bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor
Authors: Ohmura Tomomi , Tian Yufeng , Sarich Nicolene , Ke Yunbo , Meliton Angelo , Shah Alok S. , Andreasson Katrin , Birukov Konstantin G. , Birukova Anna A.
Published: April 2017

The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected against barrier dysfunction caused by vasoactive peptide thrombin and proinflammatory bacterial wall lipopolysaccharide (LPS). Receptor screening using pharmacological and molecular inhibitory approaches identified EP4 as a novel PGA2 receptor. EP4 mediated barrier-protective effects of PGA2 by activating Rap1/Rac1 GTPase and protein kinase A targets at cell adhesions and cytoskeleton: VE-cadherin, p120-catenin, ZO-1, cortactin, and VASP. PGA2 also suppressed LPS-induced inflammatory signaling by inhibiting the NFκB pathway and expression of EC adhesion molecules ICAM1 and VCAM1. These effects were abolished by pharmacological or molecular inhibition of EP4. In vivo, PGA2 was protective in two distinct models of acute lung injury (ALI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and injection of thrombin receptor–activating peptide. These protective effects were abolished in mice with endothelial-specific EP4 knockout. The results suggest a novel role for the PGA2–EP4 axis in vascular EC protection that is critical for improvement of pathological states associated with increased vascular leakage and inflammation.
The size-speed-force relationship governs migratory cell response to tumorigenic factors
Authors: Leal-Egaña Aldo , Letort Gaelle , Martiel Jean-Louis , Christ Andreas , Vignaud Timothée , Roelants Caroline , Filhol Odile , Théry Manuel
Published: April 2017

Tumor development progresses through a complex path of biomechanical changes leading first to cell growth and contraction and then cell deadhesion, scattering, and invasion. Tumorigenic factors may act specifically on one of these steps or have a wider spectrum of actions, leading to a variety of effects and thus sometimes to apparent contradictory outcomes. Here we used micropatterned lines of collagen type I/fibronectin on deformable surfaces to standardize cell behavior and measure simultaneously cell size, speed of motion and magnitude of the associated traction forces at the level of a single cell. We analyzed and compared the normal human breast cell line MCF10A in control conditions and in response to various tumorigenic factors. In all conditions, a wide range of biomechanical properties was identified. Despite this heterogeneity, normal and transformed motile cells followed a common trend whereby size and contractile forces were negatively correlated with cell speed. Some tumorigenic factors, such as activation of ErbB2 or loss of the βsubunit of casein kinase 2, shifted the whole population toward a faster speed and lower contractility state. Treatment with transforming growth factor β induced some cells to adopt opposing behaviors such as extremely high versus extremely low contractility. Thus tumor transformation amplified preexisting population heterogeneity and led some cells to exhibit biomechanical properties that were more extreme than those observed with normal cells.
RABL2 interacts with the intraflagellar transport-B complex and CEP19 and participates in ciliary assembly
Authors: Nishijima Yuya , Hagiya Yohei , Kubo Tomohiro , Takei Ryota , Katoh Yohei , Nakayama Kazuhisa
Published: April 2017

Proteins localized to the basal body and the centrosome play crucial roles in ciliary assembly and function. Although RABL2 and CEP19 are conserved in ciliated organisms and have been implicated in ciliary/flagellar functions, their roles are poorly understood. Here we show that RABL2 interacts with CEP19 and is recruited to the mother centriole and basal body in a CEP19-dependent manner and that CEP19 is recruited to the centriole probably via its binding to the centrosomal protein FGFR1OP. Disruption of the RABL2 gene in Chlamydomonas reinhardtii results in the nonflagellated phenotype, suggesting a crucial role of RABL2 in ciliary/flagellar assembly. We also show that RABL2 interacts, in its GTP-bound state, with the intraflagellar transport (IFT)-B complex via the IFT74–IFT81 heterodimer and that the interaction is disrupted by a mutation found in male infertile mice (Mot mice) with a sperm flagella motility defect. Intriguingly, RABL2 binds to CEP19 and the IFT74–IFT81 heterodimer in a mutually exclusive manner. Furthermore, exogenous expression of the GDP-locked or Mot-type RABL2 mutant in human cells results in mild defects in ciliary assembly. These results indicate that RABL2 localized to the basal body plays crucial roles in ciliary/flagellar assembly via its interaction with the IFT-B complex.
Neuro-symbolic representation learning on biological knowledge graphs
Authors: Alshahrani Mona , Khan Mohammad Asif , Maddouri Omar , Kinjo Akira R , Queralt-Rosinach Núria , Hoehndorf Robert
Published: April 2017

Motivation

Biological data and knowledge bases increasingly rely on Semantic Web technologies and the use of knowledge graphs for data integration, retrieval and federated queries. In the past years, feature learning methods that are applicable to graph-structured data are becoming available, but have not yet widely been applied and evaluated on structured biological knowledge. Results: We develop a novel method for feature learning on biological knowledge graphs. Our method combines symbolic methods, in particular knowledge representation using symbolic logic and automated reasoning, with neural networks to generate embeddings of nodes that encode for related information within knowledge graphs. Through the use of symbolic logic, these embeddings contain both explicit and implicit information. We apply these embeddings to the prediction of edges in the knowledge graph representing problems of function prediction, finding candidate genes of diseases, protein-protein interactions, or drug target relations, and demonstrate performance that matches and sometimes outperforms traditional approaches based on manually crafted features. Our method can be applied to any biological knowledge graph, and will thereby open up the increasing amount of Semantic Web based knowledge bases in biology to use in machine learning and data analytics.

Availability and implementation

https://github.com/bio-ontology-research-group/walking-rdf-and-owl

Supplementary information

Supplementary data are available at Bioinformatics online.
Multi-label classifier based on histogram of gradients for predicting the anatomical therapeutic chemical class/classes of a given compound
Authors: Nanni Loris , Brahnam Sheryl
Published: April 2017

Motivation

Given an unknown compound, is it possible to predict its Anatomical Therapeutic Chemical class/classes? This is a challenging yet important problem since such a prediction could be used to deduce not only a compound’s possible active ingredients but also its therapeutic, pharmacological and chemical properties, thereby substantially expediting the pace of drug development. The problem is challenging because some drugs and compounds belong to two or more ATC classes, making machine learning extremely difficult.

Results

In this article a multi-label classifier system is proposed that incorporates information about a compound’s chemical–chemical interaction and its structural and fingerprint similarities to other compounds belonging to the different ATC classes. The proposed system reshapes a 1D feature vector to obtain a 2D matrix representation of the compound. This matrix is then described by a histogram of gradients that is fed into a Multi-Label Learning with Label-Specific Features classifier. Rigorous cross-validations demonstrate the superior prediction quality of this method compared with other state-of-the-art approaches developed for this problem, a superiority that is reflected particularly in the absolute true rate, the most important and harshest metric for assessing multi-label systems.

Availability and implementation

The MATLAB code for replicating the experiments presented in this article is available at https://www.dropbox.com/s/7v1mey48tl9bfgz/ToolPaperATC.rar?dl=0.

Supplementary information

Supplementary data are available at Bioinformatics online.
Carbon ion irradiation abrogates Lin28B-induced X-ray resistance in melanoma cells
Authors: Park Seong-Joon , Heo Kyu , Choi Chulwon , Yang Kwangmo , Adachi Akiko , Okada Hiroko , Yoshida Yukari , Ohno Tatsuya , Nakano Takashi , Takahashi Akihisa
Published: April 2017

The Lin28/let-7 axis plays an important role in tumor initiation and developmental processes. Lin28B is upregulated in a variety of cancers, and its overexpression enhances cancer cell proliferation and radioresistance through the suppression of let-7 micro RNA expression. In this study, we investigated the role of the Lin28/let7 axis as a target for radiosensitization of melanoma cancer cells. The overexpression of Lin28B reduced mature let-7 microRNA expression in melanoma cell lines, and enhanced the sphere-forming ability of melanoma cell lines, which is a characteristic of cancer stem cell (CSC) populations. Interestingly, Lin28B-overexpressed melanoma cells were more resistant to X-ray irradiation than control cells, and Lin28B-induced radioresistance was abolished after carbon ion irradiation. Consistent with these results, Lin28B overexpression reduced the numbers of γH2A.X foci after X-ray irradiation, whereas carbon ion irradiation had no such effect. Our results suggest that a carbon ion beam is more effective than an X-ray beam in terms of killing cancer cells, possibly due to elimination of CSC populations.
Phosphorylation Does Not Improve the Solubility of Rice Protein
Authors: Chen Li‐Yu , Liu Si‐Chen , Wang Ying‐Zhi , Ye Cai‐Qing , Sheu Fuu
Published: April 2017

The present study tried to phosphorylate rice protein (RP), a known insoluble food ingredient, and determine the improvement of its solubility. RP was allowed to react with sodium trimetaphosphate (STMP) at pH 11.5 and 35°C, and the results indicated that 20.6% of the RP seryl residues were phosphorylated. Interestingly, the solubility of phosphorylated RP (2.6%) was not improved compared with that of RP (2.5%) at pH 7. The involvement of hydrophobic interactions and disulfide bonds in phosphorylated RP solubility was further evaluated. The phosphorylation of RP in the presence of urea as a chaotropic agent for weakening the hydrophobic effect resulted in 22.0% phosphoseryl residues but still did not increase RP solubility. The reduction of RP disulfide bonds prior to phosphorylation resulted in 31.3% phosphoseryl residues and increased RP solubility to 8.3% at pH 7, indicating that disulfide bonds within RP could be responsible for the failure to increase its solubility after phosphorylation.
The Effect of Insertion Technique on Temperatures for Standard and Self-Drilling External Fixation Pins
Authors: Manoogian Sarah , Lee Adam K. , Widmaier James C.
Published: April 2017

Objectives:

No studies have assessed the effects of parameters associated with insertion temperature in modern self-drilling external fixation pins. The current study assessed how varying the presence of irrigation, insertion speed, and force impacted the insertion temperatures of 2 types of standard and self-drilling external fixation half pins.

Methods:

Seventy tests were conducted with 10 trials for 4 conditions on self-drilling pins, and 3 conditions for standard pins. Each test used a thermocouple inside the pin to measure temperature rise during insertion.

Results:

Adding irrigation to the standard pin insertion significantly lowered the maximum temperature (P <0.001). Lowering the applied force for the standard pin did not have a significant change in temperature rise. Applying irrigation during the self-drilling pin tests dropped average rise in temperature from 151.3 ± 21.6°C to 124.1 ± 15.3°C (P = 0.005). When the self-drilling pin insertion was decreased considerably from 360 to 60 rpm, the temperature decreased significantly from 151.3 ± 21.6°C to 109.6 ± 14.0°C (P <0.001). When the force applied increased significantly, the corresponding self-drilling pin temperature increase was not significant.

Conclusions:

The standard pin had lower peak temperatures than the self-drilling pin for all conditions. Moreover, slowing down the insertion speed and adding irrigation helped mitigate the temperature increase of both pin types during insertion.
The Use of Liposomal Bupivacaine Administered With Standard Bupivacaine in Ankle Fractures Requiring Open Reduction Internal Fixation: A Single-Blinded Randomized Controlled Trial
Authors: Davidovitch Roy , Goch Abraham , Driesman Adam , Konda Sanjit , Pean Christian , Egol Kenneth
Published: April 2017

Objectives:

To determine the efficacy of liposomal bupivacaine compared to placebo for postoperative pain control in patients undergoing operative fixation of ankle fractures.

Design:

Prospective single-blinded randomized control trial.

Setting:

Academic Medical Center.

Patients/Participants:

After Institutional Review Board (IRB) approval, 76 patients who sustained an acute ankle fracture (OTA/AO 44A-C) requiring operative fixation met inclusion criteria.

Intervention:

Patients were randomly assigned to 1 of 2 groups, control (local intraoperative sterile saline injection under general anesthesia) or interventional (local intraoperative liposomal bupivacaine and bupivacaine injection under general anesthesia). Injections were administered in a standardized fashion and included injection of a 1:1 mixture of a 40 mL solution consisting of 1.3% Exparel and sterile saline (interventional) or a 40 mL injection of normal saline (control) into the surrounding periosteal, peritendinous, surrounding muscles and subcutaneous tissue of the surgical incision(s).

Main Outcome Measurements:

Pain medications administered and pain according to the Visual Analogue Scale was recorded at scheduled postoperative time points: 4, 24, 48, 72, and 336 hours (14 days).

Results:

Thirty-nine patients were randomized to the control group and 37 to the interventional group (mean age = 42 ± 15 years), with no statistically significant differences between groups with regards to severity of injury and patient demographics. Pain scores were significantly lower in the interventional group versus control up to 2 weeks after surgery. Percocet ingestion at 4 hours was significantly lower in the interventional group (0.7 vs. 1.3, P = 0.004), while it approached significance at 48 hours postoperatively (2.8 vs. 3.69, P = 0.07). No other significant differences were noted for Percocet ingestion postoperatively at other time points assessed. The overall satisfaction with pain control was not statistically different between the 2 groups (P = 0.93).

Conclusion:

Local intraoperative infiltration of liposomal bupivacaine administered with standard bupivacaine for ankle fractures requiring Open Reduction Internal Fixation (ORIF) affords improved pain relief in the immediate postoperative period resulting in a reduction in Percocet ingestion, with resultant effects seen up to 2 days postoperatively. Continued investigation of this drug for use with extremity fractures is warranted.

Level of Evidence:

Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Abusive Head Trauma and Mortality–An Analysis From an International Comparative Effectiveness Study of Children With Severe Traumatic Brain Injury
Authors: Miller Ferguson Nikki , Sarnaik Ajit , Miles Darryl , Shafi Nadeem , Peters Mark J. , Truemper Edward , Vavilala Monica S. , Bell Michael J. , Wisniewski Stephen R. , Luther James F. , Hartman Adam L. , Kochanek Patrick M.
Published: April 2017

Objectives:

Small series have suggested that outcomes after abusive head trauma are less favorable than after other injury mechanisms. We sought to determine the impact of abusive head trauma on mortality and identify factors that differentiate children with abusive head trauma from those with traumatic brain injury from other mechanisms.

Design:

First 200 subjects from the Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial—a comparative effectiveness study using an observational, cohort study design.

Setting:

PICUs in tertiary children’s hospitals in United States and abroad.

Patients:

Consecutive children (age < 18 yr) with severe traumatic brain injury (Glasgow Coma Scale ≤ 8; intracranial pressure monitoring).

Interventions:

None.

Measurements and Main Results:

Demographics, injury-related scores, prehospital, and resuscitation events were analyzed. Children were dichotomized based on likelihood of abusive head trauma. A total of 190 children were included (n = 35 with abusive head trauma). Abusive head trauma subjects were younger (1.87 ± 0.32 vs 9.23 ± 0.39 yr; p < 0.001) and a greater proportion were female (54.3% vs 34.8%; p = 0.032). Abusive head trauma were more likely to 1) be transported from home (60.0% vs 33.5%; p < 0.001), 2) have apnea (34.3% vs 12.3%; p = 0.002), and 3) have seizures (28.6% vs 7.7%; p < 0.001) during prehospital care. Abusive head trauma had a higher prevalence of seizures during resuscitation (31.4 vs 9.7%; p = 0.002). After adjusting for covariates, there was no difference in mortality (abusive head trauma, 25.7% vs nonabusive head trauma, 18.7%; hazard ratio, 1.758; p = 0.60). A similar proportion died due to refractory intracranial hypertension in each group (abusive head trauma, 66.7% vs nonabusive head trauma, 69.0%).

Conclusions:

In this large, multicenter series, children with abusive head trauma had differences in prehospital and in-hospital secondary injuries which could have therapeutic implications. Unlike other traumatic brain injury populations in children, female predominance was seen in abusive head trauma in our cohort. Similar mortality rates and refractory intracranial pressure deaths suggest that children with severe abusive head trauma may benefit from therapies including invasive monitoring and adherence to evidence-based guidelines.
A Retrospective Study on Mycophenolic Acid Drug Interactions: Effect of Prednisone, Sirolimus, and Tacrolimus With MPA
Authors: Alvarez-Elías Ana C. , Yoo Elisa C. , Todorova Ekaterina K. , Singh Ram N. , Filler Guido
Published: April 2017

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used as an antirejection drug after renal transplantation. There is growing evidence supporting the notion that there is substantial variability in the intra- and interpatient exposure to MPA. Drug interactions involving MPA with tacrolimus, steroids, and sirolimus have been understudied. The objective of this study was to determine the relationship between MPA, steroids, tacrolimus, and sirolimus. MPA trough concentrations from 37 pediatric renal transplant recipients (mean age 7.6 years at transplant) followed for a median follow-up of 7.8 years were analyzed retrospectively and 2131 dose-normalized MPA trough concentrations were evaluated against all known covariates including all concomitant immunosuppressant drug doses and exposure, age, albumin, hematocrit, and estimated glomerular filtration rate (eGFR). Age, hematocrit, and estimated glomerular filtration rate affected the dose-normalized MPA trough concentrations. The authors used appropriate linear regression univariate models and created 5 different multivariate models to examine individual drug–drug interactions (DDIs). Although the authors' findings support the notion that there is a DDI between MMF and both sirolimus and steroids, the sample size was small, and these findings should be confirmed in future studies. The authors found no DDIs between tacrolimus and MMF, the prodrug of MPA. These findings are important because there is a tendency to under-dose MMF early and to overdose late after transplantation. The DDI between sirolimus and MMF has not been described. Although therapeutic drug monitoring of MMF therapy is often not performed, the data presented here indicate a necessity for therapeutic drug monitoring. This is especially true when converting from tacrolimus to sirolimus, as a way to avoid MPA underexposure and organ rejection.
Superficial Circumflex Iliac Artery Perforator Flap for Dorsalis Pedis Reconstruction
Authors: Tashiro Kensuke , Yamashita Shuji
Published: April 2017

Reconstruction of dorsalis pedis with soft tissue is challenging because it needs to preserve thin structure to ensure that the patient will be able to wear shoes. Here, we report the use of a thin superficial circumflex iliac artery perforator (SCIP) flap in dorsalis pedis reconstruction. A 67-year-old man presented with a third-degree burn, which exposed his extensor tendons. A thin SCIP flap from the left inguinal region measuring 15 × 4 cm was transferred to the dorsalis pedis region. Postoperatively, no major cosmetic or functional problems were observed. Because the invasiveness of the donor site is nearly same between SCIP flap and skin graft from inguinal region, SCIP flap is better solution in point of textural qualities for dorsalis pedis reconstruction.
Mammary Malignant Ulcer after Radiotherapy: Unpleasant Surprise
Authors: Vindigni Vincenzo , Kohlscheen Eva , Kraljic Tajna , Bassetto Franco , Pavan Chiara
Published: April 2017

We present a case of a woman, 79 years old, followed by Psychiatry for depressive episodes after breast cancer removal. She was operated on for ductal breast carcinoma in 1983. Afterward she was submitted to adjuvant radiotherapy. She came to our attention for a chronic skin ulcer that developed into the radio-treated area about 4 years ago. We performed a skin biopsy and programed adipose tissue grafts to promote wound healing. The result of the biopsy was unexpected: dermal localization of not differentiated breast carcinoma. She is currently under systemic chemotherapy treatment. The key message is to always perform a skin biopsy of a chronic skin ulcer developed after breast cancer removal before planning surgical reconstruction.
Inferior Limb Salvage by Combined Free-tissue Transfer and the Crane Principle Revisited
Authors: Thione Alessandro , Cavadas Pedro C.
Published: April 2017

Aggressive treatment of ischemia of the lower extremities has decreased the number of amputations in both diabetic and nondiabetic patients; combined vascular reconstruction and microvascular free-flap transfer has been used to improve distal perfusion and cover large tissue defects caused by the critical limb ischemia during the past 30 years. We present our experience with a 71-year-old diabetic patient who underwent revascularization with a vascular bypass and a simultaneous microvascular flap reconstruction for limb salvage after domestic trauma. An extension of the “crane” principle was used to solve bypass exposure due to wound late complication. After 1-year follow-up, the patient was able to walk without pain. Combining 3 well-established methods of arterial revascularization and free-flap transfer and the old “crane principle,” we achieved limb salvage, offering an alternative to below-knee amputation.
Immunogenicity of the Inactivated Japanese Encephalitis Virus Vaccine IXIARO in Children From a Japanese Encephalitis Virus-endemic Region
Authors: Dubischar Katrin L. , Kadlecek Vera , Sablan Benjamin , Borja-Tabora Charissa Fay , Gatchalian Salvacion , Eder-Lingelbach Susanne , Kiermayr Sigrid , Spruth Martin , Westritschnig Kerstin
Published: April 2017

Background:

Japanese encephalitis (JE) is a major public health concern in Asia and poses a small but potentially fatal threat to travelers from nonendemic countries, including children. No JE vaccine for pediatric use has been available in Europe and the United States.

Methods:

Age-stratified cohorts of children between 2 months and 17 years received 2 doses of Vero cell-derived inactivated JE virus vaccine (IXIARO; Valneva Austria GmbH, Vienna, Austria) administered 28 days apart [<3 years, 0.25 mL (half adult dose); ≥3 years, 0.5 mL (full adult dose)]. Immunogenicity endpoints were seroconversion rate, 4-fold increase in JE neutralizing antibody titer and geometric mean titer assessed 56 days and 7 months after the first vaccination in 496 subjects of the intent-to-treat population. The immune response to JE virus at both time points was also analyzed according to prevaccination JE virus and dengue virus serostatus.

Results:

At day 56, seroconversion was attained in ≥99.2% of subjects with age-appropriate dosing, 4-fold increases in titer were reported for 77.4%–100% in various age groups, and geometric mean titers ranged from 176 to 687, with younger children having the strongest immune response. At month 7, seroconversion was maintained in 85.5%–100% of subjects. Pre-existing JE virus immunity did not impact on immune response at day 56; however, it led to a better persistence of protective antibody titers at month 7.

Conclusions:

IXIARO is highly immunogenic at both doses tested in the pediatric population, leading to protective antibody titers at day 56 in >99% of subjects who received the age-appropriate dose.
Elevated Immune Response Among Children 4 Years of Age With Pronounced Local Adverse Events After the Fifth Diphtheria, Tetanus, Acellular Pertussis Vaccination
Authors: van der Lee Saskia , Kemmeren Jeanet M. , de Rond Lia G. H. , Öztürk Kemal , Westerhof Anneke , de Melker Hester E. , Sanders Elisabeth A. M. , Berbers Guy A. M. , van der Maas Nicoline A. T. , Rümke Hans C. , Buisman Anne-Marie
Published: April 2017

Background:

In the Netherlands, acellular pertussis vaccines replaced the more reactogenic whole-cell pertussis vaccines. This replacement in the primary immunization schedule of infants coincided with a significant increase in pronounced local adverse events (AEs) in 4 years old children shortly after the administration of a fifth diphtheria, tetanus, acellular pertussis and inactivated polio (DTaP-IPV) vaccine. The objective of this study was to investigate possible differences in vaccine antigen-specific immune responses between children with and without a pronounced local AE after the fifth DTaP-IPV vaccination.

Methods:

Blood was sampled in 2 groups of 4-year-olds: a case group reporting pronounced local swelling and/or erythema up to extensive limb swelling at the injection site (n = 30) and a control group (n = 30). Peripheral blood mononuclear cells were stimulated with individual vaccine antigens. Plasma antigen-specific IgG, IgG subclass and total IgE concentrations and T-cell cytokine [interferon-gamma, interleukin (IL)-13, IL-17 and IL-10] production by stimulated peripheral blood mononuclear cells were determined by multiplex bead-based fluorescent multiplex immunoassays.

Results:

In children with AEs, significantly higher total IgE and vaccine antigen-specific IgG and IgG4 responses as well as levels of the T-helper 2 (Th2) cytokine IL-13 were found after pertussis, tetanus and diphtheria stimulation compared with controls.

Conclusions:

Children with pronounced local reactions show higher humoral and cellular immune responses. Acellular vaccines are known to skew toward more Th2 responses. The pronounced local AEs may be associated with more Th2 skewing after the fifth DTaP-IPV vaccination, but other biologic factors may also impact the occurrence of these pronounced local reactions.
Differentiating Delirium From Sedative/Hypnotic-Related Iatrogenic Withdrawal Syndrome: Lack of Specificity in Pediatric Critical Care Assessment Tools*
Authors: Madden Kate , Burns Michele M. , Tasker Robert C.
Published: April 2017

Objectives:

To identify available assessment tools for sedative/hypnotic iatrogenic withdrawal syndrome and delirium in PICU patients, the evidence supporting their use, and describe areas of overlap between the components of these tools and the symptoms of anticholinergic burden in children.

Data Sources:

Studies were identified using PubMed and EMBASE from the earliest available date until July 3, 2016, using a combination of MeSH terms “delirium,” “substance withdrawal syndrome,” and key words “opioids,” “benzodiazepines,” “critical illness,” “ICU,” and “intensive care.” Review article references were also searched.

Study Selection:

Human studies reporting assessment of delirium or iatrogenic withdrawal syndrome in children 0–18 years undergoing critical care. Non-English language, exclusively adult, and neonatal intensive care studies were excluded.

Data Extraction:

References cataloged by study type, population, and screening process.

Data Synthesis:

Iatrogenic withdrawal syndrome and delirium are both prevalent in the PICU population. Commonly used scales for delirium and iatrogenic withdrawal syndrome assess signs and symptoms in the motor, behavior, and state domains, and exhibit considerable overlap. In addition, signs and symptoms of an anticholinergic toxidrome (a risk associated with some common PICU medications) overlap with components of these scales, specifically in motor, cardiovascular, and psychiatric domains.

Conclusions:

Although important studies have demonstrated apparent high prevalence of iatrogenic withdrawal syndrome and delirium in the PICU population, the overlap in these scoring systems presents potential difficulty in distinguishing syndromes, both clinically and for research purposes.
Efficient conditioned pain modulation despite pain persistence in painful diabetic neuropathy
Authors: Granovsky Yelena , Nahman-Averbuch Hadas , Khamaisi Mogher , Granot Michal
Published: April 2017

Introduction:

Alleviation of pain, by either medical or surgical therapy, is accompanied by transition from less efficient, or pro-nociceptive, to efficient conditioned pain modulation (CPM). Spontaneous decrease or resolution of pain with disease progression is reported for some patients with painful diabetic neuropathy (PDN).

Objectives:

To explore whether CPM changes similarly in parallel to spontaneous resolution of pain in PDN patients.

Methods:

In this cross-sectional study, thirty-three patients with PDN underwent psychophysical assessment of pain modulation on the forearm, remote from the clinical pain.

Results:

Pain duration was not correlated with neuropathic pain intensity, yet, it correlated with CPM efficiency; patients with longer pain duration had same pain level, but more efficient CPM than those with short-pain duration (ρ = −0.417; P = 0.025, Spearman correlation). Patients with pain more than 2 years (median split) expressed efficient CPM that was not different from that of healthy controls. These patients also had lower temporal summation of pain than the short-pain duration patients group (P < 0.05). The 2 patient groups did not differ in clinical pain characteristics or use of analgesics.

Conclusion:

Pro-nociception, expressed by less efficient CPM and high temporal summation that usually accompanies clinical painful conditions, seems to “normalize” with chronicity of the pain syndrome. This is despite continuing pain, suggesting that pro-nociceptivity in pain syndromes is multifactorial. Because the pain modulation profile affects success of therapy, this suggests that different drugs might express different efficacy pending on duration of the pain in patients with PDN.
Women report higher pain intensity at a lower level of inflammation after knee surgery compared with men
Authors: Solheim Nina , Östlund Simon , Gordh Torsten , Rosseland Leiv Arne
Published: April 2017

Introduction and Objectives:

We previously found that women report more pain after knee arthroscopic procedures than men. It remains unclear whether this is due to different biochemical responses or nociceptive mechanisms.

Methods:

We analyzed acute pain-related inflammatory markers in a clinical model of patient self-reported pain immediately after knee surgery. To simultaneously measure 92 inflammatory biomarkers, we used the proximity extension assay with the Proseek Multiplex Inflammation I panel (Olink Bioscience, Uppsala, Sweden). Knee surgery was performed under general anesthesia with propofol and remifentanil. Analgesic drugs were only administered on patient request.

Results:

Women were 4.9 times more likely to report moderate or severe pain than men (95% confidence interval, 1.2–19.6,P= 0.024). Patient age, preoperative pain, and surgery duration were not significant factors. We analyzed synovial fluids from 44 patients (23 women, 21 men). After false discovery rate correction, MMP-10 was the only biomarker that was higher among men (P= 0.01). Linear discriminant analysis showed that 3 proteins (IL-8, CCL-4, and MCP-2) were expressed at higher levels in men, with differences of >1 normalized protein expression. No proteins were overexpressed by >1 normalized protein expression in women.

Conclusion:

Acute pain after knee arthroscopy was more intense in women, but pro-inflammatory biomarkers and MMP-10 were higher in men. Further knowledge of cytokine function is required before concluding that the disparities in biomarker expression are clinically unimportant. The similar biochemical signaling between sexes suggests that central mechanisms are of greater importance in sex-specific joint pain perception.
Ultrasound Molecular Imaging of Inflammation in Mouse Abdominal Aorta
Authors: Wang Shiying , Unnikrishnan Sunil , Herbst Elizabeth B. , Klibanov Alexander L. , Mauldin Frank William , Hossack John A.
Published: April 2017

Objectives

The aim of this study was to demonstrate a new clinically translatable ultrasound molecular imaging approach, modulated acoustic radiation force-based imaging, which is capable of rapid and reliable detection of inflammation as validated in mouse abdominal aorta.

Materials and Methods

Animal studies were approved by the Institutional Animal Care and Use Committee at the University of Virginia. C57BL/6 mice stimulated with tumor necrosis factor α, or fed with a high-fat diet, were used as inflammation (MInflammation) and diet-induced obesity (DIO) (MDIO) models, respectively. C57BL/6 mice, not exposed to tumor necrosis factor α or DIO, were used as controls (MNormal). P-selectin–targeted (MBP-selectin), vascular cell adhesion molecule (VCAM)-1–targeted (MBVCAM-1), and isotype control (MBControl) microbubbles were synthesized by conjugating anti–P-selectin, anti–VCAM-1, and isotype control antibodies to microbubbles, respectively. The abdominal aortas were imaged for 180 seconds during a constant infusion of microbubbles. A parameter, residual-to-saturation ratio (RSR), was used to assess P-selectin and VCAM-1. Statistical analysis was performed with the Student t test.

Results

For the inflammation model, RSR of the MInflammation + MBP-selectin group was significantly higher (40.9%, P < 0.0005) than other groups. For the DIO model, RSR of the MDIO + MBVCAM-1 group was significantly higher (60.0%, P < 0.0005) than other groups. Immunohistochemistry staining of the abdominal aorta confirmed the expression of P-selectin and VCAM-1.

Conclusions

A statistically significant assessment of P-selectin and VCAM-1 in mouse abdominal aorta was achieved. This technique yields progress toward rapid targeted molecular imaging in large blood vessels and thus has the potential for early diagnosis, treatment selection, and risk stratification of atherosclerosis.
Computed Tomography of the Head and Neck Region for Tumor Staging—Comparison of Dual-Source, Dual-Energy and Low-Kilovolt, Single-Energy Acquisitions
Authors: May Matthias Stefan , Bruegel Joscha , Brand Michael , Wiesmueller Marco , Krauss Bernhard , Allmendinger Thomas , Uder Michael , Wuest Wolfgang
Published: April 2017

Purpose

The aim of this study was to intra-individually compare the image quality obtained by dual-source, dual-energy (DSDE) computed tomography (CT) examinations and different virtual monoenergetic reconstructions to a low single-energy (SE) scan.

Materials and Methods

Third-generation DSDE-CT was performed in 49 patients with histologically proven malignant disease of the head and neck region. Weighted average images (WAIs) and virtual monoenergetic images (VMIs) for low (40 and 60 keV) and high (120 and 190 keV) energies were reconstructed. A second scan aligned to the jaw, covering the oral cavity, was performed for every patient to reduce artifacts caused by dental hardware using a SE-CT protocol with 70-kV tube voltages and matching radiation dose settings. Objective image quality was evaluated by calculating contrast-to-noise ratios. Subjective image quality was evaluated by experienced radiologists.

Results

Highest contrast-to-noise ratios for vessel and tumor attenuation were obtained in 40-keV VMI (all P < 0.05). Comparable objective results were found in 60-keV VMI, WAI, and the 70-kV SE examinations. Overall subjective image quality was also highest for 40-keV, but differences to 60-keV VMI, WAI, and 70-kV SE were nonsignificant (all P > 0.05). High kiloelectron volt VMIs reduce metal artifacts with only limited diagnostic impact because of insufficiency in case of severe dental hardware. CTDIvol did not differ significantly between both examination protocols (DSDE: 18.6 mGy; 70-kV SE: 19.4 mGy; P = 0.10).

Conclusions

High overall image quality for tumor delineation in head and neck imaging were obtained with 40-keV VMI. However, 70-kV SE examinations are an alternative and modified projections aligned to the jaw are recommended in case of severe artifacts caused by dental hardware.
Impact of Distance to Treatment Center on Care Seeking for Pelvic Floor Disorders
Authors: English Emily , Rogo-Gupta Lisa
Published: April 2017

Objective

The aim of this study was to evaluate the impact of distance from residence to treatment center on access to care for female pelvic floor disorders at an academic institution.

Methods

A retrospective cross-sectional study was conducted of women seen for pelvic floor disorders at an academic institution from 2008 to 2014. Patient characteristics were extracted from charts. Geographical and US census data was obtained from public records and used to calculate distance from patient residence to physician office. Statistical analysis was performed using R Software (Version 0.98.1102) and Microsoft Excel (Version 14.4.7). Statistical significance was defined as a 2-sided P value of less than 0.05, and the χ2 test was used to determine associations of categorical variables.

Results

A total of 3015 patients were included in the analysis. The mean distance traveled was 93 miles. Thirty percent of patients traveled more than 50 miles. Many patients (43%) reported having the symptoms for more than 2 years. Patients who traveled farther were significantly more likely to be white, English-speaking, and with pelvic organ prolapse as primary complaint. These patients were more likely to plan surgery at the first visit than patients who traveled less far (29% vs 14%). Patients who traveled farther were also more likely to live in counties with a low percentage of persons older than 65 years and low percentage of female inhabitants.

Conclusions

Women who travel the farthest for treatment of pelvic floor disorders have experienced the symptoms for longer duration and are more willing to plan surgery at presentation. These women also come from counties with fewer elderly women, suggesting future outreach care should focus on similar geographic areas.
Convergent minds: ostension, inference and Grice's third clause
Authors: Moore Richard
Published: April 2017

A prevailing view is that while human communication has an ‘ostensive-inferential’ or ‘Gricean’ intentional structure, animal communication does not. This would make the psychological states that support human and animal forms of communication fundamentally different. Against this view, I argue that there are grounds to expect ostensive communication in non-human clades. This is because it is sufficient for ostensive communication that one intentionally addresses one's utterance to one's intended interlocutor—something that is both a functional pre-requisite of successful communication and cognitively undemanding. Furthermore, while ostension is an important feature of intentional communication, the inferences required in Gricean communication may be minimal: ostension and inference may come apart. The grounds for holding that animal communication could not be Gricean are therefore weak. I finish by defending the idea that a ‘minimally Gricean’ model of communication is a valuable tool for characterizing the communicative interactions of many animal species.
Logic, passion and the problem of convergence
Authors: McShea Daniel W.
Published: April 2017

Our estimate of the likelihood of convergence on human-style intelligence depends on how we understand our various mental capacities. Here I revive David Hume's theory of motivation and action to argue that the most common understanding of the two conventionally recognized components of intelligence—reason and emotion—is confused. We say things like, ‘Reason can overcome emotion’, but to make this statement meaningful, we are forced to treat reason as a compound notion, as a forced and unhappy mixture of concepts that are incommensurate. An alternative is to parse intelligence in a different way, into two sets of capacities: (i) non-affective capacities, including logic, calculation and problem-solving; (ii) affective capacities, including wants, preferences and cares, along with the emotions. Thus, the question of convergence becomes two questions, one having to do with affective and one with non-affective capacities. What is the likelihood of convergence of these in non-human lineages, in other ecologies, on other worlds? Given certain assumptions, convergence of the non-affective capacities in thinking species seems likely, I argue, while convergence of the affective capacities seems much less likely.
Evolutionary convergence and biologically embodied cognition
Authors: Keijzer Fred A.
Published: April 2017

The study of evolutionary patterns of cognitive convergence would be greatly helped by a clear demarcation of cognition. Cognition is often used as an equivalent of mind, making it difficult to pin down empirically or to apply it confidently beyond the human condition. Recent developments in embodied cognition and philosophy of biology now suggest an interpretation that dissociates cognition from this mental context. Instead, it anchors cognition in a broad range of biological cases of intelligence, provisionally marked by a basic cognitive toolkit. This conception of cognition as an empirically based phenomenon provides a suitable and greatly expanded domain for studies of evolutionary convergence. This paper first introduces this wide, biologically embodied interpretation of cognition. Second, it discusses examples drawn from studies on bacteria, plants and fungi that all provide cases fulfilling the criteria for this wide interpretation. Third, the field of early nervous system evolution is used to illustrate how biologically embodied cognition raises new fundamental questions for research on animal cognition. Finally, an outline is given of the implications for the evolutionary convergence of cognition.
Phylogenetic origins of biological cognition: convergent patterns in the early evolution of learning
Authors: van Duijn Marc
Published: April 2017

Various forms of elementary learning have recently been discovered in organisms lacking a nervous system, such as protists, fungi and plants. This finding has fundamental implications for how we view the role of convergent evolution in biological cognition. In this article, I first review the evidence for basic forms of learning in aneural organisms, focusing particularly on habituation and classical conditioning and considering the plausibility for convergent evolution of these capacities. Next, I examine the possible role of convergent evolution regarding these basic learning abilities during the early evolution of nervous systems. The evolution of nervous systems set the stage for at least two major events relevant to convergent evolution that are central to biological cognition: (i) nervous systems evolved, perhaps more than once, because of strong selection pressures for sustaining sensorimotor strategies in increasingly larger multicellular organisms and (ii) associative learning was a subsequent adaptation that evolved multiple times within the neuralia. Although convergent evolution of basic forms of learning among distantly related organisms such as protists, plants and neuralia is highly plausible, more research is needed to verify whether these forms of learning within the neuralia arose through convergent or parallel evolution.
The effect of common inversion polymorphismsIn(2L)t and In(3R)Moon patterns of transcriptional variation inDrosophila melanogaster
Authors: Lavington Erik , Kern Andrew D.
Published: April 2017

Chromosomal inversions are an ubiquitous feature of genetic variation. Theoretical models describe several mechanisms by which inversions can drive adaptation and be maintained as polymorphisms. While inversions have been shown previously to be under selection, or contain genetic variation under selection, the specific phenotypic consequences of inversions leading to their maintenance remain unclear. Here we use genomic sequence and expression data from the Drosophila Genetic Reference Panel to explore the effects of two cosmopolitan inversions,In(2L)tandIn(3R)Mo, on patterns of transcriptional variation. We demonstrate that each inversion has a significant effect on transcript abundance for hundreds of genes across the genome. Inversion affected loci (IAL) appear both within inversions as well as on unlinked chromosomes. Importantly, IAL do not appear to be influenced by the previously reported genome-wide expression correlation structure. We found that five genes involved with sterol uptake, four of which are Niemann-Pick Type 2 orthologs, are upregulated in flies withIn(3R)Mobut do not have SNPs in LD with the inversion. We speculate that this upregulation is driven by genetic variation inmod(mdg4)that is in LD withIn(3R)Mo. We find that there is little evidence for regional or position effect of inversions on gene expression at the chromosomal level but do find evidence for the distal breakpoint ofIn(3R)Mointerrupting one gene and possibly disassociating the two flanking genes from regulatory elements.
Light GuidedIn-vivoActivation of Innate Immune Cells with Photocaged TLR 2/6 Agonist
Authors: Ah Ryu Keun , McGonnigal Bethany , Moore Troy , Mancini Rock J. , Esser-Kahn Aaron P.
Published: April 2017

The complexity of the immune system creates challenges in exploring its importance and robustness. To date, there have been few techniques developed to manipulate individual components of the immune system in an in vivo environment. Here we show a light-based dendritic cell (DC) activation allowing spatial and temporal control of immune activation in vivo. Additionally, we show time dependent changes in RNA profiles of the draining lymph node, suggesting a change in cell profile following DC migration and indicating that the cells migrating have been activated towards antigen presentation.