bluuebunny/crossref_metadata_2025 huggingface dataset:
A Prospective Study of the Causes of Bruises in Premobile Infants
Authors: Feldman Kenneth W. , Tayama Tricia M. , Strickler Leslie E. , Johnson Lee A. , Kolhatkar Gauri , DeRidder Catherine A. , Matthews Dana C. , Sidbury Robert , Taylor James A.
Published: October 2017

Objective

This study had 2 objectives. First, to determine the behavior of physicians evaluating premobile infants with bruises. Second, and most importantly, to learn whether infants with unexplained bruising who had been initially evaluated by primary care and emergency department (ED) physicians are as likely to have their bruises attributed to child abuse as those children evaluated by child abuse physicians.

Methods

Primary care, ED, and child abuse pediatricians (CAPs) in King County, Washington, San Mateo, Calif, Albuquerque, NM, La Crosse, Wis, and Torrance, Calif prospectively identified and studied infants younger than 6 months with less than 6 bruises, which were judged by the evaluating clinician to be explained or unexplained after their initial clinical examination.

Results

Between March 1, 2010, and March 1, 2017, 63 infants with initially explained and 46 infants with initially unexplained bruises were identified. Infants with unexplained bruises had complete coagulation and abuse evaluations less frequently if they were initially identified by primary care pediatricians or ED providers than by CAPs. After imaging, laboratory, and follow-up, 54.2% (26) of the infants with initially unexplained bruises, including 2 who had been initially diagnosed with accidental injuries, were diagnosed as abused. Three (6.2%) infants had accidental bruising, 6 (12.4%) abuse mimics, 1 (2.5%) self-injury, 1 (2.5%) medical injury, and 11 (22.9%) remained of unknown causation. None had causal coagulation disorders. A total of 65.4% of the 26 abused infants had occult injuries detected by their imaging and laboratory evaluations. Six (23.1%) abused infants were not diagnosed until after they sustained subsequent injuries. Three (11.5%) were recognized abused by police investigation alone. Thirty-eight percent of the abused, bruised infants had a single bruise. Clinicians' estimates of abuse likelihood based on their initial clinical evaluation were inaccurate. Primary care, ED, and child abuse physicians identified abused infants at similar rates.

Conclusions

More than half of premobile infants with initially unexplained bruises were found to be abused. Abuse was as likely for infants identified by primary care and ED providers as for those identified by CAPs. Currently, physicians often do not obtain full abuse evaluations in premobile infants with unexplained bruising. Their initial clinical judgment about abuse likelihood was inadequate. Bruised infants often have clinically occult abusive injuries or will sustain subsequent serious abuse. Bruised infants should have full abuse evaluations and referral for Protective Services and police assessments.
Use of Ondansetron for Vomiting After Head Trauma
Authors: Green-Hopkins Israel , Monuteaux Michael C. , Lee Lois K. , Nigrovic Lise E. , Mannix Rebekah , Schutzman Sara A.
Published: October 2017

Objectives

We describe ondansetron use in children with head injury evaluated in pediatric emergency departments and its association with return visits and late diagnoses of intracranial injuries requiring intervention.

Methods

Children ages 6 months to 18 years discharged without neuroimaging from 35 pediatric emergency departments with a diagnosis of head injury from 2009 to 2013 were identified retrospectively from the Pediatric Health Information System. We evaluated the rates of ondansetron use during the study period and of the association of ondansetron treatment with the diagnosis of intracranial injury, skull fracture, and return visits within 72 hours requiring admission or operative intervention.

Results

We identified 218,904 encounters during the study period. Of these, 5894 patients (2.8%) were given ondansetron. There was significant variation in the use of ondansetron during the index visit between hospitals (0.1%–5.7%), and ondansetron use significantly increased over the study period. Return visits within 72 hours were more likely for patients treated with ondansetron during the index visit (3.7% vs 1.9%; adjusted odds ratio, 1.99; 95% confidence interval, 1.7–2.4). These patients were more likely to be admitted than those not treated initially with ondansetron (7% vs 4%; adjusted odds ratio, 1.97; 95% confidence interval, 1.09–3.55). There were no significant differences in rates of skull fractures, intracranial injury, intensive care unit admission, or operative intervention between groups.

Conclusions

Ondansetron use during an initial emergency department visit for head trauma in children not requiring neuroimaging is associated with a higher likelihood of return within 72 hours and subsequent admission. There were no differences in rates of missed skull fractures, intracranial injury, intensive care admission, or operative intervention for groups who were and were not treated with ondansetron; however, this study was underpowered to detect significant differences in these categories. Future investigations with greater numbers would be required to confidently assess these critical differences.
Surgical Treatment of Dentofacial Deformities Caused by Juvenile Idiopathic Arthritis
Authors: Stoor Patricia , Hodzic Zlatan , Arte Sirpa
Published: October 2017

The purpose of our retrospective study was to evaluate the results of orthognathic treatment, distraction osteogenesis, and/or prosthetic reconstruction of the temporomandibular joints in patients with juvenile idiopathic arthritis (JIA).

Twelve patients with severely affected temporomandibular joints (TMJs) and reduced ramus height were treated with mandibular advancement with orthognathic surgery (11) and additional bilateral or unilateral mandibular ramus distraction (3) or additional bilateral or unilateral prosthetic reconstruction of the TMJ (3). One patient was treated surgically with bilateral TMJ prosthetic reconstruction only. The patients were followed up clinically and radiologically with emphasis on healing, TMJ function, stability of the occlusion, skeletal stability, and facial appearance for an average of 2.3 years after the final surgery. The mean mandibular advancement was 10.1 mm. The mean relapse at pogonion was 2.1 mm, which represents 20.8% of the surgical advancement. The occlusion was stable in 11/12 patients. The TMJ function was good and the facial esthetics improved in all patients. Orthognathic treatment and mandibular ramus distraction osteogenesis provide beneficial lengthening of the mandibular body in JIA patients with asymptomatic and stabile condyles. In adult patients with relapse of the disease or postoperative condylar relapse prosthetic total joint replacement is a reliable and safe alternative.
Long-Term Effects of Bone Morphogenetic Protein-2–Loaded Calcium Phosphate on Maxillary Sinus Lift Surgery for Delayed and Simultaneous Dental Implantation
Authors: Ding Yuefeng , Wang Xuejuan
Published: October 2017

Maxillary sinus lift surgery (MSLS) is considered to be a useful treatment method for patients with atrophic alveolar bone. Choosing a suitable surgical procedure to simultaneously decrease graft absorption and obtain long-term survival of dental implants is still a challenge. In this study, 20 patients received MSLS with graft of bone morphogenetic protein 2 (BMP2)-loaded calcium phosphate. Dental implants were placed simultaneously in 10 patients receiving MSLS (1-stage group), and in 10 patients receiving dental implants with a 3 to 6 months delay (2-stage group). The effects were evaluated based on clinical and radiographic examination during a 4 to 5 years follow-up. The results showed that only 1 perforation of the maxillary sinus mucosa was observed in 1-stage group, and was patched with a collagen membrane. An average bone gain of 6.8 mm was observed, and all implants exhibited no looseness, peri-implantitis, or fracture, all of which were stable during the follow-up and exhibited nice dental function during a 4 to 5 years follow-up. The loss of peri-implant bone height was 1.12 ± 0.47 and 1.10 ± 0.39 mm, the probing depth of periodontal pocket was 1.79 ± 0.62 and 1.81 ± 0.71 mm, the sulcular bleeding index was 1.63 ± 0.47 and 1.72 ± 0.54 in 1-stage group and 2-stage group, respectively, and no significant differences existed between these 2 groups. These findings implied that BMP2-loaded calcium phosphate may be a suitable material for MSLS, especially for patients with minimal bone height. Clinicians can use the 1- or 2-stage technique based on clinical condition, patients’ choice and clinicians’ experience. In patients where implants cannot be stabilized for patients with minimal bone height, 2-stage surgery may be more suitable.
Clinical Evaluation of Standardized Fronto-Orbital Advancement for Correction of Isolated Trigonocephaly
Authors: Safi Ali-Farid , Kreppel Matthias , Grandoch Andrea , Kauke Martin , Nickenig Hans-Joachim , Zöller Joachim
Published: October 2017

Corrective surgery of trigonocephaly is a major challenge, owing to the complex development of the craniofacial skull. Although reports on the clinical success of standardized fronto-orbital advancement have been promising, there is a lack of studies, assessing this method. Hence, the aim of our study was to evaluate the clinical outcome of a standardized fronto-orbital advancement procedure for correction of isolated nonsyndromic trigonocephaly, in our patient cohort. The retrospective study included 30 patients from 2008 to 2015. Inclusion criteria were treatment-naive children with isolated nonsyndromic trigonocephaly, being treated with standardized frontoorbital advancement in our department. We considered postoperative complications and the Whitaker Score to evaluate the success of the clinical outcome. Surgery was performed at a mean age of 9.3 months. The mean operation time was 153 minutes. All patients were assigned I according to the Whitaker score. One patient suffered from a small inconsequential subdural hematoma. Another patient suffered from dural tears, which were identified and treated intraoperatively. No major complications occurred within our patient cohort. The standardized fronto-orbital advancement is a safe and successful method, as it is associated with a high morphological outcome and low complication rate.
Importance of the Complement Alternative Pathway in Serum Chemotactic Activity During Sepsis
Authors: Xu Ganqiong , Feng Yan , Li Dan , Zhou Qichang , Chao Wei , Zou Lin
Published: October 2017

Serum chemotactic activity is important in regulating neutrophil migration. The ability of neutrophils to migrate to infectious site is crucial for host effective pathogen control, but unregulated neutrophil activation can also cause tissue damage. During bacterial sepsis, the complement alternative pathway (AP) is massively activated in blood and tissues and reportedly contributes to sepsis pathogenesis. Complement factor B (FB) is an essential component of the AP activation. However, the impact of FB/AP activation on blood chemotactic activity during bacterial infection is unclear. In this study, we found that sera of septic mice following cecal ligation and puncture (CLP) had much higher chemotactic activities on neutrophils than those of sham animals. Compared with wild-type (WT) mice, FB−/− mice had significantly attenuated serum chemotactic activity, under both nonseptic and septic conditions. Moreover, sera with the activated AP by zymosan and cobra venom factor (CVF) in vitro induced a significant increase in neutrophil migration compared with sera without the AP activation. Complement activation generates complement cleavage fragment such as Ba, C3a, and C5a. To delineate the contribution of these downstream effectors, we incubated AP-active sera (AP activated by zymosan/CVF) or sera from sham and septic mice with anti-C5a or mAb1379 (anti-Ba) neutralizing antibody. We found that anti-C5a, but not mAb1379, markedly attenuated the neutrophil chemotactic effect of the AP-activated sera and that of septic sera. Taking together, these data suggest that the complement AP activation during bacterial sepsis plays a pivotal role in promoting blood chemotactic activity through a C5a-dependent mechanism.
Role of Receptor for Advanced Glycation End Products in Regulating Lung Fluid Balance in Lipopolysaccharide-induced Acute Lung Injury and Infection-Related Acute Respiratory Distress Syndrome
Authors: Wang Hao , Wang Tao , Yuan Zhicheng , Cao Yufang , Zhou Yongfang , He Junyun , Shen Yongchun , Zeng Ni , Dai Luqi , Wen Fuqiang , Chen Lei
Published: October 2017

Receptor for advanced glycation end products (RAGE) is implicated in inflammatory responses in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), but its role in pulmonary edema formation remains unclear, especially in infection-related ARDS mainly caused by pneumonia or sepsis. In this study, we investigated the role of RAGE in alveolar fluid regulation by using RAGE gene knockout (RAGE

−/−
) mice in a murine ALI model induced by lipopolysaccharide (LPS), and by comparing soluble RAGE (sRAGE) levels in serum and bronchial alveolar lavage fluid between ARDS patients and control subjects. We found that RAGE knockout significantly improved alveolar fluid clearance and reduced pulmonary vascular albumin leakage upon LPS challenge. Furthermore, LPS-induced substantial decrease in lung expression of sodium–potassium ATPase (Na,K-ATPase), epithelial sodium channel, and zonula occluden-1 (ZO-1) were fully or partially restored by the deletion of RAGE. In addition to this, LPS-induced lung leukocyte infiltration and inflammatory cytokine and chemokine release were all attenuated in RAGE

−/−
mice as compared to wide-type mice. In infection-related ARDS patients, both serum and bronchial alveolar lavage fluid levels of the sRAGE were much higher than those in control subjects, and they were positively correlated with pulmonary vascular permeability and levels of interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-2. Taken together, we provided the first direct evidence for the essential role of RAGE in regulating lung fluid balance in infection-related ARDS/ALI. The underlying mechanisms may involve the downregulation of both ion-channel and tight junction proteins mediated by RAGE signaling in bacterial endotoxin-induced lung injury.
Spleen-preserving distal pancreatectomy in trauma
Authors: Schellenberg Morgan , Inaba Kenji , Cheng Vincent , Bardes James M. , Lam Lydia , Benjamin Elizabeth , Matsushima Kazuhide , Demetriades Demetrios
Published: October 2017

BACKGROUND

Traumatic injuries to the distal pancreas are infrequent. Universally accepted recommendations about the need for routine splenectomy with distal pancreatectomy do not exist. The aims of this study were to compare outcomes after distal pancreatectomy and splenectomy versus spleen-preserving distal pancreatectomy, and to define the appropriate patient population for splenic preservation.

METHODS

All patients who underwent distal pancreatectomy (January 1, 2007, to December 31, 2014) were identified from the National Trauma Data Bank. Patients with concomitant splenic injury and those who underwent partial splenectomy were excluded. Demographics, clinical data, procedures, and outcomes were collected. Study groups were defined by surgical procedure: distal pancreatectomy and splenectomy versus spleen-preserving distal pancreatectomy. Baseline characteristics between groups were compared with univariate analysis. Multivariate analysis was performed with logistic and linear regression to examine differences in outcomes.

RESULTS

Over the 8-year study period, 2,223 patients underwent distal pancreatectomy. After excluding 1,381 patients with concomitant splenic injury (62%) and 8 (<1%) who underwent partial splenectomy, 834 (38%) remained for analysis. Median age was 23 years (range, 0–86 years) and 634 (77%) were male. Mechanism of injury was penetrating in 413 (50%) patients. Of the 834 patients, 469 (56%) underwent splenectomy and 365 (44%) patients did not. Compared with patients who underwent distal pancreatectomy and splenectomy, those who underwent spleen-preserving distal pancreatectomy were younger (p < 0.001), more likely to have sustained blunt trauma (p < 0.001), and had a lower Injury Severity Score (p < 0.001). On multivariate analysis, only hospital length of stay (LOS) was significantly shorter among patients undergoing spleen-preserving distal pancreatectomy (p = 0.017). Complications, mortality, and intensive care unit LOS were not significantly different.

CONCLUSION

In young patients after blunt trauma who are not severely injured, a spleen-preserving distal pancreatectomy should be considered to allow for conservation of splenic function and a shorter hospital LOS. In all other patients, the surgeon should not hesitate to remove the spleen with the distal pancreas.

LEVEL OF EVIDENCE

Therapy, level IV.
Development of cyanine probes with dinitrobenzene quencher for rapid fluorogenic protein labelling
Authors: Hori Yuichiro , Hirayama Shinya , Kikuchi Kazuya
Published: October 2017

A multicolour protein labelling technique using a protein tag and fluorogenic probes is a powerful approach for spatio-temporal analyses of proteins in living cells. Since cyanine fluorophores have attractive properties for multicolour imaging of proteins, there is a huge demand to develop fluorogenic cyanine probes for specific protein labelling in living cells. Herein, we develop fluorogenic cyanine probes for labelling a protein tag by using a dinitrobenzene fluorescence quencher. The probes enhanced fluorescence intensity upon labelling reactions and emitted orange or far-red fluorescence. Intramolecular interactions between the cyanine fluorophores and the dinitrobenzene quencher led not only to fluorescence quenching of the probes in the free state but also to promotion of labelling reactions. Furthermore, the probes successfully imaged cell-surface proteins without a washing process. These findings offer valuable information on the design of fluorogenic cyanine probes and indicate that the probes are useful as novel live-cell imaging tools.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Biological effects of MRI contrast agents: gadolinium retention, potential mechanisms and a role for phosphorus
Authors: Garcia Joel , Liu Stephen Z. , Louie Angelique Y.
Published: October 2017

No discussion of challenges for chemistry in molecular imaging would be complete without addressing the elephant in the room—which is that the purest of chemical compounds needs to interact with a biological system in a manner that does not perturb normal biology while still providing efficacious feedback to assist in diagnosis of disease. In the past decade, magnetic resonance imaging (MRI) agents long considered inert have produced adverse effects in certain patient populations under certain treatment regimens. More recently, inert blood pool agents have been found to deposit in the brain. Release of free metal is often suspected as the culprit but that hypothesis has yet to be validated. In addition, even innocuous agents can cause painful side effects during injection in some patients. In this brief review, we summarize known biological effects for gadolinium- and iron-based MRI contrast agents, and discuss some of the potential mechanisms for the observed biological effects, including the potential role of phosphorus imbalance, related to kidney disease or cancer, in destabilizing gadolinium-based chelates and precipitating free gadolinium.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Spectral unmixing techniques for optoacoustic imaging of tissue pathophysiology
Authors: Tzoumas Stratis , Ntziachristos Vasilis
Published: October 2017

A key feature of optoacoustic imaging is the ability to illuminate tissue at multiple wavelengths and therefore record images with a spectral dimension. While optoacoustic images at single wavelengths reveal morphological features, in analogy to ultrasound imaging or X-ray imaging, spectral imaging concedes sensing of intrinsic chromophores and externally administered agents that can reveal physiological, cellular and subcellular functions. Nevertheless, identification of spectral moieties within images obtained at multiple wavelengths requires spectral unmixing techniques, which present a unique mathematical problem given the three-dimensional nature of the optoacoustic images. Herein we discuss progress with spectral unmixing techniques developed for multispectral optoacoustic tomography. We explain how different techniques are required for accurate sensing of intrinsic tissue chromophores such as oxygenated and deoxygenated haemoglobin versus extrinsically administered photo-absorbing agents and nanoparticles. Finally, we review recent developments that allow accurate quantification of blood oxygen saturation (sO
2
) by transforming and solving the sO
2
estimation problem from the spatial to the spectral domain.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo
Authors: Gilsbach Ralf , Schwaderer Martin , Preissl Sebastian , Grüning Björn A. , Kranzhöfer David , Schneider Pedro , Nührenberg Thomas G. , Mulero-Navarro Sonia , Weichenhan Dieter , Braun Christian , Dreßen Martina , Jacobs Adam R. , Lahm Harald , Doenst Torsten , Backofen Rolf , Krane Markus , Gelb Bruce D. , Hein Lutz
Published: October 2017

Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered. However, reshaping of the epigenome of these terminally differentiated cells during fetal development, postnatal maturation and in disease remains unknown. Thus, the aim of this study was to determine the dynamics of the cardiac myocyte epigenome during development and in chronic heart failure. Prenatal development and postnatal maturation are characterized by a cooperation of active CpG methylation and histone marks at cis-regulatory and genic regions to shape the cardiac myocyte transcriptome. In contrast, pathological gene expression in terminal heart failure is accompanied by changes in active histone marks without major alterations in CpG methylation and repressive chromatin marks. Notably, cis-regulatory regions in cardiac myocytes are significantly enriched for cardiovascular disease-associated variants. This study uncovers distinct layers of epigenetic regulation not only during prenatal development and postnatal maturation but also in diseased human cardiac myocytes.
Genome-Wide Mining, Characterization and Development of miRNA-SSRs inArabidopsis thaliana
Authors: Kumar Anuj , Chauhan Aditi , Sharma Mansi , Kompelli Sai Kumar , Gahlaut Vijay , Ijaq Johny , Singh Krishna Pal , Prasad Gajula MNV , Suravajhala Prashanth , Singh Balyan Harindra , Gupta Pushpendra Kumar
Published: October 2017

Simple Sequence Repeats (SSRs), also known as microsatellites are short tandem repeats of DNA sequences that are 1-6 bp long. In plants, SSRs serve as a source of important class of molecular markers because of their hypervariabile and co-dominant nature, making them useful both for the genetic studies and marker-assisted breeding. The SSRs are widespread throughout the genome of an organism, so that a large number of SSR datasets are available, most of them from either protein-coding regions or untranslated regions. It is only recently, that their occurrence within microRNAs (miRNA) genes has received attention. As is widely known, miRNA themselves are a class of non-coding RNAs (ncRNAs) with varying length of 19-22 nucleotides (nts), which play an important role in regulating gene expression in plants under different biotic and abiotic stresses. In this communication, we describe the results of a study, where miRNA-SSRs in full length pre-miRNA sequences ofArabidopsis thalianawere mined. The sequences were retrieved by annotations available at EnsemblPlants using BatchPrimer3 server with miRNA-SSR flanking primers found to be well distributed. Our analysis shows that miRNA-SSRs are relatively rare in protein-coding regions but abundant in non-coding region. All the observed 147 di-, tri-, tetra-, penta- and hexanucleotide SSRs were located in non-coding regions of all the 5 chromosomes ofA. thaliana. While we confirm that miRNA-SSRs were commonly spread across the full length pre-miRNAs, we envisage that such studies would allow us to identify newly discovered markers for breeding studies.
T Cell Calcium Dynamics Visualized in a Ratiometric tdTomato-GCaMP6f Transgenic Reporter Mouse
Authors: Dong Tobias X. , Othy Shivashankar , Jairaman Amit , Skupsky Jonathan , Zavala Angel , Parker Ian , Dynes Joseph L. , Cahalan Michael D.
Published: October 2017

Calcium is an essential cellular messenger that regulates numerous functions in living organisms. Here we describe development and characterization of “Salsa6f”, a fusion of GCaMP6f and tdTomato optimized for cell tracking while monitoring cytosolic Ca2+, and a transgenic Ca2+reporter mouse with Salsa6f floxed and targeted to the Rosa26 locus for expression in specific cell types. Using CD4-Cre-Salsa6f mice, we report normal development and function of T cells expressing Salsa6f and demonstrate Ca2+signaling dynamics during T cell receptor engagement in naïve T cells, helper Th17 T cells and regulatory T cells. Salsa6f expression also revealed functional expression of mechanosensitive Piezo1 channels in T cells. Transgenic expression of Salsa6f enables ratiometric imaging of Ca2+signals in complex tissue environments found in vivo. Deep tissue two-photon imaging of T cells in the steady-state lymph node revealed a highly localized Ca2+signaling behavior (“sparkles”) as cells migrate.
Non-invasive detection of bladder cancer through the analysis of driver gene mutations and aneuploidy
Authors: Springer Simeon , Rodriguez Pena Maria Del Carmen , Li Lu , Douville Christopher , Wang Yuxuan , Cohen Josh , Taheri Diana , Afsari Bahman , Silliman Natalie , Schaeffer Joy , Ptak Janine , Dobbyn Lisa , Papoli Maria , Kinde Isaac , Afsari Bahman , Tregnago Aline C. , Bezerra Stephania M. , VandenBussche Christopher , Fujita Kazutoshi , Ertoy Dilek , Cunha Isabela W. , Yu Lijia , Schoenberg Mark , Bivalacqua Trinity J. , Dickman Kathleen G. , Grollman Arthur P. , Diaz Luis A. , Karchin Rachel , Hruban Ralph , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Netto George J.
Published: October 2017

Current non-invasive approaches for bladder cancer (BC) detection are suboptimal. We report the development of non-invasive molecular test for BC using DNA recovered from cells shed into urine. This “UroSEEK” test incorporates assays for mutations in 11 genes and copy number changes on 39 chromosome arms. We first evaluated 570 urine samples from patients at risk for BC (microscopic hematuria or dysuria). UroSEEK was positive in 83% of patients that developed BC, but in only 7% of patients who did not develop BC. Combined with cytology, 95% of patients that developed BC were positive. We then evaluated 322 urine samples from patients soon after their BCs had been surgically resected. UroSEEK detected abnormalities in 66% of the urine samples from these patients, sometimes up to 4 years prior to clinical evidence of residual neoplasia, while cytology was positive in only 25% of such urine samples. The advantages of UroSEEK over cytology were particularly evident in low-grade tumors, wherein cytology detected none while UroSEEK detected 67% of 49 cases. These results establish the foundation for a new, non-invasive approach to the detection of BC in patients at risk for initial or recurrent disease.
Combining CRISPR/Cas9 mutagenesis and a small-molecule inhibitor to probe the function of MELK in cancer
Authors: Giuliano Christopher J. , Lin Ann , Smith Joan C. , Palladino Ann C. , Sheltzer Jason M.
Published: October 2017

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. On the basis of these findings, a MELK inhibitor is currently being tested in several clinical trials. Here, we report that cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK exhibit wild-type growthin vitro, under environmental stress, in the presence of multiple chemotherapy agents, andin vivo. By combining our MELK-knockout clones with a recently-described, highly-specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.
The Phonetics-Phonology Relationship in the Neurobiology of Language
Authors: Grimaldi Mirko
Published: October 2017

In this work, I address the connection of phonetic structure with phonological representations. This classical issue is discussed in the light of recent neurophysiological data which – thanks to direct measurements of temporal and spatial brain activation – provide new avenues to investigate the biological substrate of human language. After describing principal techniques and methods, I critically discuss magnetoencephalographic and electroencephalographic findings of speech processing based on event-related potentials and event-related oscillatory rhythms. The available data do not permit us to clearly disambiguate between neural evidence suggesting pure acoustic patterns and those indicating abstract phonological features. Starting from this evidence, which only at the surface represents a limit, I develop a preliminary proposal where discretization and phonological abstraction are the result of a continuous process that converts spectro-temporal (acoustic) states into neurophysiological states such that some properties of the former undergo changes interacting with the latter until a new equilibrium is reached. I assume that – at the end of the process – phonological segments (and the related categorical processes) take the form of continuous neural states represented by nested cortical oscillatory rhythms spatially distributed in the auditory cortex. Within this perspective, distinctive features (i.e., the relevant representational linguistic primitives) are represented by both spatially local and distributed neural selectivity. I suggest that this hypothesis is suitable to explain hierarchical layout of auditory cortex highly specialized in analyzing different aspects of the speech signal and to explain learning and memory processes during the acquisition of phonological systems.
Cellular reprogramming of human monocytes is regulated by time-dependent IL4 signalling and NCOR2
Authors: Sander Jil , Schmidt Susanne V. , Cirovic Branko , McGovern Naomi , Papantonopoulou Olympia , Hardt Anna-Lena , Aschenbrenner Anna C. , Kreer Christoph , Quast Kreer , Xu Alexander M. , Schmidleithner Lisa M. , Theis Heidi , Lan Do Thi Huong , Bin Sumatoh Hermi Rizal , Lauterbach Mario A. R. , Schulte-Schrepping Jonas , Gunther Patrick , Xue Jia , Baßler Kevin , Ulas Thomas , Klee Kathrin , Herresthal Stefanie , Krebs Wolfgang , Martin Bianca , Latz Eicke , Händler Kristian , Kraut Michael , Kolanus Waldemar , Beyer Marc , Falk Christine S. , Wiegmann Bettina , Burgdorf Sven , Melosh Nicholas A. , Newell Evan W. , Ginhoux Florent , Schlitzer Andreas , Schultze Joachim L.
Published: October 2017

The clinical and therapeutic value of humanin vitrogenerated monocyte-derived dendritic cell (moDC) and macrophages is well established. However, in line with recent findings regarding myeloid cell ontogeny and due to our limited understanding of their physiological counterparts, transcriptional regulation and heterogeneity, the full potential of these important cellular systems is still underestimated.

In this study, we use cutting edge high-dimensional analysis methods to better understand the transcriptional organization, phenotypic heterogeneity and functional differences between humanex vivoisolated andin vitrogenerated mononuclear phagocytes with the aim to better realize their full potential in the clinic.

We demonstrate that human monocytes activated by MCSF or GMCSF most closely resemble inflammatory macrophages identifiedin vivo, while IL4 signalling in the presence of GMCSF generates moDCs resembling inflammatory DCsin vivo, but not steady state cDC1 or cDC2. Moreover, these reprogramming regimes lead to activated monocytes that present with profoundly different transcriptomic, metabolic, phenotypic and functional profiles. Furthermore, we demonstrate that CD14+monocytes are integrating multiple exogenous activation signals such as GMCSF and IL4 in a combinatorial and temporal fashion, resulting in a high-dimensional cellular continuum of reprogrammed monocytes dependent on the mode and timing of cytokine exposure. Utilizing nanostraw-based knockdown technology, we demonstrate that the IL4-dependent generation of moDCs relies on the induction, nuclear localization and function of the transcriptional regulator NCOR2.

Finally, we unravel unappreciated heterogeneity within the clinically moDCs population and propose a novel high-dimensional phenotyping strategy to better tailor clinical quality control strategies for patient need and culture conditions to enhance therapeutic outcome.
Rats optimally accumulate and discount evidence in a dynamic environment
Authors: Piet Alex T. , El Hady Ahmed , Brody Carlos D.
Published: October 2017

How choices are made within noisy environments is a central question in the neuroscience of decision making. Previous work has characterized temporal accumulation of evidence for decision-making in static environments. However, real-world decision-making involves environments with statistics that change over time. This requires discounting old evidence that may no longer inform the current state of the world. Here we designed a rat behavioral task with a dynamic environment, to probe whether rodents can optimally discount evidence by adapting the timescale over which they accumulate it. Extending existing results about optimal inference in a dynamic environment, we show that the optimal timescale for evidence discounting depends on both the stimulus statistics and noise in sensory processing. We found that when both of these components were taken into account, rats accumulated and temporally discounted evidence almost optimally. Furthermore, we found that by changing the dynamics of the environment, experimenters could control the rats’ accumulation timescale, switching them from accumulating over short timescales to accumulating over long timescales and back. The theoretical framework also makes quantitative predictions regarding the timing of changes of mind in the dynamic environment. This study establishes a quantitative behavioral framework to control and investigate neural mechanisms underlying the adaptive nature of evidence accumulation timescales and changes of mind.
DirtyGenes: significance testing for gene or bacterial population composition changes using the Dirichlet distribution
Authors: Shaw Laurence M , Blanchard Adam , Chen Qinglin , An Xinli , Tötemeyer Sabine , Zhu Yong-Guan , Stekel Dov J
Published: October 2017

High throughput sequencing, and quantitative polymerase chain reaction (qPCR), can detect changes in bacterial communities or the genes that they carry, between different environments or treatments. These methods are applied widely to microbiomes in humans, animals, soil and water; an important application is for changes in antimicrobial resistance genes (ARGs). However, at present, there is no statistical method to determine whether observed changes in the overall composition are significant, or result from random variations between samples. Therefore researchers are limited to graphical descriptions. We describe a novel statistical method to determine whether or not observed differences in bacterial populations or their genes are significant. It can be used with data from shotgun metagenomics, 16S characterisation or qPCR. It can also be used for experimental design, to calculate the number of samples needed in future experiments. We show its application to two example data sets. The first is published data on bacterial communities and ARGs in the environment, in which we show that there are significant changes in both ARG and community composition. The second is a new data set on seasonality in bacterial communities and ARGs in hooves from four sheep. While the observed differences are not significant, we show that a minimum group size of eight sheep in a future experiment would provide sufficient power to observe significant changes, should the already observed changes be true. This method has broad uses for statistical testing and experimental design in experiments on changing microbiomes, including for studies on antimicrobial resistance.
Experiential learning in rodents: past experience enables rapid learning and localized encoding in hippocampus
Authors: Cox Conor D. , Palmer Linda C. , Pham Danielle T. , Trieu Brian H. , Gall Christine M. , Lynch Gary
Published: October 2017

Humans routinely use past experience with complexity to deal with novel, challenging circumstances. This fundamental aspect of real-world behavior has received surprisingly little attention in animal studies, and the underlying brain mechanisms are unknown. The present experiments tested for transfer from past experience in rats and then used quantitative imaging to localize synaptic modifications in hippocampus. Six daily exposures to an enriched environment (EE) caused a marked enhancement of short- and long-term memory encoded during a 30-min session in a different and complex environment relative to rats given extensive handling or access to running wheels. Relatedly, the EE animals investigated the novel environment in a different manner than the other groups, suggesting transfer of exploration strategies acquired in earlier interactions with complexity. This effect was not associated with changes in the number or size of excitatory synapses in hippocampus. Maps of synapses expressing a marker for long-term potentiation indicated that encoding in the EE group, relative to control animals, was concentrated in hippocampal field CA1. Importantly, <1% of the total population of synapses was involved in production of the regional map. These results constitute the first evidence that the transfer of experience profoundly affects the manner in which hippocampus encodes complex information.
Prazosin during threat discrimination boosts memory of the safe stimulus
Authors: Homan Philipp , Lin Qi , Murrough James W. , Soleimani Laili , Bach Dominik R. , Clem Roger L. , Schiller Daniela
Published: October 2017

The α-1 adrenoreceptor antagonist prazosin has shown promise in the treatment of post-traumatic stress disorder (PTSD) symptoms, but its mechanisms are not well understood. Here we administered prazosin or placebo prior to threat conditioning (day 1) and tested subsequent extinction (day 2) and reextinction (day 3) in healthy human participants. Prazosin did not affect threat conditioning but augmented stimulus discrimination during extinction and reextinction, via lower responding to the safe stimulus. These results suggest that prazosin during threat acquisition may have influenced encoding or consolidation of safety processing in particular, subsequently leading to enhanced discrimination between the safe and threatening stimuli.
Surface plasmon band tailoring of plasmonic nanostructure under the effect of water radiolysis by synchrotron radiation
Authors: Bharti Amardeep , Agrawal Ashish K. , Singh Balwant , Gautam Sanjeev , Goyal Navdeep
Published: October 2017

Plasmonic metal nanostructures have a significant impact on a diverse domain of fields, including photocatalysis, antibacterial, drug vector, biosensors, photovoltaic cell, optical and electronic devices. Metal nanoparticles (MNps) are the simplest nanostructure promising ultrahigh stability, ease of manufacturing and tunable optical response. Silver nanoparticles (AgNp) dominate in the class of MNps because of their relatively high abundance, chemical activity and unique physical properties. Although MNps offer the desired physical properties, most of the synthesis and fabrication methods lag at the electronic grade due to an unbidden secondary product as a result of the direct chemical reduction process. In this paper, a facile protocol is presented for fabricating high-yield in situ plasmonic AgNps under monochromatic X-rays irradiation, without the use of any chemical reducing agent which prevents the formation of secondary products. The ascendancy of this protocol is to produce high quantitative yield with control over the reaction rate, particle size and localized surface plasmon resonance response, and also to provide the feasibility for in situ characterization. The role of X-ray energy, beam flux and integrated dose towards the fabrication of plasmonic nanostructures has been studied. This experiment extends plasmonic research and provides avenues for upgrading production technologies of MNps.
Adiponitrile at 100 K
Authors: Seidel Rüdiger W. , Goddard Richard , Nöthling Nils , Lehmann Christian W.
Published: October 2017

Adiponitrile, C6H8N2, is a key intermediate in the synthesis of the polyamide Nylon 66 and is produced industrially on a large scale. We have determined the crystal and molecular structure of adiponitrile by single-crystal X-ray analysis at 100 K, a suitable crystal (m.p. 275 K) having been grown from the melt at low temperature. The compound crystallizes in the monoclinic space group P21/c with Z = 2. In the crystal structure, the molecule adopts an exact C
i-symmetric gauche–anti–gauche conformation of the C—C—C—C skeleton about an inversion centre. The molecules are densely packed, with short intermolecular contacts between the α-H and nitrile N atoms.
South African health decentralisation: requiring contextually intelligent leaders
Authors: Meyer Ellenore , Thomas Leena , Smith Selma , Scheepers Caren
Published: October 2017

Subject area

Public Health; Leadership; Organisational Development; Organisational Behaviour; Public Administration Management.

Study level/applicability

Postgraduate level for honours or masters programmes in courses on public health; executive leadership and management programmes; MBA level.

Case overview

The case unpacks decentralisation as a means to promote and improve local decision-making and accountability through community participation and engagements. Ayanda Nkele was a programme manager in a health district in South Africa. He was faced with many challenges when trying to implement his programme, most of which were related to local authority, responsibilities and decision-making abilities at his level. This case describes briefly the South African health system. and how it functions. It describes the proposed changes to the health system and its transformation towards Universal Health Coverage. The decision space analysis as discussed in the case illustrates the types of decentralisation in the country and how this also applies to Nkele’s level.

Expected learning outcomes

Understanding the concepts and principles of decentralisation within the context of strengthening district health services, the re-engineering of primary health care (PHC) and rolling out a National Health Insurance in South Africa. Applying the “decision space” approach to analyse the extent of decentralisation. Grasping the requirement of leaders to be “contextually intelligent” and identify the important contextual variables to take into account when analysing public health care.

Supplementary materials

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Subject code

CSS 7: Management Science.
Resource extractivism, health and climate change in small islands
Authors: Bambrick Hilary
Published: October 2017

Purpose

The extraction of natural resources has long been part of economic development in small islands. The damage to environment and health is extensive, even rendering once productive islands virtually uninhabitable. Rather than providing long-term benefits to the population or to the environment, the culture of “extractivism” – a nonreciprocal approach where resources are removed and used with little care or regard to consequences – has instead left many in far more fragile circumstances, increasingly dependent on external income. The purpose of this paper is to show how continued extractivism in small islands is contributing to global climate change and increasing climate risks to the local communities.

Design/methodology/approach

Through a series of case studies, this paper examines the history of extractivism in small islands in Oceania, its contribution to environmental degradation locally and its impacts on health.

Findings

It examines how extractivism continues today, with local impacts on environment, health and wellbeing and its much more far-reaching consequences for global climate change and human health. At the same time, these island countries have heightened sensitivity to climate change due to their isolation, poverty and already variable climate, whereas the damage to natural resources, the disruption, economic dependence and adverse health impacts caused by extractivism impart reduced resilience to the new climate hazards in those communities.

Practical implications

This paper proposes alternatives to resource extractivism with options for climate compatible development in small islands that are health-promoting and build community resilience in the face of increasing threats from climate change.

Originality/value

Extractivism is a new concept that has not previously been applied to understanding health implications of resource exploitation thorough the conduit of climate change. Small-island countries are simultaneously exposed to widespread extractivism, including of materials contributing to global climate change, and are among the most vulnerable to the hazards that climate change brings.
Mainstreaming climate change into the EIA procedures: a perspective from China
Authors: Gao Qi
Published: October 2017

Purpose

In the face of climate change, environmental impact assessment (EIA) and strategic environmental assessment (SEA) are expected to translate global or national mitigation and adaptation targets to project and plan levels of decision-making. This paper aims to examine how to transform China’s EIA procedures to accommodate consideration of climate change and what constraints might be for doing so.

Design/methodology/approach

The main methodology used in this paper is doctrinal research, which is the primary legal methodology to find the law and interpret and analyse the document. Theoretical research is applied to analyse the ideas and assumptions of the mainstreaming approach. Comparative research is done to consider relevant international experiences.

Findings

Despite well-founded rationale for the mainstreaming approach, entrenched institutional, legal and technical obstacles cannot be neglected in the context of China. Urgent needs to fix existing EIA/SEA loopholes and improve the general enabling environment are also highlighted as a fundamental aspect of mainstreaming.

Originality/value

The potential of mainstreaming climate change into China’s EIA procedures remains largely unexplored. As a ground-breaking work from China’s perspective, the findings of this paper can serve as an important foundation for future research from legal and other perspectives.