ischaemic necrosis in the subarticular growth cartilage as the primary event. The aetiological factors that influence the process of the development of lesions are many and comprise both genetic and environmental factors. The genetic background ofOC(dissecans) is highly complex with quantitative trait loci associated with some form ofOCfound on not fewer than 22 of the 33 chromosomes of the horse, and different manifestations and locations ofOChaving probably different genetic backgrounds. The environmental factors can be divided into nutritional factors and factors influencing the biomechanical loading of joints. Feeding large quantities of easily digestible carbohydrates is a clear risk factor and also the availability of sufficient copper for mares in the last part of pregnancy is important. Factors influencing the biomechanical loading of joints include the exercise regimen of foals, paddock size and roughness of terrain, and conformation. EquineOCis rarely a life‐threatening disease and the prognosis of (surgical) treatment is good to very good. However, the impact on economics of the equine industry and on horse welfare is large. This impact can only be lessened by the judicious management of both horse breeding and horse husbandry. Some of the measures that would alleviate the burden ofOCconflict with (commercial) pressures from the industry and a balance between human‐imposed breeding and performance goals and the interest of the animal itself should be sought.
The E3 ligase Itch knockout mice show hyperproliferation and wound healing alteration
Authors: Giamboi‐Miraglia Alessandro , Cianfarani Francesca , Cattani Caterina , Lena Anna Maria , Serra Valeria , Campione Elena , Terrinoni Alessandro , Zambruno Giovanna , Odorisio Teresa , Di Daniele Nicola , Melino Gerry , Candi Eleonora
Published: September 2015

The HECT‐type E3 ubiquitin ligase Itch is absent in the non‐agouti‐lethal 18H or Itchy mice, which develop a severe immunological disease. Several of the known Itch substrates are relevant for epidermal development and homeostasis, such as p63, Notch, c‐Jun and JunB. By analysing Itchy mice before the onset of immunological alterations, we investigated the contribution of Itch in skin development and wound healing. Itchy newborn mice manifested hyperplastic epidermis, which is not present in adulthood. Itch−/− cultured keratinocytes showed overexpression of proliferating markers and increased capability to proliferate, migrate and to repair a scratch injury in vitro. These data correlated with improved in vivo wound healing in Itchy mice, at late time points of the repair process when Itch is physiologically upregulated. Despite healing acceleration, epidermal remodelling was delayed in the scars of Itch−/− mice, as indicated by enhanced epidermal thickening, keratinocyte proliferation and keratin 6 expression, and retarded keratin 14 polarization to the basal layer. Itch−/− keratinocyte prolonged activation was not associated with increased immune cell persistence in the scars. Our in vitro and in vivo results indicate that Itch plays a role in epidermal homeostasis and remodelling and this feature does not seem to depend on immunological alterations.
Comparison between different D‐Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: analysis of results obtained in the DULCIS study
Authors: Palareti G. , Legnani C. , Cosmi B. , Antonucci E. , Erba N. , Poli D. , Testa S. , Tosetto A. ,   the DULCIS (D‐dimer‐ULtrasonography in Combination Italian Study) Investigators (See Appendix)
Published: September 2015

Introduction

D‐dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE).

Methods

Commercial D‐dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10.

Results

In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age‐adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event.

Conclusion

The results confirm the usefulness of the cutoff levels used in DULCIS.
Developmental Change in Infants' Detection of Visual Faces that Match Auditory Vowels
Authors: Streri Arlette , Coulon Marion , Marie Julien , Yeung H. Henny
Published: September 2015

Infants demonstrate robust audiovisual (AV) perception, detecting, for example, which visual face matches auditory speech in many paradigms. For simple phonetic segments, like vowels, previous work has assumed developmental stability in AV matching. This study shows dramatic differences in matching performance for different vowels across the first year of life: 3‐, 6‐, and 9‐month‐olds were familiarized for 40 sec with a visual face articulating a vowel in synchrony with auditory presentations of that vowel, but crucially, the mouth of the face was occluded. At test, infants were shown two still photos of the same face without occlusion for 1 min in silence. One face had a static articulatory configuration matching the previously heard vowel, while the other face had a static configuration matching a different vowel. Three auditory vowels were used: /a/, /i/, and /u/. Results suggest that AV matching performance varies according to age and to the familiarized vowel. Interestingly, results are not linked to the frequency of vowels in auditory input, but may instead be related to infants' ability to produce the target vowel. A speculative hypothesis is that vowel production in infancy modulates AV vowel matching.
Association of periodontitis with persistent, pro‐atherogenic antibody responses
Authors: Buhlin Kåre , Holmer Jacob , Gustafsson Anders , Hörkkö Sohvi , Pockley Alan Graham , Johansson Anders , Paju Susanna , Klinge Björn , Pussinen Pirkko J.
Published: September 2015

Aim

To study antibody responses associated with molecular mimicry in periodontitis.

Material & Methods

Fifty‐four periodontitis cases (mean age 54.0 years) and 44 controls (53.6 years) were examined, after which cases received periodontal treatment. Established immunoassays were used to analyse levels of antibodies against two pathogens, Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg), heat shock proteins (Hsp), Hsp60, Hsp65, and Hsp70, and epitopes of oxidized low‐density lipoprotein (oxLDL) (CuOx‐LDL and MDA‐LDL) in plasma samples that were collected at baseline and after 3 (n = 48) and 6 (n = 30) months.

Results

When age, sex, smoking habit, and the number of teeth were considered in multivariate logistic regressions, Aa and Pg IgG, Hsp65‐IgA, CuOx‐LDL‐IgG and ‐IgM, and MDA‐LDL‐IgG antibody levels were associated with periodontitis, whereas Hsp60‐IgG2 antibody levels were inversely associated. The Aa antibody levels significantly correlated with the levels of IgA antibodies to Hsp65 and Hsp70, and both OxLDL IgA antibody levels. The levels of antibodies to Pg correlated with IgG antibodies to Hsp60, Hsp70, and both oxLDL antibody epitopes. None of the antibody levels changed significantly after treatment.

Conclusions

Periodontitis is associated with persistently high levels of circulating antibodies that are reactive with pathogen‐ and host‐derived antigens.
Bone reconstruction after surgical treatment of experimental peri‐implantitis defects at a sandblasted/acid‐etched hydroxyapatite‐coated implant: an experimental study in the dog
Authors: Namgoong Hee , Kim Myung duck , Ku Young , Rhyu In‐Chul , Lee Yong Moo , Seol Yang Jo , Gu Hee jin , Susin Cristiano , Wikesjö Ulf ME , Koo Ki‐Tae
Published: September 2015

Objectives

The objective of this study was to evaluate bone formation/osseointegration following surgical treatment of experimental peri‐implantitis at dental implants with different surface characteristics exposed to ligature‐induced breakdown conditions.

Methods

Ten turned (control), 10 sandblasted/acid‐etched (SA), and 10 SA/hydroxyapatite nanocoated (HA) implants were installed into the edentulated posterior mandible in five Beagle dogs and allowed to osseointegrate for 12 weeks. Ligature‐induced breakdown defects were then induced over 23 weeks using stainless steel wire ligatures. The ligatures were removed and soft tissues were allowed to heal for 3 weeks. Next, exposed implant surfaces were decontaminated followed by guided bone regeneration using a collagen membrane and submerged wound healing. The animals were euthanized for histometric analysis at 12 weeks post‐surgery.

Results

The radiographic analysis showed vertical bone loss following ligature‐induced breakdown without statistically significant differences among implant technologies. The histometric analysis showed significantly enhanced bone formation (height) at SA and SA/HA compared with turned implants (p = 0.028) following reconstructive surgery. Bone formation area was greater at SA/HA compared with turned implants, however the difference did not reach statistical significance.

Conclusions

While ligature‐induced defect progression does not appear implant surface dependent in this animal model, bone formation at the decontaminated implant surfaces appears more favourable at SA and SA/HA over turned implants following reconstructive surgery.
Elevational speciation in action? Restricted gene flow associated with adaptive divergence across an altitudinal gradient
Authors: Funk W. C. , Murphy M. A. , Hoke K. L. , Muths E. , Amburgey S. M. , Lemmon E. M. , Lemmon A. R.
Published: September 2015

Evolutionary theory predicts that divergent selection pressures across elevational gradients could cause adaptive divergence and reproductive isolation in the process of ecological speciation. Although there is substantial evidence for adaptive divergence across elevation, there is less evidence that this restricts gene flow. Previous work in the boreal chorus frog (Pseudacris maculata) has demonstrated adaptive divergence in morphological, life history and physiological traits across an elevational gradient from approximately 1500–3000 m in the Colorado Front Range, USA. We tested whether this adaptive divergence is associated with restricted gene flow across elevation – as would be expected if incipient speciation were occurring – and, if so, whether behavioural isolation contributes to reproductive isolation. Our analysis of 12 microsatellite loci in 797 frogs from 53 populations revealed restricted gene flow across elevation, even after controlling for geographic distance and topography. Calls also varied significantly across elevation in dominant frequency, pulse number and pulse duration, which was partly, but not entirely, due to variation in body size and temperature across elevation. However, call variation did not result in strong behavioural isolation: in phonotaxis experiments, low‐elevation females tended to prefer an average low‐elevation call over a high‐elevation call, and vice versa for high‐elevation females, but this trend was not statistically significant. In summary, our results show that adaptive divergence across elevation restricts gene flow in P. maculata, but the mechanisms for this potential incipient speciation remain open.
Why Do We Read On‐Pack Nutrition Information so Differently? A Typology of Reading Heuristics Based on Food Consumption Goals
Authors: Chalamon Isabelle , Nabec Lydiane
Published: September 2015

While prior research has extensively studied nutrition labeling use and consumer errors of judgment in the nutrition evaluation process, less attention has been paid to the consumer motivations that simplify the reading of on‐pack nutrition information. To address this gap, this study examines how food consumption goals affect consumer reading of this information. On the basis of a qualitative study, eight food consumption goals have been identified and classified into four types of motivations which impact reading behaviors: “Food Optimization,” “Food Regulation,” “Food Gratification,” and “Food as Mere Necessity.” From this typology, we derive eight on‐pack nutrition information reading heuristics as well as specific inference biases resulting from these simplifying reading strategies. This research also provides guidelines for policymakers so that nutritional messages given to consumers will be more targeted in order to promote better reading of on‐pack nutrition information at the point of sales.
Ex vivo lymphocyte phenotyping during Plasmodium falciparum sporozoite immunization in humans
Authors: Bijker E. M. , Schats R. , Visser L. G. , Sauerwein R. W. , Scholzen A.
Published: September 2015

Immunization of malaria‐naïve volunteers under chemoprophylaxis with Plasmodium falciparum sporozoites (CPS) efficiently and reproducibly induces sterile protection and thus constitutes an excellent model to study protective immune responses against malaria. Here, we performed the first longitudinal assessment of lymphocyte activation and differentiation kinetics during sporozoite immunization in 15 volunteers by ex vivo lymphocyte flow cytometry analysis. Both CD4 and CD8 T cells as well as γδT cells, NK cells and CD3+ CD56+ cells showed increased activation and proliferation following immunization. Transient induction of the transcription factor T‐bet and the cytotoxic molecule granzyme B indicated a role of Th1 responses and cytotoxic T cells in CPS‐induced immunity. The absolute number of γδT cells as well as the proportion of granzyme B‐containing γδT cells showed a significant and sustained increase. Regulatory T‐cell (Treg) proliferation was significantly higher after the second immunization in subjects subsequently not protected against challenge infection. These findings indicate an important role for γδT cells, Th1 and cytotoxic responses in whole sporozoite immunization with a possibly suppressive role of Tregs.