Opioid and α2 adrenergic mechanisms are activated by GABA agonists in the lateral parabrachial nucleus to induce sodium intake

Publication date: Available online 9 February 2018
Source:Brain Research Bulletin
Author(s): Lisandra B. De Oliveira, Carina A.F. Andrade, Laurival A. De Luca, Débora S.A. Colombari, José V. Menani
The activation of GABA, opioid or α2 adrenergic mechanisms in the lateral parabrachial nucleus (LPBN) facilitates hypertonic NaCl intake in rats. In the present study, we combined opioid or α2 adrenergic antagonists with GABA agonists into the LPBN in order to investigate if NaCl intake caused by GABAergic activation in normohydrated rats depends on opioid or α2-adrenergic mechanisms in this area. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of muscimol or baclofen (GABAA and GABAB agonists, respectively, 0.5 nmol/0.2 μl) into the LPBN induced strong ingestion of 0.3 M NaCl (45.8 ± 7.3 and 21.8 ± 4.8 ml/240 min, respectively) and water intake (22.7 ± 3.4 and 6.6 ± 2.5 ml/240 min, respectively). Naloxone (opioid antagonist, 150 nmol/0.2 μl) into the LPBN abolished 0.3 M NaCl and water intake to muscimol (2.0 ± 0.6 and 0.9 ± 0.2 ml/240 min, respectively) or baclofen (2.3 ± 1.1 and 0.8 ± 0.4 ml/240 min, respectively). RX 821002 (α2 adrenoceptor antagonist, 10 nmol/0.2 μl) into the LPBN reduced 0.3 M NaCl intake induced by the injections of muscimol or baclofen (26.6 ± 8.0 and 10.1 ± 4.9 ml/240 min, respectively). RX 821002 reduced water intake induced by muscimol (7.7 ± 2.9 ml/240 min), not by baclofen. The results suggest that sodium intake caused by gabaergic activation in the LPBN in normohydrated rats is totally dependent on the activation of opioid mechanisms and partially dependent on the activation of α2 adrenergic mechanisms in the LPBN.



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Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion

Publication date: Available online 9 February 2018
Source:Brain Research Bulletin
Author(s): Jingxi Ma, Lina Zhang, Tengfei Niu, Chibo Ai, Gongwei Jia, Xinhao Jin, Lan Wen, Keming Zhang, Qinbin Zhang, Changqing Li
The recent suggestion that growth differentiation factor 11 (GDF11) acts as a rejuvenation factor has remained controversial. However, in addition to its role in aging, the relationship between GDF11 and cerebral ischemia is still an important area that needs more investigation. Here we examined effects of GDF11 on angiogenesis and recovery of neurological function in a rat model of stroke.Exogenous recombinant GDF11 (rGDF11) at different doses were directly injected into the tail vein in rats subjected to cerebral ischemia/reperfusion (I/R). Neurobehavioral tests were performed, the proliferation of endothelial cells (ECs) and GDF11 downstream signal activin-like kinase 5 (ALK5) were assessed, and functional microvessels were measured.Results showed that rGDF11 at a dosage of 0.1 mg/kg/day could effectively activate cerebral angiogenesis in vivo. In addition, rGDF11 improved the modified neurological severity scores and the adhesive removal somatosensory test, promoted proliferation of ECs, induced ALK5 and increased vascular surface area and the number of vascular branch points in the peri-infarct cerebral cortex after cerebral I/R. These effects were suppressed by blocking ALK5.Our novel findings shed new light on the role of GDF11. Our results strongly suggest that GDF11 improves neurofunctional recovery from cerebral I/R injury and that this effect is mediated partly through its proangiogenic effect in the peri-infarct cerebral cortex, which is associated with ALK5. Thus, GDF11/ALK5 may represent new therapeutic targets for aiding recovery from stroke.



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Communication Practices of Mammography Facilities and Timely Follow-up of a Screening Mammogram with a BI-RADS 0 Assessment

Publication date: Available online 9 February 2018
Source:Academic Radiology
Author(s): Marilyn M. Schapira, William E. Barlow, Emily F. Conant, Brian L. Sprague, Anna N.A. Tosteson, Jennifer S. Haas, Tracy Onega, Elisabeth F. Beaber, Martha Goodrich, Anne Marie McCarthy, Sally D. Herschorn, Celette Sugg Skinner, Tory O. Harrington, Berta Geller
Rationale and ObjectivesThe objective of this study was to evaluate the association of communication practices with timely follow-up of screening mammograms read as Breast Imaging Reporting and Data Systems (BI-RADS) 0 in the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium.Materials and MethodsA radiology facility survey was conducted in 2015 with responses linked to screening mammograms obtained in 2011–2014. We considered timely follow-up to be within 15 days of the screening mammogram. Generalized estimating equation models were used to evaluate the association between modes of communication with patients and providers and timely follow-up, adjusting for PROSPR site, patient age, and race and ethnicity.ResultsThe analysis included 34,680 mammography examinations with a BI-RADS 0 assessment among 28 facilities. Across facilities, 85.6% of examinations had a follow-up within 15 days. Patients in a facility where routine practice was to contact the patient by phone if follow-up imaging was recommended were more likely to have timely follow-up (odds ratio [OR] 4.63, 95% confidence interval [CI] 2.76–7.76), whereas standard use of mail was associated with reduced timely follow-up (OR 0.47, 95% CI 0.30–0.75). Facilities that had standard use of electronic medical records to report the need for follow-up imaging to a provider had less timely follow-up (OR 0.56, 95% CI 0.35–0.90). Facilities that routinely contacted patients by mail if they missed a follow-up imaging visit were more likely to have timely follow-up (OR 1.65, 95% CI 1.02–2.69).ConclusionsOur findings support the value of telephone communication to patients in relation to timely follow-up. Future research is needed to evaluate the role of communication in completing the breast cancer screening episode.



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An ontology-driven clinical decision support system (IDDAP) for infectious disease diagnosis and antibiotic prescription

Publication date: Available online 9 February 2018
Source:Artificial Intelligence in Medicine
Author(s): Ying Shen, Kaiqi Yuan, Daoyuan Chen, Joël Colloc, Min Yang, Yaliang Li, Kai Lei
BackgroundThe available antibiotic decision-making systems were developed from a physician's perspective. However, because infectious diseases are common, many patients desire access to knowledge via a search engine. Although the use of antibiotics should, in principle, be subject to a doctor's advice, many patients take them without authorization, and some people cannot easily or rapidly consult a doctor. In such cases, a reliable antibiotic prescription support system is needed.Methods and resultsThis study describes the construction and optimization of the sensitivity and specificity of a decision support system named IDDAP, which is based on ontologies for infectious disease diagnosis and antibiotic therapy. The ontology for this system was constructed by collecting existing ontologies associated with infectious diseases, syndromes, bacteria and drugs into the ontology's hierarchical conceptual schema. First, IDDAP identifies a potential infectious disease based on a patient's self-described disease state. Then, the system searches for and proposes an appropriate antibiotic therapy specifically adapted to the patient based on factors such as the patient's body temperature, infection sites, symptoms/signs, complications, antibacterial spectrum, contraindications, drug–drug interactions between the proposed therapy and previously prescribed medication, and the route of therapy administration.The constructed domain ontology contains 1,267,004 classes, 7,608,725 axioms, and 1,266,993 members of "SubClassOf" that pertain to infectious diseases, bacteria, syndromes, anti-bacterial drugs and other relevant components. The system includes 507 infectious diseases and their therapy methods in combination with 332 different infection sites, 936 relevant symptoms of the digestive, reproductive, neurological and other systems, 371 types of complications, 838,407 types of bacteria, 341 types of antibiotics, 1504 pairs of reaction rates (antibacterial spectrum) between antibiotics and bacteria, 431 pairs of drug interaction relationships and 86 pairs of antibiotic-specific population contraindicated relationships.Compared with the existing infectious disease-relevant ontologies in the field of knowledge comprehension, this ontology is more complete. Analysis of IDDAP's performance in terms of classifiers based on receiver operating characteristic (ROC) curve results (89.91%) revealed IDDAP's advantages when combined with our ontology.Conclusions and significanceThis study attempted to bridge the patient/caregiver gap by building a sophisticated application that uses artificial intelligence and machine learning computational techniques to perform data-driven decision-making at the point of primary care. The first level of decision-making is conducted by the IDDAP and provides the patient with a first-line therapy. Patients can then make a subjective judgment, and if any questions arise, should consult a physician for subsequent decisions, particularly in complicated cases or in cases in which the necessary information is not yet available in the knowledge base.



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High strength, biodegradable and cytocompatible alpha tricalcium phosphate-iron composites for temporal reduction of bone fractures

Publication date: Available online 9 February 2018
Source:Acta Biomaterialia
Author(s): E.B. Montufar, M. Casas-Luna, M. Horynová, S. Tkachenko, Z. Fohlerová, S. Diaz-de-la-Torre, K. Dvorak, L. Celko, J. Kaiser
In this work alpha tricalcium phosphate (α-TCP)/ iron (Fe) composites were developed as a new family of biodegradable, load-bearing and cytocompatible materials. The composites with composition from pure ceramic to pure metallic samples were consolidated by pulsed electric current assisted sintering to minimise processing time and temperature while improving their mechanical performance. The mechanical strength of the composites was increased and controlled with the Fe content, passing from brittle to ductile failure. In particular, the addition of 25 vol.% of Fe produced a ceramic matrix composite with elastic modulus much closer to cortical bone than that of titanium or biodegradable magnesium alloys and specific compressive strength above that of stainless steel, chromium-cobalt alloys and pure titanium, currently used in clinic for internal fracture fixation. All the composites studied exhibited higher degradation rate than their individual components, presenting values around 200 μm/year, but also their compressive strength did not show a significant reduction in the period required for bone fracture consolidation. Composites showed preferential degradation of α-TCP areas rather than β-TCP areas, suggesting that α-TCP can produce composites with higher degradation rate. The composites were cytocompatible both in indirect and direct contact with bone cells. Osteoblast-like cells attached and spread on the surface of the composites, presenting proliferation rate similar to cells on tissue culture-grade polystyrene and they showed alkaline phosphatase activity. Therefore, this new family of composites is a potential alternative to produce implants for temporal reduction of bone fractures.Statement of SignificanceBiodegradable alpha-tricalcium phosphate/iron (α-TCP/Fe) composites are promising candidates for the fabrication of temporal osteosynthesis devices. Similar to biodegradable metals, these composites can avoid implant removal after bone fracture healing, particularly in young patients. In this work, α-TCP/Fe composites are studied for the first time in a wide range of compositions, showing not only higher degradation rate in vitro than pure components, but also good cytocompatibility and mechanical properties controllable with the Fe content. Ceramic matrix composites show high specific strength and low elastic modulus, thus better fulfilling the requirements for bone fractures fixation. A significant advance over previous works on the topic is the use of pulsed electric current assisted sintering together with α-TCP, convenient to improve the mechanical performance and degradation rate, respectively.

Graphical abstract

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A Continuum of Mineralization from Human Renal Pyramid to Stones on Stems

Publication date: Available online 9 February 2018
Source:Acta Biomaterialia
Author(s): Benjamin A Sherer, Ling Chen, Misun Kang, Alex R. Shimotake, Scott V Wiener, Tom Chi, Marshall L Stoller, Sunita P. Ho
The development of new modalities for kidney stone prevention rests upon understanding the progression of mineralization within the renal pyramid. The progression from small foci of mineralization within the renal pyramid to larger interstitial plaques that ultimately lead to the formation of clinically detectable calcium-based stones on calcium phosphate stems will be presented through correlative microscopy approach. High resolution X-ray computed tomography (micro-XCT), electron microscopy, and energy dispersive X-ray (EDX) compositional analyses of interstitial plaques, stems, and attached stones were performed.Increase in mineral density progressed with mineralization severity, with the highest mineral densities detected within mature Randall's plaque and stems to which kidney stones were attached. EDX analyses revealed variable elemental composition within interstitial plaque, stems, and stones. Micro-XCT reconstructions of stones with stems enabled visualization of unoccluded tubules within stems, with average tubule diameters corresponding to thin limbs of Henle, blood vessels, and collecting ducts. Correlative microscopy confirmed that the progression of mineralization leading to calcium-based nephrolithiasis occurs through a continuum involving four anatomically and structurally distinct biomineralization regions: 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones.Statement of SignificanceNephrolithiasis is a common condition affecting nearly 1 in 11 Americans. The most common type of stone, calcium oxalate is known to form on a calcium phosphate deposit on the renal papilla known as Randall's plaque. Novel imaging techniques have identified distinct regions of biomineralization not just at the tip, but throughout the renal papilla. The classic understanding of Randall's plaque formation is reformulated using correlative imaging techniques. This study establishes a stepwise progression of anatomically-specific biomineralization events including, 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones, and provides insights into the need for plausible site-specific therapeutic intervention.

Graphical abstract

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In vitro methods for the evaluation of antimicrobial surface designs

Publication date: Available online 10 February 2018
Source:Acta Biomaterialia
Author(s): Jelmer Sjollema, Sebastian A.J. Zaat, Veronique Fontaine, Madeleine Ramstedt, Reto Luginbuehl, Karin Thevissen, Jiuyi Li, Henny C. van der Mei, Henk J. Busscher
Bacterial adhesion and subsequent biofilm formation on biomedical implants and devices are a major cause of their failure. As systemic antibiotic treatment is often ineffective, there is an urgent need for antimicrobial biomaterials and coatings. The term "antimicrobial" can encompass different mechanisms of action (here termed "antimicrobial surface designs"), such as antimicrobial-releasing, contact-killing or non-adhesivity. Biomaterials equipped with antimicrobial surface designs based on different mechanisms of action require different in vitro evaluation methods. Available industrial standard evaluation tests do not address the specific mechanisms of different antimicrobial surface designs and have therefore been modified over the past years, adding to the myriad of methods available in the literature to evaluate antimicrobial surface designs. The aim of this review is to categorize fourteen presently available methods including industrial standard tests for the in vitro evaluation of antimicrobial surface designs according to their suitability with respect to their antimicrobial mechanism of action. There is no single method or industrial test that allows to distinguish antimicrobial designs according to all three mechanisms identified here. However, critical consideration of each method clearly relates the different methods to a specific mechanism of antimicrobial action. It is anticipated that use of the provided table with the fourteen methods will avoid the use of wrong methods for evaluating new antimicrobial designs and therewith facilitate translation of novel antimicrobial biomaterials and coatings to clinical use. The need for more and better updated industrial standard tests is emphasized.Statement of SignificanceEuropean COST-action TD1305, IPROMEDAI aims to provide better understanding of mechanisms of antimicrobial surface designs of biomaterial implants and devices. Current industrial evaluation standard tests do not sufficiently account for different, advanced antimicrobial surface designs, yet are urgently needed to obtain convincing in vitro data for approval of animal experiments and clinical trials. This review aims to provide an innovative and clear guide to choose appropriate evaluation methods for three distinctly different mechanisms of antimicrobial design: (1) antimicrobial-releasing, (2) contact-killing and (3) non-adhesivity. Use of antimicrobial evaluation methods and definition of industrial standard tests, tailored toward the antimicrobial mechanism of the design, as identified here, fulfill a missing link in the translation of novel antimicrobial surface designs to clinical use.

Graphical abstract

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