Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis.

PubMed

Kim, Soo-Hyun; Redvers, Richard P; Chi, Lap Hing; Ling, Xiawei; Lucke, Andrew J; Reid, Robert C; Fairlie, David P; Baptista Moreno Martin, Ana Carolina; Anderson, Robin L; Denoyer, Delphine; Pouliot, Normand

2018-05-21

Breast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis. © 2018. Published by The Company of Biologists Ltd.

Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs

PubMed Central

Burr, David B.; Liu, Ziyue; Allen, Matthew R.

2014-01-01

Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than bone’s material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1 ml/kg/day) or alendronate (ALN) at a clinical dose (0.2 mg/kg/day). Treatment duration ranged from 3 months to 3 years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of femoral cortical bone in humans. PMID:25445446

Seventeen Years of Using Flowable Resin Restoratives--A Dental Practitioner's Personal Clinical Review.

PubMed

Firla, Markus Th

2015-04-01

Seen through the author's eyes on the basis of his practising dentistry for almost three decades, light-activated flowable resin restoratives (FRCs) or, in common clinical dental terminology, flowable composites have gradually gained major importance in restorative dentistry. Inputs to this ongoing trend are coming from continuous improvements in material properties and the favourable handling characteristics experienced with this particular group of restoratives. Intended to be used in direct adhesive filling procedures, the number and variety of recent generations of flowable composites for lining, restoration of all cavity classes (I-V), core build-ups and, more recently, 'bulk-fill-restorations', however, necessitates a profound clinical understanding of the selective use of flowable composites to ensure clinical success and guarantee long-term high quality results. Clinical relevance: Today's flowable composites allow for reliable restoration of all kinds of defects. However, both the handling characteristics and the material properties of FRCs must be fully understood before taking advantage of their potentially excellent clinical performance.

Fluorescence properties of human teeth and dental calculus for clinical applications

NASA Astrophysics Data System (ADS)

Lee, Yong-Keun

2015-04-01

Fluorescent emission of human teeth and dental calculus is important for the esthetic rehabilitation of teeth, diagnosis of dental caries, and detection of dental calculus. The purposes of this review were to summarize the fluorescence and phosphorescence of human teeth by ambient ultraviolet (UV) light, to investigate the clinically relevant fluorescence measurement methods in dentistry, and to review the fluorescence of teeth and dental calculus by specific wavelength light. Dentine was three times more phosphorescent than enamel. When exposed to light sources containing UV components, the fluorescence of human teeth gives them the quality of vitality, and fluorescent emission with a peak of 440 nm is observed. Esthetic restorative materials should have fluorescence properties similar to those of natural teeth. Based on the fluorescence of teeth and restorative materials as determined with a spectrophotometer, a fluorescence parameter was defined. As to the fluorescence spectra by a specific wavelength, varied wavelengths were investigated for clinical applications, and several methods for the diagnosis of dental caries and the detection of dental calculus were developed. Since fluorescent properties of dental hard tissues have been used and would be expanded in diverse fields of clinical practice, these properties should be investigated further, embracing newly developed optical techniques.

Fluorescence properties of human teeth and dental calculus for clinical applications.

PubMed

Lee, Yong-Keun

2015-04-01

Fluorescent emission of human teeth and dental calculus is important for the esthetic rehabilitation of teeth, diagnosis of dental caries, and detection of dental calculus. The purposes of this review were to summarize the fluorescence and phosphorescence of human teeth by ambient ultraviolet (UV) light, to investigate the clinically relevant fluorescence measurement methods in dentistry, and to review the fluorescence of teeth and dental calculus by specific wavelength light. Dentine was three times more phosphorescent than enamel. When exposed to light sources containing UV components, the fluorescence of human teeth gives them the quality of vitality, and fluorescent emission with a peak of 440 nm is observed. Esthetic restorative materials should have fluorescence properties similar to those of natural teeth. Based on the fluorescence of teeth and restorative materials as determined with a spectrophotometer, a fluorescence parameter was defined. As to the fluorescence spectra by a specific wavelength, varied wavelengths were investigated for clinical applications, and several methods for the diagnosis of dental caries and the detection of dental calculus were developed. Since fluorescent properties of dental hard tissues have been used and would be expanded in diverse fields of clinical practice, these properties should be investigated further, embracing newly developed optical techniques.

Comparsion analysis of data mining models applied to clinical research in traditional Chinese medicine.

PubMed

Zhao, Yufeng; Xie, Qi; He, Liyun; Liu, Baoyan; Li, Kun; Zhang, Xiang; Bai, Wenjing; Luo, Lin; Jing, Xianghong; Huo, Ruili

2014-10-01

To help researchers selecting appropriate data mining models to provide better evidence for the clinical practice of Traditional Chinese Medicine (TCM) diagnosis and therapy. Clinical issues based on data mining models were comprehensively summarized from four significant elements of the clinical studies: symptoms, symptom patterns, herbs, and efficacy. Existing problems were further generalized to determine the relevant factors of the performance of data mining models, e.g. data type, samples, parameters, variable labels. Combining these relevant factors, the TCM clinical data features were compared with regards to statistical characters and informatics properties. Data models were compared simultaneously from the view of applied conditions and suitable scopes. The main application problems were the inconsistent data type and the small samples for the used data mining models, which caused the inappropriate results, even the mistake results. These features, i.e. advantages, disadvantages, satisfied data types, tasks of data mining, and the TCM issues, were summarized and compared. By aiming at the special features of different data mining models, the clinical doctors could select the suitable data mining models to resolve the TCM problem.

Flowable Resin Composites: A Systematic Review and Clinical Considerations

PubMed Central

Rodrigues, Jean C.

2015-01-01

Background Little is known about flowable composite materials. Most literature mentions conventional composite materials at large, giving minimal emphasis to flowables in particular. This paper briefly gives an in depth insight to the multiple facets of this versatile material. Aim To exclusively review the most salient features of flowable composite materials in comparison to conventional composites and to give clinicians a detailed understanding of the advantages, drawbacks, indications and contraindications based on composition and physical/mechanical properties. Methodology Data Sources: A thorough literature search from the year 1996 up to January 2015 was done on PubMed Central, The Cochrane Library, Science Direct, Wiley Online Library, and Google Scholar. Grey literature (pending patents, technical reports etc.) was also screened. The search terms used were “dental flowable resin composites”. Search Strategy After omitting the duplicates/repetitions, a total of 491 full text articles were assessed. As including all articles were out of the scope of this paper. Only relevant articles that fulfilled the reviewer’s objectives {mentioning indications, contraindications, applications, assessment of physical/mechanical/biological properties (in vitro/ in vivo /ex vivo)} were considered. A total of 92 full text articles were selected. Conclusion Flowable composites exhibit a variable composition and consequently variable mechanical/ physical properties. Clinicians must be aware of this aspect to make a proper material selection based on specific properties and indications of each material relevant to a particular clinical situation. PMID:26266238

In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

PubMed Central

Beedie, Shaunna L.; Rore, Holly M.; Barnett, Shelby; Chau, Cindy H.; Luo, Weiming; Greig, Nigel H.; Figg, William D.; Vargesson, Neil

2016-01-01

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions. PMID:27120781

SFINX-a drug-drug interaction database designed for clinical decision support systems.

PubMed

Böttiger, Ylva; Laine, Kari; Andersson, Marine L; Korhonen, Tuomas; Molin, Björn; Ovesjö, Marie-Louise; Tirkkonen, Tuire; Rane, Anders; Gustafsson, Lars L; Eiermann, Birgit

2009-06-01

The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.

The Dot Pattern Expectancy Task: Reliability and Replication of Deficits in Schizophrenia

ERIC Educational Resources Information Center

Jones, Jessica A. H.; Sponheim, Scott R.; MacDonald, Angus W., III

2010-01-01

The dot pattern expectancy (DPX) task was created to efficiently assess context-processing deficits in patients with schizophrenia. Three studies investigated the characteristics of the DPX relevant for clinical applications. To answer questions regarding the psychometric properties of the task, performance on this task was studied in 2 healthy…

The effect of clinically relevant thermocycling on the flexural properties of endodontic post materials.

PubMed

Stewardson, Dominic A; Shortall, Adrian C; Marquis, Peter M

2010-05-01

It is suggested that fibre-reinforced composite (FRC) posts have lower elastic moduli than metal posts and this will reduce the incidence of root fracture. However, the mechanical properties may be altered in the oral environment. The aims of this study were to determine the effect on the flexural properties of FRC and metal post materials produced by: (1) a thermocycling regime which was clinically relevant and representative of that which would occur during 1 year in the mouth and (2) storage for 1 year at body temperature. Nine FRC and two metal post material samples were sealed in polythene sleeves and thermocycled between 10 degrees C and 50 degrees C for 10,000 cycles. Additional samples were stored dry at 37 degrees C for 1 year. The flexural strength and moduli were determined by three-point bending and compared with untreated control samples. Thermocycling and storage at 37 degrees C for 1 year decreased the mean flexural modulus of all materials. This was statistically significant for 8 of 11 materials after thermocycling, and 4 of 11 materials after storage at 37 degrees C (p<0.05). Thermocycling and storage at 37 degrees C produced a non-significant increase in yield strength for both metal post materials. Thermocycling significantly increased the flexural strength of Postec while it decreased for the other FRC materials. Storage at 37 degrees C increased the flexural strength of three FRC materials (significantly for Postec) while it was decreased among the other materials. Although some of the changes noticed in flexural properties were statistically significant, it is doubtful that they are of sufficient magnitude to affect clinical performance.

Dental Cements for Luting and Bonding Restorations: Self-Adhesive Resin Cements.

PubMed

Manso, Adriana P; Carvalho, Ricardo M

2017-10-01

Self-adhesive resin cements combine easy application of conventional luting materials with improved mechanical properties and bonding capability of resin cements. The presence of functional acidic monomers, dual cure setting mechanism, and fillers capable of neutralizing the initial low pH of the cement are essential elements of the material and should be understood when selecting the ideal luting material for each clinical situation. This article addresses the most relevant aspects of self-adhesive resin cements and their potential impact on clinical performance. Although few clinical studies are available to establish solid clinical evidence, the information presented provides clinical guidance in the dynamic environment of material development. Copyright © 2017 Elsevier Inc. All rights reserved.

Clinical appraisal of arterial stiffness: the Argonauts in front of the Golden Fleece

PubMed Central

Vlachopoulos, C; Aznaouridis, K; Stefanadis, C

2006-01-01

Interest in evaluating arterial elastic properties has grown in parallel with the widespread availability of non‐invasive methods for assessing arterial stiffness. A clinically useful diagnostic index must be pathophysiologically relevant, must be readily measurable, and must indicate the severity of the disease and predict the corresponding risk. Interventional modification of this index must parallel disease regression and benefit prognosis. The current evidence for the clinical value of estimating arterial stiffness (mainly of large, elastic‐type arteries, such as the aorta and the carotids) in the contemporary era of cardiovascular medicine is reviewed. PMID:16339817

Development and Evaluation of the Balanced Index of Psychological Mindedness (BIPM)

ERIC Educational Resources Information Center

Nyklicek, Ivan; Denollet, Johan

2009-01-01

Psychological mindedness (PM) refers to a person's interest and ability to be in touch with and reflect on his or her psychological states and processes. In this multipart study, the authors present the Balanced Index of Psychological Mindedness (BIPM). The psychometric properties and clinical relevance of this 14-item self-report scale were…

[30 years since the first AIDS cases were reported: history and the present. Part II].

PubMed

Brůcková, Marie

2012-09-01

HIV taxonomy, morphology, biophysical properties, and replication cycle as well as modes of HIV transmission in humans are described. State of the art laboratory diagnosis of HIV/AIDS, core clinical diagnostic criteria for AIDS, and AIDS treatment guidelines are summarized. Global HIV/AIDS epidemic and relevant prevention activities are discussed.

[Analysis on replacement of traditional Chinese medicine bear bile with bile acids based on drug properties].

PubMed

Yuan, Bin; Ren, Ying-Long; Ma, Li; Gu, Hao; Wang, Yun; Qiao, Yan-Jiang

2014-02-01

To discuss the rationality of the clinical replacement of traditional Chinese medicine (TCM) bear bile with bile acid constituents, and analyze the difference between these constituents and bear bile in drug properties. Summarizing the drug properties of bear bile by reference to medical literatures for drug properties of TCM bear bile and Science of Traditional Chinese Medicine (China Press of Traditional Chinese Medicine, 2007). Analyzing and summarizing the pharmacological effects of main bile acid constituents according to relevant literatures for studies on pharmacological effects of main bile acid constituents in CNKI database. Predicating the drug properties of these bile acid constituents by using the drug property predication model established by the study group according the pharmacological effects of main bile acid constituents in the paper, and compare the prediction results with the drug properties of bear bile. Bile acid constituents in bear bile were mostly cold in property, bitter in taste, and the combination of their drug properties could reflect the combined drug properties of bear bile. All of these bile acid constituents in bear bile could show part of effects of bear bile. Attention shall be given to regulate the medication scheme in clinical application according to actual conditions.

Oligonucleotide-based pharmaceuticals: Non-clinical and clinical safety signals and non-clinical testing strategies.

PubMed

Mustonen, Enni-Kaisa; Palomäki, Tiina; Pasanen, Markku

2017-11-01

Antisense oligonucleotides, short interfering RNAs (siRNAs) and aptamers are oligonucleotide-based pharmaceuticals with a promising role in targeted therapies. Currently, five oligonucleotide-based pharmaceuticals have achieved marketing authorization in Europe or USA and many more are undergoing clinical testing. However, several safety concerns have been raised in non-clinical and clinical studies. Oligonucleotides share properties with both chemical and biological pharmaceuticals and therefore they pose challenges also from the regulatory point of view. We have analyzed the safety data of oligonucleotides and evaluated the applicability of current non-clinical toxicological guidelines for assessing the safety of oligonucleotide-based pharmaceuticals. Oligonucleotide-based pharmaceuticals display a similar toxicological profile, exerting adverse effects on liver and kidney, evoking hematological alterations, as well as causing immunostimulation and prolonging the coagulation time. It is possible to extrapolate some of these effects from non-clinical studies to humans. However, evaluation strategies for genotoxicity testing of "non-natural" oligonucleotides should be revised. Additionally, the selective use of surrogates and prediction of clinical endpoints for non-clinically observed immunostimulation is complicated by its multiple potential manifestations, demanding improvements in the testing strategies. Utilizing more relevant and mechanistic-based approaches and taking better account of species differences, could possibly improve the prediction of relevant immunological/proinflammatory effects in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

Shear lag sutures: Improved suture repair through the use of adhesives

PubMed Central

Linderman, Stephen W.; Kormpakis, Ioannis; Gelberman, Richard H.; Birman, Victor; Wegst, Ulrike G. K.; Genin, Guy M.; Thomopoulos, Stavros

2015-01-01

Suture materials and surgical knot tying techniques have improved dramatically since their first use over five millennia ago. However, the approach remains limited by the ability of the suture to transfer load to tissue at suture anchor points. Here, we predict that adhesive-coated sutures can improve mechanical load transfer beyond the range of performance of existing suture methods, thereby strengthening repairs and decreasing the risk of failure. The mechanical properties of suitable adhesives were identified using a shear lag model. Examination of the design space for an optimal adhesive demonstrated requirements for strong adhesion and low stiffness to maximize the strength of the adhesive-coated suture repair construct. To experimentally assess the model, we evaluated single strands of sutures coated with highly flexible cyanoacrylates (Loctite 4903 and 4902), cyanoacrylate (Loctite QuickTite Instant Adhesive Gel), rubber cement, rubber/gasket adhesive (1300 Scotch-Weld Neoprene High Performance Rubber & Gasket Adhesive), an albumin-glutaraldehyde adhesive (BioGlue), or poly(dopamine). As a clinically relevant proof-of-concept, cyanoacrylate-coated sutures were then used to perform a clinically relevant flexor digitorum tendon repair in cadaver tissue. The repair performed with adhesive-coated suture had significantly higher strength compared to the standard repair without adhesive. Notably, cyanoacrylate provides strong adhesion with high stiffness and brittle behavior, and is therefore not an ideal adhesive for enhancing suture repair. Nevertheless, the improvement in repair properties in a clinically relevant setting, even using a non-ideal adhesive, demonstrates the potential for the proposed approach to improve outcomes for treatments requiring suture fixation. Further study is necessary to develop a strongly adherent, compliant adhesive within the optimal design space described by the model. PMID:26022966

Biologically relevant photoacoustic imaging phantoms with tunable optical and acoustic properties

PubMed Central

Vogt, William C.; Jia, Congxian; Wear, Keith A.; Garra, Brian S.; Joshua Pfefer, T.

2016-01-01

Abstract. Established medical imaging technologies such as magnetic resonance imaging and computed tomography rely on well-validated tissue-simulating phantoms for standardized testing of device image quality. The availability of high-quality phantoms for optical-acoustic diagnostics such as photoacoustic tomography (PAT) will facilitate standardization and clinical translation of these emerging approaches. Materials used in prior PAT phantoms do not provide a suitable combination of long-term stability and realistic acoustic and optical properties. Therefore, we have investigated the use of custom polyvinyl chloride plastisol (PVCP) formulations for imaging phantoms and identified a dual-plasticizer approach that provides biologically relevant ranges of relevant properties. Speed of sound and acoustic attenuation were determined over a frequency range of 4 to 9 MHz and optical absorption and scattering over a wavelength range of 400 to 1100 nm. We present characterization of several PVCP formulations, including one designed to mimic breast tissue. This material is used to construct a phantom comprised of an array of cylindrical, hemoglobin-filled inclusions for evaluation of penetration depth. Measurements with a custom near-infrared PAT imager provide quantitative and qualitative comparisons of phantom and tissue images. Results indicate that our PVCP material is uniquely suitable for PAT system image quality evaluation and may provide a practical tool for device validation and intercomparison. PMID:26886681

Biomechanical properties of the spinal cord: implications for tissue engineering and clinical translation.

PubMed

Bartlett, Richard D; Choi, David; Phillips, James B

2016-10-01

Spinal cord injury is a severely debilitating condition which can leave individuals paralyzed and suffering from autonomic dysfunction. Regenerative medicine may offer a promising solution to this problem. Previous research has focused primarily on exploring the cellular and biological aspects of the spinal cord, yet relatively little remains known about the biomechanical properties of spinal cord tissue. Given that a number of regenerative strategies aim to deliver cells and materials in the form of tissue-engineered therapies, understanding the biomechanical properties of host spinal cord tissue is important. We review the relevant biomechanical properties of spinal cord tissue and provide the baseline knowledge required to apply these important physical concepts to spinal cord tissue engineering.

Epileptic activity in Alzheimer’s disease: causes and clinical relevance

PubMed Central

Vossel, Keith A; Tartaglia, Maria C; Nygaard, Haakon B; Zeman, Adam Z; Miller, Bruce L

2018-01-01

Epileptic activity is frequently associated with Alzheimer’s disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer’s disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer’s disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer’s disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer’s disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer’s disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer’s disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline. PMID:28327340

The Safety Attitudes Questionnaire: psychometric properties, benchmarking data, and emerging research.

PubMed

Sexton, John B; Helmreich, Robert L; Neilands, Torsten B; Rowan, Kathy; Vella, Keryn; Boyden, James; Roberts, Peter R; Thomas, Eric J

2006-04-03

There is widespread interest in measuring healthcare provider attitudes about issues relevant to patient safety (often called safety climate or safety culture). Here we report the psychometric properties, establish benchmarking data, and discuss emerging areas of research with the University of Texas Safety Attitudes Questionnaire. Six cross-sectional surveys of health care providers (n = 10,843) in 203 clinical areas (including critical care units, operating rooms, inpatient settings, and ambulatory clinics) in three countries (USA, UK, New Zealand). Multilevel factor analyses yielded results at the clinical area level and the respondent nested within clinical area level. We report scale reliability, floor/ceiling effects, item factor loadings, inter-factor correlations, and percentage of respondents who agree with each item and scale. A six factor model of provider attitudes fit to the data at both the clinical area and respondent nested within clinical area levels. The factors were: Teamwork Climate, Safety Climate, Perceptions of Management, Job Satisfaction, Working Conditions, and Stress Recognition. Scale reliability was 0.9. Provider attitudes varied greatly both within and among organizations. Results are presented to allow benchmarking among organizations and emerging research is discussed. The Safety Attitudes Questionnaire demonstrated good psychometric properties. Healthcare organizations can use the survey to measure caregiver attitudes about six patient safety-related domains, to compare themselves with other organizations, to prompt interventions to improve safety attitudes and to measure the effectiveness of these interventions.

Multifunctional Quantum Dots for Personalized Medicine

PubMed Central

Zrazhevskiy, Pavel; Gao, Xiaohu

2009-01-01

Successes in biomedical research and state-of-the-art medicine have undoubtedly improved the quality of life. However, a number of diseases, such as cancer, immunodeficiencies, and neurological disorders, still evade conventional diagnostic and therapeutic approaches. A transformation towards personalized medicine may help to combat these diseases. For this, identification of disease molecular fingerprints and their association with prognosis and targeted therapy must become available. Quantum dots (QDs), semiconductor nanocrystals with unique photo-physical properties, represent a novel class of fluorescence probes to address many of the needs of personalized medicine. This review outlines the properties of QDs that make them a suitable platform for advancing personalized medicine, examines several proof-of-concept studies showing utility of QDs for clinically relevant applications, and discusses current challenges in introducing QDs into clinical practice. PMID:20161004

Clinical relevance vs. statistical significance: Using neck outcomes in patients with temporomandibular disorders as an example.

PubMed

Armijo-Olivo, Susan; Warren, Sharon; Fuentes, Jorge; Magee, David J

2011-12-01

Statistical significance has been used extensively to evaluate the results of research studies. Nevertheless, it offers only limited information to clinicians. The assessment of clinical relevance can facilitate the interpretation of the research results into clinical practice. The objective of this study was to explore different methods to evaluate the clinical relevance of the results using a cross-sectional study as an example comparing different neck outcomes between subjects with temporomandibular disorders and healthy controls. Subjects were compared for head and cervical posture, maximal cervical muscle strength, endurance of the cervical flexor and extensor muscles, and electromyographic activity of the cervical flexor muscles during the CranioCervical Flexion Test (CCFT). The evaluation of clinical relevance of the results was performed based on the effect size (ES), minimal important difference (MID), and clinical judgement. The results of this study show that it is possible to have statistical significance without having clinical relevance, to have both statistical significance and clinical relevance, to have clinical relevance without having statistical significance, or to have neither statistical significance nor clinical relevance. The evaluation of clinical relevance in clinical research is crucial to simplify the transfer of knowledge from research into practice. Clinical researchers should present the clinical relevance of their results. Copyright © 2011 Elsevier Ltd. All rights reserved.

The optical, photothermal, and facile surface chemical properties of gold and silver nanoparticles in biodiagnostics, therapy, and drug delivery

PubMed Central

Austin, Lauren A.; Mackey, Megan A.; Dreaden, Erik C.

2014-01-01

Nanotechnology is a rapidly growing area of research in part due to its integration into many biomedical applications. Within nanotechnology, gold and silver nanostructures are some of the most heavily utilized nanomaterial due to their unique optical, photothermal, and facile surface chemical properties. In this review, common colloid synthesis methods and biofunctionalization strategies of gold and silver nanostructures are highlighted. Their unique properties are also discussed in terms of their use in biodiagnostic, imaging, therapeutic, and drug delivery applications. Furthermore, relevant clinical applications utilizing gold and silver nanostructures are also presented. We also provide a table with reviews covering related topics. PMID:24894431

Defining functioning levels in patients with schizophrenia: A combination of a novel clustering method and brain SPECT analysis.

PubMed

Catherine, Faget-Agius; Aurélie, Vincenti; Eric, Guedj; Pierre, Michel; Raphaëlle, Richieri; Marine, Alessandrini; Pascal, Auquier; Christophe, Lançon; Laurent, Boyer

2017-12-30

This study aims to define functioning levels of patients with schizophrenia by using a method of interpretable clustering based on a specific functioning scale, the Functional Remission Of General Schizophrenia (FROGS) scale, and to test their validity regarding clinical and neuroimaging characterization. In this observational study, patients with schizophrenia have been classified using a hierarchical top-down method called clustering using unsupervised binary trees (CUBT). Socio-demographic, clinical, and neuroimaging SPECT perfusion data were compared between the different clusters to ensure their clinical relevance. A total of 242 patients were analyzed. A four-group functioning level structure has been identified: 54 are classified as "minimal", 81 as "low", 64 as "moderate", and 43 as "high". The clustering shows satisfactory statistical properties, including reproducibility and discriminancy. The 4 clusters consistently differentiate patients. "High" functioning level patients reported significantly the lowest scores on the PANSS and the CDSS, and the highest scores on the GAF, the MARS and S-QoL 18. Functioning levels were significantly associated with cerebral perfusion of two relevant areas: the left inferior parietal cortex and the anterior cingulate. Our study provides relevant functioning levels in schizophrenia, and may enhance the use of functioning scale. Copyright © 2017 Elsevier B.V. All rights reserved.

Molecular allergy diagnostics using IgE singleplex determinations: methodological and practical considerations for use in clinical routine: Part 18 of the Series Molecular Allergology.

PubMed

Kleine-Tebbe, Jörg; Jakob, Thilo

Allergen molecules (synonyms: single allergens, allergen components) open up new horizons for the targeted allergen-specific diagnostics of immunoglobulin E (IgE) in singleplex determination. The following rationales support the targeted use of allergen molecules and, more importantly, improve test properties: (1) increased test sensitivity ("analytical sensitivity"), particularly when important allergens are under-represented or lacking in the extract; (2) improved test selectivity (analytical specificity), particularly when the selected IgE repertoire against an allergen yields additional information on: (a) potential risk, (b) possible cross-reactivity, or (c) primary (species-specific) sensitization. However, the appropriate indication for the use of single allergens can only be established on a case-by-case basis (depending on the clinical context and previous history) and in an allergen-specific manner (depending on the allergen source and the single allergens available), rather than in a standardized way. Numerous investigations on suspected food allergy, insect venom allergy, or sensitization to respiratory allergens have meanwhile demonstrated the successful use of defined molecules for allergen-specific singleplex IgE diagnosis. Specific IgE to single allergens is limited in its suitability to predict the clinical relevance of sensitivity on an individual basis. In food allergies, one can at best identify the relative risk of a clinical reaction on the basis of an IgE profile, but no absolutely reliable prediction on (future) tolerance can be made. Ultimately, the clinical relevance of all IgE findings depends on the presence of corresponding symptoms and can only be assessed on an individual basis (previous history, symptom log, and provocation testing with the relevant allergen source where appropriate). Thus, also in molecular allergology, the treating physician and not the test result should determine the clinical relevance of diagnostic findings. Supplementary material is available for this article at 10.1007/s40629-015-0067-z and is accessible for authorized users.

Clinical instruments: reliability and validity critical appraisal.

PubMed

Brink, Yolandi; Louw, Quinette A

2012-12-01

RATIONALE, AIM AND OBJECTIVES: There is a lack of health care practitioners using objective clinical tools with sound psychometric properties. There is also a need for researchers to improve their reporting of the validity and reliability results of these clinical tools. Therefore, to promote the use of valid and reliable tools or tests for clinical evaluation, this paper reports on the development of a critical appraisal tool to assess the psychometric properties of objective clinical tools. A five-step process was followed to develop the new critical appraisal tool: (1) preliminary conceptual decisions; (2) defining key concepts; (3) item generation; (4) assessment of face validity; and (5) formulation of the final tool. The new critical appraisal tool consists of 13 items, of which five items relate to both validity and reliability studies, four items to validity studies only and four items to reliability studies. The 13 items could be scored as 'yes', 'no' or 'not applicable'. This critical appraisal tool will aid both the health care practitioner to critically appraise the relevant literature and researchers to improve the quality of reporting of the validity and reliability of objective clinical tools. © 2011 Blackwell Publishing Ltd.

From Single Nucleotide Polymorphisms to Constant Immunosuppression: Mesenchymal Stem Cell Therapy for Autoimmune Diseases

PubMed Central

Galipeau, Jacques; Nooka, Ajay K.

2013-01-01

The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs) make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS), linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs) in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs. PMID:24350294

The impact of the glial spatial buffering on the K(+) Nernst potential.

PubMed

Noori, H R

2011-09-01

Astrocytes play a critical role in CNS metabolism, regulation of volume and ion homeostasis of the interstitial space. Of special relevance is their clearance of K(+) that is released by active neurons into the extracellular space. Mathematical analysis of a modified Nernst equation for the electrochemical equilibrium of neuronal plasma membranes, suggests that K(+) uptake by glial cells is not only relevant during neuronal activity but also has a non-neglectable impact on the basic electrical membrane properties, specifically the resting membrane potential, of neurons and might be clinically valuable as a factor in the genetics and epigenetics of the epilepsy and tuberous sclerosis complex.

The Structured Clinically Relevant Interview for Psychiatrists in Training (SCRIPT): A New Standardized Assessment Tool for Recruitment in the UK

ERIC Educational Resources Information Center

Rao, Rahul

2007-01-01

Objective: The multifaceted nature of training and the diverse backgrounds of potential Senior House Officers (Postgraduate Residents) require a novel approach to the selection of trainees wishing to pursue a career in psychiatry. The author reports the properties of a semi-structured interview (the SCRIPT) for assessing doctors short-listed for a…

Decoupling Polymer Properties to Elucidate Mechanisms Governing Cell Behavior

PubMed Central

Wang, Xintong; Boire, Timothy C.; Bronikowski, Christine; Zachman, Angela L.; Crowder, Spencer W.

2012-01-01

Determining how a biomaterial interacts with cells (“structure-function relationship”) reflects its eventual clinical applicability. Therefore, a fundamental understanding of how individual material properties modulate cell-biomaterial interactions is pivotal to improving the efficacy and safety of clinically translatable biomaterial systems. However, due to the coupled nature of material properties, their individual effects on cellular responses are difficult to understand. Structure-function relationships can be more clearly understood by the effective decoupling of each individual parameter. In this article, we discuss three basic decoupling strategies: (1) surface modification, (2) cross-linking, and (3) combinatorial approaches (i.e., copolymerization and polymer blending). Relevant examples of coupled material properties are briefly reviewed in each section to highlight the need for improved decoupling methods. This follows with examples of more effective decoupling techniques, mainly from the perspective of three primary classes of synthetic materials: polyesters, polyethylene glycol, and polyacrylamide. Recent strides in decoupling methodologies, especially surface-patterning and combinatorial techniques, offer much promise in further understanding the structure-function relationships that largely govern the success of future advancements in biomaterials, tissue engineering, and drug delivery. PMID:22536977

Minnesota Impulse Disorders Interview (MIDI): Validation of a structured diagnostic clinical interview for impulse control disorders in an enriched community sample.

PubMed

Chamberlain, Samuel R; Grant, Jon E

2018-07-01

Disorders of impulsivity are common, functionally impairing, and highly relevant across different clinical and research settings. Few structured clinical interviews for the identification and diagnosis of impulse control disorders exist, and none have been validated in a community sample in terms of psychometric properties. The Minnesota Impulse control disorders Interview (MIDI v2.0) was administered to an enriched sample of 293 non-treatment seeking adults aged 18-35 years, recruited using media advertisements in two large US cities. In addition to the MIDI, participants undertook extended clinical interview for other mental disorders, the Barratt impulsiveness questionnaire, and the Padua obsessive-compulsive inventory. The psychometric properties of the MIDI were characterized. In logistic regression, the MIDI showed good concurrent validity against the reference measures (versus gambling disorder interview, p < 0.001; Barratt impulsiveness attentional and non-planning scores p < 0.05), and good discriminant validity versus primarily non-impulsive symptoms, including against anxiety, depression, and obsessive-compulsive symptoms (all p > 0.05). Test re-test reliability was excellent (0.95). The MIDI has good psychometric properties and thus may be a valuable interview tool for clinical and research studies involving impulse control disorders. Further research is needed to better understanding the optimal diagnostic classification and neurobiology of these neglected disorders. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

BIOPHYSICAL PROPERTIES OF NUCLEIC ACIDS AT SURFACES RELEVANT TO MICROARRAY PERFORMANCE.

PubMed

Rao, Archana N; Grainger, David W

2014-04-01

Both clinical and analytical metrics produced by microarray-based assay technology have recognized problems in reproducibility, reliability and analytical sensitivity. These issues are often attributed to poor understanding and control of nucleic acid behaviors and properties at solid-liquid interfaces. Nucleic acid hybridization, central to DNA and RNA microarray formats, depends on the properties and behaviors of single strand (ss) nucleic acids (e.g., probe oligomeric DNA) bound to surfaces. ssDNA's persistence length, radius of gyration, electrostatics, conformations on different surfaces and under various assay conditions, its chain flexibility and curvature, charging effects in ionic solutions, and fluorescent labeling all influence its physical chemistry and hybridization under assay conditions. Nucleic acid (e.g., both RNA and DNA) target interactions with immobilized ssDNA strands are highly impacted by these biophysical states. Furthermore, the kinetics, thermodynamics, and enthalpic and entropic contributions to DNA hybridization reflect global probe/target structures and interaction dynamics. Here we review several biophysical issues relevant to oligomeric nucleic acid molecular behaviors at surfaces and their influences on duplex formation that influence microarray assay performance. Correlation of biophysical aspects of single and double-stranded nucleic acids with their complexes in bulk solution is common. Such analysis at surfaces is not commonly reported, despite its importance to microarray assays. We seek to provide further insight into nucleic acid-surface challenges facing microarray diagnostic formats that have hindered their clinical adoption and compromise their research quality and value as genomics tools.

BIOPHYSICAL PROPERTIES OF NUCLEIC ACIDS AT SURFACES RELEVANT TO MICROARRAY PERFORMANCE

PubMed Central

Rao, Archana N.; Grainger, David W.

2014-01-01

Both clinical and analytical metrics produced by microarray-based assay technology have recognized problems in reproducibility, reliability and analytical sensitivity. These issues are often attributed to poor understanding and control of nucleic acid behaviors and properties at solid-liquid interfaces. Nucleic acid hybridization, central to DNA and RNA microarray formats, depends on the properties and behaviors of single strand (ss) nucleic acids (e.g., probe oligomeric DNA) bound to surfaces. ssDNA’s persistence length, radius of gyration, electrostatics, conformations on different surfaces and under various assay conditions, its chain flexibility and curvature, charging effects in ionic solutions, and fluorescent labeling all influence its physical chemistry and hybridization under assay conditions. Nucleic acid (e.g., both RNA and DNA) target interactions with immobilized ssDNA strands are highly impacted by these biophysical states. Furthermore, the kinetics, thermodynamics, and enthalpic and entropic contributions to DNA hybridization reflect global probe/target structures and interaction dynamics. Here we review several biophysical issues relevant to oligomeric nucleic acid molecular behaviors at surfaces and their influences on duplex formation that influence microarray assay performance. Correlation of biophysical aspects of single and double-stranded nucleic acids with their complexes in bulk solution is common. Such analysis at surfaces is not commonly reported, despite its importance to microarray assays. We seek to provide further insight into nucleic acid-surface challenges facing microarray diagnostic formats that have hindered their clinical adoption and compromise their research quality and value as genomics tools. PMID:24765522

Quality Measurement Recommendations Relevant to Clinical Guidelines in Germany and the United Kingdom: (What) Can We Learn From Each Other?

PubMed Central

Petzold, Thomas; Deckert, Stefanie; Williamson, Paula R.; Schmitt, Jochen

2018-01-01

We conducted a systematic review of clinical guidelines (CGs) to examine the methodological approaches of quality indicator derivation in CGs, the frequency of quality indicators to check CG recommendations in routine care, and clinimetric properties of quality indicators. We analyzed the publicly available CG databases of the Association of the Scientific Medical Societies in Germany (AWMF) and National Institute for Health and Care Excellence (NICE). Data on the methodology of subsequent quality indicator derivation, the content and definition of recommended quality indicators, and clinimetric properties of measurement instruments were extracted. In Germany, no explicit methodological guidance exists, but 3 different approaches are used. For NICE, a general approach is used for the derivation of quality indicators out of quality standards. Quality indicators were defined in 34 out of 87 CGs (39%) in Germany and for 58 out of 133 (43%) NICE CGs. Statements regarding measurement properties of instruments for quality indicator assessment were missing in German and NICE documents. Thirteen pairs of CGs (32%) have associated quality indicators. Thirty-four quality indicators refer to the same aspect of the quality of care, which corresponds to 27% of the German and 7% of NICE quality indicators. The development of a standardized and internationally accepted methodology for the derivation of quality indicators relevant to CGs is needed to measure and compare quality of care in health care systems. PMID:29591538

Concise Review: Apoptotic Cell-Based Therapies-Rationale, Preclinical Results and Future Clinical Developments.

PubMed

Saas, Philippe; Daguindau, Etienne; Perruche, Sylvain

2016-06-01

The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases. Based on these studies, we have identified critical steps to design future clinical trials. This includes: the administration route, the number and schedule of administration, the appropriate apoptotic cell type to be used, as well as the apoptotic signal. We also have analyzed the clinical relevancy of apoptotic-cell-based therapies in experimental models. Additional experimental data are required concerning the treatment of inflammatory diseases (excepted for sepsis) before considering future clinical trials. In contrast, apoptotic cells have been shown to favor engraftment and to reduce acute graft-versus-host disease (GvHD) in different relevant models of transplantation. This has led to the conduct of a phase 1/2a clinical trial to alleviate GvHD. The absence of toxic effects obtained in this trial may support the development of other clinical studies based on this new cell therapy. Stem Cells 2016;34:1464-1473. © 2016 AlphaMed Press.

The palmitoylethanolamide family: a new class of anti-inflammatory agents?

PubMed

Lambert, Didier M; Vandevoorde, Severine; Jonsson, Kent-Olov; Fowler, Christopher J

2002-03-01

The discovery of anandamide as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides. However, N-palmitoylethanolamine (PEA), a shorter and fully saturated analogue of anandamide, has been known since the fifties. This endogenous compound is a member of the N-acylethanolamines, found in most mammalian tissues. PEA is accumulated during inflammation and has been demonstrated to have a number of anti-inflammatory effects, including beneficial effects in clinically relevant animal models of inflammatory pain. It is now engaged in phase II clinical development, and two studies regarding the treatment of chronic lumbosciatalgia and multiple sclerosis are in progress. However, its precise mechanism of action remains debated. In the present review, the biochemical and pharmacological properties of PEA are discussed, in particular with respect to its analgesic and anti-inflammatory properties.

Exploration of the Medicinal Peptide Space.

PubMed

Gevaert, Bert; Stalmans, Sofie; Wynendaele, Evelien; Taevernier, Lien; Bracke, Nathalie; D'Hondt, Matthias; De Spiegeleer, Bart

2016-01-01

The chemical properties of peptide medicines, known as the 'medicinal peptide space' is considered a multi-dimensional subset of the global peptide space, where each dimension represents a chemical descriptor. These descriptors can be linked to biofunctional, medicinal properties to varying degrees. Knowledge of this space can increase the efficiency of the peptide-drug discovery and development process, as well as advance our understanding and classification of peptide medicines. For 245 peptide drugs, already available on the market or in clinical development, multivariate dataexploration was performed using peptide relevant physicochemical descriptors, their specific peptidedrug target and their clinical use. Our retrospective analysis indicates that clusters in the medicinal peptide space are located in a relatively narrow range of the physicochemical space: dense and empty regions were found, which can be explored for the discovery of novel peptide drugs.

Imaging macrophages with nanoparticles

NASA Astrophysics Data System (ADS)

Weissleder, Ralph; Nahrendorf, Matthias; Pittet, Mikael J.

2014-02-01

Nanomaterials have much to offer, not only in deciphering innate immune cell biology and tracking cells, but also in advancing personalized clinical care by providing diagnostic and prognostic information, quantifying treatment efficacy and designing better therapeutics. This Review presents different types of nanomaterial, their biological properties and their applications for imaging macrophages in human diseases, including cancer, atherosclerosis, myocardial infarction, aortic aneurysm, diabetes and other conditions. We anticipate that future needs will include the development of nanomaterials that are specific for immune cell subsets and can be used as imaging surrogates for nanotherapeutics. New in vivo imaging clinical tools for noninvasive macrophage quantification are thus ultimately expected to become relevant to predicting patients' clinical outcome, defining treatment options and monitoring responses to therapy.

The Safety Attitudes Questionnaire: psychometric properties, benchmarking data, and emerging research

PubMed Central

Sexton, John B; Helmreich, Robert L; Neilands, Torsten B; Rowan, Kathy; Vella, Keryn; Boyden, James; Roberts, Peter R; Thomas, Eric J

2006-01-01

Background There is widespread interest in measuring healthcare provider attitudes about issues relevant to patient safety (often called safety climate or safety culture). Here we report the psychometric properties, establish benchmarking data, and discuss emerging areas of research with the University of Texas Safety Attitudes Questionnaire. Methods Six cross-sectional surveys of health care providers (n = 10,843) in 203 clinical areas (including critical care units, operating rooms, inpatient settings, and ambulatory clinics) in three countries (USA, UK, New Zealand). Multilevel factor analyses yielded results at the clinical area level and the respondent nested within clinical area level. We report scale reliability, floor/ceiling effects, item factor loadings, inter-factor correlations, and percentage of respondents who agree with each item and scale. Results A six factor model of provider attitudes fit to the data at both the clinical area and respondent nested within clinical area levels. The factors were: Teamwork Climate, Safety Climate, Perceptions of Management, Job Satisfaction, Working Conditions, and Stress Recognition. Scale reliability was 0.9. Provider attitudes varied greatly both within and among organizations. Results are presented to allow benchmarking among organizations and emerging research is discussed. Conclusion The Safety Attitudes Questionnaire demonstrated good psychometric properties. Healthcare organizations can use the survey to measure caregiver attitudes about six patient safety-related domains, to compare themselves with other organizations, to prompt interventions to improve safety attitudes and to measure the effectiveness of these interventions. PMID:16584553

Melaleuca alternifolia and its application against dental plaque and periodontal diseases: A systematic review.

PubMed

Casarin, Maísa; Pazinatto, Josiele; Santos, Roberto Christ Vianna; Zanatta, Fabricio Batistin

2018-02-01

This is a systematic review of clinical and laboratory studies evaluating the effect of Melaleuca alternifolia on periodontopathogens, dental plaque, gingivitis, periodontitis, and inflammatory responses. The PubMed, Cochrane, Web of science, Bireme, Lilacs, Prospero, Open Grey, and Clinical Trials databases were searched to identify potentially eligible studies through October 2016. Of 1,654 potentially eligible studies, 25 were included in the systematic review. Their methodology was evaluated through the Cochrane Handbook for clinical studies and the GRADE system for in vivo/in vitro studies. Although clinical studies must be interpreted with caution due to methodological limitations, laboratory studies have found promising results. In vitro evidences showed that M. alternifolia has bactericidal and bacteriostatic effects against the most prevalent periodontopathogens. Clinical studies found comparable effects to chlorhexidine 0.12% in reducing gingival inflammation, although the antiplaque effect was lower. M. alternifolia also showed antioxidant properties, which are beneficial to the host, allied to the reduction on immune-inflammatory responses to pathogens. This systematic review suggests that the M. alternifolia has potential anti-inflammatory and antimicrobial properties, which can be easily applied to the periodontal tissues. However, further clinical trials are needed to elucidate the clinical relevance of its application. Copyright © 2017 John Wiley & Sons, Ltd.

Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

PubMed

Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

2016-08-01

Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The effect of different classes of beta-antagonists on clinical and experimental hypertension.

PubMed

Fitzgerald, J D

1982-01-01

The reference beta adrenoceptor antagonist propranolol reduces blood pressure in about 60% of patients with essential hypertension. Pressure is reduced in the supine, and erect positions without postural hypotension as well as during exercise. The average extent of pressure reduction is approximately 26/16 mm.Hg. Though all clinically available beta antagonists reduce blood pressure, the profile may be modified by both adrenotropic and non-adrenotropic ancillary properties. Of the adrenotropic properties, potency influences dose frequency and total body burden of drug. Selective beta 1 antagonism may enhance safety without reducing efficacy in patients with obstructive airways disease. Selective beta 2 blockade does not reduce blood pressure in experimental models or normal subjects, but the response in patients is unknown. Partial agonism may reduce efficacy if the degree of stimulant activity is too great. Of the non-adrenotropic properties, membrane stabilising properties are of relevance only in so far as such agents undergo extensive biotransformation resulting in either reduced efficacy when drugs are used at fixed doses or the formation of biologically active metabolites. The additional properties of either alpha adrenergic blockade or inhibition of vascular smooth muscle tone modify both the speed of onset and the haemodynamic profile. The interaction of these ancillary pharmacological properties is evaluated in this review.

Psychometric properties of the Beck Depression Inventory-II: a comprehensive review.

PubMed

Wang, Yuan-Pang; Gorenstein, Clarice

2013-01-01

To review the psychometric properties of the Beck Depression Inventory-II (BDI-II) as a self-report measure of depression in a variety of settings and populations. Relevant studies of the BDI-II were retrieved through a search of electronic databases, a hand search, and contact with authors. Retained studies (k = 118) were allocated into three groups: non-clinical, psychiatric/institutionalized, and medical samples. The internal consistency was described as around 0.9 and the retest reliability ranged from 0.73 to 0.96. The correlation between BDI-II and the Beck Depression Inventory (BDI-I) was high and substantial overlap with measures of depression and anxiety was reported. The criterion-based validity showed good sensitivity and specificity for detecting depression in comparison to the adopted gold standard. However, the cutoff score to screen for depression varied according to the type of sample. Factor analysis showed a robust dimension of general depression composed by two constructs: cognitive-affective and somatic-vegetative. The BDI-II is a relevant psychometric instrument, showing high reliability, capacity to discriminate between depressed and non-depressed subjects, and improved concurrent, content, and structural validity. Based on available psychometric evidence, the BDI-II can be viewed as a cost-effective questionnaire for measuring the severity of depression, with broad applicability for research and clinical practice worldwide.

A preclinical Talbot-Lau prototype for x-ray dark-field imaging of human-sized objects.

PubMed

Hauke, C; Bartl, P; Leghissa, M; Ritschl, L; Sutter, S M; Weber, T; Zeidler, J; Freudenberger, J; Mertelmeier, T; Radicke, M; Michel, T; Anton, G; Meinel, F G; Baehr, A; Auweter, S; Bondesson, D; Gaass, T; Dinkel, J; Reiser, M; Hellbach, K

2018-06-01

Talbot-Lau x-ray interferometry provides information about the scattering and refractive properties of an object - in addition to the object's attenuation features. Until recently, this method was ineligible for imaging human-sized objects as it is challenging to adapt Talbot-Lau interferometers (TLIs) to the relevant x-ray energy ranges. In this work, we present a preclinical Talbot-Lau prototype capable of imaging human-sized objects with proper image quality at clinically acceptable dose levels. The TLI is designed to match a setup of clinical relevance as closely as possible. The system provides a scan range of 120 × 30 cm 2 by using a scanning beam geometry. Its ultimate load is 100 kg. High aspect ratios and fine grid periods of the gratings ensure a reasonable setup length and clinically relevant image quality. The system is installed in a university hospital and is, therefore, exposed to the external influences of a clinical environment. To demonstrate the system's capabilities, a full-body scan of a euthanized pig was performed. In addition, freshly excised porcine lungs with an extrinsically provoked pneumothorax were mounted into a human thorax phantom and examined with the prototype. Both examination sequences resulted in clinically relevant image quality - even in the case of a skin entrance air kerma of only 0.3 mGy which is in the range of human thoracic imaging. The presented case of a pneumothorax and a reader study showed that the prototype's dark-field images provide added value for pulmonary diagnosis. We demonstrated that a dedicated design of a Talbot-Lau interferometer can be applied to medical imaging by constructing a preclinical Talbot-Lau prototype. We experienced that the system is feasible for imaging human-sized objects and the phase-stepping approach is suitable for clinical practice. Hence, we conclude that Talbot-Lau x-ray imaging has potential for clinical use and enhances the diagnostic power of medical x-ray imaging. © 2018 American Association of Physicists in Medicine.

Investigation of mixed saliva by optoelectronic methods

NASA Astrophysics Data System (ADS)

Savchenko, Ekaterina; Nepomnyashchaya, Elina; Baranov, Maksim; Velichko, Elena; Aksenov, Evgenii; Bogomaz, Tatyana

2018-04-01

At present, saliva and its properties are being actively studied. Human saliva is a unique biological material that has potential in clinical practice. A detailed analysis of the characteristics and properties of saliva is relevant for diagnostic purposes. In this paper, the properties and characteristics of saliva are studied using optoelectronic methods: dynamic light scattering, electrophoretic light scattering and optical microscopy. Mixed saliva from a healthy patient and patient with diabetes mellitus type 2 was used as an object of the study. The dynamics of the behavior of a healthy and patient with diabetes mellitus type 2 is visible according to the results obtained. All three methods confirm hypothesis of structural changes in mixed saliva in the disease of diabetes mellitus type 2.

Osteoarthritis of the knee and hip. Part II: therapy with ibuprofen and a review of clinical trials.

PubMed

Adatia, Aleem; Rainsford, K D; Kean, Walter F

2012-05-01

We review the pharmacological properties and clinical evidence pertaining to the efficacy of ibuprofen as a first-line treatment in hip and knee osteoarthritis (OA). In the context of our previous paper's exploration of the aetiology and pathogenesis of OA as a basis for pharmacotherapy, we discuss the pharmacokinetics (PK) and clinical pharmacodynamics (PD) of ibuprofen relevant to OA. Although widely used, the benefits and risks of ibuprofen, especially compared with other non-steroidal anti-inflammatory drugs (NSAIDs) and placebo, have only recently been evaluated in OA of the hip and knee in randomized-controlled clinical trials (RCT). The efficacy and occurrence of adverse reactions from ibuprofen was compared with placebo in a structural review of the literature and systematic review of RCTs in large-scale clinical trials. Ibuprofen has been found to result in approximately 50-60% improvement over placebo in WOMAC scores, including those reflecting inflammatory joint pain in knee and hip OA or other indices of pain, disability and impaired function. Mega-trials performed in comparison with the newer NSAIDs, the coxibs, have shown that ibuprofen has comparable therapeutic benefits and although serious gastrointestinal conditions are sometimes more frequent after short-term treatment, longer-term (several months) therapy in OA reduces the advantages of the coxibs over other NSAIDs including ibuprofen. Cardiovascular risk, though present with coxibs and some NSAIDs in OA, is lower or slightly so with ibuprofen compared with coxibs. Ibuprofen is effective and relatively safe (especially at low over-the-counter doses and in the short term) for mild-to-moderate OA of the knee and hip. The PK properties of ibuprofen in OA (short plasma t½) confer advantages of this drug for OA, while evidence for clinically relevant PD benefits in joints of patients with OA, though limited, is suggestive of local anti-inflammatory activity. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Validation and cross-cultural pilot testing of compliance with standard precautions scale: self-administered instrument for clinical nurses.

PubMed

Lam, Simon C

2014-05-01

To perform detailed psychometric testing of the compliance with standard precautions scale (CSPS) in measuring compliance with standard precautions of clinical nurses and to conduct cross-cultural pilot testing and assess the relevance of the CSPS on an international platform. A cross-sectional and correlational design with repeated measures. Nursing students from a local registered nurse training university, nurses from different hospitals in Hong Kong, and experts in an international conference. The psychometric properties of the CSPS were evaluated via internal consistency, 2-week and 3-month test-retest reliability, concurrent validation, and construct validation. The cross-cultural pilot testing and relevance check was examined by experts on infection control from various developed and developing regions. Among 453 participants, 193 were nursing students, 165 were enrolled nurses, and 95 were registered nurses. The results showed that the CSPS had satisfactory reliability (Cronbach α = 0.73; intraclass correlation coefficient, 0.79 for 2-week test-retest and 0.74 for 3-month test-retest) and validity (optimum correlation with criterion measure; r = 0.76, P < .001; satisfactory results on known-group method and hypothesis testing). A total of 19 experts from 16 countries assured that most of the CSPS findings were relevant and globally applicable. The CSPS demonstrated satisfactory results on the basis of the standard international criteria on psychometric testing, which ascertained the reliability and validity of this instrument in measuring the compliance of clinical nurses with standard precautions. The cross-cultural pilot testing further reinforced the instrument's relevance and applicability in most developed and developing regions.

Clinical relevance in anesthesia journals.

PubMed

Lauritsen, Jakob; Møller, Ann M

2006-04-01

The purpose of this review is to present the latest knowledge and research on the definition and distribution of clinically relevant articles in anesthesia journals. It will also discuss the importance of the chosen methodology and outcome of articles. In the last few years, more attention has been paid to evidence-based medicine in anesthesia. Several articles on the subject have focused on the need to base clinical decisions on sound research employing both methodological rigor and clinically relevant outcomes. The number of systematic reviews in anesthesia literature is increasing as well as the focus on diminishing the number of surrogate outcomes. It has been shown that the impact factor is not a valid measure of establishing the level of clinical relevance to a journal. This review presents definitions of clinically relevant anesthesia articles. A clinically relevant article employs both methodological rigor and a clinically relevant outcome. The terms methodological rigor and clinical outcomes are fully discussed in the review as well as problems with journal impact factors.

Creation of a Bioengineered Skin Flap Scaffold with a Perfusable Vascular Pedicle.

PubMed

Jank, Bernhard J; Goverman, Jeremy; Guyette, Jacques P; Charest, Jon M; Randolph, Mark; Gaudette, Glenn R; Gershlak, Joshua R; Purschke, Martin; Javorsky, Emilia; Nazarian, Rosalynn M; Leonard, David A; Cetrulo, Curtis L; Austen, William G; Ott, Harald C

2017-07-01

Full-thickness skin loss is a challenging problem due to limited reconstructive options, demanding 75 million surgical procedures annually in the United States. Autologous skin grafting is the gold standard treatment, but results in donor-site morbidity and poor aesthetics. Numerous skin substitutes are available on the market to date, however, none truly functions as full-thickness skin due to lack of a vascular network. The creation of an autologous full-thickness skin analogue with a vascular pedicle would result in a paradigm shift in the management of wounds and in reconstruction of full-thickness skin defects. To create a clinically relevant foundation, we generated an acellular skin flap scaffold (SFS) with a perfusable vascular pedicle of clinically relevant size by perfusion decellularization of porcine fasciocutaneous flaps. We then analyzed the yielded SFS for mechanical properties, biocompatibility, and regenerative potential in vitro and in vivo. Furthermore, we assessed the immunological response using an in vivo model. Finally, we recellularized the vascular compartment of an SFS and reconnected it to a recipient's blood supply to test for perfusability. Perfusion decellularization removed all cellular components with preservation of native extracellular matrix composition and architecture. Biaxial testing revealed preserved mechanical properties. Immunologic response and biocompatibility assessed via implantation and compared with native xenogenic skin and commercially available dermal substitutes revealed rapid neovascularization and complete tissue integration. Composition of infiltrating immune cells showed no evidence of allorejection and resembled the inflammatory phase of wound healing. Implantation into full-thickness skin defects demonstrated good tissue integration and skin regeneration without cicatrization. We have developed a protocol for the generation of an SFS of clinically relevant size, containing a vascular pedicle, which can be utilized for perfusion decellularization and, ultimately, anastomosis to the recipient vascular system after precellularization. The observed favorable immunological response and good tissue integration indicate the substantial regenerative potential of this platform.

Marine Natural Products with P-Glycoprotein Inhibitor Properties

PubMed Central

Lopez, Dioxelis; Martinez-Luis, Sergio

2014-01-01

P-glycoprotein (P-gp) is a protein belonging to the ATP-binding cassette (ABC) transporters superfamily that has clinical relevance due to its role in drug metabolism and multi-drug resistance (MDR) in several human pathogens and diseases. P-gp is a major cause of drug resistance in cancer, parasitic diseases, epilepsy and other disorders. This review article aims to summarize the research findings on the marine natural products with P-glycoprotein inhibitor properties. Natural compounds that modulate P-gp offer great possibilities for semi-synthetic modification to create new drugs and are valuable research tools to understand the function of complex ABC transporters. PMID:24451193

High performance dental resin composites with hydrolytically stable monomers.

PubMed

Wang, Xiaohong; Huyang, George; Palagummi, Sri Vikram; Liu, Xiaohui; Skrtic, Drago; Beauchamp, Carlos; Bowen, Rafael; Sun, Jirun

2018-02-01

The objectives of this project were to: 1) develop strong and durable dental resin composites by employing new monomers that are hydrolytically stable, and 2) demonstrate that resin composites based on these monomers perform superiorly to the traditional bisphenol A glycidyl dimethacrylate/triethylene glycol dimethacrylate (Bis-GMA/TEGDMA) composites under testing conditions relevant to clinical applications. New resins comprising hydrolytically stable, ether-based monomer, i.e., triethylene glycol divinylbenzyl ether (TEG-DVBE), and urethane dimethacrylate (UDMA) were produced via composition-controlled photo-polymerization. Their composites contained 67.5wt% of micro and 7.5wt% of nano-sized filler. The performances of both copolymers and composites were evaluated by a battery of clinically-relevant assessments: degree of vinyl conversion (DC: FTIR and NIR spectroscopy); refractive index (n: optical microscopy); elastic modulus (E), flexural strength (F) and fracture toughness (K IC ) (universal mechanical testing); Knoop hardness (HK; indentation); water sorption (W sp ) and solubility (W su ) (gravimetry); polymerization shrinkage (S v ; mercury dilatometry) and polymerization stress (tensometer). The experimental UDMA/TEG-DVBE composites were compared with the Bis-GMA/TEGDMA composites containing the identical filler contents, and with the commercial micro hybrid flowable composite. UDMA/TEG-DBVE composites exhibited n, E, W sp , W su and S v equivalent to the controls. They outperformed the controls with respect to F (up to 26.8% increase), K IC (up to 27.7% increase), modulus recovery upon water sorption (full recovery vs. 91.9% recovery), and stress formation (up to 52.7% reduction). In addition, new composites showed up to 27.7% increase in attainable DC compared to the traditional composites. Bis-GMA/TEGDMA controls exceeded the experimental composites with respect to only one property, the composite hardness. Significantly, up to 18.1% lower HK values in the experimental series (0.458GPa) were still above the clinically required threshold of approx. 0.4GPa. Hydrolytic stability, composition-controlled polymerization and the overall enhancement in clinically-relevant properties of the new resin composites make them viable candidates to replace traditional resin composites as a new generation of strong and durable dental restoratives. Copyright © 2017 The Academy of Dental Materials. All rights reserved.

Advances in quantitative UV-visible spectroscopy for clinical and pre-clinical application in cancer.

PubMed

Brown, J Quincy; Vishwanath, Karthik; Palmer, Gregory M; Ramanujam, Nirmala

2009-02-01

Methods of optical spectroscopy that provide quantitative, physically or physiologically meaningful measures of tissue properties are an attractive tool for the study, diagnosis, prognosis, and treatment of various cancers. Recent development of methodologies to convert measured reflectance and fluorescence spectra from tissue to cancer-relevant parameters such as vascular volume, oxygenation, extracellular matrix extent, metabolic redox states, and cellular proliferation have significantly advanced the field of tissue optical spectroscopy. The number of publications reporting quantitative tissue spectroscopy results in the UV-visible wavelength range has increased sharply in the past three years, and includes new and emerging studies that correlate optically measured parameters with independent measures such as immunohistochemistry, which should aid in increased clinical acceptance of these technologies.

Publications in anesthesia journals: quality and clinical relevance.

PubMed

Lauritsen, Jakob; Moller, Ann M

2004-11-01

Clinicians performing evidence-based anesthesia rely on anesthesia journals for clinically relevant information. The objective of this study was to analyze the proportion of clinically relevant articles in five high impact anesthesia journals. We evaluated all articles published in Anesthesiology, Anesthesia & Analgesia, British Journal of Anesthesia, Anesthesia, and Acta Anaesthesiologica Scandinavica from January to June, 2000. Articles were assessed and classified according to type, outcome, and design; 1379 articles consisting of 5468 pages were evaluated and categorized. The most common types of article were animal and laboratory research (31.2%) and randomized clinical trial (20.4%). A clinically relevant article was defined as an article that used a statistically valid method and had a clinically relevant end-point. Altogether 18.6% of the pages had as their subject matter clinically relevant trials. We compared the Journal Impact Factor (a measure of the number of citations per article in a journal) and the proportion of clinically relevant pages and found that they were inversely proportional to each other.

Mesenchymal stem cell therapy in cats: Current knowledge and future potential.

PubMed

Quimby, Jessica M; Borjesson, Dori L

2018-03-01

Practical relevance: Stem cell therapy is an innovative field of scientific investigation with tremendous potential for clinical application in veterinary medicine. Based on the known desirable immunomodulatory properties of mesenchymal stem cells, this therapy holds promise for the treatment of a variety of inflammatory diseases in cats. This review details our current understanding of feline stem cell biology and proposed mechanism of action. Studies performed in feline clinical trials for diseases including gingivostomatitis, chronic enteropathy, asthma and kidney disease are summarized, with the goal of providing an overview of the current status of this treatment modality and its potential for the future.

Quantum cascade lasers (QCLs) in biomedical spectroscopy.

PubMed

Schwaighofer, Andreas; Brandstetter, Markus; Lendl, Bernhard

2017-10-02

Quantum cascade lasers (QCL) are the first room temperature semiconductor laser source for the mid-IR spectral region, triggering substantial development for the advancement of mid-IR spectroscopy. Mid-IR spectroscopy in general provides rapid, label-free and objective analysis, particularly important in the field of biomedical analysis. Due to their unique properties, QCLs offer new possibilities for development of analytical methods to enable quantification of clinically relevant concentration levels and to support medical diagnostics. Compared to FTIR spectroscopy, novel and elaborated measurement techniques can be implemented that allow miniaturized and portable instrumentation. This review illustrates the characteristics of QCLs with a particular focus on their benefits for biomedical analysis. Recent applications of QCL-based spectroscopy for analysis of a variety of clinically relevant samples including breath, urine, blood, interstitial fluid, and biopsy samples are summarized. Further potential for technical advancements is discussed in combination with future prospects for employment of QCL-based devices in routine and point-of-care diagnostics.

Semiconductor Quantum Dots for Bioimaging and Biodiagnostic Applications

NASA Astrophysics Data System (ADS)

Kairdolf, Brad A.; Smith, Andrew M.; Stokes, Todd H.; Wang, May D.; Young, Andrew N.; Nie, Shuming

2013-06-01

Semiconductor quantum dots (QDs) are light-emitting particles on the nanometer scale that have emerged as a new class of fluorescent labels for chemical analysis, molecular imaging, and biomedical diagnostics. Compared with traditional fluorescent probes, QDs have unique optical and electronic properties such as size-tunable light emission, narrow and symmetric emission spectra, and broad absorption spectra that enable the simultaneous excitation of multiple fluorescence colors. QDs are also considerably brighter and more resistant to photobleaching than are organic dyes and fluorescent proteins. These properties are well suited for dynamic imaging at the single-molecule level and for multiplexed biomedical diagnostics at ultrahigh sensitivity. Here, we discuss the fundamental properties of QDs; the development of next-generation QDs; and their applications in bioanalytical chemistry, dynamic cellular imaging, and medical diagnostics. For in vivo and clinical imaging, the potential toxicity of QDs remains a major concern. However, the toxic nature of cadmium-containing QDs is no longer a factor for in vitro diagnostics, so the use of multicolor QDs for molecular diagnostics and pathology is probably the most important and clinically relevant application for semiconductor QDs in the immediate future.

Semiconductor quantum dots for bioimaging and biodiagnostic applications.

PubMed

Kairdolf, Brad A; Smith, Andrew M; Stokes, Todd H; Wang, May D; Young, Andrew N; Nie, Shuming

2013-01-01

Semiconductor quantum dots (QDs) are light-emitting particles on the nanometer scale that have emerged as a new class of fluorescent labels for chemical analysis, molecular imaging, and biomedical diagnostics. Compared with traditional fluorescent probes, QDs have unique optical and electronic properties such as size-tunable light emission, narrow and symmetric emission spectra, and broad absorption spectra that enable the simultaneous excitation of multiple fluorescence colors. QDs are also considerably brighter and more resistant to photobleaching than are organic dyes and fluorescent proteins. These properties are well suited for dynamic imaging at the single-molecule level and for multiplexed biomedical diagnostics at ultrahigh sensitivity. Here, we discuss the fundamental properties of QDs; the development of next-generation QDs; and their applications in bioanalytical chemistry, dynamic cellular imaging, and medical diagnostics. For in vivo and clinical imaging, the potential toxicity of QDs remains a major concern. However, the toxic nature of cadmium-containing QDs is no longer a factor for in vitro diagnostics, so the use of multicolor QDs for molecular diagnostics and pathology is probably the most important and clinically relevant application for semiconductor QDs in the immediate future.

Semiconductor Quantum Dots for Bioimaging and Biodiagnostic Applications

PubMed Central

Kairdolf, Brad A.; Smith, Andrew M.; Stokes, Todd H.; Wang, May D.; Young, Andrew N.; Nie, Shuming

2013-01-01

Semiconductor quantum dots (QDs) are light-emitting particles on the nanometer scale that have emerged as a new class of fluorescent labels for chemical analysis, molecular imaging, and biomedical diagnostics. Compared with traditional fluorescent probes, QDs have unique optical and electronic properties such as size-tunable light emission, narrow and symmetric emission spectra, and broad absorption spectra that enable the simultaneous excitation of multiple fluorescence colors. QDs are also considerably brighter and more resistant to photobleaching than are organic dyes and fluorescent proteins. These properties are well suited for dynamic imaging at the single-molecule level and for multiplexed biomedical diagnostics at ultrahigh sensitivity. Here, we discuss the fundamental properties of QDs; the development of next-generation QDs; and their applications in bioanalytical chemistry, dynamic cellular imaging, and medical diagnostics. For in vivo and clinical imaging, the potential toxicity of QDs remains a major concern. However, the toxic nature of cadmium-containing QDs is no longer a factor for in vitro diagnostics, so the use of multicolor QDs for molecular diagnostics and pathology is probably the most important and clinically relevant application for semiconductor QDs in the immediate future. PMID:23527547

A versatile 3D tissue matrix scaffold system for tumor modeling and drug screening

PubMed Central

Rijal, Girdhari; Li, Weimin

2017-01-01

Most of the anticancer drug candidates entering preclinical trials fail to be approved for clinical applications. The following are among the main causes of these failures: studying molecular mechanisms of cancer development, identifying therapeutic targets, and testing drug candidates using inappropriate tissue culture models, which do not recapitulate the native microenvironment where the cancer cells originate. It has become clear that three-dimensional (3D) cell cultures are more biologically and clinically relevant than 2D models. The spatial and mechanical conditions of 3D cultures enable the cancer cells to display heterogeneous growth, assume diverse phenotypes, express distinct gene and protein products, and attain metastatic potential and resistance to drugs that are reminiscent of tumors in humans. However, the current 3D culture systems using synthetic polymers or selected components of the extracellular matrix (ECM) are defective (particularly the biophysical and biochemical properties of the native ECM) and remain distant to optimally support the signaling cue–oriented cell survival and growth. We introduce a reconstitutable tissue matrix scaffold (TMS) system fabricated using native tissue ECM, with tissue-like architecture and resilience. The structural and compositional properties of TMS favor robust cell survival, proliferation, migration, and invasion in culture and vascularized tumor formation in animals. The combination of porous and hydrogel TMS allows compartmental culture of cancerous and stromal cells, which are distinguishable by biomarkers. The response of the cancer cells grown on TMS to drugs well reflects animal and clinical observations. TMS enables more biologically relevant studies and is suitable for preclinical drug screening. PMID:28924608

Molindone hydrochloride: a review of laboratory and clinical findings.

PubMed

Owen, R R; Cole, J O

1989-08-01

Molindone hydrochloride, a dihydroindolone neuroleptic, is structurally distinct from other classes of neuroleptics. Molindone exhibits many similarities to other neuroleptics, including dopamine receptor blockade, antipsychotic efficacy, and extrapyramidal side effects. Despite these similarities, molindone also has atypical properties and inhibits the enzyme monoamine oxidase in vitro and in vivo. Several studies have shown that molindone causes less dopamine receptor supersensitivity than other neuroleptics and thus may be less likely to cause tardive dyskinesia. It also appears to have a greater effect on mesolimbic and mesocortical dopamine neurons than on those in the nigrostriatal dopamine system. Clinically, molindone has a tendency to cause weight loss and may have less effect on seizure threshold than conventional antipsychotic agents. The authors review the laboratory and clinical data on molindone and discuss the relevance of atypical research findings to the clinical characteristics of this antipsychotic agent.

Clinical descriptors for the recognition of central sensitization pain in patients with knee osteoarthritis.

PubMed

Lluch, Enrique; Nijs, Jo; Courtney, Carol A; Rebbeck, Trudy; Wylde, Vikki; Baert, Isabel; Wideman, Timothy H; Howells, Nick; Skou, Søren T

2017-08-02

Despite growing awareness of the contribution of central pain mechanisms to knee osteoarthritis pain in a subgroup of patients, routine evaluation of central sensitization is yet to be incorporated into clinical practice. The objective of this perspective is to design a set of clinical descriptors for the recognition of central sensitization in patients with knee osteoarthritis that can be implemented in clinical practice. A narrative review of original research papers was conducted by nine clinicians and researchers from seven different countries to reach agreement on clinically relevant descriptors. It is proposed that identification of a dominance of central sensitization pain is based on descriptors derived from the subjective assessment and the physical examination. In the former, clinicians are recommended to inquire about intensity and duration of pain and its association with structural joint changes, pain distribution, behavior of knee pain, presence of neuropathic-like or centrally mediated symptoms and responsiveness to previous treatment. The latter includes assessment of response to clinical test, mechanical hyperalgesia and allodynia, thermal hyperalgesia, hypoesthesia and reduced vibration sense. This article describes a set of clinically relevant descriptors that might indicate the presence of central sensitization in patients with knee osteoarthritis in clinical practice. Although based on research data, the descriptors proposed in this review require experimental testing in future studies. Implications for Rehabilitation Laboratory evaluation of central sensitization for people with knee osteoarthritis is yet to be incorporated into clinical practice. A set of clinical indicators for the recognition of central sensitization in patients with knee osteoarthritis is proposed. Although based on research data, the clinical indicators proposed require further experimental testing of psychometric properties.

Nanomaterials for In Vivo Imaging.

PubMed

Smith, Bryan Ronain; Gambhir, Sanjiv Sam

2017-02-08

In vivo imaging, which enables us to peer deeply within living subjects, is producing tremendous opportunities both for clinical diagnostics and as a research tool. Contrast material is often required to clearly visualize the functional architecture of physiological structures. Recent advances in nanomaterials are becoming pivotal to generate the high-resolution, high-contrast images needed for accurate, precision diagnostics. Nanomaterials are playing major roles in imaging by delivering large imaging payloads, yielding improved sensitivity, multiplexing capacity, and modularity of design. Indeed, for several imaging modalities, nanomaterials are now not simply ancillary contrast entities, but are instead the original and sole source of image signal that make possible the modality's existence. We address the physicochemical makeup/design of nanomaterials through the lens of the physical properties that produce contrast signal for the cognate imaging modality-we stratify nanomaterials on the basis of their (i) magnetic, (ii) optical, (iii) acoustic, and/or (iv) nuclear properties. We evaluate them for their ability to provide relevant information under preclinical and clinical circumstances, their in vivo safety profiles (which are being incorporated into their chemical design), their modularity in being fused to create multimodal nanomaterials (spanning multiple different physical imaging modalities and therapeutic/theranostic capabilities), their key properties, and critically their likelihood to be clinically translated.

Specialisation of extracellular matrix for function in tendons and ligaments

PubMed Central

Birch, Helen L.; Thorpe, Chavaunne T.; Rumian, Adam P.

2013-01-01

Summary Tendons and ligaments are similar structures in terms of their composition, organisation and mechanical properties. The distinction between them stems from their anatomical location; tendons form a link between muscle and bone while ligaments link bones to bones. A range of overlapping functions can be assigned to tendon and ligaments and each structure has specific mechanical properties which appear to be suited for particular in vivo function. The extracellular matrix in tendon and ligament varies in accordance with function, providing appropriate mechanical properties. The most useful framework in which to consider extracellular matrix differences therefore is that of function rather than anatomical location. In this review we discuss what is known about the relationship between functional requirements, structural properties from molecular to gross level, cellular gene expression and matrix turnover. The relevance of this information is considered by reviewing clinical aspects of tendon and ligament repair and reconstructive procedures. PMID:23885341

Healthcare professionals' agreement on clinical relevance of drug-related problems among elderly patients.

PubMed

Bech, Christine Flagstad; Frederiksen, Tine; Villesen, Christine Tilsted; Højsted, Jette; Nielsen, Per Rotbøll; Kjeldsen, Lene Juel; Nørgaard, Lotte Stig; Christrup, Lona Louring

2018-02-01

Background Disagreement among healthcare professionals on the clinical relevance of drug-related problems can lead to suboptimal treatment and increased healthcare costs. Elderly patients with chronic non-cancer pain and comorbidity are at increased risk of drug related problems compared to other patient groups due to complex medication regimes and transition of care. Objective To investigate the agreement among healthcare professionals on their classification of clinical relevance of drug-related problems in elderly patients with chronic non-cancer pain and comorbidity. Setting Multidisciplinary Pain Centre, Rigshospitalet, Copenhagen, Denmark. Method A pharmacist performed medication review on elderly patients with chronic non-cancer pain and comorbidity, identified their drug-related problems and classified these problems in accordance with an existing categorization system. A five-member clinical panel rated the drug-related problems' clinical relevance in accordance with a five-level rating scale, and their agreement was compared using Fleiss' κ. Main outcome measure Healthcare professionals' agreement on clinical relevance of drug related problems, using Fleiss' κ. Results Thirty patients were included in the study. A total of 162 drug related problems were identified, out of which 54% were of lower clinical relevance (level 0-2) and 46% of higher clinical relevance (level 3-4). Only slight agreement (κ = 0.12) was found between the panellists' classifications of clinical relevance using a five-level rating scale. Conclusion The clinical pharmacist identified drug related problems of lower and higher clinical relevance. Poor overall agreement on the severity of the drug related problems was found among the panelists.

Antidiabetic Properties of Germinated Brown Rice: A Systematic Review

PubMed Central

Bhanger, Muhammad Iqbal; Ismail, Norsharina; Ismail, Maznah

2012-01-01

Diet is an important variable in the course of type 2 diabetes, which has generated interest in dietary options like germinated brown rice (GBR) for effective management of the disease among rice-consuming populations. In vitro data and animal experiments show that GBR has potentials as a functional diet for managing this disease, and short-term clinical studies indicate encouraging results. Mechanisms for antidiabetic effects of GBR due to bioactive compounds like γ-aminobutyric acid (GABA), γ-oryzanol, dietary fibre, phenolics, vitamins, acylated steryl β-glucoside, and minerals include antihyperglycemia, low insulin index, antioxidative effect, antithrombosis, antihypertensive effect, hypocholesterolemia, and neuroprotective effects. The evidence so far suggests that there may be enormous benefits for diabetics in rice-consuming populations if white rice is replaced with GBR. However, long-term clinical studies are still needed to verify these findings on antidiabetic effects of GBR. Thus, we present a review on the antidiabetic properties of GBR from relevant preclinical and clinical studies, in order to provide detailed information on this subject for researchers to review the potential of GBR in combating this disease. PMID:23304216

Astaxanthin: A Potential Therapeutic Agent in Cardiovascular Disease

PubMed Central

Fassett, Robert G.; Coombes, Jeff S.

2011-01-01

Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin. PMID:21556169

Developments in drug delivery of bioactive alkaloids derived from traditional Chinese medicine.

PubMed

Zheng, Xiao; Wu, Fei; Lin, Xiao; Shen, Lan; Feng, Yi

2018-11-01

The bioactive alkaloids (e.g. vincristine, hydroxycamptothecin, ligustrazine, and so on) from traditional Chinese medicine (TCM) have exerted potent efficacies (e.g. anti-tumor, anti-inflammation, immunosuppression, etc.). However, a series of undesirable physicochemical properties (like low solubility and weak stability) and baneful pharmacokinetic (PK) profiles (e.g. low bioavailability, short half time, rapid clearance, etc.) have severely restricted their applications in clinic. In addition, some side effects (like cumulative toxicities caused by high-frequency administration and their own toxicities) have recently been reported and also confined their clinical uses. Therefore, developments in drug delivery of such alkaloids are of significance in improving their drug-like properties and, thus, treatment efficiencies in clinic. Strategies, including (i) specific delivery via liposomes; (ii) sustained delivery via nanoparticles, gels, and emulsions; and (iii) transdermal delivery via ethosomes, solid lipid nanoparticles, and penetrating enhancers, have been reported to improve the pharmacokinetic and physicochemical characters of problematic TCM alkaloids, decline their adverse effects, and thus, boost their curative efficacies. In this review, the recent reports in this field were comprehensively summarized with the aim of providing an informative reference for relevant readers.

Novel anticoagulants for stroke prevention in patients with atrial fibrillation.

PubMed

Jalota, A; Scarabelli, T M; Saravolatz, L; Bakhsh, M U; Agrawal, P; Jalota, R; Chen-Scarabelli, C; Fuster, V; Halperin, J

2014-06-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia that can potentially result in stroke. Vitamin K antagonists (VKA) like warfarin were for many decades the only oral anticoagulants available for stroke prevention in patients with non-valvular atrial fibrillation (AF) at high risk of stroke. Recently, new oral anticoagulants (NOACS) have been introduced that act via direct inhibition of thrombin (dabigatran) or activated factor X (edoxaban, rivaroxaban and apixaban). Unlike VKAs, these anticoagulants do not require routine INR monitoring and posses favorable pharmacological properties. NOACs act rapidly, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. Phase III trials comparing these agents to warfarin for stroke prevention in patients with non-valvular AF demonstrated that they are at least as efficacious and safe as warfarin. Evolution of clinical guidelines to incorporate the new anticoagulants for stroke prevention in non-valvular AF may result in a reduction in the incidence of AF-related strokes. Safe and effective use of these new drugs in clinical practice requires understanding of their distinct pharmacological properties.

Butyric acid – a well-known molecule revisited

PubMed Central

Banasiewicz, Tomasz; Rydzewska, Grażyna

2017-01-01

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for many years. However, the newest research shows that butyric acid still remains a molecule with a potential that has not as yet been fully exploited. The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the expert position on the clinical benefits of using butyric acid products in the therapy of gastrointestinal diseases. PMID:28702095

Butyric acid - a well-known molecule revisited.

PubMed

Borycka-Kiciak, Katarzyna; Banasiewicz, Tomasz; Rydzewska, Grażyna

2017-01-01

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for many years. However, the newest research shows that butyric acid still remains a molecule with a potential that has not as yet been fully exploited. The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the expert position on the clinical benefits of using butyric acid products in the therapy of gastrointestinal diseases.

Inflammation and Immune Regulation as Potential Drug Targets in Antidepressant Treatment

PubMed Central

Schmidt, Frank M.; Kirkby, Kenneth C.; Lichtblau, Nicole

2016-01-01

Growing evidence supports a mutual relationship between inflammation and major depression. A variety of mechanisms are outlined, indicating how inflammation may be involved in the pathogenesis, course and treatment of major depression. In particular, this review addresses 1) inflammatory cytokines as markers of depression and potential predictors of treatment response, 2) findings that cytokines interact with antidepressants and non-pharmacological antidepressive therapies, such as electroconvulsive therapy, deep brain stimulation and physical activity, 3) the influence of cytokines on the cytochrome (CYP) p450-system and drug efflux transporters, and 4) how cascades of inflammation might serve as antidepressant drug targets. A number of clinical trials have focused on agents with immunmodulatory properties in the treatment of depression, of which this review covers nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, ketamine, polyunsaturated fatty acids, statins and curcumin. A perspective is also provided on possible future immune targets for antidepressant therapy, such as toll-like receptor-inhibitors, glycogen synthase kinase-3 inhibitors, oleanolic acid analogs and minocycline. Concluding from the available data, markers of inflammation may become relevant factors for more personalised planning and prediction of response of antidepressant treatment strategies. Agents with anti-inflammatory properties have the potential to serve as clinically relevant antidepressants. Further studies are required to better define and identify subgroups of patients responsive to inflammatory agents as well as to define optimal time points for treatment onset and duration. PMID:26769225

Stress and Memory: A Selective Review on Recent Developments in the Understanding of Stress Hormone Effects on Memory and Their Clinical Relevance.

PubMed

Wolf, O T; Atsak, P; de Quervain, D J; Roozendaal, B; Wingenfeld, K

2016-08-01

Stress causes a neuroendocrine response cascade, leading to the release of catecholamines and glucocorticoids (GCs). GCs influence learning and memory by acting on mineralocorticoid (MR) and glucocorticoid (GR) receptors. Typically, GCs enhance the consolidation of memory processing at the same time as impairing the retrieval of memory of emotionally arousing experiences. The present selective review addresses four recent developments in this area. First, the role of the endocannabinoid system in mediating the rapid, nongenomic effects of GCs on memory is illustrated in rodents. Subsequently, studies on the impact of the selective stimulation of MRs on different memory processes in humans are summarised. Next, a series of human experiments on the impact of stress or GC treatment on fear extinction and fear reconsolidation is presented. Finally, the clinical relevance of the effects of exogenous GC administration is highlighted by the description of patients with anxiety disorders who demonstrate an enhancement of extinction-based therapies by GC treatment. The review highlights the substantial progress made in our mechanistic understanding of the memory-modulating properties of GCs, as well as their clinical potential. © 2015 British Society for Neuroendocrinology.

Incidental findings in multislice computed tomography prior to transcatheter aortic valve implantation: frequency, clinical relevance and outcome.

PubMed

Trenkwalder, Teresa; Lahmann, Anna Lena; Nowicka, Magdalena; Pellegrini, Costanza; Rheude, Tobias; Mayr, N Patrick; Voss, Stephanie; Bleiziffer, Sabine; Lange, Rüdiger; Joner, Michael; Kasel, Albert M; Kastrati, Adnan; Schunkert, Heribert; Husser, Oliver; Hadamitzky, Martin; Hengstenberg, Christian

2018-02-21

Multislice computed tomography (MSCT) has emerged as the mainstay in patients planned for transcatheter aortic valve implantation (TAVI). Incidental findings (IF) in MSCT are common. However, the exact incidence, clinical relevance and further consequences of IF are unclear and it is controversial whether IF adversely affect patients' outcome. We analyzed MSCT data of 1050 patients screened for TAVI between January 2011 and December 2014. Median follow-up of patients was 20 months. In total, 3194 IF were identified, which were classified into clinically non-relevant IF (2872, 90%) and clinically relevant IF (322, 10%). In 25% of patients (258/1050) at least one clinically relevant IF was present. Age (80 ± 7 vs. 80 ± 7 years; p = 0.198) and EuroSCORE II (3.6% [2.1-5.7] vs. 3.6% [2.1-5.9]; p = 0.874) was similar between patients with and without a clinically relevant IF. TAVI was performed less frequently in patients with a clinically relevant IF (76% vs. 85%; p < 0.001), with more patients receiving surgical aortic valve replacement in that group (14% vs. 11%; p = 0.042), possibly due to the high rate of incidental aneurysms of the ascending aorta (n = 48). If TAVI was performed mortality did not differ (30-days: 4% vs. 3%; p = 0.339, 1-year: 11% vs. 14%; p = 0.226) between patients with and without a clinically relevant IF. Our study is the largest study to analyze prevalence, clinical relevance and therapeutic consequences of IF during screening for TAVI. IF in pre-procedural MSCT are common and clinically relevant in one-quarter of patients. However, these findings had no impact on overall mortality.

Clinically relevant genetic biomarkers from the brain in alcoholism with representation on high resolution chromosome ideograms.

PubMed

Manzardo, Ann M; McGuire, Austen; Butler, Merlin G

2015-04-15

Alcoholism arises from combined effects of multiple biological factors including genetic and non-genetic causes with gene/environmental interaction. Intensive research and advanced genetic technology has generated a long list of genes and biomarkers involved in alcoholism neuropathology. These markers reflect complex overlapping and competing effects of possibly hundreds of genes which impact brain structure, function, biochemical alcohol processing, sensitivity and risk for dependence. We compiled a tabular list of clinically relevant genetic biomarkers for alcoholism targeting expression disturbances in the human brain through an extensive search of keywords related to alcoholism, alcohol abuse, and genetics from peer reviewed medical research articles and related nationally sponsored websites. Gene symbols were then placed on high resolution human chromosome ideograms with gene descriptions in tabular form. We identified 337 clinically relevant genetic biomarkers and candidate genes for alcoholism and alcohol-responsiveness from human brain research. Genetic biomarkers included neurotransmitter pathways associated with brain reward processes for dopaminergic (e.g., DRD2, MAOA, and COMT), serotoninergic (e.g., HTR3A, HTR1B, HTR3B, and SLC6A4), GABAergic (e.g., GABRA1, GABRA2, and GABRG1), glutaminergic (GAD1, GRIK3, and GRIN2C) and opioid (e.g., OPRM1, OPRD1, and OPRK1) pathways which presumably impact reinforcing properties of alcohol. Gene level disturbances in cellular and molecular networks impacted by alcohol and alcoholism pathology include transketolase (TKT), transferrin (TF), and myelin (e.g., MBP, MOBP, and MOG). High resolution chromosome ideograms provide investigators, physicians, geneticists and counselors a convenient visual image of the distribution of alcoholism genetic biomarkers from brain research with alphabetical listing of genes in tabular form allowing comparison between alcoholism-related phenotypes, and clinically-relevant alcoholism gene(s) at the chromosome band level to guide research, diagnosis, and treatment. Chromosome ideograms may facilitate gene-based personalized counseling of alcohol dependent individuals and their families. Copyright © 2015 Elsevier B.V. All rights reserved.

Clinico-Pathologic Relevance of Survivin Splice Variant Expression in Cancer

PubMed Central

de Necochea-Campion, Rosalia; Chen, Chien-Shing; Mirshahidi, Saied; Howard, Frank D.; Wall, Nathan R.

2013-01-01

Survivin is a member of the inhibitor of apoptosis (IAP) family and has multifunctional properties that include aspects of proliferation, invasion and cell survival control. Survivin is a promising candidate for targeted cancer therapy as its expression is associated with poor clinical outcome, more aggressive clinico-pathologic features, and resistance to radiation and chemotherapy. In the present review the different properties of the Survivin splice variants are discussed and their activities correlated with different aspects of cancer cell biology, to include subcellular location. Special emphasis is placed on our current understanding of these Survivin splice variants influence on each other and on the phenotypic responses to therapy that they may control. PMID:23791888

3D molecular descriptors important for clinical success.

PubMed

Kombo, David C; Tallapragada, Kartik; Jain, Rachit; Chewning, Joseph; Mazurov, Anatoly A; Speake, Jason D; Hauser, Terry A; Toler, Steve

2013-02-25

The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers. We have deduced the relevant descriptor values required for a ligand to be nonpromiscuous. Investigating the MDL Drug Data Report (MDDR) database as compounds move from the preclinical stage toward the market, we have found that these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD. Further, these computed 3D molecular descriptors correlate well with experimentally observed solubility, which is among well-known physicochemical properties that drive clinical success. We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria. Our studies suggest that spherical compounds (rather than their elongated counterparts) with a minimal number of aromatic rings may exhibit a high propensity to advance from clinical trials to market.

Effect of Chemical and Physical Properties on the In Vitro Degradation of 3D Printed High Resolution Poly(propylene fumarate) Scaffolds.

PubMed

Walker, Jason M; Bodamer, Emily; Krebs, Olivia; Luo, Yuanyuan; Kleinfehn, Alex; Becker, Matthew L; Dean, David

2017-04-10

Two distinct molecular masses of poly(propylene fumarate) (PPF) are combined with an additive manufacturing process to fabricate highly complex scaffolds possessing controlled chemical properties and porous architecture. Scaffolds were manufactured with two polymer molecular masses and two architecture styles. Degradation was assessed in an accelerated in vitro environment. The purpose of the degradation study is not to model or mimic in vivo degradation, but to efficiently compare the effect of modulating scaffold properties. This is the first study addressing degradation of chain-growth synthesized PPF, a process that allows for considerably more control over molecular mass distribution. It demonstrates that, with greater process control, not only is scaffold fabrication reproducible, but the mechanical properties and degradation kinetics can be tailored by altering the physical properties of the scaffold. This is a clear step forward in using PPF to address unmet medical needs while meeting regulatory demands and ultimately obtaining clinical relevancy.

Genital herpes stigma: Toward the Measurement and Validation of a highly prevalent yet hidden public health problem.

PubMed

Wang, Katie; Merin, Abigail; Rendina, H Jonathon; Pachankis, John E

2018-02-01

Despite its highly prevalent and stigmatizing nature, genital herpes has received little attention from stigma researchers relative to other sexually transmitted infections. This limitation is of great relevance to researchers and practitioners in both clinical and healthcare settings, given that stigma can cause psychological distress and hinder disclosure to sexual partners, hence contributing to the spread of genital herpes. The present research developed and examined the psychometric properties of a quantitative measure of genital herpes stigma. Two hundred individuals diagnosed with genital herpes recruited through online genital herpes support groups completed a survey containing 37 items adapted from the HIV Stigma Scale, questions about demographic and herpes-related characteristics, and measures of relevant psychosocial variables. A confirmatory factor analysis yielded an 18-item scale with four factors: personalized stigma, disclosure concerns, negative self-image, and concern with public attitudes. All subscales demonstrated good internal consistency, with Cronbach alphas ranging from 0.74 to 0.87. Construct validity was supported by correlations with relevant psychosocial variables, including negative affect, rumination, and perceived social support. As a psychometrically sound assessment tool, the Genital Herpes Stigma Scale can be used in both clinical and research settings to facilitate future efforts to alleviate the negative psychological consequences of this incurable viral infection.

Building and assessing anatomically relevant phantoms for neonatal transcranial ultrasound

NASA Astrophysics Data System (ADS)

Memoli, G.; Gatto, M.; Sadhoo, N.; Gélat, P.; Harris, R. A.; Shaw, A.

2011-02-01

This study describes the design and construction of a clinically relevant phantom to survey the temperature increase caused by ultrasound equipment, as currently used in neonatal head-scanning in the UK. The phantom is an ellipsoid of bone-mimic material, filled with brain-mimic; a circular hole in the external surface mimicks the fontanel, through which most clinically relevant scans are made. Finite-element simulations were used to identify possible hot spots and decide the most effective thermocouple positions within the phantom to investigate temperature rise during a typical scan. Novel materials were purposively designed to simulate key acoustic and thermal properties. Three Dimensional Printing (3DP) was employed for the fabrication of the skull phantom, and a specific strategy was successfully pursued to embed a thermocouple within the 3DP skull phantom during the manufacturing process. An in-process Non-Destructive Analysis (NDA) was used to assess the correct position of the deposited thermocouple inside the fabricated skull phantom. The temperature increase in the phantom for a typical trans-fontanellar scan is also presented here. The current phantom will be used in a hospital survey in the UK and, in its final design, will allow for a more reliable evaluation of ultrasound heating than is currently possible.

Development, physical properties and clinical applicability of a mechanical Multileaf Collimator for the use in Cobalt-60 radiotherapy

NASA Astrophysics Data System (ADS)

Langhans, Marco; Echner, Gernot; Runz, Armin; Baumann, Martin; Xu, Mark; Ueltzhöffer, Stefan; Häring, Peter; Schlegel, Wolfgang

2015-04-01

According to the Directory of Radiotherapy Centres (DIRAC) there are 2348 Cobalt-60 (Co-60) teletherapy units worldwide, most of them in low and middle income countries, compared to 11046 clinical accelerators. To improve teletherapy with Co-60, a mechanical Multi-Leaf Collimator (MLC) was developed, working with pneumatic pressure and thus independent of electricity supply. Instead of tungsten, brass was used as leaf material to make the mechanical MLC more affordable. The physical properties and clinical applicability of this mechanical MLC are presented here. The leakage strongly depends on the fieldsize of the therapy unit due to scatter effects. The maximum transmission through the leaves measured 2.5 cm from the end-to-end gap, within a field size of 20 cm × 30 cm defined by jaws of the therapy unit at 80 cm SAD, amounts 4.2%, normalized to an open 10 cm × 10 cm field, created by the mechanical MLC. Within a precollimated field size of 12.5 cm × 12.5 cm, the end-to-end leakage is 6.5% normalized to an open 10 cm × 10 cm field as well. This characteristic is clinically acceptable considering the criteria for non-IMRT MLCs of the International Electrotechnical Commission (IEC 60601-2-1). The penumbra for a 10 cm × 10 cm field was measured to be 9.14 mm in plane and 8.38 mm cross plane. The clinical applicability of the designed mechanical MLC was affirmed by measurements relating to all relevant clinical properties such as penumbra, leakage, output factors and field widths. Hence this novel device presents an apt way forward to make radiotherapy with conformal fields possible in low-infrastructure environments, using gantry based Co-60 therapy units.

Olodaterol Attenuates Citric Acid-Induced Cough in Naïve and Ovalbumin-Sensitized and Challenged Guinea Pigs

PubMed Central

Wex, Eva; Bouyssou, Thierry

2015-01-01

Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the cough reflex, the mechanism underlying the pro-tussive property of indacaterol is not known. PMID:25781609

Design and testing of classroom and clinical teaching evaluation tools for nursing education.

PubMed

Emerson, Roberta J; Records, Kathie

2007-01-01

Student evaluations of teaching provide administrators an overall picture of the effectiveness of personnel and contribute data for promotion and merit decisions. These evaluations must be assessed for their relevance, validity, and reliability. This paper describes the development process and psychometric testing for clinical (n = 149) and didactic (n = 148) student evaluation of teaching forms for undergraduate and graduate courses in one college of nursing. Validity and reliability results were quite strong for the instruments, both of which evidenced a one-factor solution with factor loadings ranging from .68-.88 and Cronbach's alphas of .96 (Classroom) and .95 (Clinical). The clinical and classroom evaluation tools are relatively short, decreasing the burden on students who need to complete the instruments for multiple instructors in any one semester. Initial testing of the psychometric properties of the tools supports their continued use in colleges of nursing.

Nitric oxide-releasing polyacrylonitrile disperses biofilms formed by wound-relevant pathogenic bacteria.

PubMed

Craven, M; Kasper, S H; Canfield, M J; Diaz-Morales, R R; Hrabie, J A; Cady, N C; Strickland, A D

2016-04-01

To test the antimicrobial and antibiofilm properties of a nitric oxide (NO)-releasing polymer against wound-relevant bacterial pathogens. Using a variety of 96-well plate assay systems that include standard well plates and the minimum biofilm eradication concentration biofilm assay well plate, a NO-releasing polymer based on (poly)acrylonitrile (PAN/NO) was studied for antimicrobial and antibiofilm activity against the common wound pathogens Pseudomonas aeruginosa (PAO1), Staphylococcus aureus (Mu50) and Enterococcus faecalis (V583). The polymer was capable of dispersing single-species biofilms of Ps. aeruginosa as well as a more clinically relevant multispecies biofilm that incorporates Ps. aeruginosa along with Staph. aureus and Ent. faecalis. PAN/NO also synergistically enhanced the susceptibility of the multispecies biofilms to the common broad-spectrum antibiotic, ciprofloxacin. Multiple in vitro biocompatibility assays show that PAN/NO has limited potential for mammalian cytotoxicity. This study demonstrates the feasibility of utilizing the NO-releasing polymer, PAN/NO, to manage biofilms formed by wound-relevant pathogens, and provides proof-of-concept for use of this NO-releasing polymer platform across multiple disciplines where bacterial biofilms pose significant problems. In the clinical sector, bacterial biofilms represent a substantial treatment challenge for health care professionals and are widely recognized as a key factor in prolonging patient morbidity. This study highlights the potential role for the ubiquitous signalling molecule nitric oxide (NO) as an antibiofilm therapy. © 2016 The Society for Applied Microbiology.

B Cell-Directed Therapeutics in Multiple Sclerosis: Rationale and Clinical Evidence.

PubMed

Kinzel, Silke; Weber, Martin S

2016-12-01

Over the last decade, evidence condensed that B cells, B cell-derived plasma cells and antibodies play a key role in the pathogenesis and progression of multiple sclerosis (MS). In many patients with MS, peripheral B cells show signs of chronic activation; within the cerebrospinal fluid clonally expanded plasma cells produce oligoclonal immunoglobulins, which remain a hallmark diagnostic finding. Confirming the clinical relevance of these immunological alterations, recent trials testing anti-CD20-mediated depletion of peripheral B cells showed an instantaneous halt in development of new central nervous system lesions and occurrence of relapses. Notwithstanding this enormous success, not all B cells or B cell subsets may contribute in a pathogenic manner, and may, in contrast, exert anti-inflammatory and, thus, therapeutically desirable properties in MS. Naïve B cells, in MS patients similar to healthy controls, are a relevant source of regulatory cytokines such as interleukin-10, which dampens the activity of other immune cells and promotes recovery from acute disease flares in experimental MS models. In this review, we describe in detail pathogenic but also regulatory properties of B and plasma cells in the context of MS and its animal model experimental autoimmune encephalomyelitis. In the second part, we review what impact current and future therapies may have on these B cell properties. Within this section, we focus on the highly encouraging data on anti-CD20 antibodies as future therapy for MS. Lastly, we discuss how B cell-directed therapy in MS could be possibly advanced even further in regard to efficacy and safety by integrating the emerging information on B cell regulation in MS into future therapeutic strategies.

Physicochemical properties of radiographic contrast media, potential nephrotoxicity and prophylaxis.

PubMed

Hogstrom, Barry; Ikei, Nobuhiro

2015-12-01

Contrast induced nephropathy (CIN) remains a controversial topic. The clinical relevance of changes in laboratory parameters has been challenged; some authors have even suggested that CIN simply reflects natural fluctuations. Other areas of controversy include the pathophysiology of CIN, effectiveness of prophylactic approaches and differences in nephrotoxicity between individual contrast media (CM). The aim of this review is to summarize the current understanding of laboratory findings and explore its relationship to CM toxicity. © 2015 Wiley Publishing Asia Pty Ltd.

Phenotype Instance Verification and Evaluation Tool (PIVET): A Scaled Phenotype Evidence Generation Framework Using Web-Based Medical Literature.

PubMed

Henderson, Jette; Ke, Junyuan; Ho, Joyce C; Ghosh, Joydeep; Wallace, Byron C

2018-05-04

Researchers are developing methods to automatically extract clinically relevant and useful patient characteristics from raw healthcare datasets. These characteristics, often capturing essential properties of patients with common medical conditions, are called computational phenotypes. Being generated by automated or semiautomated, data-driven methods, such potential phenotypes need to be validated as clinically meaningful (or not) before they are acceptable for use in decision making. The objective of this study was to present Phenotype Instance Verification and Evaluation Tool (PIVET), a framework that uses co-occurrence analysis on an online corpus of publically available medical journal articles to build clinical relevance evidence sets for user-supplied phenotypes. PIVET adopts a conceptual framework similar to the pioneering prototype tool PheKnow-Cloud that was developed for the phenotype validation task. PIVET completely refactors each part of the PheKnow-Cloud pipeline to deliver vast improvements in speed without sacrificing the quality of the insights PheKnow-Cloud achieved. PIVET leverages indexing in NoSQL databases to efficiently generate evidence sets. Specifically, PIVET uses a succinct representation of the phenotypes that corresponds to the index on the corpus database and an optimized co-occurrence algorithm inspired by the Aho-Corasick algorithm. We compare PIVET's phenotype representation with PheKnow-Cloud's by using PheKnow-Cloud's experimental setup. In PIVET's framework, we also introduce a statistical model trained on domain expert-verified phenotypes to automatically classify phenotypes as clinically relevant or not. Additionally, we show how the classification model can be used to examine user-supplied phenotypes in an online, rather than batch, manner. PIVET maintains the discriminative power of PheKnow-Cloud in terms of identifying clinically relevant phenotypes for the same corpus with which PheKnow-Cloud was originally developed, but PIVET's analysis is an order of magnitude faster than that of PheKnow-Cloud. Not only is PIVET much faster, it can be scaled to a larger corpus and still retain speed. We evaluated multiple classification models on top of the PIVET framework and found ridge regression to perform best, realizing an average F1 score of 0.91 when predicting clinically relevant phenotypes. Our study shows that PIVET improves on the most notable existing computational tool for phenotype validation in terms of speed and automation and is comparable in terms of accuracy. ©Jette Henderson, Junyuan Ke, Joyce C Ho, Joydeep Ghosh, Byron C Wallace. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 04.05.2018.

Phenotype Instance Verification and Evaluation Tool (PIVET): A Scaled Phenotype Evidence Generation Framework Using Web-Based Medical Literature

PubMed Central

Ke, Junyuan; Ho, Joyce C; Ghosh, Joydeep; Wallace, Byron C

2018-01-01

Background Researchers are developing methods to automatically extract clinically relevant and useful patient characteristics from raw healthcare datasets. These characteristics, often capturing essential properties of patients with common medical conditions, are called computational phenotypes. Being generated by automated or semiautomated, data-driven methods, such potential phenotypes need to be validated as clinically meaningful (or not) before they are acceptable for use in decision making. Objective The objective of this study was to present Phenotype Instance Verification and Evaluation Tool (PIVET), a framework that uses co-occurrence analysis on an online corpus of publically available medical journal articles to build clinical relevance evidence sets for user-supplied phenotypes. PIVET adopts a conceptual framework similar to the pioneering prototype tool PheKnow-Cloud that was developed for the phenotype validation task. PIVET completely refactors each part of the PheKnow-Cloud pipeline to deliver vast improvements in speed without sacrificing the quality of the insights PheKnow-Cloud achieved. Methods PIVET leverages indexing in NoSQL databases to efficiently generate evidence sets. Specifically, PIVET uses a succinct representation of the phenotypes that corresponds to the index on the corpus database and an optimized co-occurrence algorithm inspired by the Aho-Corasick algorithm. We compare PIVET’s phenotype representation with PheKnow-Cloud’s by using PheKnow-Cloud’s experimental setup. In PIVET’s framework, we also introduce a statistical model trained on domain expert–verified phenotypes to automatically classify phenotypes as clinically relevant or not. Additionally, we show how the classification model can be used to examine user-supplied phenotypes in an online, rather than batch, manner. Results PIVET maintains the discriminative power of PheKnow-Cloud in terms of identifying clinically relevant phenotypes for the same corpus with which PheKnow-Cloud was originally developed, but PIVET’s analysis is an order of magnitude faster than that of PheKnow-Cloud. Not only is PIVET much faster, it can be scaled to a larger corpus and still retain speed. We evaluated multiple classification models on top of the PIVET framework and found ridge regression to perform best, realizing an average F1 score of 0.91 when predicting clinically relevant phenotypes. Conclusions Our study shows that PIVET improves on the most notable existing computational tool for phenotype validation in terms of speed and automation and is comparable in terms of accuracy. PMID:29728351

Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina ceramic wear particles in vitro.

PubMed

Germain, M A; Hatton, A; Williams, S; Matthews, J B; Stone, M H; Fisher, J; Ingham, E

2003-02-01

Concern over polyethylene wear particle induced aseptic loosening of metal-on-polyethylene hip prostheses has led to renewed interest in alternative materials such as metal-on-metal and alumina ceramic-on-alumina ceramic for total hip replacement. This study compared the effects of clinically relevant cobalt-chromium and alumina ceramic wear particles on the viability of U937 histiocytes and L929 fibroblasts in vitro. Clinically relevant cobalt-chromium wear particles were generated using a flat pin-on-plate tribometer. The mean size of the clinically relevant metal particles was 29.5+/-6.3 nm (range 5-200 nm). Clinically relevant alumina ceramic particles were generated in the Leeds MkII anatomical hip simulator from a Mittelmieier prosthesis using micro-separation motion. This produced particles with a bimodal size distribution. The majority (98%) of the clinically relevant alumina ceramic wear debris was 5-20 nm in size. The cytotoxicity of the clinically relevant wear particles was compared to commercially available cobalt-chromium (9.87 microm+/-5.67) and alumina ceramic (0.503+/-0.19 microm) particles. The effects of the particles on the cells over a 5 day period at different particle volume (microm(3)) to cell number ratios were tested and viability determined using ATP-Lite(TM). Clinically relevant cobalt-chromium particles 50 and 5 microm(3) per cell reduced the viability of U937 cells by 97% and 42% and reduced the viability of L929 cells by 95% and 73%, respectively. At 50 microm(3) per cell, the clinically relevant ceramic particles reduced U937 cell viability by 18%. None of the other concentrations of the clinically relevant particles were toxic. The commercial cobalt-chromium and alumina particles did not affect the viability of either the U937 histiocytes or the L929 fibroblasts.Thus at equivalent particle volumes the clinically relevant cobalt-chromium particles were more toxic then the alumina ceramic particles. This study has emphasised the fact that the nature, size and volume of particles are important in assessing biological effects of wear debris on cells in vitro.

Adsorption properties of polar/apolar inducers at a charged interface and their relevance to leukemia cell differentiation.

PubMed

Carlà, M; Cuomo, M; Arcangeli, A; Olivotto, M

1995-06-01

The interfacial adsorption properties of polar/apolar inducers of cell differentiation (PAIs) were studied on a mercury electrode. This study, on a clean and reproducible charged surface, unraveled the purely physical interactions among these compounds and the surface, apart from the complexity of the biological membrane. The interfacial behavior of two classical inducers, hexamethylenebisacetamide (HMBA) and dimethylsulfoxide, was compared with that of a typical apolar aliphatic compound, 1-octanol, that has a similar hydrophobic moiety as HMBA but a much smaller dipolar moment. Both HMBA and Octanol adsorb flat in contact with the surface because of hydrophobic forces, with a very similar free energy of adsorption. However, the ratio of polar to apolar moieties in PAIs turned out to be crucial to drive the adsorption maximum toward physiological values of surface charge density, where octanol is desorbed. The electrostatic effects in the interfacial region reflected the adsorption properties: the changes in the potential drop across the interfacial region as a function of the surface charge density, in the physiological range, were opposite in PAIs as compared with apolar aliphatic compounds, as exemplified by octanol. This peculiar electrostatic effect of PAIs has far-reaching relevance for the design of inducers with an adequate therapeutic index to be used in clinical trials.

Measurement instruments to assess posture, gait, and balance in Parkinson's disease: Critique and recommendations.

PubMed

Bloem, Bastiaan R; Marinus, Johan; Almeida, Quincy; Dibble, Lee; Nieuwboer, Alice; Post, Bart; Ruzicka, Evzen; Goetz, Christopher; Stebbins, Glenn; Martinez-Martin, Pablo; Schrag, Anette

2016-09-01

Disorders of posture, gait, and balance in Parkinson's disease (PD) are common and debilitating. This MDS-commissioned task force assessed clinimetric properties of existing rating scales, questionnaires, and timed tests that assess these features in PD. A literature review was conducted. Identified instruments were evaluated systematically and classified as "recommended," "suggested," or "listed." Inclusion of rating scales was restricted to those that could be used readily in clinical research and practice. One rating scale was classified as "recommended" (UPDRS-derived Postural Instability and Gait Difficulty score) and 2 as "suggested" (Tinetti Balance Scale, Rating Scale for Gait Evaluation). Three scales requiring equipment (Berg Balance Scale, Mini-BESTest, Dynamic Gait Index) also fulfilled criteria for "recommended" and 2 for "suggested" (FOG score, Gait and Balance Scale). Four questionnaires were "recommended" (Freezing of Gait Questionnaire, Activities-specific Balance Confidence Scale, Falls Efficacy Scale, Survey of Activities, and Fear of Falling in the Elderly-Modified). Four tests were classified as "recommended" (6-minute and 10-m walk tests, Timed Up-and-Go, Functional Reach). We identified several questionnaires that adequately assess freezing of gait and balance confidence in PD and a number of useful clinical tests. However, most clinical rating scales for gait, balance, and posture perform suboptimally or have been evaluated insufficiently. No instrument comprehensively and separately evaluates all relevant PD-specific gait characteristics with good clinimetric properties, and none provides separate balance and gait scores with adequate content validity for PD. We therefore recommend the development of such a PD-specific, easily administered, comprehensive gait and balance scale that separately assesses all relevant constructs. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Spanish Version of the Avoidance-Endurance Questionnaire: Factor Structure and Psychometric Properties.

PubMed

Ruiz-Párraga, Gema T; López-Martínez, Alicia E; Rusu, Adina C; Hasenbring, Monika I

2015-11-20

To analyze the factorial structure and psychometric properties of the Spanish adaptation of the AEQ, and to validate it by reporting relevant pain-related variables, which were not investigated in the original study. One hundred and fifty Spanish patients diagnosed with chronic back and neck pain were referred by physicians from different pain clinics in Spain; all the patients filled out the questionnaires at their clinic. A series of principal components analyses (PCA) was performed to develop the Spanish version of the AEQ. Reliability and validity were also calculated. The PCAs revealed five fear-avoidance scales (Kaiser-Meyer-Olkin measures were between .60 and .88, and Bartlett's tests were significant, p .73) and suitable validity (p < .05). New results associated with pain-related cognitive/affective and behavioural responses are discussed. This instrument will probably help clinicians to identify Spanish patients at a high risk of chronicity and to develop treatments tailored to the different profiles in order to improve secondary and tertiary prevention in back and neck pain.

Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer

PubMed Central

Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R.; Tang, Dean G.

2016-01-01

The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. PMID:26924072

Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer.

PubMed

Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R; Tang, Dean G

2016-02-29

The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.

Methods in Clinical Pharmacology Series

PubMed Central

Beaumont, Claire; Young, Graeme C; Cavalier, Tom; Young, Malcolm A

2014-01-01

Human radiolabel studies are traditionally conducted to provide a definitive understanding of the human absorption, distribution, metabolism and excretion (ADME) properties of a drug. However, advances in technology over the past decade have allowed alternative methods to be employed to obtain both clinical ADME and pharmacokinetic (PK) information. These include microdose and microtracer approaches using accelerator mass spectrometry, and the identification and quantification of metabolites in samples from classical human PK studies using technologies suitable for non-radiolabelled drug molecules, namely liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. These recently developed approaches are described here together with relevant examples primarily from experiences gained in support of drug development projects at GlaxoSmithKline. The advantages of these study designs together with their limitations are described. We also discuss special considerations which should be made for a successful outcome to these new approaches and also to the more traditional human radiolabel study in order to maximize knowledge around the human ADME properties of drug molecules. PMID:25041729

International guidelines for the in vivo assessment of skin properties in non-clinical settings: part 1. pH

PubMed Central

Stefaniak, Aleksandr B; du Plessis, Johan; John, Swen M; Eloff, Fritz; Agner, Tove; Chou, Tzu-Chieh; Nixon, Rosemary; Steiner, Markus F C; Kudla, Irena; Holness, D Linn

2013-01-01

Background Skin surface pH is known to influence the dissolution and partitioning of chemicals and may influence exposures that lead to skin diseases. Non-clinical environments (e.g. workplaces) are highly variable, thereby presenting unique measurement challenges that are not typically encountered in clinical settings. Hence, guidelines are needed for consistent measurement of skin surface pH in environments that are difficult to control. Methods An expert workshop was convened at the 5th International Conference on Occupational and Environmental Exposure of Skin to Chemicals to review available data on factors that could influence the determination of skin surface pH in non-clinical settings with emphasis on the workplace as a worst case scenario. Results The key elements of the guidelines are: (i) minimize, to the extent feasible, the influences of relevant endogenous (anatomical position, skin health, time of day), exogenous (hand washing, barrier creams, soaps and detergents, occlusion), environmental (seasonality), and measurement (atmospheric conditions) factors; (ii) report pH measurements results as a difference or percent change (not absolute values) using a measure of central tendency and variability; and (iii) report notable deviations from these guidelines and other relevant factors that may influence measurements. Conclusion Guidelines on the measurement and reporting of skin surface pH in non-clinical settings should promote consistency in data reporting, facilitate inter-comparison of study results, and aid in understanding and preventing occupational skin diseases. PMID:23279097

Combination nucleoside/nucleotide reverse transcriptase inhibitors for treatment of HIV infection.

PubMed

Akanbi, Maxwell O; Scarsi, Kimberly K; Scarci, Kimberly; Taiwo, Babafemi; Murphy, Robert L

2012-01-01

The combination of two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) and a third agent from another antiretroviral class is currently recommended for initial antiretroviral therapy. In general, N(t)RTIs remain relevant in subsequent regimens. There are currently six nucleoside reverse transcriptase inhibitors and one nucleotide reverse transcriptase inhibitor drug entities available, and several formulations that include two or more N(t)RTIs in a fixed-dose combination. These entities have heterogeneous pharmacological and clinical properties. Accordingly, toxicity, pill burden, dosing frequency, potential drug-drug interaction, preexisting antiretroviral drug resistance and comorbid conditions should be considered when constructing a regimen. This approach is critical in order to optimize virologic efficacy and clinical outcomes. This article reviews N(t)RTI combinations used in the treatment of HIV-infected adults. The pharmacological properties of each N(t)RTI, and the clinical trials that have influenced treatment guidelines are discussed. It is likely that N(t)RTIs will continue to dominate the global landscape of HIV treatment and prevention, despite emerging interest in N(t)RTI-free combination therapy. Clinical domains where only few alternatives to N(t)RTIs exist include treatment of HIV/HBV coinfection and HIV-2. There is a need for novel N(t)RTIs with enhanced safety and resistance profiles compared with current N(t)RTIs.

Multifunctional nanodiamonds in regenerative medicine: Recent advances and future directions.

PubMed

Whitlow, Jonathan; Pacelli, Settimio; Paul, Arghya

2017-09-10

With recent advances in the field of nanomedicine, many new strategies have emerged for diagnosing and treating diseases. At the forefront of this multidisciplinary research, carbon nanomaterials have demonstrated unprecedented potential for a variety of regenerative medicine applications including novel drug delivery platforms that facilitate the localized and sustained release of therapeutics. Nanodiamonds (NDs) are a unique class of carbon nanoparticles that are gaining increasing attention for their biocompatibility, highly functional surfaces, optical properties, and robust physical properties. Their remarkable features have established NDs as an invaluable regenerative medicine platform, with a broad range of clinically relevant applications ranging from targeted delivery systems for insoluble drugs, bioactive substrates for stem cells, and fluorescent probes for long-term tracking of cells and biomolecules in vitro and in vivo. This review introduces the synthesis techniques and the various routes of surface functionalization that allow for precise control over the properties of NDs. It also provides an in-depth overview of the current progress made toward the use of NDs in the fields of drug delivery, tissue engineering, and bioimaging. Their future outlook in regenerative medicine including the current clinical significance of NDs, as well as the challenges that must be overcome to successfully translate the reviewed technologies from research platforms to clinical therapies will also be discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Soluble HLA-G: Are They Clinically Relevant?

PubMed Central

Pistoia, Vito; Morandi, Fabio; Wang, Xinhui; Ferrone, Soldano

2007-01-01

HLA-G is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. Its main function in physiological conditions is to abrogate maternal NK cell activity against foetal tissue and to establish immune tolerance at maternal-foetal interface. HLA-G is expressed not only as a membrane bound molecule on the surface of cells, but also as a soluble moiety in body fluids. The major isoforms of HLA-G present in serum are soluble HLA-G1 and HLA-G5 which are generated by shedding or proteolytic cleavage of the membrane bound isoform and by secretion of a soluble isoform, respectively. Here we review the data about soluble HLA-G (sHLA-G) serum levels in different pathological conditions, including immune-mediated disorders, transplantation, and malignancies. In particular, we focus on sHLA-G expression and function in human neuroblastoma, a pediatric tumor, with special emphasis on a novel potential immuno escape mechanism utilized by NB to instruct monocytes to produce and release sHLA-G. Finally, the potential clinical relevance of sHLA-G serum levels is discussed. PMID:17825579

Next generation patient-derived prostate cancer xenograft models

PubMed Central

Lin, Dong; Xue, Hui; Wang, Yuwei; Wu, Rebecca; Watahiki, Akira; Dong, Xin; Cheng, Hongwei; Wyatt, Alexander W; Collins, Colin C; Gout, Peter W; Wang, Yuzhuo

2014-01-01

There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients’ tumor tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer. PMID:24589467

Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities

PubMed Central

Schweizer, Frank

2017-01-01

Fluoroquinolones are synthetic antibacterial agents that stabilize the ternary complex of prokaryotic topoisomerase II enzymes (gyrase and Topo IV), leading to extensive DNA fragmentation and bacteria death. Despite the similar structural folds within the critical regions of prokaryotic and eukaryotic topoisomerases, clinically relevant fluoroquinolones display a remarkable selectivity for prokaryotic topoisomerase II, with excellent safety records in humans. Typical agents that target human topoisomerases (such as etoposide, doxorubicin and mitoxantrone) are associated with significant toxicities and secondary malignancies, whereas clinically relevant fluoroquinolones are not known to exhibit such propensities. Although many fluoroquinolones have been shown to display topoisomerase-independent antiproliferative effects against various human cancer cells, those that are significantly active against eukaryotic topoisomerase show the same DNA damaging properties as other topoisomerase poisons. Empirical models also show that fluoroquinolones mediate some unique immunomodulatory activities of suppressing pro-inflammatory cytokines and super-inducing interleukin-2. This article reviews the extended roles of fluoroquinolones and their prospects as lead for the unmet needs of “small and safe” multimodal-targeting drug scaffolds. PMID:29112154

Design and development of reactive injectable and settable polymeric biomaterials.

PubMed

Page, Jonathan M; Harmata, Andrew J; Guelcher, Scott A

2013-12-01

Injectable and settable biomaterials are a growing class of therapeutic technologies within the field of regenerative medicine. These materials offer advantages compared to prefabricated implants because of their ability to be utilized as part of noninvasive surgical procedures, fill complex defect shapes, cure in situ, and incorporate cells and other active biologics. However, there are significant technical barriers to clinical translation of injectable and settable biomaterials, such as achieving clinically relevant handling properties and benign reaction conditions. This review focuses on the engineering challenges associated with the design and development of injectable and chemically settable polymeric biomaterials. Additionally, specific examples of the diverse chemistries utilized to overcome these challenges are covered. The future translation of injectable and settable biomaterials is anticipated to improve patient outcomes for a number of clinical conditions. Copyright © 2013 Wiley Periodicals, Inc., a Wiley Company.

A Critical Review of Dental Implant Materials with an Emphasis on Titanium versus Zirconia

PubMed Central

Osman, Reham B.; Swain, Michael V.

2015-01-01

The goal of the current publication is to provide a comprehensive literature review on the topic of dental implant materials. The following paper focuses on conventional titanium implants and more recently introduced and increasingly popular zirconia implants. Major subtopics include the material science and the clinical considerations involving both implant materials and the influence of their physical properties on the treatment outcome. Titanium remains the gold standard for the fabrication of oral implants, even though sensitivity does occur, though its clinical relevance is not yet clear. Zirconia implants may prove to be promising in the future; however, further in vitro and well-designed in vivo clinical studies are needed before such a recommendation can be made. Special considerations and technical experience are needed when dealing with zirconia implants to minimize the incidence of mechanical failure. PMID:28787980

Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates.

PubMed

Sirvent, Juan Alberto; Lücking, Ulrich

2017-04-06

Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAY 1143572 (P-TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and in vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Torsional and axial compressive properties of tibiotarsal bones of red-tailed hawks (Buteo jamaicensis).

PubMed

Kerrigan, Shannon M; Kapatkin, Amy S; Garcia, Tanya C; Robinson, Duane A; Guzman, David Sanchez-Migallon; Stover, Susan M

2018-04-01

OBJECTIVE To describe the torsional and axial compressive properties of tibiotarsal bones of red-tailed hawks (Buteo jamaicensis). SAMPLE 16 cadaveric tibiotarsal bones from 8 red-tailed hawks. PROCEDURES 1 tibiotarsal bone from each bird was randomly assigned to be tested in torsion, and the contralateral bone was tested in axial compression. Intact bones were monotonically loaded in either torsion (n = 8) or axial compression (8) to failure. Mechanical variables were derived from load-deformation curves. Fracture configurations were described. Effects of sex, limb side, and bone dimensions on mechanical properties were assessed with a mixed-model ANOVA. Correlations between equivalent torsional and compressive properties were determined. RESULTS Limb side and bone dimensions were not associated with any mechanical property. During compression tests, mean ultimate cumulative energy and postyield energy for female bones were significantly greater than those for male bones. All 8 bones developed a spiral diaphyseal fracture and a metaphyseal fissure or fracture during torsional tests. During compression tests, all bones developed a crushed metaphysis and a fissure or comminuted fracture of the diaphysis. Positive correlations were apparent between most yield and ultimate torsional and compressive properties. CONCLUSIONS AND CLINICAL RELEVANCE The torsional and axial compressive properties of tibiotarsal bones described in this study can be used as a reference for investigations into fixation methods for tibiotarsal fractures in red-tailed hawks. Although the comminuted and spiral diaphyseal fractures induced in this study were consistent with those observed in clinical practice, the metaphyseal disruption observed was not and warrants further research.

21 CFR 1271.75 - How do I screen a donor?

Code of Federal Regulations, 2011 CFR

2011-04-01

...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... risk factors for and clinical evidence of relevant cell-associated communicable disease agents and... having either of the following: (1) A risk factor for or clinical evidence of any of the relevant...

Brain Reward Circuits in Morphine Addiction

PubMed Central

Kim, Juhwan; Ham, Suji; Hong, Heeok; Moon, Changjong; Im, Heh-In

2016-01-01

Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate’s innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences. PMID:27506251

Immunogenicity of biologic therapies: causes and consequences.

PubMed

Boehncke, Wolf-Henning; Brembilla, Nicolo Costantino

2018-04-25

Antibodies or fusion proteins termed biologics allow the targeted therapy of diseases. Many of these agents have proven superior efficacy and safety to conventional therapies, and subsequently revolutionized the management of numerous chronic diseases. Repetitive administration of these protein-based therapeutics to immunocompetent patients elicit immune responses in the form of Anti Drug Antibodies (ADAs), which in turn impact their pharmacological properties and may trigger adverse events. Areas covered: Structural characteristics determining the immunogenicity of biologics are reviewed along with strategies to minimize it. Next, the different types of treatment-emerging ADAs, their potential clinical implications, and assays to detect them are addressed. Emphasis is put on the review of data on the immunogenicity of different types of biologics across numerous indications. Finally, practical considerations are discussed on how to manage patients with issues around the immunogenicity of their biologic treatment. Expert commentary: Immunogenicity is a clinically relevant criterion when selecting a biologic. Besides intrinsic properties of the agent (namely its structure), its respective mode of action, dosing regimen, comedication, and the indication treated must be considered. ADA detection assays need to be standardized to improve comparability of available data and to allow clinical decision-making.

Mobile phone interference with medical equipment and its clinical relevance: a systematic review.

PubMed

Lawrentschuk, Nathan; Bolton, Damien M

2004-08-02

To conduct a systematic review of studies on clinically relevant digital mobile phone electromagnetic interference with medical equipment. MEDLINE and SUMSEARCH were searched for the period 1966-2004. The Cochrane Library and Database of Abstracts of Reviews of Effects were also searched for systematic reviews. Studies were eligible if published in a peer-reviewed journal in English, and if they included testing of digital mobile phones for clinically relevant interference with medical equipment used to monitor or treat patients, but not implantable medical devices. As there was considerable heterogeneity in medical equipment studied and the conduct of testing, results were summarised rather than subjected to meta-analysis. Clinically relevant electromagnetic interference (EMI) secondary to mobile phones potentially endangering patients occurred in 45 of 479 devices tested at 900 MHz and 14 of 457 devices tested at 1800 MHz. However, in the largest studies, the prevalence of clinically relevant EMI was low. Most clinically relevant EMI occurred when mobile phones were used within 1 m of medical equipment. Although testing was not standardised between studies and equipment tested was not identical, it is of concern that at least 4% of devices tested in any study were susceptible to clinically relevant EMI. All studies recommend some type of restriction of mobile phone use in hospitals, with use greater than 1 m from equipment and restrictions in clinical areas being the most common.

Plasma-Lyte 148: A clinical review

PubMed Central

Weinberg, Laurence; Collins, Neil; Van Mourik, Kiara; Tan, Chong; Bellomo, Rinaldo

2016-01-01

AIM To outline the physiochemical properties and specific clinical uses of Plasma-Lyte 148 as choice of solution for fluid intervention in critical illness, surgery and perioperative medicine. METHODS We performed an electronic literature search from Medline and PubMed (via Ovid), anesthesia and pharmacology textbooks, and online sources including studies that compared Plasma-Lyte 148 to other crystalloid solutions. The following keywords were used: “surgery”, “anaesthesia”, “anesthesia”, “anesthesiology”, “anaesthesiology”, “fluids”, “fluid therapy”, “crystalloid”, “saline”, “plasma-Lyte”, “plasmalyte”, “hartmann’s”, “ringers” “acetate”, “gluconate”, “malate”, “lactate”. All relevant articles were accessed in full. We summarized the data and reported the data in tables and text. RESULTS We retrieved 104 articles relevant to the choice of Plasma-Lyte 148 for fluid intervention in critical illness, surgery and perioperative medicine. We analyzed the data and reported the results in tables and text. CONCLUSION Plasma-Lyte 148 is an isotonic, buffered intravenous crystalloid solution with a physiochemical composition that closely reflects human plasma. Emerging data supports the use of buffered crystalloid solutions in preference to saline in improving physicochemical outcomes. Further large randomized controlled trials assessing the comparative effectiveness of Plasma-Lyte 148 and other crystalloid solutions in measuring clinically important outcomes such as morbidity and mortality are needed. PMID:27896148

Pharmacokinetic Properties of Fostamatinib in Patients With Renal or Hepatic Impairment: Results From 2 Phase I Clinical Studies.

PubMed

Martin, Paul; Oliver, Stuart; Gillen, Michael; Marbury, Thomas; Millson, David

2015-12-01

Phase III trials of fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis have been completed. Herein, we report the effects of renal and hepatic impairment on the pharmacokinetic (PK) properties of the active metabolite of fostamatinib, R406, in plasma, and on the urinary excretion of R406 and its metabolite N-glucuronide. Two Phase I, single-center, open-label clinical trials determined the PK properties and tolerability of fostamatinib in subjects with normal or impaired renal or hepatic function. Twenty-four subjects in the study in renal impairment (8 per group: normal renal function, moderate renal dysfunction, or end-stage renal disease [ESRD]), and 32 subjects in the study in hepatic impairment (8 per group: normal hepatic function or mild, moderate, or severe hepatic impairment) received a single 150-mg dose of fostamatinib. Patients with ESRD in the study in renal impairment participated in 2 treatment periods separated by a ≥1-week washout. In these patients, fostamatinib was administered after dialysis or 2 hours before dialysis. Geometric mean R406 Cmax and AUC values were less in the combined renally impaired group than in the group with normal renal function; Tmax was similar across groups. However, renal impairment had no apparent effect considered clinically relevant on unbound R406. In patients with ESRD, R406 exposure was less when fostamatinib was administered after compared with before dialysis. Urinary excretion of R406 N-glucuronide was decreased with increasing severity of renal impairment. Renal elimination of R406 was negligible in all groups. Varying degrees of hepatic impairment had no consistent effects on the PK properties of R406. R406 Cmax values were 10% to 15% less in all hepatically impaired groups than in the group with normal hepatic function. AUC and Tmax values were similar between the groups with normal and severely impaired hepatic function; in the groups with mild or moderate hepatic impairment, AUC was less and Tmax was greater. The geometric mean percentage of unbound R406 ranged from 0.64% to 1.95% and was greatest in the group with severe hepatic impairment. The urinary excretion of R406 was minimal. The amount of R406 N-glucuronide excreted in urine was greater in severely hepatically impaired patients. Fostamatinib 150 mg was generally well tolerated. In these patients, renal or hepatic impairment did not affect exposure to the active metabolite of fostamatinib, R406, to a clinically relevant extent. ClinicalTrials.gov identifiers: NCT01245790 (renal) and NCT01222455 (hepatic). Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

A systematic review of measurement of endoscopic disease activity and mucosal healing in Crohn's disease: recommendations for clinical trial design.

PubMed

Khanna, Reena; Bouguen, Guillaume; Feagan, Brian G; DʼHaens, Geert; Sandborn, William J; Dubcenco, Elena; Baker, K Adam; Levesque, Barrett G

2014-10-01

Crohn's disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. Recently, mucosal healing has been proposed as a goal of therapy because clinical symptoms are subjective. Evaluative indices that measure endoscopic disease activity are required to define mucosal healing for clinical trials. The primary objective of this systematic review was to assess the existing evaluative indices that measure disease activity in CD and evaluate their role as outcome measures in clinical trials. A systematic literature review was performed using MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and DDW abstracts to identify randomized controlled trials and controlled clinical trials that used a relevant evaluative index from inception to February 2013. The data obtained from these trials were reviewed and summarized. The initial literature searches identified 2300 citations. After duplicates were removed, 1454 studies remained. After application of the apriori inclusion and exclusion criteria, 109 articles were included and 3 were identified with handsearches. In total, 9 evaluative indices for CD were identified and reviewed. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score in Crohn's Disease (SES-CD) are indices with the most extensively described operating properties. Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for CD. Currently, the CDEIS and SES-CD have the most data regarding operating properties; however, further validation is required.

Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules.

PubMed

Ochoa-Aguilar, Abraham; Ventura-Martinez, Rosa; Sotomayor-Sobrino, Marco Antonio; Gómez, Claudia; Morales-Espinoza, María del Rosario

2016-01-01

Beta-lactam molecules are a family of drugs commonly used for their antibiotic properties; however, recent research has shown that several members of this group present a large number of other effects such as neuroprotective, antioxidant, analgesic or immunomodulatory capabilities. These properties have been used in both preclinical and clinical studies in different diseases such as hypoxic neuronal damage or acute and chronic pain. The present work briefly reviews the antibiotic effect of these molecules, and will then focus specially on the non-antibiotic effects of three beta-lactam subfamilies: penicillins, cephalosporins and beta lactamase inhibitors, each of which have different molecular structure and pharmacokinetics and therefore have several potential clinical applications. A thorough search of bibliographic databases for peer-reviewed research was performed including only classic experiments or high quality reviews for the antibiotic mechanisms of beta-lactam molecules and only experimental research papers where included when the non-antibiotic properties of these molecules were searched. Only published articles from indexed journals were included. Quality of retrieved papers was assessed using standard tools. The characteristics of screened papers were described and findings of included studies were contextualized to either a mechanistic or a clinical framework. Seventy-eight papers were included in the review; the majority (56) were relative to the non-antibiotic properties of beta-lactam molecules. The non-antibiotic effects reviewed were divided accordingly to the amount of information available for each one. Twelve papers outlined the epileptogenic effects induced by beta-lactam molecules administration; these included both clinical and basic research as well as probable mechanistic explanations. Eighteen papers described a potential neuroprotective effect, mostly in basic in vitro and in vivo experiments. Analgesic properties where identified in twelve papers and basic research was described alongside with both experimental and serendipic clinical findings. Seven papers described a down-regulation effect exerted by beta-lactam molecules administration in different addiction animal models. Finally other effects such as penile erection, dopamine release facilitation and anti-neoplasic effects where described from seven papers. The findings of this review show that beta-lactam molecules may induce several effects, which may be clinically relevant in a lot of different diseases. This paper is, to our knowledge, the first comprehensive review of the non-antibiotic effects shown by beta-lactam molecules and may help increase the interest in this field, which may result in a direct translation of this effects to a clinical context.

Clinical relevance of findings in trials of CBT for depression.

PubMed

Lepping, P; Whittington, R; Sambhi, R S; Lane, S; Poole, R; Leucht, S; Cuijpers, P; McCabe, R; Waheed, W

2017-09-01

Cognitive behavioural therapy (CBT) is beneficial in depression. Symptom scores can be translated into Clinical Global Impression (CGI) scale scores to indicate clinical relevance. We aimed to assess the clinical relevance of findings of randomised controlled trials (RCTs) of CBT in depression. We identified RCTs of CBT that used the Hamilton Rating Scale for Depression (HAMD). HAMD scores were translated into Clinical Global Impression - Change scale (CGI-I) scores to measure clinical relevance. One hundred and seventy datasets from 82 studies were included. The mean percentage HAMD change for treatment arms was 53.66%, and 29.81% for control arms, a statistically significant difference. Combined active therapies showed the biggest improvement on CGI-I score, followed by CBT alone. All active treatments had better than expected HAMD percentage reduction and CGI-I scores. CBT has a clinically relevant effect in depression, with a notional CGI-I score of 2.2, indicating a significant clinical response. The non-specific or placebo effect of being in a psychotherapy trial was a 29% reduction of HAMD. Copyright © 2017. Published by Elsevier Masson SAS.

Drug development in neuropsychopharmacology.

PubMed

Fritze, Jürgen

2008-03-01

Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

The influence of pregnancy on the pharmacokinetic properties of artemisinin combination therapy (ACT): a systematic review.

PubMed

Burger, Renée J; Visser, Benjamin J; Grobusch, Martin P; van Vugt, Michèle

2016-02-18

Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs, including the different components of artemisinin-based combination therapy (ACT). However, small sample sizes make it difficult to draw strong conclusions based on individual pharmacokinetic studies. The aim of this review is to summarize the evidence of the influence of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. A PROSPERO-registered systematic review to identify clinical trials that investigated the influence of pregnancy on the pharmacokinetic properties of different forms of ACT was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to November 2015. The following components of ACT that are currently recommend by the World Health Organization as first-line treatment of malaria in pregnancy were reviewed: artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil. The literature search identified 121 reports, 27 original studies were included. 829 pregnant women were included in the analysis. Comparison of the available studies showed lower maximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the active metabolite of all artemisinin derivatives, after oral administration of artemether, artesunate and dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seen in lumefantrine studies, indicating a low exposure and possibly reduced efficacy. The influence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant. Sulfadoxine plasma concentration was significantly reduced and clearance rates were higher in pregnancy, while pyrimethamine and mefloquine need more research as no general conclusion can be drawn based on the available evidence. For atovaquone, the available data showed a lower maximum concentration and exposure. Finally, the maximum concentration of cycloguanil, the active metabolite of proguanil, was significantly lower, possibly compromising the efficacy. These findings suggest that reassessment of the dose of the artemisinin derivate and some components of ACT are necessary to ensure the highest possible efficacy of malaria treatment in pregnant women. However, for most components of ACT, data were insufficient and extensive research with larger sample sizes will be necessary to identify the exact influences of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. In addition, different clinical studies used diverse study designs with various reported relevant outcomes. Future pharmacokinetic studies could benefit from more uniform designs, in order to increase quality, robustness and effectiveness. CRD42015023756 (PROSPERO).

Effects of moclobemide on sexual performance and nocturnal erections in psychogenic erectile dysfunction.

PubMed

Mann, K; Pankok, J; Leissner, J; Benkert, O

2001-06-01

We tested the hypothesis that the selective reversible MAO-A inhibitor moclobemide has a specific therapeutic effect on erectile dysfunction independent of its antidepressive properties. In a double-blind placebo controlled study, 12 male outpatients suffering from psychogenic erectile dysfunction without any other psychiatric disorder were investigated. Based on comprehensive diagnosis before the beginning of the study, organic factors relevant for sexual function were excluded. The treatment period was 8 weeks. Half the patients received 450 mg moclobemide during the first week, and 600 mg afterwards; the others received placebo. Apart from assessment of erectile function by means of the Clinical Global Impression (CGI) scale, nocturnal erections were measured under polysomnographic control at baseline and at the end of the treatment period. The evaluation of the CGI scale revealed a clearly stronger improvement under moclobemide compared to placebo during the study period. The therapeutic efficacy found on the subjective level had no clear correlate on the neurophysiological level. No alterations of nocturnal erectile parameters were obvious under treatment, neither were clinically relevant alterations found regarding sleep EEG parameters. The medication was well tolerated without serious adverse events. The findings support the hypothesis that moclobemide has a specific effect on erectile dysfunction. Thus, patients suffering from psychogenic erectile dysfunction who are not depressed might benefit from moclobemide without relevant side effects.

Nutraceutical Properties of Olive Oil Polyphenols. An Itinerary from Cultured Cells through Animal Models to Humans

PubMed Central

Rigacci, Stefania; Stefani, Massimo

2016-01-01

The increasing interest in the Mediterranean diet hinges on its healthy and anti-ageing properties. The composition of fatty acids, vitamins and polyphenols in olive oil, a key component of this diet, is considered a key feature of its healthy properties. Therefore, it is of significance that the Rod of Asclepius lying on a world map surrounded by olive tree branches has been chosen by the World Health Organization as a symbol of both peace and well-being. This review travels through most of the current and past research, recapitulating the biochemical and physiological correlations of the beneficial properties of olive tree (Olea europaea) polyphenols and their derivatives found in olive oil. The factors influencing the content and beneficial properties of olive oil polyphenols will also be taken into account together with their bioavailability. Finally, the data on the clinical and epidemiological relevance of olive oil and its polyphenols for longevity and against age- and lifestyle-associated pathologies such as cancer, cardiovascular, metabolic and neurodegenerative diseases are reviewed. PMID:27258251

Tensile strength of biological fibrin sealants: a comparative study.

PubMed

Lacaze, Laurence; Le Dem, Nicolas; Bubenheim, Michael; Tsilividis, Basile; Mezghani, Julien; Schwartz, Lilian; Francois, Arnaud; Ertaud, Jean Yves; Bagot d'Arc, Maurice; Scotté, Michel

2012-08-01

Fibrin sealants are commonly used in liver surgery, although their effectiveness in routine clinical practice remains controversial. Individual sealant characteristics are based on hemostatic effects and adhesion properties that can be experimentally measured using the 'rat skin test' or the 'pig skin test'. This study used a more relevant and realistic experimental canine model to compare the differences in the adhesive properties of four fibrin sealants in hepatectomy: Tisseel/Tissucol, Tachosil, Quixil, and Beriplast. A partial hepatectomy was performed in beagle dogs under general anesthesia to obtain liver cross-sections. Fibrin sealants were allocated to dog livers using a Youden square design. The tensile strength measurement was performed using a traction system to measure the rupture stress point of a small wooden cylinder bonded to the liver cross-section. Significantly greater adhesion properties were observed with Tisseel/Tissucol compared with Quixil or Beriplast (P = 0.002 and 0.001, respectively). Similarly, Tachosil demonstrated significantly greater adhesive properties compared with Beriplast (P = 0.009) or Quixil (P = 0.014). No significant differences were observed between Tisseel/Tissucol and Tachosil or between Beriplast and Quixil. The results of this comparative study demonstrate that different fibrin sealants exhibit different adhesive properties. Tisseel/Tissucol and Tachosil provided greatest adhesion to liver cross-section in our canine model of hepatectomy. These results may enable the optimal choice of fibrin sealants for this procedure in clinical practice. Copyright © 2012 Elsevier Inc. All rights reserved.

Intelligent polymeric micelles: development and application as drug delivery for docetaxel.

PubMed

Li, Yimu; Zhang, Hui; Zhai, Guang-Xi

2017-04-01

Recent years, docetaxel (DTX)-loaded intelligent polymeric micelles have been regarded as a promising vehicle for DTX for the reason that compared with conventional DTX-loaded micelles, DTX-loaded intelligent micelles not only preserve the basic functions of micelles such as DTX solubilization, enhanced accumulation in tumor tissue, and improved bioavailability and biocompatibility of DTX, but also possess other new properties, for instance, tumor-specific DTX delivery and series of responses to endogenous or exogenous stimulations. In this paper, basic theories and action mechanism of intelligent polymeric micelles are discussed in detail, especially the related theories of DTX-loaded stimuli-responsive micelles. The relevant examples of stimuli-responsive DTX-loaded micelles are also provided in this paper to sufficiently illustrate the advantages of relevant technology for the clinical application of anticancer drug, especially for the medical application of DTX.

Application of basic physics principles to clinical neuroradiology: differentiating artifacts from true pathology on MRI.

PubMed

Hakky, Michael; Pandey, Shilpa; Kwak, Ellie; Jara, Hernan; Erbay, Sami H

2013-08-01

This article outlines artifactual findings commonly encountered in neuroradiologic MRI studies and offers clues to differentiate them from true pathology on the basis of their physical properties. Basic MR physics concepts are used to shed light on the causes of these artifacts. MRI is one of the most commonly used techniques in neuroradiology. Unfortunately, MRI is prone to image distortion and artifacts that can be difficult to identify. Using the provided case illustrations, practical clues, and relevant physical applications, radiologists may devise algorithms to troubleshoot these artifacts.

IL-15/IL-15 receptor biology: a guided tour through an expanding universe.

PubMed

Budagian, Vadim; Bulanova, Elena; Paus, Ralf; Bulfone-Paus, Silvia

2006-08-01

The cytokine interleukin-15 (IL-15) has a key role in promoting survival, proliferation and activation of natural killer (NK) and CD8+ T cells. Despite its functional similarities to IL-2, IL-15 affects a wider range of target cell populations and utilizes different mechanisms of signaling. Here, we review recent advances in the IL-15-mediated signaling, and in the functional properties on cells besides T lymphocytes and NK cells. These are discussed in the context of their potential clinical and therapeutic relevance.

Free software to analyse the clinical relevance of drug interactions with antiretroviral agents (SIMARV®) in patients with HIV/AIDS.

PubMed

Giraldo, N A; Amariles, P; Monsalve, M; Faus, M J

Highly active antiretroviral therapy has extended the expected lifespan of patients with HIV/AIDS. However, the therapeutic benefits of some drugs used simultaneously with highly active antiretroviral therapy may be adversely affected by drug interactions. The goal was to design and develop a free software to facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. A comprehensive Medline/PubMed database search of drug interactions was performed. Articles that recognized any drug interactions in HIV disease were selected. The publications accessed were limited to human studies in English or Spanish, with full texts retrieved. Drug interactions were analyzed, assessed, and grouped into four levels of clinical relevance according to gravity and probability. Software to systematize the information regarding drug interactions and their clinical relevance was designed and developed. Overall, 952 different references were retrieved and 446 selected; in addition, 67 articles were selected from the citation lists of identified articles. A total of 2119 pairs of drug interactions were identified; of this group, 2006 (94.7%) were drug-drug interactions, 1982 (93.5%) had an identified pharmacokinetic mechanism, and 1409 (66.5%) were mediated by enzyme inhibition. In terms of clinical relevance, 1285 (60.6%) drug interactions were clinically significant in patients with HIV (levels 1 and 2). With this information, a software program that facilitates identification and assessment of the clinical relevance of antiretroviral drug interactions (SIMARV ® ) was developed. A free software package with information on 2119 pairs of antiretroviral drug interactions was designed and developed that could facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. Copyright © 2016 Elsevier Inc. All rights reserved.

Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease?

PubMed Central

Broekman, Winifred; Khedoe, Padmini P S J; Schepers, Koen; Roelofs, Helene; Stolk, Jan; Hiemstra, Pieter S

2018-01-01

COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research. PMID:29653970

Conformal piezoelectric systems for clinical and experimental characterization of soft tissue biomechanics

NASA Astrophysics Data System (ADS)

Dagdeviren, Canan; Shi, Yan; Joe, Pauline; Ghaffari, Roozbeh; Balooch, Guive; Usgaonkar, Karan; Gur, Onur; Tran, Phat L.; Crosby, Jessi R.; Meyer, Marcin; Su, Yewang; Chad Webb, R.; Tedesco, Andrew S.; Slepian, Marvin J.; Huang, Yonggang; Rogers, John A.

2015-07-01

Mechanical assessment of soft biological tissues and organs has broad relevance in clinical diagnosis and treatment of disease. Existing characterization methods are invasive, lack microscale spatial resolution, and are tailored only for specific regions of the body under quasi-static conditions. Here, we develop conformal and piezoelectric devices that enable in vivo measurements of soft tissue viscoelasticity in the near-surface regions of the epidermis. These systems achieve conformal contact with the underlying complex topography and texture of the targeted skin, as well as other organ surfaces, under both quasi-static and dynamic conditions. Experimental and theoretical characterization of the responses of piezoelectric actuator-sensor pairs laminated on a variety of soft biological tissues and organ systems in animal models provide information on the operation of the devices. Studies on human subjects establish the clinical significance of these devices for rapid and non-invasive characterization of skin mechanical properties.

Clinical trials with rasagiline: evidence for short-term and long-term effects.

PubMed

Siderowf, Andrew; Stern, Matthew

2006-05-23

Rasagiline (N-propargyl-1 (R)-aminoindan) is a selective, potent irreversible inhibitor of MAO-B that possesses neuroprotective and anti-apoptotic properties in a variety of in vitro and in vivo animal models relevant to Parkinson's disease (PD). Several randomized controlled clinical trials have demonstrated the safety and efficacy of rasagiline as monotherapy in PD and as adjunctive therapy for patients receiving levodopa. In addition, the 1-year randomized, delayed-start analysis of the TEMPO study suggests that rasagiline may slow the rate of progression of PD. The randomized delayed-start paradigm has potential to differentiate short-term symptomatic effects from long-term effects of anti-parkinsonian agents. In the future, long-term trials to examine the potential disease-modifying effects of rasagiline, which incorporate biological markers as well as clinical endpoints, may further elucidate the role of rasagiline in the treatment of both early and advanced PD.

Clinicomanometric factors associated with clinically relevant esophagogastric junction outflow obstruction from the Sandhill high-resolution manometry system.

PubMed

Song, B G; Min, Y W; Lee, H; Min, B-H; Lee, J H; Rhee, P-L; Kim, J J

2018-03-01

Integrated relaxation pressure (IRP) is a key metric for diagnosing esophagogastric junction outflow obstruction (EGJOO). However, its normal value might be different according to the manufacturer of high-resolution manometry (HRM). This study aimed to investigate optimal value of IRP for diagnosing EGJOO in Sandhill HRM and to find clinicomanometric variables to segregate clinically relevant EGJOO. We analyzed 262 consecutive subjects who underwent HRM between June 2011 and December 2016 showing elevated median IRP (> 15 mm Hg) but did not satisfy criteria for achalasia. Clinically relevant subjects were defined as follows: (i) subsequent HRM met achalasia criteria during follow-up (early achalasia); (ii) Eckardt score was decreased at least two points without exceeding a score of 3 after pneumatic dilatation (variant achalasia); and (iii) significant passage disturbance on esophagogram without structural abnormality (possible achalasia). Seven subjects were clinically relevant, including two subjects with early achalasia, four subjects with variant achalasia, and one subject with possible achalasia. All clinically relevant subjects had IRP 20 mm Hg or above. Among subjects (n = 122) with IRP 20 mm Hg or more, clinically relevant group (n = 7) had significantly higher rate of dysphagia (100% vs 24.3%, P < .001) and compartmentalized pressurization (85.7% vs 21.7%, P = .001) compared to clinically non-relevant group (n = 115). Our results suggest that IRP of 20 mm Hg or higher could segregate clinically relevant subjects showing EGJOO in Sandhill HRM. Additionally, if subjects have both dysphagia and compartmentalized pressurization, careful follow-up is essential. © 2017 John Wiley & Sons Ltd.

Recent advances in the use of therapeutic cancer vaccines in genitourinary malignancies.

PubMed

Surolia, Ira; Gulley, James; Madan, Ravi A

2014-12-01

Despite a recent increase in US FDA-approved treatments, genitourinary malignancies remain a source of significant morbidity and mortality. One focus of research is the use of therapeutic cancer vaccines in these diseases, and a significant body of clinical trial experience now exists for refining vaccine strategies to enhance antitumor efficacy and develop immune-based combination regimens. In recent years, clinical data from multiple trials in genitourinary malignancies have enhanced our understanding of the potential for immunotherapy in these cancers. There are also emerging clinical strategies that combine cancer vaccines with chemotherapy, radiation, androgen-deprivation therapy and immune checkpoint inhibitors. This review is based on a search of relevant literature for data presented over the past 5 years from clinical trials of cancer vaccines in prostate, bladder and renal carcinomas. In the coming years, clinical trials informed by decades of preclinical data and emerging clinical data will help to define the role of immunotherapy in genitourinary malignancies. Combination strategies that capitalize on the immune properties of standard treatments will bring greater clinical benefits, and immune-based combinations will likely be moved to the neoadjuvant setting, where they may have optimal clinical impact.

Cell attachment properties of Portland cement-based endodontic materials: biological and methodological considerations.

PubMed

Ahmed, Hany Mohamed Aly; Luddin, Norhayati; Kannan, Thirumulu Ponnuraj; Mokhtar, Khairani Idah; Ahmad, Azlina

2014-10-01

The attachment and spreading of mammalian cells on endodontic biomaterials are an area of active research. The purpose of this review is to discuss the cell attachment properties of Portland cement (PC)-based materials by using scanning electron microscope (SEM). In addition, methodological aspects and technical challenges are discussed. A PubMed electronic search was conducted by using appropriate key words to identify the available investigations on the cell attachment properties of PC-based endodontic materials. After retrieving the full text of related articles, the cross citations were also identified. A total of 23 articles published between January 1993 and October 2013 were identified. This review summarizes the cell attachment properties of commercial and experimental PC-based materials on different cell cultures by using SEM. Methodological procedures, technical challenges, and relevance of SEM in determining the biological profile of PC-based materials are discussed. SEM observations demonstrate that commercial MTA formulations show favorable cell attachment properties, which is consistent with their successful clinical outcomes. The favorable cell attachment properties of PC and its modified formulations support its potential use as a substitute for mineral trioxide aggregate. However, researchers should carefully select cell types for their SEM investigations that would be in contact with the proposed PC-based combinations in the clinical situation. Despite being a technical challenge, SEM provides useful information on the cell attachment properties of PC-based materials; however, other assays for cell proliferation and viability are essential to come up with an accurate in vitro biological profile of any given PC-based formulation. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Reference point indentation is insufficient for detecting alterations in traditional mechanical properties of bone under common experimental conditions.

PubMed

Krege, John B; Aref, Mohammad W; McNerny, Erin; Wallace, Joseph M; Organ, Jason M; Allen, Matthew R

2016-06-01

Reference point indentation (RPI) was developed as a novel method to assess mechanical properties of bone in vivo, yet it remains unclear what aspects of bone dictate changes/differences in RPI-based parameters. The main RPI parameter, indentation distance increase (IDI), has been proposed to be inversely related to the ability of bone to form/tolerate damage. The goal of this work was to explore the relationshipre-intervention RPI measurebetween RPI parameters and traditional mechanical properties under varying experimental conditions (drying and ashing bones to increase brittleness, demineralizing bones and soaking in raloxifene to decrease brittleness). Beams were machined from cadaveric bone, pre-tested with RPI, subjected to experimental manipulation, post-tested with RPI, and then subjected to four-point bending to failure. Drying and ashing significantly reduced RPI's IDI, as well as ultimate load (UL), and energy absorption measured from bending tests. Demineralization increased IDI with minimal change to bending properties. Ex vivo soaking in raloxifene had no effect on IDI but tended to enhance post-yield behavior at the structural level. These data challenge the paradigm of an inverse relationship between IDI and bone toughness, both through correlation analyses and in the individual experiments where divergent patterns of altered IDI and mechanical properties were noted. Based on these results, we conclude that RPI measurements alone, as compared to bending tests, are insufficient to reach conclusions regarding mechanical properties of bone. This proves problematic for the potential clinical use of RPI measurements in determining fracture risk for a single patient, as it is not currently clear that there is an IDI, or even a trend of IDI, that can determine clinically relevant changes in tissue properties that may contribute to whole bone fracture resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

Reference point indentation is insufficient for detecting alterations in traditional mechanical properties of bone under common experimental conditions

PubMed Central

Krege, John B.; Aref, Mohammad W.; McNerny, Erin; Wallace, Joseph M.; Organ, Jason M.; Allen, Matthew R.

2016-01-01

Reference point indentation (RPI) was developed as a novel method to assess mechanical properties of bone in vivo, yet it remains unclear what aspects of bone dictate changes/differences in RPI-based parameters. The main RPI parameter, indentation distance increase (IDI), has been proposed to be inversely related to the ability of bone to form/tolerate damage. The goal of this work was to explore the relationship between RPI parameters and traditional mechanical properties under varying experimental conditions (drying and ashing bones to increase brittleness, demineralizing bones and soaking in raloxifene to decrease brittleness). Beams were machined from cadaveric bone, pre-tested with RPI, subjected to experimental manipulation, post-tested with RPI, and then subjected to four-point bending to failure. Drying and ashing significantly reduced RPI’s IDI, as well as ultimate load (UL), and energy absorption measured from bending tests. Demineralization increased IDI with minimal change to bending properties. Ex vivo soaking in raloxifene had no effect on IDI but tended to enhance post-yield behavior at the structural level. These data challenge the paradigm of an inverse relationship between IDI and bone toughness, both through correlation analyses and in the individual experiments where divergent patterns of altered IDI and mechanical properties were noted. Based on these results, we conclude that RPI measurements alone, as compared to bending tests, are insufficient to reach conclusions regarding mechanical properties of bone. This proves problematic for the potential clinical use of RPI measurements in determining fracture risk for a single patient, as it is not currently clear that there is an IDI, or even a trend of IDI, that can determine clinically relevant changes in tissue properties that may contribute to whole bone fracture resistance. PMID:27072518

Supporting Biomaterials for Articular Cartilage Repair

PubMed Central

Duarte Campos, Daniela Filipa; Drescher, Wolf; Rath, Björn; Tingart, Markus

2012-01-01

Orthopedic surgeons and researchers worldwide are continuously faced with the challenge of regenerating articular cartilage defects. However, until now, it has not been possible to completely mimic the biological and biochemical properties of articular cartilage using current research and development approaches. In this review, biomaterials previously used for articular cartilage repair research are addressed. Furthermore, a brief discussion of the state of the art of current cell printing procedures mimicking native cartilage is offered in light of their use as future alternatives for cartilage tissue engineering. Inkjet cell printing, controlled deposition cell printing tools, and laser cell printing are cutting-edge techniques in this context. The development of mimetic hydrogels with specific biological properties relevant to articular cartilage native tissue will support the development of improved, functional, and novel engineered tissue for clinical application. PMID:26069634

Nanodiamonds as platforms for biology and medicine.

PubMed

Man, Han B; Ho, Dean

2013-02-01

Nanoparticles possess a wide range of exceptional properties applicable to biology and medicine. In particular, nanodiamonds (NDs) are being studied extensively because they possess unique characteristics that make them suitable as platforms for diagnostics and therapeutics. This carbon-based material (2-8 nm) is medically relevant because it unites several key properties necessary for clinical applications, such as stability and compatibility in biological environments, and scalability in production. Research by the Ho group and others has yielded ND particles with a variety of capabilities ranging from delivery of chemotherapeutic drugs to targeted labeling and uptake studies. In addition, encouraging new findings have demonstrated the ability for NDs to effectively treat chemoresistant tumors in vivo. In this review, we highlight the progress made toward bringing nanodiamonds from the bench to the bedside.

An Overview of the Evidence and Mechanisms of Herb–Drug Interactions

PubMed Central

Fasinu, Pius S.; Bouic, Patrick J.; Rosenkranz, Bernd

2012-01-01

Despite the lack of sufficient information on the safety of herbal products, their use as alternative and/or complementary medicine is globally popular. There is also an increasing interest in medicinal herbs as precursor for pharmacological actives. Of serious concern is the concurrent consumption of herbal products and conventional drugs. Herb–drug interaction (HDI) is the single most important clinical consequence of this practice. Using a structured assessment procedure, the evidence of HDI presents with varying degree of clinical significance. While the potential for HDI for a number of herbal products is inferred from non-human studies, certain HDIs are well established through human studies and documented case reports. Various mechanisms of pharmacokinetic HDI have been identified and include the alteration in the gastrointestinal functions with consequent effects on drug absorption; induction and inhibition of metabolic enzymes and transport proteins; and alteration of renal excretion of drugs and their metabolites. Due to the intrinsic pharmacologic properties of phytochemicals, pharmacodynamic HDIs are also known to occur. The effects could be synergistic, additive, and/or antagonistic. Poor reporting on the part of patients and the inability to promptly identify HDI by health providers are identified as major factors limiting the extensive compilation of clinically relevant HDIs. A general overview and the significance of pharmacokinetic and pharmacodynamic HDI are provided, detailing basic mechanism, and nature of evidence available. An increased level of awareness of HDI is necessary among health professionals and drug discovery scientists. With the increasing number of plant-sourced pharmacological actives, the potential for HDI should always be assessed in the non-clinical safety assessment phase of drug development process. More clinically relevant research is also required in this area as current information on HDI is insufficient for clinical applications. PMID:22557968

What is the benefit of using amniotic membrane in oral surgery? A comprehensive review of clinical studies.

PubMed

Fénelon, M; Catros, S; Fricain, J C

2018-06-01

Since its first use for the reconstruction of tissue defects in the oral cavity in 1985, human amniotic membrane (hAM) has been widely studied in the field of oral surgery. Despite the growing number of publications in this field, there is no systematic review or meta-analysis concerning its clinical applications, outcome assessments, and relevance in oral surgery. The aim of this review is to provide a thorough understanding of the potential use of hAM for soft and hard tissue reconstruction in the oral cavity. A systematic electronic and a manual literature search of the MEDLINE-PubMed database and Scopus database was completed. Patient, Intervention, Comparison and Outcomes (PICO) technique was used to select the relevant articles to meet the objective. Studies using hAM for oral reconstruction, and conducted on human subjects, were included in this survey. A total of 17 articles were analyzed. Five areas of interest were identified as potential clinical application: periodontal surgery, cleft palate and tumor reconstruction, prosthodontics and peri-implant surgery. Overall, periodontal surgery was the only discipline to assess the efficacy of hAM with randomized clinical trials. The wide variability of preservation methods of hAM and the lack of objective measurements were observed in this study. hAM is already used in the field of oral surgery. Despite this, there is weak clinical evidence demonstrating convincingly the benefit of hAM in this area compared to standard surgery. Several studies now suggest the interest of hAM for periodontal tissue repair. Due to its biological and mechanical properties, hAM seems to be a promising treatment for wound healing in various areas of oral reconstruction. However, further randomized clinical trials are needed to confirm these preliminary results.

A comparison of the psychometric properties of the psychopathic personality inventory full-length and short-form versions.

PubMed

Kastner, Rebecca M; Sellbom, Martin; Lilienfeld, Scott O

2012-03-01

The Psychopathic Personality Inventory (PPI) has shown promising construct validity as a measure of psychopathy. Because of its relative efficiency, a short-form version of the PPI (PPI-SF) was developed and has proven useful in many psychopathy studies. The validity of the PPI-SF, however, has not been thoroughly examined, and no studies have directly compared the validity of the short form with that of the full-length version. The current study was designed to compare the psychometric properties of both PPI versions, with an emphasis on convergent and discriminant validity in predicting external criteria conceptually relevant to psychopathy. We used both prison (n = 558) and college samples (n = 322) for this investigation. PPI scale scores were more reliable and more strongly correlated with the conceptually relevant criterion measures compared with the PPI-SF, particularly in the prison sample. There were no differences in relative discriminant validity. Thus, overall, the PPI full-length version showed more evidence of construct validity than did the short form, and the consequences of this psychometric difference should be considered when evaluating the clinical utility of each measure.

Trustworthiness and relevance in web-based clinical question answering.

PubMed

Cruchet, Sarah; Boyer, Célia; van der Plas, Lonneke

2012-01-01

Question answering systems try to give precise answers to a user's question posed in natural language. It is of utmost importance that the answers returned are relevant to the user's question. For clinical QA, the trustworthiness of answers is another important issue. Limiting the document collection to certified websites helps to improve the trustworthiness of answers. On the other hand, limited document collections are known to harm the relevancy of answers. We show, however, in a comparative evaluation, that promoting trustworthiness has no negative effect on the relevance of the retrieved answers in our clinical QA system. On the contrary, the answers found are in general more relevant.

Vascular Biology of Glucagon Receptor Superfamily Peptides: Mechanistic and Clinical Relevance.

PubMed

Pujadas, Gemma; Drucker, Daniel J

2016-12-01

Regulatory peptides produced in islet and gut endocrine cells, including glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide, exert actions with considerable metabolic importance and translational relevance. Although the clinical development of GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors has fostered research into how these hormones act on the normal and diseased heart, less is known about the actions of these peptides on blood vessels. Here we review the effects of these peptide hormones on normal blood vessels and highlight their vascular actions in the setting of experimental and clinical vascular injury. The cellular localization and signal transduction properties of the receptors for glucagon, GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide are discussed, with emphasis on endothelial cells and vascular smooth muscle cells. The actions of these peptides on the control of blood flow, blood pressure, angiogenesis, atherosclerosis, and vascular inflammation are reviewed with a focus on elucidating direct and indirect mechanisms of action. How these peptides traverse the blood-brain barrier is highlighted, with relevance to the use of GLP-1 receptor agonists to treat obesity and neurodegenerative disorders. Wherever possible, we compare actions identified in cell lines and primary cell culture with data from preclinical studies and, when available, results of human investigation, including studies in subjects with diabetes, obesity, and cardiovascular disease. Throughout the review, we discuss pitfalls, limitations, and challenges of the existing literature and highlight areas of controversy and uncertainty. The increasing use of peptide-based therapies for the treatment of diabetes and obesity underscores the importance of understanding the vascular biology of peptide hormone action.

Review of optical breast imaging and spectroscopy

NASA Astrophysics Data System (ADS)

Grosenick, Dirk; Rinneberg, Herbert; Cubeddu, Rinaldo; Taroni, Paola

2016-09-01

Diffuse optical imaging and spectroscopy of the female breast is an area of active research. We review the present status of this field and discuss the broad range of methodologies and applications. Starting with a brief overview on breast physiology, the remodeling of vasculature and extracellular matrix caused by solid tumors is highlighted that is relevant for contrast in optical imaging. Then, the various instrumental techniques and the related methods of data analysis and image generation are described and compared including multimodality instrumentation, fluorescence mammography, broadband spectroscopy, and diffuse correlation spectroscopy. We review the clinical results on functional properties of malignant and benign breast lesions compared to host tissue and discuss the various methods to improve contrast between healthy and diseased tissue, such as enhanced spectroscopic information, dynamic variations of functional properties, pharmacokinetics of extrinsic contrast agents, including the enhanced permeability and retention effect. We discuss research on monitoring neoadjuvant chemotherapy and on breast cancer risk assessment as potential clinical applications of optical breast imaging and spectroscopy. Moreover, we consider new experimental approaches, such as photoacoustic imaging and long-wavelength tissue spectroscopy.

Silk-based biomaterials.

PubMed

Altman, Gregory H; Diaz, Frank; Jakuba, Caroline; Calabro, Tara; Horan, Rebecca L; Chen, Jingsong; Lu, Helen; Richmond, John; Kaplan, David L

2003-02-01

Silk from the silkworm, Bombyx mori, has been used as biomedical suture material for centuries. The unique mechanical properties of these fibers provided important clinical repair options for many applications. During the past 20 years, some biocompatibility problems have been reported for silkworm silk; however, contamination from residual sericin (glue-like proteins) was the likely cause. More recent studies with well-defined silkworm silk fibers and films suggest that the core silk fibroin fibers exhibit comparable biocompatibility in vitro and in vivo with other commonly used biomaterials such as polylactic acid and collagen. Furthermore, the unique mechanical properties of the silk fibers, the diversity of side chain chemistries for 'decoration' with growth and adhesion factors, and the ability to genetically tailor the protein provide additional rationale for the exploration of this family of fibrous proteins for biomaterial applications. For example, in designing scaffolds for tissue engineering these properties are particularly relevant and recent results with bone and ligament formation in vitro support the potential role for this biomaterial in future applications. To date, studies with silks to address biomaterial and matrix scaffold needs have focused on silkworm silk. With the diversity of silk-like fibrous proteins from spiders and insects, a range of native or bioengineered variants can be expected for application to a diverse set of clinical needs.

Pomegranate Consumption and Blood Pressure: A Review.

PubMed

Asgary, Sedigheh; Keshvari, Mahtab; Sahebkar, Amirhossein; Sarrafzadegan, Nizal

2017-01-01

Pomegranate (Punica granatum L.) is a polyphenol-rich fruit with diverse medicinal properties. Several lines of experimental and clinical evidence have shown that pomegranate intake helps lowering blood pressure (BP) through different mechanisms. This study aimed to present a narrative review on the anti-hypertensive properties of different parts of pomegranate such as pomegranate juice (PJ), pomegranate peels (PP), pomegranate seed oil (PSO), pomegranate fruit extract (PFE) and the mechanisms and phytochemicals responsible for these effects. A review on the efficacy of consuming different parts of pomegranate (juice, peels, fruit extract and seed oil) in lowering BP has been performed. To find relevant studies, a search in PubMed, Science Direct and Scopus up from inception to May 4, 2015 was performed. Human, animals and in vitro studies investigating the anti-hypertensive effects of pomegranate were included in the search. Findings arising from animal and clinical studies have shown pomegranate juice can reduce BP in both short-term and long-term course. These effects are accompanied by antioxidant and anti-atherosclerotic actions that collectively improve cardiovascular health. The anti-hypertensive effects have been reported for both pomegranate juice and seed oil. Both systolic and diastolic pressures are affected. Pomegranate juice possesses antioxidant, anti-hypertensive and anti-atherosclerotic properties. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Numerical Modelling of Effects of Biphasic Layers of Corrosion Products to the Degradation of Magnesium Metal In Vitro

PubMed Central

Ahmed, Safia K.; Ward, John P.; Liu, Yang

2017-01-01

Magnesium (Mg) is becoming increasingly popular for orthopaedic implant materials. Its mechanical properties are closer to bone than other implant materials, allowing for more natural healing under stresses experienced during recovery. Being biodegradable, it also eliminates the requirement of further surgery to remove the hardware. However, Mg rapidly corrodes in clinically relevant aqueous environments, compromising its use. This problem can be addressed by alloying the Mg, but challenges remain at optimising the properties of the material for clinical use. In this paper, we present a mathematical model to provide a systematic means of quantitatively predicting Mg corrosion in aqueous environments, providing a means of informing standardisation of in vitro investigation of Mg alloy corrosion to determine implant design parameters. The model describes corrosion through reactions with water, to produce magnesium hydroxide Mg(OH)2, and subsequently with carbon dioxide to form magnesium carbonate MgCO3. The corrosion products produce distinct protective layers around the magnesium block that are modelled as porous media. The resulting model of advection–diffusion equations with multiple moving boundaries was solved numerically using asymptotic expansions to deal with singular cases. The model has few free parameters, and it is shown that these can be tuned to predict a full range of corrosion rates, reflecting differences between pure magnesium or magnesium alloys. Data from practicable in vitro experiments can be used to calibrate the model’s free parameters, from which model simulations using in vivo relevant geometries provide a cheap first step in optimising Mg-based implant materials. PMID:29267244

Pharmacological Activity and Clinical Use of PDRN

PubMed Central

Squadrito, Francesco; Bitto, Alessandra; Irrera, Natasha; Pizzino, Gabriele; Pallio, Giovanni; Minutoli, Letteria; Altavilla, Domenica

2017-01-01

PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout) or Oncorhynchus keta (Chum Salmon) sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A2A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects. PMID:28491036

A review on usnic acid, an interesting natural compound

NASA Astrophysics Data System (ADS)

Cocchietto, Moreno; Skert, Nicola; Nimis, Pier Luigi; Sava, Gianni

2002-03-01

Lichens are a world-widespread consortium of fungal and photosynthetic partners. Usnic acid is one of the most common and abundant lichen metabolites, well known as an antibiotic, but also endowed with several other interesting properties. This review summarises the most relevant studies on usnic acid, focusing on a number of biological activities in different fields. On the basis of the existing literature, usnic acid seems to be an exclusive lichen product. No synthetic derivatives more effective than the natural form are known. Both the (+) and (-) enantiomers of usnic acid are effective against a large variety of Gram-positive (G+) bacterial strains, including strains from clinical isolates, irrespective of their resistant phenotype. Of particular relevance is the inhibition of growth of multi-resistant strains of Streptococcus aureus, enterococci and mycobacteria. The (+)-usnic acid enantiomer appears to be selective against Streptococcus mutans without inducing perturbing side effects on the oral saprophyte flora. On the other hand, the (-)-usnic acid enantiomer is a selective natural herbicide because of its blocking action against a specific key plant enzyme. Other recognised characteristics of usnic acid are ultraviolet absorption and preserving properties. The toxicology, the in vitro anti-inflammatory effects and the mechanism of action of usnic acid need to be investigated in greater detail in order to reach clinical trials and to allow further applications. Furthermore, more research is needed to make possible intensive lichen culture, in order to produce large quantities of lichen substances for pharmaceutical, cosmetic and agricultural purposes. Some biological aspects, i.e. the possible biological roles of usnic acid, are discussed.

Connecting drug delivery reality to smart materials design.

PubMed

Grainger, David W

2013-09-15

Inflated claims to both design and mechanistic novelty in drug delivery and imaging systems, including most nanotechnologies, are not supported by the generally poor translation of these systems to clinical efficacy. The "form begets function" design paradigm is seductive but perhaps over-simplistic in translation to pharmaceutical efficacy. Most innovations show few clinically important distinctions in their therapeutic benefits in relevant preclinical disease and delivery models, despite frequent claims to the contrary. Long-standing challenges in drug delivery issues must enlist more realistic, back-to-basics approaches to address fundamental materials properties in complex biological systems, preclinical test beds, and analytical methods to more reliably determine fundamental pharmaceutical figures of merit, including drug carrier purity and batch-batch variability, agent biodistribution, therapeutic index (safety), and efficacy. Copyright © 2013 Elsevier B.V. All rights reserved.

Defibrotide: a review on clinical use and future development.

PubMed

Larocca, A; Cavallo, F; Magarotto, V; Rossi, D; Patriarca, F; Boccadoro, M; Palumbo, A

2008-08-01

Defibrotide is a deoxyribonucleic acid derivative that has been developed for the treatment of different vascular disorders. The authors reviewed the literature to give due representation to the spectrum of pharmacological properties and clinical application of this drug, evaluating consolidate and innovative application. The authors used PubMed from November 1982 to December 2007 and meeting abstracts (form American Society of Hematology Annual Meeting) with updated data as the sources for this review and selecting the most relevant papers when two or more articles covered the same point of interest. Defibrotide has been used effectively in the treatment of endothelial complications of allogeneic stem cell transplantation and recent preclinical evidences suggest an antiangiogenic effect and an anticancer activity. Further in vivo and in vitro investigations are needed.

Sensitivity, Specificity, and Receiver Operating Characteristics: A Primer for Neuroscience Nurses.

PubMed

McNett, Molly; Amato, Shelly; Olson, DaiWai M

2017-04-01

It is important for neuroscience nurses to have a solid understanding of the instruments they use in clinical practice. Specifically, when reviewing reports of research instruments, nurses should be knowledgeable of analytical terms when determining the applicability of instruments for use in clinical practice. The purpose of this article is to review 3 such analytical terms: sensitivity, specificity, and receiver operating characteristic curves. Examples of how these terms are used in the neuroscience literature highlight the relevance of these terms to neuroscience nursing practice. As the role of the nurse continues to expand, it is important not to simply accept all instruments as valid but to be able to critically evaluate their properties for applicability to nursing practice and evidence-based care of our patients.

[Religious/spiritual well-being in mentally ill persons II: the development of a short scale and comparison scores for clinical psychiatric groups and healthy controls].

PubMed

Unterrainer, Human-Friedrich; Kapfhammer, Hans-Peter

2014-01-01

The Multidimensional Inventory for Religious/Spiritual Well-Being (MI-RSWB) was successfully applied in several clinical as well as non-clinical studies. However, the original version of the scale often showed to be as too comprehensive especially for clinical surroundings. There for the aim of this study is to develop a short version of the scale comprising 12 items. Based on a sample representative of the Austrian general population (N = 1,500), a first MI-RSWB short version is developed by means of factor- and reliability analysis. Furthermore the new short version of the scale is initially validated through several indicators of mental illness. The MI-RSWB short version shows convincing psychometric properties. The total scale as well as the sub scales exhibit at least a sufficient internal consistency. A significant negative association with several indicators of psychiatric illness is also confirmed for the short version of the scale. The MI-RWSB 12 scale is especially recommended for further research focusing on the clinical relevance of religiosity and spirituality.

The C-terminal Helix of Pseudomonas aeruginosa Elongation Factor Ts Tunes EF-Tu Dynamics to Modulate Nucleotide Exchange.

PubMed

De Laurentiis, Evelina Ines; Mercier, Evan; Wieden, Hans-Joachim

2016-10-28

Little is known about the conservation of critical kinetic parameters and the mechanistic strategies of elongation factor (EF) Ts-catalyzed nucleotide exchange in EF-Tu in bacteria and particularly in clinically relevant pathogens. EF-Tu from the clinically relevant pathogen Pseudomonas aeruginosa shares over 84% sequence identity with the corresponding elongation factor from Escherichia coli Interestingly, the functionally closely linked EF-Ts only shares 55% sequence identity. To identify any differences in the nucleotide binding properties, as well as in the EF-Ts-mediated nucleotide exchange reaction, we performed a comparative rapid kinetics and mutagenesis analysis of the nucleotide exchange mechanism for both the E. coli and P. aeruginosa systems, identifying helix 13 of EF-Ts as a previously unnoticed regulatory element in the nucleotide exchange mechanism with species-specific elements. Our findings support the base side-first entry of the nucleotide into the binding pocket of the EF-Tu·EF-Ts binary complex, followed by displacement of helix 13 and rapid binding of the phosphate side of the nucleotide, ultimately leading to the release of EF-Ts. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Biliary tract cancer stem cells - translational options and challenges

PubMed Central

Mayr, Christian; Ocker, Matthias; Ritter, Markus; Pichler, Martin; Neureiter, Daniel; Kiesslich, Tobias

2017-01-01

Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells - the cancer stem cells - possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells. PMID:28465631

Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells.

PubMed

Reinisch, Andreas; Chan, Steven M; Thomas, Daniel; Majeti, Ravindra

2015-07-01

Evidence for the cancer stem cell model was first demonstrated in xenotransplanted blood and bone marrow samples from patients with acute myeloid leukemia (AML) almost two decades ago, supporting the concept that a rare clonal and mutated leukemic stem cell (LSC) population is sufficient to drive leukemic growth. The inability to eliminate LSCs with conventional therapies is thought to be the primary cause of disease relapse in AML patients, and as such, novel therapies with the ability to target this population are required to improve patient outcomes. An important step towards this goal is the identification of common immunophenotypic surface markers and biological properties that distinguish LSCs from normal hematopoietic stem and progenitor cells (HSPCs) across AML patients. This work has resulted in the development of a large number of potential LSC-selective therapies that target cell surface molecules, intracellular signaling pathways, and the bone marrow microenvironment. Here, we will review the basic biology, immunophenotypic detection, and clinical relevance of LSCs, as well as emerging biological and small-molecule strategies that either directly target LSCs or indirectly target these cells through modulation of their microenvironment. Copyright © 2015 Elsevier Inc. All rights reserved.

Reflections on relevance: Psychotherapy and Psychosomatics in 2004.

PubMed

Balon, Richard

2005-01-01

Relevance of an article is a highly desirable yet hardly predictable quality at the time of its publication. Article relevance is frequently measured by the impact factor of the journal where the article is published. Furthermore, impact factor, citation index and citation analysis are used as a measure of research progress and scientific wealth of a nation. The wisdom and significance of this approach to relevance is debatable and thus discussed here. In 2004, Psychotherapy and Psychosomatics published a variety of articles which, in the author's view, are clinically relevant. Several selected clinically relevant issues reviewed in this article include: the conceptualization of fibromyalgia as a stress disorder; the psychosocial impact and psychosocial interventions in cancer; the impact of alexithymia on patient care; the possible relationship between depression and nutrition (namely intake of folate and pyridoxal phosphate); the significance of hypercoagulability in panic-like anxiety; the questionable value of single isomer drugs, and the relevance and adequacy of clinimetrics versus psychometrics in clinical research. The reviewed issues seem to be relevant to clinical practice, research or both, but also to our critical thinking, and the critical review of the developments in psychiatry and psychology. Copyright 2005 S. Karger AG, Basel.

Diagnostic value of clinical tests for degenerative rotator cuff disease in medical practice.

PubMed

Lasbleiz, S; Quintero, N; Ea, K; Petrover, D; Aout, M; Laredo, J D; Vicaut, E; Bardin, T; Orcel, P; Beaudreuil, J

2014-06-01

To assess the diagnostic value of clinical tests for degenerative rotator cuff disease (DRCD) in medical practice. Patients with DRCD were prospectively included. Eleven clinical tests of the rotator cuff have been done. One radiologist performed ultrasonography (US) of the shoulder. Results of US were expressed as normal tendon, tendinopathy or full-thickness tear (the reference). For each clinical test and each US criteria, sensitivity, specificity, negative predictive value and positive predictive value, accuracy, negative likelihood ratio (NLR) and positive likelihood ratio (PLR) were calculated. Clinical relevance was defined as PLR ≥2 and NLR ≤0.5. For 35 patients (39 shoulders), Jobe (PLR: 2.08, NLR: 0.31) and full-can (2, 0.5) test results were relevant for diagnosis of supraspinatus tears and resisted lateral rotation (2.42, 0.5) for infraspinatus tears, with weakness as response criteria. The lift-off test (8.50, 0.27) was relevant for subscapularis tears with lag sign as response criteria. Yergason's test (3.7, 0.41) was relevant for tendinopathy of the long head of the biceps with pain as a response criterion. There was no relevant clinical test for diagnosis of tendinopathy of supraspinatus, infraspinatus or subscapularis. Five of 11 clinical tests were relevant for degenerative rotator cuff disease. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease

PubMed Central

Serneels, Lutgarde; Van Biervliet, Jérôme; Craessaerts, Katleen; Dejaegere, Tim; Horré, Katrien; Van Houtvin, Tine; Esselmann, Hermann; Paul, Sabine; Schäfer, Martin K.; Berezovska, Oksana; Hyman, Bradley T.; Sprangers, Ben; Sciot, Raf; Moons, Lieve; Jucker, Mathias; Yang, Zhixiang; May, Patrick C.; Karran, Eric; Wiltfang, Jens; D’Hooge, Rudi; De Strooper, Bart

2009-01-01

The γ-secretase complex plays a role in Alzheimer’s disease (AD) and cancer progression. The development of clinical useful inhibitors, however, is complicated by the role of the γ-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different γ-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B γ-secretase in a murine Alzheimer’s disease model led to improvements of Alzheimer’s disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total γ-secretase activity in the human brain, thus specific targeting of Aph1B-containing γ-secretase complexes may be helpful in generating less toxic therapies for Alzheimer’s disease. PMID:19299585

Multiple fMRI system-level baseline connectivity is disrupted in patients with consciousness alterations.

PubMed

Demertzi, Athena; Gómez, Francisco; Crone, Julia Sophia; Vanhaudenhuyse, Audrey; Tshibanda, Luaba; Noirhomme, Quentin; Thonnard, Marie; Charland-Verville, Vanessa; Kirsch, Murielle; Laureys, Steven; Soddu, Andrea

2014-03-01

In healthy conditions, group-level fMRI resting state analyses identify ten resting state networks (RSNs) of cognitive relevance. Here, we aim to assess the ten-network model in severely brain-injured patients suffering from disorders of consciousness and to identify those networks which will be most relevant to discriminate between patients and healthy subjects. 300 fMRI volumes were obtained in 27 healthy controls and 53 patients in minimally conscious state (MCS), vegetative state/unresponsive wakefulness syndrome (VS/UWS) and coma. Independent component analysis (ICA) reduced data dimensionality. The ten networks were identified by means of a multiple template-matching procedure and were tested on neuronality properties (neuronal vs non-neuronal) in a data-driven way. Univariate analyses detected between-group differences in networks' neuronal properties and estimated voxel-wise functional connectivity in the networks, which were significantly less identifiable in patients. A nearest-neighbor "clinical" classifier was used to determine the networks with high between-group discriminative accuracy. Healthy controls were characterized by more neuronal components compared to patients in VS/UWS and in coma. Compared to healthy controls, fewer patients in MCS and VS/UWS showed components of neuronal origin for the left executive control network, default mode network (DMN), auditory, and right executive control network. The "clinical" classifier indicated the DMN and auditory network with the highest accuracy (85.3%) in discriminating patients from healthy subjects. FMRI multiple-network resting state connectivity is disrupted in severely brain-injured patients suffering from disorders of consciousness. When performing ICA, multiple-network testing and control for neuronal properties of the identified RSNs can advance fMRI system-level characterization. Automatic data-driven patient classification is the first step towards future single-subject objective diagnostics based on fMRI resting state acquisitions. Copyright © 2013 Elsevier Ltd. All rights reserved.

Psychometric evaluation of ADAS-Cog and NTB for measuring drug response.

PubMed

Karin, A; Hannesdottir, K; Jaeger, J; Annas, P; Segerdahl, M; Karlsson, P; Sjögren, N; von Rosen, T; Miller, F

2014-02-01

To conduct a psychometric analysis to determine the adequacy of instruments that measure cognition in Alzheimer's disease trials. Both the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) and the Neuropsychological Test Battery (NTB) are validated outcome measures for clinical trials in Alzheimer's disease and are approved also for regulatory purposes. However, it is not clear how comparable they are in measuring cognitive function. In fact, many recent trials in Alzheimer's disease patients have failed and it has been questioned if ADAS-Cog still is a sensitive measure. The present paper examines the psychometric properties of ADAS-Cog and NTB, based on a post hoc analysis of data from a clinical trial (NCT01024660), which was conducted by AstraZeneca, in mild-to-moderate Alzheimer's disease (AD) patients, with a Mini Mental State Examination (MMSE) Total score 16-24. Acceptability, reliability, different types of validity and ability to detect change were assessed using relevant statistical methods. Total scores of both tests, as well as separate domains of both tests, including the Wechsler Memory Scale (WMS), Rey Auditory Verbal Learning Test (RAVLT) and Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Condition, were analyzed. Overall, NTB performed well, with acceptable reliability and ability to detect change, while ADAS-Cog had insufficient psychometric properties, including ceiling effects in 8 out of a total of 11 ADAS-Cog items in mild AD patients, as well as low test-retest reliability in some of the items. Based on a direct comparison on the same patient sample, we see advantages of the NTB compared with the ADAS-Cog for the evaluation of cognitive function in the population of mild-to-moderate AD patients. The results suggest that not all of ADAS-Cog items are relevant for both mild and moderate AD population. This validation study demonstrates satisfactory psychometric properties of the NTB, while ADAS-Cog was found to be psychometrically inadequate. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mechanisms for pattern specificity of deep-brain stimulation in Parkinson’s disease

PubMed Central

Mato, Germán; Dellavale, Damián

2017-01-01

Deep brain stimulation (DBS) has become a widely used technique for treating advanced stages of neurological and psychiatric illness. In the case of motor disorders related to basal ganglia (BG) dysfunction, several mechanisms of action for the DBS therapy have been identified which might be involved simultaneously or in sequence. However, the identification of a common key mechanism underlying the clinical relevant DBS configurations has remained elusive due to the inherent complexity related to the interaction between the electrical stimulation and the neural tissue, and the intricate circuital structure of the BG-thalamocortical network. In this work, it is shown that the clinically relevant range for both, the frequency and intensity of the electrical stimulation pattern, is an emergent property of the BG anatomy at the system-level that can be addressed using mean-field descriptive models of the BG network. Moreover, it is shown that the activity resetting mechanism elicited by electrical stimulation provides a natural explanation to the ineffectiveness of irregular (i.e., aperiodic) stimulation patterns, which has been commonly observed in previously reported pathophysiology models of Parkinson’s disease. Using analytical and numerical techniques, these results have been reproduced in both cases: 1) a reduced mean-field model that can be thought as an elementary building block capable to capture the underlying fundamentals of the relevant loops constituting the BG-thalamocortical network, and 2) a detailed model constituted by the direct and hyperdirect loops including one-dimensional spatial structure of the BG nuclei. We found that the optimal ranges for the essential parameters of the stimulation patterns can be understood without taking into account biophysical details of the relevant structures. PMID:28813460

Retrieval of diagnostic and treatment studies for clinical use through PubMed and PubMed's Clinical Queries filters.

PubMed

Lokker, Cynthia; Haynes, R Brian; Wilczynski, Nancy L; McKibbon, K Ann; Walter, Stephen D

2011-01-01

Clinical Queries filters were developed to improve the retrieval of high-quality studies in searches on clinical matters. The study objective was to determine the yield of relevant citations and physician satisfaction while searching for diagnostic and treatment studies using the Clinical Queries page of PubMed compared with searching PubMed without these filters. Forty practicing physicians, presented with standardized treatment and diagnosis questions and one question of their choosing, entered search terms which were processed in a random, blinded fashion through PubMed alone and PubMed Clinical Queries. Participants rated search retrievals for applicability to the question at hand and satisfaction. For treatment, the primary outcome of retrieval of relevant articles was not significantly different between the groups, but a higher proportion of articles from the Clinical Queries searches met methodologic criteria (p=0.049), and more articles were published in core internal medicine journals (p=0.056). For diagnosis, the filtered results returned more relevant articles (p=0.031) and fewer irrelevant articles (overall retrieval less, p=0.023); participants needed to screen fewer articles before arriving at the first relevant citation (p<0.05). Relevance was also influenced by content terms used by participants in searching. Participants varied greatly in their search performance. Clinical Queries filtered searches returned more high-quality studies, though the retrieval of relevant articles was only statistically different between the groups for diagnosis questions. Retrieving clinically important research studies from Medline is a challenging task for physicians. Methodological search filters can improve search retrieval.

Clinical relevance of diagnosing COPD by fixed ratio or lower limit of normal: a systematic review.

PubMed

van Dijk, Wouter D; Gupta, Nisha; Tan, Wan C; Bourbeau, Jean

2014-02-01

Different spirometric criteria in diagnosing COPD have been advocated by different groups, debilitating adequate diagnosis and treatment of COPD. We reviewed the clinical relevance of fixed ratio and lower limit of normal (LLN) in diagnosing COPD and explored if modifying factors may affect their clinical relevance. Two reviewers independently searched PubMed and Embase for papers that compared both criteria on any clinically relevant outcome, published before June 1st, 2012, without any language restriction. Two reviewers independently extracted the study characteristics, including study design, population characteristics and diagnostic criteria used, and summarized the results of clinical relevance. Study quality was assessed by scoring forms for bias and level of evidence. Of 394 studies retrieved, 11 studies were included, with a median of 1,258 participants. Although both criteria appeared related with various clinically relevant outcomes, we were unable to prefer one criterion over the other, with various performances of the criteria for different outcomes. Should the criteria disagree on diagnosis, an alternative diagnosis should be suspected, in particular in those (elderly) with less severe airflow limitation for whom the LLN appears a better criterion. The fixed ratio appears to perform better in subjects with more severe airflow limitation. In diagnosing COPD, severity of airflow limitation appears an important factor for choosing whether the fixed ratio or LLN. Disagreement between the criteria is suggestive for an alternative diagnosis. Future studies on clinical relevance should further reveal the criterion of choice, in order to improve adequate diagnosis and consequent treatments.

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition.

PubMed

Tortorella, Stephanie M; Royce, Simon G; Licciardi, Paul V; Karagiannis, Tom C

2015-06-01

Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies.

A Biophysical Basis for Mucus Solids Concentration as a Candidate Biomarker for Airways Disease

PubMed Central

Hill, David B.; Vasquez, Paula A.; Mellnik, John; McKinley, Scott A.; Vose, Aaron; Mu, Frank; Henderson, Ashley G.; Donaldson, Scott H.; Alexis, Neil E.; Boucher, Richard C.; Forest, M. Gregory

2014-01-01

In human airways diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), host defense is compromised and airways inflammation and infection often result. Mucus clearance and trapping of inhaled pathogens constitute key elements of host defense. Clearance rates are governed by mucus viscous and elastic moduli at physiological driving frequencies, whereas transport of trapped pathogens in mucus layers is governed by diffusivity. There is a clear need for simple and effective clinical biomarkers of airways disease that correlate with these properties. We tested the hypothesis that mucus solids concentration, indexed as weight percent solids (wt%), is such a biomarker. Passive microbead rheology was employed to determine both diffusive and viscoelastic properties of mucus harvested from human bronchial epithelial (HBE) cultures. Guided by sputum from healthy (1.5–2.5 wt%) and diseased (COPD, CF; 5 wt%) subjects, mucus samples were generated in vitro to mimic in vivo physiology, including intermediate range wt% to represent disease progression. Analyses of microbead datasets showed mucus diffusive properties and viscoelastic moduli scale robustly with wt%. Importantly, prominent changes in both biophysical properties arose at ∼4 wt%, consistent with a gel transition (from a more viscous-dominated solution to a more elastic-dominated gel). These findings have significant implications for: (1) penetration of cilia into the mucus layer and effectiveness of mucus transport; and (2) diffusion vs. immobilization of micro-scale particles relevant to mucus barrier properties. These data provide compelling evidence for mucus solids concentration as a baseline clinical biomarker of mucus barrier and clearance functions. PMID:24558372

Insights from clinical research completed during the west Africa Ebola virus disease epidemic

PubMed Central

Rojek, Amanda; Horby, Peter; Dunning, Jake

2018-01-01

The west Africa Ebola virus disease (EVD) epidemic was extraordinary in scale. Now that the epidemic has ended, it is a relevant time to examine published studies with direct relevance to clinical care and, more broadly, to examine the implications of the clinical research response mounted. Clinically relevant research includes literature detailing risk factors for and clinical manifestations of EVD, laboratory and other investigation findings in patients, experimental vaccine and therapeutic clinical trials, and analyses of survivor syndrome. In this Review, we discuss new insights from patient-oriented research completed during the west Africa epidemic, identify ongoing knowledge gaps, and suggest priorities for future research. PMID:28461209

Antimicrobial activity of extracts from macroalgae Ulva lactuca against clinically important Staphylococci is impacted by lunar phase of macroalgae harvest.

PubMed

Deveau, A M; Miller-Hope, Z; Lloyd, E; Williams, B S; Bolduc, C; Meader, J M; Weiss, F; Burkholder, K M

2016-05-01

Staphylococcus aureus is a common human bacterial pathogen that causes skin and soft tissue infections. Methicillin-resistant Staph. aureus (MRSA) are increasingly drug-resistant, and thus there is great need for new therapeutics to treat Staph. aureus infections. Attention has focused on potential utility of natural products, such as extracts of marine macroalgae, as a source of novel antimicrobial compounds. The green macroalgae Ulva lactuca produces compounds inhibitory to human pathogens, although the effectiveness of U. lactuca extracts against clinically relevant strains of Staph. aureus is poorly understood. In addition, macroalgae produce secondary metabolites that may be influenced by exogenous factors including lunar phase, but whether lunar phase affects U. lactuca antimicrobial capacity is unknown. We sought to evaluate the antibacterial properties of U. lactuca extracts against medically important Staphylococci, and to determine the effect of lunar phase on antimicrobial activity. We report that U. lactuca methanolic extracts inhibit a range of Staphylococci, and that lunar phase of macrolagae harvest significantly impacts antimicrobial activity, suggesting that antimicrobial properties can be maximized by manipulating time of algal harvest. These findings provide useful parameters for future studies aimed at isolating and characterizing U. lactuca anti-Staphylococcal agents. The growing prevalence of antibiotic-resistant human pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) has intensified efforts towards discovery and development of novel therapeutics. Marine macroalgae like Ulva lactuca are increasingly recognized as potential sources of antimicrobials, but the efficacy of U. lactuca extracts against common, virulent strains of Staph. aureus is poorly understood. We demonstrate that U. lactuca methanolic extracts inhibit a variety of clinically relevant Staphylococcus strains, and that the antimicrobial activity can be maximized by optimizing time of algal harvest. These findings provide potentially useful parameters for future work of isolating and identifying novel antimicrobial agents from macroalgae. © 2016 The Society for Applied Microbiology.

Biomedically relevant chemical and physical properties of coal combustion products.

PubMed Central

Fisher, G L

1983-01-01

The evaluation of the potential public and occupational health hazards of developing and existing combustion processes requires a detailed understanding of the physical and chemical properties of effluents available for human and environmental exposures. These processes produce complex mixtures of gases and aerosols which may interact synergistically or antagonistically with biological systems. Because of the physicochemical complexity of the effluents, the biomedically relevant properties of these materials must be carefully assessed. Subsequent to release from combustion sources, environmental interactions further complicate assessment of the toxicity of combustion products. This report provides an overview of the biomedically relevant physical and chemical properties of coal fly ash. Coal fly ash is presented as a model complex mixture for health and safety evaluation of combustion processes. PMID:6337824

Integrating the glioblastoma microenvironment into engineered experimental models

PubMed Central

Xiao, Weikun; Sohrabi, Alireza; Seidlits, Stephanie K

2017-01-01

Glioblastoma (GBM) is the most lethal cancer originating in the brain. Its high mortality rate has been attributed to therapeutic resistance and rapid, diffuse invasion – both of which are strongly influenced by the unique microenvironment. Thus, there is a need to develop new models that mimic individual microenvironmental features and are able to provide clinically relevant data. Current understanding of the effects of the microenvironment on GBM progression, established experimental models of GBM and recent developments using bioengineered microenvironments as ex vivo experimental platforms that mimic the biochemical and physical properties of GBM tumors are discussed. PMID:28883992

The role of cocrystals in pharmaceutical science.

PubMed

Shan, Ning; Zaworotko, Michael J

2008-05-01

Pharmaceutical cocrystals, a subset of a long known but little-studied class of compounds, represent an emerging class of crystal forms in the context of pharmaceutical science. They are attractive to pharmaceutical scientists because they can significantly diversify the number of crystal forms that exist for a particular active pharmaceutical ingredient (API), and they can lead to improvements in physical properties of clinical relevance. In this article we address pharmaceutical cocrystals from the perspective of design (crystal engineering) and present a series of case studies that demonstrate how they can enhance the solubility, bioavailability, and/or stability of API crystal forms.

The Measurement of Term Importance in Automatic Indexing.

ERIC Educational Resources Information Center

Salton, G.; And Others

1981-01-01

Reviews major term-weighting theories, presents methods for estimating the relevance properties of terms based on their frequency characteristics in a document collection, and compares weighting systems using term relevance properties with more conventional frequency-based methodologies. Eighteen references are cited. (Author/FM)

Measurement properties and feasibility of clinical tests to assess sit-to-stand/stand-to-sit tasks in subjects with neurological disease: a systematic review

PubMed Central

Silva, Paula F. S.; Quintino, Ludmylla F.; Franco, Juliane; Faria, Christina D. C. M.

2014-01-01

Background Subjects with neurological disease (ND) usually show impaired performance during sit-to-stand and stand-to-sit tasks, with a consequent reduction in their mobility levels. Objective To determine the measurement properties and feasibility previously investigated for clinical tests that evaluate sit-to-stand and stand-to-sit in subjects with ND. Method A systematic literature review following the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) protocol was performed. Systematic literature searches of databases (MEDLINE/SCIELO/LILACS/PEDro) were performed to identify relevant studies. In all studies, the following inclusion criteria were assessed: investigation of any measurement property or the feasibility of clinical tests that evaluate sit-to-stand and stand-to-sit tasks in subjects with ND published in any language through December 2012. The COSMIN checklist was used to evaluate the methodological quality of the included studies. Results Eleven studies were included. The measurement properties/feasibility were most commonly investigated for the five-repetition sit-to-stand test, which showed good test-retest reliability (Intraclass Correlation Coefficient:ICC=0.94-0.99) for subjects with stroke, cerebral palsy and dementia. The ICC values were higher for this test than for the number of repetitions in the 30-s test. The five-repetition sit-to-stand test also showed good inter/intra-rater reliabilities (ICC=0.97-0.99) for stroke and inter-rater reliability (ICC=0.99) for subjects with Parkinson disease and incomplete spinal cord injury. For this test, the criterion-related validity for subjects with stroke, cerebral palsy and incomplete spinal cord injury was, in general, moderate (correlation=0.40-0.77), and the feasibility and safety were good for subjects with Alzheimer's disease. Conclusions The five-repetition sit-to-stand test was used more often in subjects with ND, and most of the measurement properties were investigated and showed adequate results. PMID:24839043

Efficient implementation of a real-time estimation system for thalamocortical hidden Parkinsonian properties

NASA Astrophysics Data System (ADS)

Yang, Shuangming; Deng, Bin; Wang, Jiang; Li, Huiyan; Liu, Chen; Fietkiewicz, Chris; Loparo, Kenneth A.

2017-01-01

Real-time estimation of dynamical characteristics of thalamocortical cells, such as dynamics of ion channels and membrane potentials, is useful and essential in the study of the thalamus in Parkinsonian state. However, measuring the dynamical properties of ion channels is extremely challenging experimentally and even impossible in clinical applications. This paper presents and evaluates a real-time estimation system for thalamocortical hidden properties. For the sake of efficiency, we use a field programmable gate array for strictly hardware-based computation and algorithm optimization. In the proposed system, the FPGA-based unscented Kalman filter is implemented into a conductance-based TC neuron model. Since the complexity of TC neuron model restrains its hardware implementation in parallel structure, a cost efficient model is proposed to reduce the resource cost while retaining the relevant ionic dynamics. Experimental results demonstrate the real-time capability to estimate thalamocortical hidden properties with high precision under both normal and Parkinsonian states. While it is applied to estimate the hidden properties of the thalamus and explore the mechanism of the Parkinsonian state, the proposed method can be useful in the dynamic clamp technique of the electrophysiological experiments, the neural control engineering and brain-machine interface studies.

Microfluidics to Mimic Blood Flow in Health and Disease

NASA Astrophysics Data System (ADS)

Sebastian, Bernhard; Dittrich, Petra S.

2018-01-01

Throughout history, capillary systems have aided the establishment of the fundamental laws of blood flow and its non-Newtonian properties. The advent of microfluidics technology in the 1990s propelled the development of highly integrated lab-on-a-chip platforms that allow highly accurate replication of vascular systems' dimensions, mechanical properties, and biological complexity. Applications include the detection of pathological changes to red blood cells, white blood cells, and platelets at unparalleled sensitivity and the efficacy assessment of drug treatment. Recent efforts have aimed at the development of microfluidics-based tests usable in a clinial environment or the replication of more complex diseases such as thrombosis. These microfluidic disease models enable the study of onset and progression of disease as well as the identification of key players and risk factors, which have led to a spectrum of clinically relevant findings.

Nanomedicine – challenge and perspectives

PubMed Central

Riehemann, Kristina; Schneider, Stefan W.; Luger, Thomas A.; Godin, Biana; Ferrari, Mauro; Fuchs, Harald

2014-01-01

Nanomedicine introduces nanotechnology concepts into medicine and thus joins two large cross disciplinary fields with an unprecedented societal and economical potential arising from the natural combination of specific achievements in the respective fields. The common basis evolves from the molecular scale properties relevant in the two fields. Nanoanalytical tools such as local probes and molecular imaging techniques, allow us to characterize surface and interface properties at a nanometer scale at predefined locations, while elaborated chemical approaches offer the opportunity for the control and addressing of surfaces e. g. for targeted drug delivery, enhanced biocompatibility and neuroprosthetic purposes. This commonality opens a wide variety of economic fields both of industrial and clinical interests. However, concerns arise in this cross disciplinary area about toxicological aspects and ethical implications. This review gives an overview of selected recent developments of nanotechnology applied on medical objectives. PMID:19142939

Identifying Opportunities for Vertical Integration of Biochemistry and Clinical Medicine.

PubMed

Wendelberger, Karen J.; Burke, Rebecca; Haas, Arthur L.; Harenwattananon, Marisa; Simpson, Deborah

1998-01-01

Objectives: Retention of basic science knowledge, as judged by National Board of Medical Examiners' (NBME) data, suffers due to lack of apparent relevance and isolation of instruction from clinical application, especially in biochemistry. However, the literature reveals no systematic process for identifying key biochemical concepts and associated clinical conditions. This study systematically identified difficult biochemical concepts and their common clinical conditions as a critical step towards enhancing relevance and retention of biochemistry.Methods: A multi-step/ multiple stakeholder process was used to: (1) identify important biochemistry concepts; (2) determine students' perceptions of concept difficulty; (3) assess biochemistry faculty, student, and clinical teaching scholars' perceived relevance of identified concepts; and (4) identify associated common clinical conditions for relevant and difficult concepts. Surveys and a modified Delphi process were used to gather data, subsequently analyzed using SPSS for Windows.Results: Sixteen key biochemical concepts were identified. Second year medical students rated 14/16 concepts as extremely difficult while fourth year students rated nine concepts as moderately to extremely difficult. On average, each teaching scholar generated common clinical conditions for 6.2 of the 16 concepts, yielding a set of seven critical concepts and associated clinical conditions.Conclusions: Key stakeholders in the instructional process struggle to identify biochemistry concepts that are critical, difficult to learn and associated with common clinical conditions. However, through a systematic process beginning with identification of concepts and associated clinical conditions, relevance of basic science instruction can be enhanced.

Retention of knowledge and perceived relevance of basic sciences in an integrated case-based learning (CBL) curriculum

PubMed Central

2013-01-01

Background Knowledge and understanding of basic biomedical sciences remain essential to medical practice, particularly when faced with the continual advancement of diagnostic and therapeutic modalities. Evidence suggests, however, that retention tends to atrophy across the span of an average medical course and into the early postgraduate years, as preoccupation with clinical medicine predominates. We postulated that perceived relevance demonstrated through applicability to clinical situations may assist in retention of basic science knowledge. Methods To test this hypothesis in our own medical student cohort, we administered a paper-based 50 MCQ assessment to a sample of students from Years 2 through 5. Covariates pertaining to demographics, prior educational experience, and the perceived clinical relevance of each question were also collected. Results A total of 232 students (Years 2–5, response rate 50%) undertook the assessment task. This sample had comparable demographic and performance characteristics to the whole medical school cohort. In general, discipline-specific and overall scores were better for students in the latter years of the course compared to those in Year 2; male students and domestic students tended to perform better than their respective counterparts in certain disciplines. In the clinical years, perceived clinical relevance was significantly and positively correlated with item performance. Conclusions This study suggests that perceived clinical relevance is a contributing factor to the retention of basic science knowledge and behoves curriculum planners to make clinical relevance a more explicit component of applied science teaching throughout the medical course. PMID:24099045

Does the choice of display system influence perception and visibility of clinically relevant features in digital pathology images?

NASA Astrophysics Data System (ADS)

Kimpe, Tom; Rostang, Johan; Avanaki, Ali; Espig, Kathryn; Xthona, Albert; Cocuranu, Ioan; Parwani, Anil V.; Pantanowitz, Liron

2014-03-01

Digital pathology systems typically consist of a slide scanner, processing software, visualization software, and finally a workstation with display for visualization of the digital slide images. This paper studies whether digital pathology images can look different when presenting them on different display systems, and whether these visual differences can result in different perceived contrast of clinically relevant features. By analyzing a set of four digital pathology images of different subspecialties on three different display systems, it was concluded that pathology images look different when visualized on different display systems. The importance of these visual differences is elucidated when they are located in areas of the digital slide that contain clinically relevant features. Based on a calculation of dE2000 differences between background and clinically relevant features, it was clear that perceived contrast of clinically relevant features is influenced by the choice of display system. Furthermore, it seems that the specific calibration target chosen for the display system has an important effect on the perceived contrast of clinically relevant features. Preliminary results suggest that calibrating to DICOM GSDF calibration performed slightly worse than sRGB, while a new experimental calibration target CSDF performed better than both DICOM GSDF and sRGB. This result is promising as it suggests that further research work could lead to better definition of an optimized calibration target for digital pathology images resulting in a positive effect on clinical performance.

A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia.

PubMed

Osborne, Ashleigh L; Solowij, Nadia; Weston-Green, Katrina

2017-01-01

Cognitive impairment is a core symptom domain of schizophrenia, neurological disorders and substance abuse. It is characterised by deficits in learning, memory, attention and executive functioning and can severely impact daily living. Antipsychotic drugs prescribed to treat schizophrenia provide limited cognitive benefits and novel therapeutic targets are required. Cannabidiol (CBD), a component of the cannabis plant, has anti-inflammatory and antipsychotic-like properties; however, its ability to improve cognitive impairment has not been thoroughly explored. The aim of this systematic review was to evaluate preclinical and clinical literature on the effects of CBD in cognitive domains relevant to schizophrenia. A systematic literature search was performed across numerous electronic databases for English language articles (January 1990-March 2016), with 27 articles (18 preclinical and 9 clinical studies) included in the present review. CBD improves cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric (schizophrenia), neurodegenerative (Alzheimer's disease), neuro-inflammatory (meningitis, sepsis and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia). To date, there is one clinical investigation into the effects of CBD on cognition in schizophrenia patients, with negative results for the Stroop test. CBD attenuates Δ 9 -THC-induced cognitive deficits. The efficacy of CBD to improve cognition in schizophrenia cannot be elucidated due to lack of clinical evidence; however, given the ability of CBD to restore cognition in multiple studies of impairment, further investigation into its efficacy in schizophrenia is warranted. Potential mechanisms underlying the efficacy of CBD to improve cognition are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Application of Platelet-Rich Plasma to Disorders of the Knee Joint

PubMed Central

Mandelbaum, Bert R.; McIlwraith, C. Wayne

2013-01-01

Importance. The promising therapeutic potential and regenerative properties of platelet-rich plasma (PRP) have rapidly led to its widespread clinical use in musculoskeletal injury and disease. Although the basic scientific rationale surrounding PRP products is compelling, the clinical application has outpaced the research. Objective. The purpose of this article is to examine the current concepts around the basic science of PRP application, different preparation systems, and clinical application of PRP in disorders in the knee. Evidence Acquisition. A systematic search of PubMed for studies that evaluated the basic science, preparation and clinical application of platelet concentrates was performed. The search used terms, including platelet-rich plasma or PRP preparation, activation, use in the knee, cartilage, ligament, and meniscus. Studies found in the initial search and related studies were reviewed. Results. A comprehensive review of the literature supports the potential use of PRP both nonoperatively and intraoperatively, but highlights the absence of large clinical studies and the lack of standardization between method, product, and clinical efficacy. Conclusions and Relevance. In addition to the call for more randomized, controlled clinical studies to assess the clinical effect of PRP, at this point, it is necessary to investigate PRP product composition and eventually have the ability to tailor the therapeutic product for specific indications. PMID:26069674

Detecting clinically relevant new information in clinical notes across specialties and settings.

PubMed

Zhang, Rui; Pakhomov, Serguei V S; Arsoniadis, Elliot G; Lee, Janet T; Wang, Yan; Melton, Genevieve B

2017-07-05

Automated methods for identifying clinically relevant new versus redundant information in electronic health record (EHR) clinical notes is useful for clinicians and researchers involved in patient care and clinical research, respectively. We evaluated methods to automatically identify clinically relevant new information in clinical notes, and compared the quantity of redundant information across specialties and clinical settings. Statistical language models augmented with semantic similarity measures were evaluated as a means to detect and quantify clinically relevant new and redundant information over longitudinal clinical notes for a given patient. A corpus of 591 progress notes over 40 inpatient admissions was annotated for new information longitudinally by physicians to generate a reference standard. Note redundancy between various specialties was evaluated on 71,021 outpatient notes and 64,695 inpatient notes from 500 solid organ transplant patients (April 2015 through August 2015). Our best method achieved at best performance of 0.87 recall, 0.62 precision, and 0.72 F-measure. Addition of semantic similarity metrics compared to baseline improved recall but otherwise resulted in similar performance. While outpatient and inpatient notes had relatively similar levels of high redundancy (61% and 68%, respectively), redundancy differed by author specialty with mean redundancy of 75%, 66%, 57%, and 55% observed in pediatric, internal medicine, psychiatry and surgical notes, respectively. Automated techniques with statistical language models for detecting redundant versus clinically relevant new information in clinical notes do not improve with the addition of semantic similarity measures. While levels of redundancy seem relatively similar in the inpatient and ambulatory settings in the Fairview Health Services, clinical note redundancy appears to vary significantly with different medical specialties.

Identification and Pathogenic Potential of Clinical Bacillus and Paenibacillus Isolates

PubMed Central

Celandroni, Francesco; Salvetti, Sara; Gueye, Sokhna Aissatou; Mazzantini, Diletta; Lupetti, Antonella; Senesi, Sonia; Ghelardi, Emilia

2016-01-01

The soil-related Bacillus and Paenibacillus species have increasingly been implicated in various human diseases. Nevertheless, their identification still poses problems in the clinical microbiology laboratory and, with the exception of Bacillus anthracis and Bacillus cereus, little is known on their pathogenicity for humans. In this study, we evaluated the use of matrix-assisted laser desorption—ionization time of flight mass spectrometry (MALDI-TOF MS) in the identification of clinical isolates of these genera and conducted genotypic and phenotypic analyses to highlight specific virulence properties. Seventy-five clinical isolates were subjected to biochemical and MALDI-TOF MS identification. 16S rDNA sequencing and supplemental tests were used to solve any discrepancies or failures in the identification results. MALDI-TOF MS significantly outperformed classical biochemical testing for correct species identification and no misidentification was obtained. One third of the collected strains belonged to the B. cereus species, but also Bacillus pumilus and Bacillus subtilis were isolated at high rate. Antimicrobial susceptibility testing showed that all the B. cereus, B. licheniformis, B. simplex, B. mycoides, Paenibacillus glucanolyticus and Paenibacillus lautus isolates are resistant to penicillin. The evaluation of toxin/enzyme secretion, toxin-encoding genes, motility, and biofilm formation revealed that B. cereus displays the highest virulence potential. However, although generally considered nonpathogenic, most of the other species were shown to swim, swarm, produce biofilms, and secrete proteases that can have a role in bacterial virulence. In conclusion, MALDI-TOF MS appears useful for fast and accurate identification of Bacillus and Paenibacillus strains whose virulence properties make them of increasing clinical relevance. PMID:27031639

The Effects of Clinically Relevant Multiple-Choice Items on the Statistical Discrimination of Physician Clinical Competence.

ERIC Educational Resources Information Center

Downing, Steven M.; Maatsch, Jack L.

To test the effect of clinically relevant multiple-choice item content on the validity of statistical discriminations of physicians' clinical competence, data were collected from a field test of the Emergency Medicine Examination, test items for the certification of specialists in emergency medicine. Two 91-item multiple-choice subscales were…

Development of Standardized Material Testing Protocols for Prosthetic Liners

PubMed Central

Cagle, John C.; Reinhall, Per G.; Hafner, Brian J.; Sanders, Joan E.

2017-01-01

A set of protocols was created to characterize prosthetic liners across six clinically relevant material properties. Properties included compressive elasticity, shear elasticity, tensile elasticity, volumetric elasticity, coefficient of friction (CoF), and thermal conductivity. Eighteen prosthetic liners representing the diverse range of commercial products were evaluated to create test procedures that maximized repeatability, minimized error, and provided clinically meaningful results. Shear and tensile elasticity test designs were augmented with finite element analysis (FEA) to optimize specimen geometries. Results showed that because of the wide range of available liner products, the compressive elasticity and tensile elasticity tests required two test maxima; samples were tested until they met either a strain-based or a stress-based maximum, whichever was reached first. The shear and tensile elasticity tests required that no cyclic conditioning be conducted because of limited endurance of the mounting adhesive with some liner materials. The coefficient of friction test was based on dynamic coefficient of friction, as it proved to be a more reliable measurement than static coefficient of friction. The volumetric elasticity test required that air be released beneath samples in the test chamber before testing. The thermal conductivity test best reflected the clinical environment when thermal grease was omitted and when liner samples were placed under pressure consistent with load bearing conditions. The developed procedures provide a standardized approach for evaluating liner products in the prosthetics industry. Test results can be used to improve clinical selection of liners for individual patients and guide development of new liner products. PMID:28233885

The PEACE project review of clinical instruments for hospice and palliative care.

PubMed

Hanson, Laura C; Scheunemann, Leslie P; Zimmerman, Sheryl; Rokoske, Franziska S; Schenck, Anna P

2010-10-01

Hospice and palliative care organizations are expanding their use of standardized instruments and other approaches to measure quality. We undertook a systematic review and evaluation of published patient-level instruments for potential application in hospice and palliative care clinical quality measurement. We searched prior reviews and computerized reference databases from 1990 through February 2007 for studies of instruments relevant to physical, psychological, social, cultural, spiritual, or ethical aspects of palliative care, or measuring prognosis, function or continuity of care. Publications were selected for full review if they provided evidence of psychometric properties or practical application of an instrument tested in or appropriate for a hospice or palliative care population. Selected instruments were evaluated and scored for scientific soundness and potential application in clinical quality measurement. The search found 1427 publications, with 229 selected for full manuscript review. Manuscripts provided information on 129 instruments which were evaluated using a structured scoring guide for psychometric properties. Thirty-nine instruments scoring near or above the 75th percentile were recommended. Most instruments covered multiple domains or focused on care for physical symptoms, psychological or social aspects of care. Few instruments were available to measure cultural aspects of care, structure and process of care, and continuity of care. Numerous patient-level instruments are available to measure physical, psychological and social aspects of palliative care with adequate evidence for scientific soundness and practical clinical use for quality improvement and research. Other aspects of palliative care may benefit from further instrument development research.

Quality of life instruments used in mental health research: properties and utilization.

PubMed

Prigent, Amélie; Simon, Sandrine; Durand-Zaleski, Isabelle; Leboyer, Marion; Chevreul, Karine

2014-01-30

Quality of life (QoL) assessment is increasingly used in mental health. Multiple instruments exist, but the conditions for choosing one instrument over another for purposes of a specific study are not clear. We performed a systematic review to identify the QoL instruments used in mental health. The instruments were systematically described regarding their intrinsic properties (e.g., generic v. disease-specific) and their characteristics of utilization in studies (e.g., study objectives). Using cluster analyses, we investigated the existence of similar instruments with respect to each of these sets of characteristics and studied potential links between instruments' intrinsic properties and their characteristics of utilization. We included 149 studies in which 56 distinct instruments were used. Similarities were found among instruments in terms of their intrinsic properties as well as their characteristics of utilization, leading to the construction of four clusters of instruments in each case. However, no relevant links were identified between instruments' intrinsic properties and their characteristics of utilization, suggesting that the choice of QoL instruments did not depend on their properties. A consensus about common QoL instruments must be reached to facilitate the choice of instruments, the comparison of results and thus to have an impact on clinical and policy decision-making. © 2013 Published by Elsevier Ireland Ltd.

Multiparametric MRI of Prostate Cancer: An Update on State-of-the-Art Techniques and Their Performance in Detecting and Localizing Prostate Cancer

PubMed Central

Hegde, John V.; Mulkern, Robert V.; Panych, Lawrence P.; Fennessy, Fiona M.; Fedorov, Andriy; Maier, Stephan E.; Tempany, Clare M.C.

2013-01-01

Magnetic resonance (MR) examinations of men with prostate cancer are most commonly performed for detecting, characterizing, and staging the extent of disease to best determine diagnostic or treatment strategies, which range from biopsy guidance to active surveillance to radical prostatectomy. Given both the exam's importance to individual treatment plans and the time constraints present for its operation at most institutions, it is essential to perform the study effectively and efficiently. This article reviews the most commonly employed modern techniques for prostate cancer MR examinations, exploring the relevant signal characteristics from the different methods discussed and relating them to intrinsic prostate tissue properties. Also, a review of recent articles using these methods to enhance clinical interpretation and assess clinical performance is provided. PMID:23606141

PDE4 as a target for cognition enhancement

PubMed Central

Richter, Wito; Menniti, Frank S.; Zhang, Han-Ting; Conti, Marco

2014-01-01

Introduction The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors. PMID:23883342

Quantitative real-time optical imaging of the tissue metabolic rate of oxygen consumption

NASA Astrophysics Data System (ADS)

Ghijsen, Michael; Lentsch, Griffin R.; Gioux, Sylvain; Brenner, Matthew; Durkin, Anthony J.; Choi, Bernard; Tromberg, Bruce J.

2018-03-01

The tissue metabolic rate of oxygen consumption (tMRO2) is a clinically relevant marker for a number of pathologies including cancer and arterial occlusive disease. We present and validate a noncontact method for quantitatively mapping tMRO2 over a wide, scalable field of view at 16 frames / s. We achieve this by developing a dual-wavelength, near-infrared coherent spatial frequency-domain imaging (cSFDI) system to calculate tissue optical properties (i.e., absorption, μa, and reduced scattering, μs‧, parameters) as well as the speckle flow index (SFI) at every pixel. Images of tissue oxy- and deoxyhemoglobin concentration ( [ HbO2 ] and [HHb]) are calculated from optical properties and combined with SFI to calculate tMRO2. We validate the system using a series of yeast-hemoglobin tissue-simulating phantoms and conduct in vivo tests in humans using arterial occlusions that demonstrate sensitivity to tissue metabolic oxygen debt and its repayment. Finally, we image the impact of cyanide exposure and toxicity reversal in an in vivo rabbit model showing clear instances of mitochondrial uncoupling and significantly diminished tMRO2. We conclude that dual-wavelength cSFDI provides rapid, quantitative, wide-field mapping of tMRO2 that can reveal unique spatial and temporal dynamics relevant to tissue pathology and viability.

Brain tissue stiffness is a sensitive marker for acidosis.

PubMed

Holtzmann, Kathrin; Gautier, Hélène O B; Christ, Andreas F; Guck, Jochen; Káradóttir, Ragnhildur Thóra; Franze, Kristian

2016-09-15

Carbon dioxide overdose is frequently used to cull rodents for tissue harvesting. However, this treatment may lead to respiratory acidosis, which potentially could change the properties of the investigated tissue. Mechanical tissue properties often change in pathological conditions and may thus offer a sensitive generic readout for changes in biological tissues with clinical relevance. In this study, we performed force-indentation measurements with an atomic force microscope on acute cerebellar slices from adult rats to test if brain tissue undergoes changes following overexposure to CO2 compared to other methods of euthanasia. The pH significantly decreased in brain tissue of animals exposed to CO2. Concomitant with the drop in pH, cerebellar grey matter significantly stiffened. Tissue stiffening was reproduced by incubation of acute cerebellar slices in acidic medium. Tissue stiffness provides an early, generic indicator for pathophysiological changes in the CNS. Atomic force microscopy offers unprecedented high spatial resolution to detect such changes. Our results indicate that the stiffness particularly of grey matter strongly correlates with changes of the pH in the cerebellum. Furthermore, the method of tissue harvesting and preparation may not only change tissue stiffness but very likely also other physiologically relevant parameters, highlighting the importance of appropriate sample preparation. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Impact of a novel teaching method based on feedback, activity, individuality and relevance on students' learning.

PubMed

Edafe, Ovie; Brooks, William S; Laskar, Simone N; Benjamin, Miles W; Chan, Philip

2016-03-20

This study examines the perceived impact of a novel clinical teaching method based on FAIR principles (feedback, activity, individuality and relevance) on students' learning on clinical placement. This was a qualitative research study. Participants were third year and final year medical students attached to one UK vascular firm over a four-year period (N=108). Students were asked to write a reflective essay on how FAIRness approach differs from previous clinical placement, and its advantages and disadvantages. Essays were thematically analysed and globally rated (positive, negative or neutral) by two independent researchers. Over 90% of essays reported positive experiences of feedback, activity, individuality and relevance model. The model provided multifaceted feedback; active participation; longitudinal improvement; relevance to stage of learning and future goals; structured teaching; professional development; safe learning environment; consultant involvement in teaching. Students perceived preparation for tutorials to be time intensive for tutors/students; a lack of teaching on medical sciences and direct observation of performance; more than once weekly sessions would be beneficial; some issues with peer and public feedback, relevance to upcoming exam and large group sizes. Students described negative experiences of "standard" clinical teaching. Progressive teaching programmes based on the FAIRness principles, feedback, activity, individuality and relevance, could be used as a model to improve current undergraduate clinical teaching.

Is it time to introduce repetitive transcranial magnetic stimulation into standard clinical practice for the treatment of depressive disorders?

PubMed

Fitzgerald, Paul

2003-02-01

To examine issues relating to the potential introduction of repetitive transcranial magnetic stimulation (rTMS) into clinical practice as a treatment for depression. A review of the outcomes literature accompanied by an analysis of issues relating to the potential advantages and pitfalls of the introduction of rTMS as a treatment strategy. Evidence is progressively accumulating that rTMS has antidepressant properties that are clinically relevant. These effects are biologically plausible and supported by basic research. Patients with therapy-resistant depression have few treatment alternatives and experience significant suffering, thus justifying the early introduction of a new treatment such as rTMS for this patient group. However, this must be balanced by a need to foster considerable further research and not to raise expectations unreasonably. It is timely for rTMS to be made more available to patients with treatment-resistant mood disorders. This need not be limited to clinical research trials but should only occur in medical settings where continual evaluation and research is conducted.

Recent advances in liquid-phase separations for clinical metabolomics.

PubMed

Kohler, Isabelle; Giera, Martin

2017-01-01

Over the last decades, several technological improvements have been achieved in liquid-based separation techniques, notably, with the advent of fully porous sub-2 μm particles and superficially porous sub-3 μm particles, the comeback of supercritical fluid chromatography, and the development of alternative chromatographic modes such as hydrophilic interaction chromatography. Combined with mass spectrometry, these techniques have demonstrated their added value, substantially increasing separation efficiency, selectivity, and speed of analysis. These benefits are essential in modern clinical metabolomics typically involving the study of large-scale sample cohorts and the analysis of thousands of metabolites showing extensive differences in physicochemical properties. This review presents a brief overview of the recent developments in liquid-phase separation sciences in the context of clinical metabolomics, focusing on increased throughput as well as metabolite coverage. Relevant metabolomics applications highlighting the benefits of ultra-high performance liquid chromatography, core-shell technology, high-temperature liquid chromatography, capillary electrophoresis, supercritical fluid chromatography, and hydrophilic interaction chromatography are discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pregabalin Modulation of Neurotransmitter Release Is Mediated by Change in Intrinsic Activation/Inactivation Properties of Cav2.1 Calcium ChannelsS⃞

PubMed Central

Di Guilmi, Mariano N.; Urbano, Francisco J.; Inchauspe, Carlota Gonzalez

2011-01-01

In this work, we studied the effects of the anticonvulsant and analgesic drug pregabalin (PGB) on excitatory postsynaptic currents (EPSCs) at principal neurons of the mouse medial nucleus of the trapezoid body and on presynaptic calcium currents at the calyx of Held. We found that the acute application of PGB reduced the amplitude of EPSCs in a dose-dependent manner with a maximal blocking effect of approximately 30%. A clinical high-concentration dose of PGB (e.g., 500 μM) blocked Cav2.1 channel-mediated currents and decreased their facilitation during a 100-Hz train, without changing their voltage-dependent activation. Furthermore, PGB also removed the inactivation of Cav2.1 channels at a clinically relevant low concentration of 100 μM. These results suggest novel modulatory mechanisms mediated by the acute administration of PGB on fast excitatory synaptic transmission and might contribute to better understanding PGB anticonvulsant/analgesic clinical effects. PMID:21177783

Fat-soluble vitamins as disease modulators in multiple sclerosis.

PubMed

Torkildsen, Ø; Løken-Amsrud, K I; Wergeland, S; Myhr, K-M; Holmøy, T

2013-01-01

Fat-soluble vitamins (A, D, E and K) have properties that could be relevant as modulators of disease activity in multiple sclerosis (MS). We performed a systematic search on PubMed and Medline up to May 2012, using the search strings 'vitamin A', 'retinol', 'retinal', 'carotenoids', 'vitamin D', 'vitamin E', 'alpha-tocopherol', 'vitamin K' in conjunction with 'multiple sclerosis', 'animal model' and 'experimental autoimmune encephalitis (EAE)'. In addition, the reference lists of the publications identified were examined for further citations of relevance. There is comprehensive evidence from epidemiological, observational, and experimental studies that vitamin D may be beneficial in MS. Results from small-scale clinical studies are inconclusive, and large-scale, adequately powered, randomized, controlled trials are still lacking. For vitamin D, Oxford Centre for Evidence-Based Medicine level 2c evidence exists for a positive therapeutic effect. Evidence from animal models indicates that all the examined fat-soluble vitamins could have potential as modulators of disease activity in MS. For vitamin A and E, level 4 and 5 evidence exists for a modulatory effect in MS; for vitamin K, too few studies have been conducted to indicate an effect in humans. Vitamin D is a promising candidate as modulator of disease activity in MS, and controlled studies are currently being conducted. All the fat-soluble vitamins have, however, been demonstrated to be effective in different animal models for the disease, and vitamin A and E have biological properties that could be relevant for MS pathogenesis. Thus, vitamin A and E seem to be promising candidates for future case-control and cohort studies. © 2012 John Wiley & Sons A/S.

There's an App for That? Highlighting the Difficulty in Finding Clinically Relevant Smartphone Applications.

PubMed

Wiechmann, Warren; Kwan, Daniel; Bokarius, Andrew; Toohey, Shannon L

2016-03-01

The use of personal mobile devices in the medical field has grown quickly, and a large proportion of physicians use their mobile devices as an immediate resource for clinical decision-making, prescription information and other medical information. The iTunes App Store (Apple, Inc.) contains approximately 20,000 apps in its "Medical" category, providing a robust repository of resources for clinicians; however, this represents only 2% of the entire App Store. The App Store does not have strict criteria for identifying content specific to practicing physicians, making the identification of clinically relevant content difficult. The objective of this study is to quantify the characteristics of existing medical applications in the iTunes App Store that could be used by emergency physicians, residents, or medical students. We found applications related to emergency medicine (EM) by searching the iTunes App Store for 21 terms representing core content areas of EM, such as "emergency medicine," "critical care," "orthopedics," and "procedures." Two physicians independently reviewed descriptions of these applications in the App Store and categorized each as the following: Clinically Relevant, Book/Published Source, Non-English, Study Tools, or Not Relevant. A third physician reviewer resolved disagreements about categorization. Descriptive statistics were calculated. We found a total of 7,699 apps from the 21 search terms, of which 17.8% were clinical, 9.6% were based on a book or published source, 1.6% were non-English, 0.7% were clinically relevant patient education resources, and 4.8% were study tools. Most significantly, 64.9% were considered not relevant to medical professionals. Clinically relevant apps make up approximately 6.9% of the App Store's "Medical" Category and 0.1% of the overall App Store. Clinically relevant apps represent only a small percentage (6.9%) of the total App volume within the Medical section of the App Store. Without a structured search-and-evaluation strategy, it may be difficult for the casual user to identify this potentially useful content. Given the increasing adoption of devices in healthcare, national EM associations should consider curating these resources for their members.

A randomized trial comparing INR monitoring devices in patients with anticoagulation self-management: evaluation of a novel error-grid approach.

PubMed

Hemkens, Lars G; Hilden, Kristian M; Hartschen, Stephan; Kaiser, Thomas; Didjurgeit, Ulrike; Hansen, Roland; Bender, Ralf; Sawicki, Peter T

2008-08-01

In addition to the metrological quality of international normalized ratio (INR) monitoring devices used in patients' self-management of long-term anticoagulation, the effectiveness of self-monitoring with such devices has to be evaluated under real-life conditions with a focus on clinical implications. An approach to evaluate the clinical significance of inaccuracies is the error-grid analysis as already established in self-monitoring of blood glucose. Two anticoagulation monitors were compared in a real-life setting and a novel error-grid instrument for oral anticoagulation has been evaluated. In a randomized crossover study 16 patients performed self-management of anticoagulation using the INRatio and the CoaguChek S system. Main outcome measures were clinically relevant INR differences according to established criteria and to the error-grid approach. A lower rate of clinically relevant disagreements according to Anderson's criteria was found with CoaguChek S than with INRatio without statistical significance (10.77% vs. 12.90%; P = 0.787). Using the error-grid we found principally consistent results: More measurement pairs with discrepancies of no or low clinical relevance were found with CoaguChek S, whereas with INRatio we found more differences with a moderate clinical relevance. A high rate of patients' satisfaction with both of the point of care devices was found with only marginal differences. A principal appropriateness of the investigated point-of-care devices to adequately monitor the INR is shown. The error-grid is useful for comparing monitoring methods with a focus on clinical relevance under real-life conditions beyond assessing the pure metrological quality, but we emphasize that additional trials using this instrument with larger patient populations are needed to detect differences in clinically relevant disagreements.

Commercial Applications of Metal Foams: Their Properties and Production

PubMed Central

García-Moreno, Francisco

2016-01-01

This work gives an overview of the production, properties and industrial applications of metal foams. First, it classifies the most relevant manufacturing routes and methods. Then, it reviews the most important properties, with special interest in the mechanical and functional aspects, but also taking into account costs and feasibility considerations. These properties are the motivation and basis of related applications. Finally, a summary of the most relevant applications showing a large number of actual examples is presented. Concluding, we can forecast a slow, but continuous growth of this industrial sector. PMID:28787887

Sensitivity and Predictive Value of 15 PubMed Search Strategies to Answer Clinical Questions Rated Against Full Systematic Reviews

PubMed Central

Merglen, Arnaud; Courvoisier, Delphine S; Combescure, Christophe; Garin, Nicolas; Perrier, Arnaud; Perneger, Thomas V

2012-01-01

Background Clinicians perform searches in PubMed daily, but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge. Little is known about the performance of search strategies when they are applied to answer specific clinical questions. Objective To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions. Methods We used Cochrane systematic reviews to identify relevant trials for 30 clinical questions. Search terms were extracted from the abstract using a predefined procedure based on the population, interventions, comparison, outcomes (PICO) framework and combined into queries. We tested 15 search strategies that varied in their query (PIC or PICO), use of PubMed’s Clinical Queries therapeutic filters (broad or narrow), search limits, and PubMed links to related articles. We assessed sensitivity (recall) and positive predictive value (precision) of each strategy on the first 2 PubMed pages (40 articles) and on the complete search output. Results The performance of the search strategies varied widely according to the clinical question. Unfiltered searches and those using the broad filter of Clinical Queries produced large outputs and retrieved few relevant articles within the first 2 pages, resulting in a median sensitivity of only 10%–25%. In contrast, all searches using the narrow filter performed significantly better, with a median sensitivity of about 50% (all P < .001 compared with unfiltered queries) and positive predictive values of 20%–30% (P < .001 compared with unfiltered queries). This benefit was consistent for most clinical questions. Searches based on related articles retrieved about a third of the relevant studies. Conclusions The Clinical Queries narrow filter, along with well-formulated queries based on the PICO framework, provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages. These results can help clinicians apply effective strategies to answer their questions at the point of care. PMID:22693047

Sensitivity and predictive value of 15 PubMed search strategies to answer clinical questions rated against full systematic reviews.

PubMed

Agoritsas, Thomas; Merglen, Arnaud; Courvoisier, Delphine S; Combescure, Christophe; Garin, Nicolas; Perrier, Arnaud; Perneger, Thomas V

2012-06-12

Clinicians perform searches in PubMed daily, but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge. Little is known about the performance of search strategies when they are applied to answer specific clinical questions. To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions. We used Cochrane systematic reviews to identify relevant trials for 30 clinical questions. Search terms were extracted from the abstract using a predefined procedure based on the population, interventions, comparison, outcomes (PICO) framework and combined into queries. We tested 15 search strategies that varied in their query (PIC or PICO), use of PubMed's Clinical Queries therapeutic filters (broad or narrow), search limits, and PubMed links to related articles. We assessed sensitivity (recall) and positive predictive value (precision) of each strategy on the first 2 PubMed pages (40 articles) and on the complete search output. The performance of the search strategies varied widely according to the clinical question. Unfiltered searches and those using the broad filter of Clinical Queries produced large outputs and retrieved few relevant articles within the first 2 pages, resulting in a median sensitivity of only 10%-25%. In contrast, all searches using the narrow filter performed significantly better, with a median sensitivity of about 50% (all P < .001 compared with unfiltered queries) and positive predictive values of 20%-30% (P < .001 compared with unfiltered queries). This benefit was consistent for most clinical questions. Searches based on related articles retrieved about a third of the relevant studies. The Clinical Queries narrow filter, along with well-formulated queries based on the PICO framework, provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages. These results can help clinicians apply effective strategies to answer their questions at the point of care.

Jackknife variance of the partial area under the empirical receiver operating characteristic curve.

PubMed

Bandos, Andriy I; Guo, Ben; Gur, David

2017-04-01

Receiver operating characteristic analysis provides an important methodology for assessing traditional (e.g., imaging technologies and clinical practices) and new (e.g., genomic studies, biomarker development) diagnostic problems. The area under the clinically/practically relevant part of the receiver operating characteristic curve (partial area or partial area under the receiver operating characteristic curve) is an important performance index summarizing diagnostic accuracy at multiple operating points (decision thresholds) that are relevant to actual clinical practice. A robust estimate of the partial area under the receiver operating characteristic curve is provided by the area under the corresponding part of the empirical receiver operating characteristic curve. We derive a closed-form expression for the jackknife variance of the partial area under the empirical receiver operating characteristic curve. Using the derived analytical expression, we investigate the differences between the jackknife variance and a conventional variance estimator. The relative properties in finite samples are demonstrated in a simulation study. The developed formula enables an easy way to estimate the variance of the empirical partial area under the receiver operating characteristic curve, thereby substantially reducing the computation burden, and provides important insight into the structure of the variability. We demonstrate that when compared with the conventional approach, the jackknife variance has substantially smaller bias, and leads to a more appropriate type I error rate of the Wald-type test. The use of the jackknife variance is illustrated in the analysis of a data set from a diagnostic imaging study.

Optical diagnostics of osteoblast cells and osteogenic drug screening

NASA Astrophysics Data System (ADS)

Kolanti, Elayaraja; Veerla, Sarath C.; Khajuria, Deepak K.; Roy Mahapatra, D.

2016-02-01

Microfluidic device based diagnostics involving optical fibre path, in situ imaging and spectroscopy are gaining importance due to recent advances in diagnostics instrumentation and methods, besides other factors such as low amount of reagent required for analysis, short investigation times, and potential possibilities to replace animal model based study in near future. It is possible to grow and monitor tissues in vitro in microfluidic lab-on-chip. It may become a transformative way of studying how cells interact with drugs, pathogens and biomaterials in physiologically relevant microenvironments. To a large extent, progress in developing clinically viable solutions has been constrained because of (i) contradiction between in vitro and in vivo results and (ii) animal model based and clinical studies which is very expensive. Our study here aims to evaluate the usefulness of microfluidic device based 3D tissue growth and monitoring approach to better emulate physiologically and clinically relevant microenvironments in comparison to conventional in vitro 2D culture. Moreover, the microfluidic methodology permits precise high-throughput investigations through real-time imaging while using very small amounts of reagents and cells. In the present study, we report on the details of an osteoblast cell based 3D microfluidic platform which we employ for osteogenic drug screening. The drug formulation is functionalized with fluorescence and other biomarkers for imaging and spectroscopy, respectively. Optical fibre coupled paths are used to obtain insight regarding the role of stress/flow pressure fluctuation and nanoparticle-drug concentration on the osteoblast growth and osteogenic properties of bone.

Anticoagulation by factor Xa inhibitors.

PubMed

Orfeo, T; Butenas, S; Brummel-Ziedins, K E; Gissel, M; Mann, K G

2010-08-01

Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders, with the selective targeting of factor (F) Xa emerging as a promising approach. To assess anticoagulant strategies targeting FXa. A deterministic computational model of tissue factor (Tf)-initiated thrombin generation and two empirical experimental systems (a synthetic coagulation proteome reconstruction using purified proteins and a whole blood model) were used to evaluate clinically relevant examples of the two available types of FXa-directed anticoagulants [an antithrombin (AT)-dependent agent, fondaparinux, and an AT-independent inhibitor, Rivaroxaban] in experimental regimens relevant to long-term (suppression of new Tf-initiated events) and acute (suppression of ongoing coagulation processes) clinical applications. Computational representations of each anticoagulant's efficacy in suppressing thrombin generation over a range of anticoagulant concentrations in both anticoagulation regimens were validated by results from corresponding empirical reconstructions and were consistent with those recommended for long-term and acute clinical applications, respectively. All three model systems suggested that Rivaroxaban would prove more effective in the suppression of an ongoing coagulation process than fondaparinux, reflecting its much higher reactivity toward the prothrombinase complex. The success of fondaparinux in acute settings in vivo is not explained solely by its properties as an FXa inhibitor. We have reported that FIXa contributes to the long-term capacity of clot-associated catalysts to restart a coagulation process, suggesting that the enhanced anti-FIXa activity of fondaparinux-AT may be critical to its success in acute settings in vivo. © 2010 International Society on Thrombosis and Haemostasis.

Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry.

PubMed

Bravery, Christopher A; Carmen, Jessica; Fong, Timothy; Oprea, Wanda; Hoogendoorn, Karin H; Woda, Juliana; Burger, Scott R; Rowley, Jon A; Bonyhadi, Mark L; Van't Hof, Wouter

2013-01-01

The evaluation of potency plays a key role in defining the quality of cellular therapy products (CTPs). Potency can be defined as a quantitative measure of relevant biologic function based on the attributes that are linked to relevant biologic properties. To achieve an adequate assessment of CTP potency, appropriate in vitro or in vivo laboratory assays and properly controlled clinical data need to be created. The primary objective of a potency assay is to provide a mechanism by which the manufacturing process and the final product for batch release are scrutinized for quality, consistency and stability. A potency assay also provides the basis for comparability assessment after process changes, such as scale-up, site transfer and new starting materials (e.g., a new donor). Potency assays should be in place for early clinical development, and validated assays are required for pivotal clinical trials. Potency is based on the individual characteristics of each individual CTP, and the adequacy of potency assays will be evaluated on a case-by-case basis by regulatory agencies. We provide an overview of the expectations and challenges in development of potency assays specific for CTPs; several real-life experiences from the cellular therapy industry are presented as illustrations. The key observation and message is that aggressive early investment in a solid potency evaluation strategy can greatly enhance eventual CTP deployment because it can mitigate the risk of costly product failure in late-stage development. Copyright © 2013. Published by Elsevier Inc.

Articular cartilage: from formation to tissue engineering.

PubMed

Camarero-Espinosa, Sandra; Rothen-Rutishauser, Barbara; Foster, E Johan; Weder, Christoph

2016-05-26

Hyaline cartilage is the nonlinear, inhomogeneous, anisotropic, poro-viscoelastic connective tissue that serves as friction-reducing and load-bearing cushion in synovial joints and is vital for mammalian skeletal movements. Due to its avascular nature, low cell density, low proliferative activity and the tendency of chondrocytes to de-differentiate, cartilage cannot regenerate after injury, wear and tear, or degeneration through common diseases such as osteoarthritis. Therefore severe damage usually requires surgical intervention. Current clinical strategies to generate new tissue include debridement, microfracture, autologous chondrocyte transplantation, and mosaicplasty. While articular cartilage was predicted to be one of the first tissues to be successfully engineered, it proved to be challenging to reproduce the complex architecture and biomechanical properties of the native tissue. Despite significant research efforts, only a limited number of studies have evolved up to the clinical trial stage. This review article summarizes the current state of cartilage tissue engineering in the context of relevant biological aspects, such as the formation and growth of hyaline cartilage, its composition, structure and biomechanical properties. Special attention is given to materials development, scaffold designs, fabrication methods, and template-cell interactions, which are of great importance to the structure and functionality of the engineered tissue.

The Interpersonal Shame Inventory for Asian Americans: Scale Development and Psychometric Properties

PubMed Central

Wong, Y. Joel; Kim, Bryan S. K.; Nguyen, Chi P.; Cheng, Janice Ka Yan; Saw, Anne

2016-01-01

This article reports the development and psychometric properties of the Interpersonal Shame Inventory (ISI), a culturally salient and clinically relevant measure of interpersonal shame for Asian Americans. Across 4 studies involving Asian American college students, the authors provided evidence for this new measure’s validity and reliability. Exploratory factor analyses and confirmatory factor analyses provided support for a model with 2 correlated factors: external shame (arising from concerns about others’ negative evaluations) and family shame (arising from perceptions that one has brought shame to one’s family), corresponding to 2 subscales: ISI-E and ISI-F, respectively. Evidence for criterion-related, concurrent, discriminant, and incremental validity was demonstrated by testing the associations between external shame and family shame and immigration/international status, generic state shame, face concerns, thwarted belongingness, perceived burdensomeness, self-esteem, depressive symptoms, and suicide ideation. External shame and family shame also exhibited differential relations with other variables. Mediation findings were consistent with a model in which family shame mediated the effects of thwarted belongingness on suicide ideation. Further, the ISI subscales demonstrated high alpha coefficients and test–retest reliability. These findings are discussed in light of the conceptual, methodological, and clinical contributions of the ISI. PMID:24188650

Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors

NASA Astrophysics Data System (ADS)

Sgrignani, Jacopo; De Luca, Filomena; Torosyan, Hayarpi; Docquier, Jean-Denis; Duan, Da; Novati, Beatrice; Prati, Fabio; Colombo, Giorgio; Grazioso, Giovanni

2016-10-01

β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of 1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K i value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase.

Relationships between conversion, temperature and optical properties during composite photopolymerization.

PubMed

Howard, Benjamin; Wilson, Nicholas D; Newman, Sheldon M; Pfeifer, Carmem S; Stansbury, Jeffrey W

2010-06-01

Optical properties of composite restoratives, both cured and uncured, are of obvious importance in a procedure reliant on photoactivation, since they may affect light transmission and therefore materials conversion upon which mechanical properties and ultimate clinical performance are dependent. The objective of the present study was to evaluate simultaneous, real-time conversion, and the development of the temperature and optical properties. The dimethacrylate resin (Bis-GMA/TEGDMA 70/30mass%) was prepared at three filler loading (0, 35 or 70mass%: no fill, low and high fill, respectively) combined with three initiator concentrations (CQ/EDMAB: 0/0, 0.2/0.8 or 1.0/1.6mass%). Specimens were exposed to either low (50mWcm(-2)) or high (500mWcm(-2)) irradiance. Simultaneous conversion (near-IR peak area), temperature (thermocouple) and visible light transmission (UV-vis spectroscopy) measurements were conducted throughout the polymerization process. The refractive index of the resin rises linearly with conversion (r(2)=0.976), producing a refractive index match between resin/filler at approximately 58% conversion in these materials. The percentage increase in light transmission during conversion was greater for increasing filler levels. Higher CQ content led to maximum light transmission at slightly higher levels of conversion (60-65% and 50-55% for the high and low filled materials, respectively). The broad distribution of filler concentrations allows for the clinically relevant generalization that highly filled composites not only jeopardize absolute light transmission, conversion and depth of cure, but also demonstrate the complex interrelationship that exists between materials, processing conditions and the optical properties of dental composites. Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition

PubMed Central

Tortorella, Stephanie M.; Royce, Simon G.; Licciardi, Paul V.

2015-01-01

Abstract Significance: Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. Critical Issues: In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. Future Directions: Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies. Antioxid. Redox Signal. 22, 1382–1424. PMID:25364882

Pharmacokinetic drug evaluation of paliperidone in the treatment of schizoaffective disorder.

PubMed

Macaluso, Matthew; Oliver, Hannah; Sohail, Zohaib

2017-08-01

This paper reviews the pharmacokinetics, receptor binding, clinical efficacy and safety of paliperidone in the treatment of patients with schizoaffective disorder. Areas covered: We reviewed the literature using keywords 'paliperidone', 'schizoaffective disorder' and 'clinical trials' with a focus on seminal data papers and information that is clinically relevant to the treatment of schizoaffective disorder. The purpose of this paper is to provide a clinically oriented review of the pharmacokinetic and pharmacodynamic properties of paliperidone including receptor binding, clinical efficacy, safety and tolerability. Expert opinion: Paliperidone is currently the only medication FDA approved specifically for the treatment of schizoaffective disorder. Paliperidone is an active metabolite of risperidone, is minimally metabolized in the liver and is primarily known to be cleared through the kidneys. For this reason, paliperidone could be considered for some patients with schizoaffective disorder who also have hepatic impairment. After correcting for the reduced protein binding that is characteristic of hepatically impaired patients, the Cmax was 12% lower than in healthy subjects while the AUC and CL/F were comparable [14]. In addition, the availability of long acting injectable formulations may be useful for patients who are non-adherent with oral medications. The cost of paliperidone may be a disadvantage.

A New Challenge to Research Ethics: Patients-Led Research (PLR) and the Role of Internet Based Social Networks.

PubMed

Lamas, Eugenia; Salinas, Rodrigo; Vuillaume, Dominique

2016-01-01

A characteristic feature of the development of health-related social networks is the emergence of internet-based virtual communities, composed of patients. These communities go beyond the mere interchange of information concerning their conditions, intervening in the planning and execution of clinical research, including randomised controlled trials, in collaboration with health professionals. That was the case, in 2009, when patients suffering amyotrophic lateral sclerosis, a rare and severe disease, conducted a clinical trial in USA, organising themselves through an online platform. This initiative launched a new model for the planning and conduction of clinical research: "Participants-Led Research" (PLR). The distinctive particularities of this new research paradigm represent a challenge to the traditional standards used for judging the ethical soundness of clinical investigation. That is the case, for example, of informed consent. This article aims at identifying the ethical, legal, and social issues (ELSI) posed by PLR and the relevant concepts that may help in solving them. The following issues, in particular, are analysed, that may give place to a new social contract for the ethical assessment of clinical research: consent for participating in research and personal integrity; data protection and confidentiality; benefits sharing and intellectual property.

Nanoparticles and clinically applicable cell tracking

PubMed Central

Guenoun, Jamal; van Tiel, Sandra T; Krestin, Gabriel P

2015-01-01

In vivo cell tracking has emerged as a much sought after tool for design and monitoring of cell-based treatment strategies. Various techniques are available for pre-clinical animal studies, from which much has been learned and still can be learned. However, there is also a need for clinically translatable techniques. Central to in vivo cell imaging is labelling of cells with agents that can give rise to signals in vivo, that can be detected and measured non-invasively. The current imaging technology of choice for clinical translation is MRI in combination with labelling of cells with magnetic agents. The main challenge encountered during the cell labelling procedure is to efficiently incorporate the label into the cell, such that the labelled cells can be imaged at high sensitivity for prolonged periods of time, without the labelling process affecting the functionality of the cells. In this respect, nanoparticles offer attractive features since their structure and chemical properties can be modified to facilitate cellular incorporation and because they can carry a high payload of the relevant label into cells. While these technologies have already been applied in clinical trials and have increased the understanding of cell-based therapy mechanism, many challenges are still faced. PMID:26248872

Development of a wheelchair mobility skills test for children and adolescents: combining evidence with clinical expertise.

PubMed

Sol, Marleen Elisabeth; Verschuren, Olaf; de Groot, Laura; de Groot, Janke Frederike

2017-02-13

Wheelchair mobility skills (WMS) training is regarded by children using a manual wheelchair and their parents as an important factor to improve participation and daily physical activity. Currently, there is no outcome measure available for the evaluation of WMS in children. Several wheelchair mobility outcome measures have been developed for adults, but none of these have been validated in children. Therefore the objective of this study is to develop a WMS outcome measure for children using the current knowledge from literature in combination with the clinical expertise of health care professionals, children and their parents. Mixed methods approach. Phase 1: Item identification of WMS items through a systematic review using the 'COnsensus-based Standards for the selection of health Measurement Instruments' (COSMIN) recommendations. Phase 2: Item selection and validation of relevant WMS items for children, using a focus group and interviews with children using a manual wheelchair, their parents and health care professionals. Phase 3: Feasibility of the newly developed Utrecht Pediatric Wheelchair Mobility Skills Test (UP-WMST) through pilot testing. Phase 1: Data analysis and synthesis of nine WMS related outcome measures showed there is no widely used outcome measure with levels of evidence across all measurement properties. However, four outcome measures showed some levels of evidence on reliability and validity for adults. Twenty-two WMS items with the best clinimetric properties were selected for further analysis in phase 2. Phase 2: Fifteen items were deemed as relevant for children, one item needed adaptation and six items were considered not relevant for assessing WMS in children. Phase 3: Two health care professionals administered the UP-WMST in eight children. The instructions of the UP-WMST were clear, but the scoring method of the height difference items needed adaptation. The outdoor items for rolling over soft surface and the side slope item were excluded in the final version of the UP-WMST due to logistic reasons. The newly developed 15 item UP-WMST is a validated outcome measure which is easy to administer in children using a manual wheelchair. More research regarding reliability, construct validity and responsiveness is warranted before the UP-WMST can be used in practice.

Insulin therapy in diabetes and cancer risk: current understanding and implications for future study: proceedings from a meeting of a European Insulin Safety Consensus Panel, convened and sponsored by Novo Nordisk, held Tuesday October 5, 2010 at The Radisson Edwardian Heathrow Hotel, Hayes, Middlesex, UK.

PubMed

Gough, Stephen C L; Belda-Iniesta, Cristóbal; Poole, Christopher; Weber, Matthias; Russell-Jones, David; Hansen, Bo Falck; Mannucci, Edoardo; Tuomilehto, Jaakko

2011-09-01

Interest in the possibility of certain insulin treatments having the potential to modify cancer development and prognosis was reawakened in 2009, following publication of several epidemiological studies addressing this issue. This interest extends to how diabetes itself and cancer might be linked, and makes desirable an exchange of expert views and knowledge to enhance understanding in this subject among those treating diabetes and cancer, or those developing diabetes therapies. A European meeting was convened with participants invited based on known relevant interests in endocrinology, oncology, epidemiology, and insulin analog design and investigation. Experts in these fields were invited to present on relevant topics, with open discussions held after each presentation. Concern over the potential mitogenic properties of certain insulin analogs has arisen from some (but not all) epidemiological studies, although confounding factors render interpretation controversial. Future epidemiological studies are likely to strengthen confidence in drawing conclusions. Meanwhile, pharmacological studies, and a consideration of cancer pathophysiology, implicate increased insulin-like growth factor-1 receptor affinity, and/or deranged insulin receptor interaction/signaling properties as possible a priori causes for concern with some insulin analogs. Again, interpretation of the body of pharmacological evidence is confounded by the array of test systems and methodologies used, and by studies frequently succumbing to methodological pitfalls. Reassuringly, most available insulin analogs do not differ in their receptor interaction response profile to human insulin, and for those that do there are reasons to question any potential clinical relevance. Nevertheless, it is desirable that new experimental models are devised that can better determine the likely clinical consequences of any variance in receptor response profile versus human insulin. More data are required to increase our understanding of this issue. To facilitate and disseminate such understanding, close cooperation and communication between diabetologists, epidemiologists, oncologists, and insulin engineers will be essential.

Spanish Adaptation and Validation of the Outcome Questionnaire OQ-30.2

PubMed Central

Errázuriz, Paula; Opazo, Sebastián; Behn, Alex; Silva, Oscar; Gloger, Sergio

2017-01-01

This study assessed the psychometric properties of a Spanish version of the Shortened Outcome Questionnaire (OQ-30.2, Lambert et al., 2004) validated with a sample of 546 patients in an outpatient mental health clinic and 100 non-clinical adults in Chile. Our results show that this measure has similar normative data to the original measure, with a cutoff score for the Chilean population set at 43.36, and the reliable change index at 14. This Spanish OQ-30.2 has good internal consistency (α = 0.90), has concurrent validity with the Depressive, Anxious, and Somatoform disorders measuring scale (Alvarado and Vera, 1991), and is sensitive to change during psychotherapy. Consistent with previous studies, factorial analyses showed that both, the one-factor solution for a general scale and the three-factor solution containing three theoretical scales yielded poor fit estimates. Overall, our results are similar to past research on the OQ-45 and the OQ-30. The short version has adequate psychometric properties, comparable to those of the OQ-45, but provides a gain in application time that could be relevant in the setting of psychotherapy research with large samples, frequent assessments over time, and/or samples that may require more assistance completing items (e.g., low-literacy). We conclude that this measure will be a valuable instrument for research and clinical practice. PMID:28559857

Toward modeling locomotion using electromyography-informed 3D models: application to cerebral palsy.

PubMed

Sartori, M; Fernandez, J W; Modenese, L; Carty, C P; Barber, L A; Oberhofer, K; Zhang, J; Handsfield, G G; Stott, N S; Besier, T F; Farina, D; Lloyd, D G

2017-03-01

This position paper proposes a modeling pipeline to develop clinically relevant neuromusculoskeletal models to understand and treat complex neurological disorders. Although applicable to a variety of neurological conditions, we provide direct pipeline applicative examples in the context of cerebral palsy (CP). This paper highlights technologies in: (1) patient-specific segmental rigid body models developed from magnetic resonance imaging for use in inverse kinematics and inverse dynamics pipelines; (2) efficient population-based approaches to derive skeletal models and muscle origins/insertions that are useful for population statistics and consistent creation of continuum models; (3) continuum muscle descriptions to account for complex muscle architecture including spatially varying material properties with muscle wrapping; (4) muscle and tendon properties specific to CP; and (5) neural-based electromyography-informed methods for muscle force prediction. This represents a novel modeling pipeline that couples for the first time electromyography extracted features of disrupted neuromuscular behavior with advanced numerical methods for modeling CP-specific musculoskeletal morphology and function. The translation of such pipeline to the clinical level will provide a new class of biomarkers that objectively describe the neuromusculoskeletal determinants of pathological locomotion and complement current clinical assessment techniques, which often rely on subjective judgment. WIREs Syst Biol Med 2017, 9:e1368. doi: 10.1002/wsbm.1368 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Early Passage Dependence of Mesenchymal Stem Cell Mechanics Influences Cellular Invasion and Migration.

PubMed

Spagnol, Stephen T; Lin, Wei-Chun; Booth, Elizabeth A; Ladoux, Benoit; Lazarus, Hillard M; Dahl, Kris Noel

2016-07-01

The cellular structures and mechanical properties of human mesenchymal stem cells (hMSCs) vary significantly during culture and with differentiation. Previously, studies to measure mechanics have provided divergent results using different quantitative parameters and mechanical models of deformation. Here, we examine hMSCs prepared for clinical use and subject them to mechanical testing conducive to the relevant deformability associated with clinical injection procedures. Micropipette aspiration of hMSCs shows deformation as a viscoelastic fluid, with little variation from cell to cell within a population. After two passages, hMSCs deform as viscoelastic solids. Further, for clinical applicability during stem cell migration in vivo, we investigated the ability of hMSCs to invade into micropillar arrays of increasing confinement from 12 to 8 μm spacing between adjacent micropillars. We find that hMSC samples with reduced deformability and cells that are more solid-like with passage are more easily able to enter the micropillar arrays. Increased cell fluidity is an advantage for injection procedures and optimization of cell selection based on mechanical properties may enhance efficacy of injected hMSC populations. However, the ability to invade and migrate within tight interstitial spaces appears to be increased with a more solidified cytoskeleton, likely from increased force generation and contractility. Thus, there may be a balance between optimal injection survival and in situ tissue invasion.

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.

PubMed

Rohleder, Cathrin; Müller, Juliane K; Lange, Bettina; Leweke, F M

2016-01-01

There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ 9 -THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile. As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations. Although, a plethora of mechanisms of action has been suggested, their potential relevance for the antipsychotic effects of cannabidiol still needs to be investigated. The clarification of these mechanisms as well as the establishment of cannabidiol's antipsychotic efficacy and its hopefully benign side-effect profile remains the subject of a number of previously started clinical trials.

Cold atmospheric air plasma sterilization against spores and other microorganisms of clinical interest.

PubMed

Klämpfl, Tobias G; Isbary, Georg; Shimizu, Tetsuji; Li, Yang-Fang; Zimmermann, Julia L; Stolz, Wilhelm; Schlegel, Jürgen; Morfill, Gregor E; Schmidt, Hans-Ulrich

2012-08-01

Physical cold atmospheric surface microdischarge (SMD) plasma operating in ambient air has promising properties for the sterilization of sensitive medical devices where conventional methods are not applicable. Furthermore, SMD plasma could revolutionize the field of disinfection at health care facilities. The antimicrobial effects on Gram-negative and Gram-positive bacteria of clinical relevance, as well as the fungus Candida albicans, were tested. Thirty seconds of plasma treatment led to a 4 to 6 log(10) CFU reduction on agar plates. C. albicans was the hardest to inactivate. The sterilizing effect on standard bioindicators (bacterial endospores) was evaluated on dry test specimens that were wrapped in Tyvek coupons. The experimental D(23)(°)(C) values for Bacillus subtilis, Bacillus pumilus, Bacillus atrophaeus, and Geobacillus stearothermophilus were determined as 0.3 min, 0.5 min, 0.6 min, and 0.9 min, respectively. These decimal reduction times (D values) are distinctly lower than D values obtained with other reference methods. Importantly, the high inactivation rate was independent of the material of the test specimen. Possible inactivation mechanisms for relevant microorganisms are briefly discussed, emphasizing the important role of neutral reactive plasma species and pointing to recent diagnostic methods that will contribute to a better understanding of the strong biocidal effect of SMD air plasma.

Cold Atmospheric Air Plasma Sterilization against Spores and Other Microorganisms of Clinical Interest

PubMed Central

Isbary, Georg; Shimizu, Tetsuji; Li, Yang-Fang; Zimmermann, Julia L.; Stolz, Wilhelm; Schlegel, Jürgen; Morfill, Gregor E.; Schmidt, Hans-Ulrich

2012-01-01

Physical cold atmospheric surface microdischarge (SMD) plasma operating in ambient air has promising properties for the sterilization of sensitive medical devices where conventional methods are not applicable. Furthermore, SMD plasma could revolutionize the field of disinfection at health care facilities. The antimicrobial effects on Gram-negative and Gram-positive bacteria of clinical relevance, as well as the fungus Candida albicans, were tested. Thirty seconds of plasma treatment led to a 4 to 6 log10 CFU reduction on agar plates. C. albicans was the hardest to inactivate. The sterilizing effect on standard bioindicators (bacterial endospores) was evaluated on dry test specimens that were wrapped in Tyvek coupons. The experimental D23°C values for Bacillus subtilis, Bacillus pumilus, Bacillus atrophaeus, and Geobacillus stearothermophilus were determined as 0.3 min, 0.5 min, 0.6 min, and 0.9 min, respectively. These decimal reduction times (D values) are distinctly lower than D values obtained with other reference methods. Importantly, the high inactivation rate was independent of the material of the test specimen. Possible inactivation mechanisms for relevant microorganisms are briefly discussed, emphasizing the important role of neutral reactive plasma species and pointing to recent diagnostic methods that will contribute to a better understanding of the strong biocidal effect of SMD air plasma. PMID:22582068

Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins.

PubMed

Bloomquist, Cameron J; Mecham, Michael B; Paradzinsky, Mark D; Janusziewicz, Rima; Warner, Samuel B; Luft, J Christopher; Mecham, Sue J; Wang, Andrew Z; DeSimone, Joseph M

2018-05-28

Mass customization along with the ability to generate designs using medical imaging data makes 3D printing an attractive method for the fabrication of patient-tailored drug and medical devices. Herein we describe the application of Continuous Liquid Interface Production (CLIP) as a method to fabricate biocompatible and drug-loaded devices with controlled release properties, using liquid resins containing active pharmaceutical ingredients (API). In this work, we characterize how the release kinetics of a model small molecule, rhodamine B-base (RhB), are affected by device geometry, network crosslink density, and the polymer composition of polycaprolactone- and poly (ethylene glycol)-based networks. To demonstrate the applicability of using API-loaded liquid resins with CLIP, the UV stability was evaluated for a panel of clinically-relevant small molecule drugs. Finally, select formulations were tested for biocompatibility, degradation and encapsulation of docetaxel (DTXL) and dexamethasone-acetate (DexAc). Formulations were shown to be biocompatible over the course of 175 days of in vitro degradation and the clinically-relevant drugs could be encapsulated and released in a controlled fashion. This study reveals the potential of the CLIP manufacturing platform to serve as a method for the fabrication of patient-specific medical and drug-delivery devices for personalized medicine. Copyright © 2018. Published by Elsevier B.V.

Adequate Patient Characterization in COPD: Reasons to Go Beyond GOLD Classification

PubMed Central

Verhage, Tewe L; Heijdra, Yvonne F; Molema, Johan; Daudey, Leonie; Dekhuijzen, P.N Richard; Vercoulen, Jan H

2009-01-01

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) serves as a guide to treat and manage different severity classes of patients with COPD. It was suggested that the five categories of FEV1 % predicted (GOLD 0–4), can be applied for selecting different therapeutic approaches. However, validation of these selective properties is very poor. To determine the relevance of the GOLD staging system for estimating the severity of clinical problems, GOLD 2 (n=70) and GOLD 3 (n=65) patients were drawn from a prospective cohort of patients with COPD and evaluated crosssectionally by a newly developed Nijmegen Integral Assessment Framework (NIAF). The NIAF is a detailed assessment of a wide range of aspects of health status (HS). Significant, though small, differences were found in Static Lung Volumes, Exercise Capacity, Subjective Pulmonary Complaints, Subjective Impairment, and Health-Related QoL, besides Airflow of course. Moreover, overlap between scores of these five HS sub-domains was substantial, indicating small clinical relevance for discernment. No significant differences were found in nine other aspects of HS. It is concluded that GOLD stages do not discriminate in any aspect of HS other than airflow obstruction, and therefore do not help the clinician in deciding which treatment modalities are appropriate. PMID:19452033

Assessing the body image: relevance, application and instruments for oncological settings.

PubMed

Annunziata, Maria Antonietta; Giovannini, Lorena; Muzzatti, Barbara

2012-05-01

Body image is the sum of physical, cognitive, emotional, and relational elements that, when integrated, allow the development of a whole, healthy self-identity. Even though body image is normally studied in relation to eating disorders, it can also be influenced by other pathologies, including cancer. In oncology, an effective body image assessment is fundamental. The physical effects of cancer and cancer treatments are important and frequently irreversible also on a functional and emotional level; however, only few surveys have investigated body image in this peculiar context. An extensive literature review was carried out in PubMed and PsycINFO. We considered articles published from 1990 to 2010. Two hundred sixty-three papers matched the search criteria. Assessment methodologies included clinical interviews, self-report measures, questionnaires, symptom check lists, and graphic tests and projective techniques. After excluding the instruments that referred to eating disorders, validated only for adolescents, and/or projective and graphic tests, we found 81 articles with six questionnaires specifically dedicated to body image assessment in oncology. From our systematic review, we could identify six instruments specifically designed for assessing body image in the oncological area. In this paper, we discuss their general characteristics, psychometrics properties and the clinical implications, and body image relevance on the quality of life in cancer patients.

The Development and Evaluation of the Psychometric Properties of the Negative Beliefs about Post-Event Processing Scale.

PubMed

Rodriguez, Hayley; Kissell, Kellie; Lucas, Lloyd; Fisak, Brian

2017-11-01

Although negative beliefs have been found to be associated with worry symptoms and depressive rumination, negative beliefs have yet to be examined in relation to post-event processing and social anxiety symptoms. The purpose of the current study was to examine the psychometric properties of the Negative Beliefs about Post-Event Processing Questionnaire (NB-PEPQ). A large, non-referred undergraduate sample completed the NB-PEPQ along with validation measures, including a measure of post-event processing and social anxiety symptoms. Based on factor analysis, a single-factor model was obtained, and the NB-PEPQ was found to exhibit good validity, including positive associations with measures of post-event processing and social anxiety symptoms. These findings add to the literature on the metacognitive variables that may lead to the development and maintenance of post-event processing and social anxiety symptoms, and have relevant clinical applications.

Assessing blood coagulation status with laser speckle rheology

PubMed Central

Tripathi, Markandey M.; Hajjarian, Zeinab; Van Cott, Elizabeth M.; Nadkarni, Seemantini K.

2014-01-01

We have developed and investigated a novel optical approach, Laser Speckle Rheology (LSR), to evaluate a patient’s coagulation status by measuring the viscoelastic properties of blood during coagulation. In LSR, a blood sample is illuminated with laser light and temporal speckle intensity fluctuations are measured using a high-speed CMOS camera. During blood coagulation, changes in the viscoelastic properties of the clot restrict Brownian displacements of light scattering centers within the sample, altering the rate of speckle intensity fluctuations. As a result, blood coagulation status can be measured by relating the time scale of speckle intensity fluctuations with clinically relevant coagulation metrics including clotting time and fibrinogen content. Our results report a close correlation between coagulation metrics measured using LSR and conventional coagulation results of activated partial thromboplastin time, prothrombin time and functional fibrinogen levels, creating the unique opportunity to evaluate a patient’s coagulation status in real-time at the point of care. PMID:24688816

Dissecting engineered cell types and enhancing cell fate conversion via CellNet

PubMed Central

Morris, Samantha A.; Cahan, Patrick; Li, Hu; Zhao, Anna M.; San Roman, Adrianna K.; Shivdasani, Ramesh A.; Collins, James J.; Daley, George Q.

2014-01-01

SUMMARY Engineering clinically relevant cells in vitro holds promise for regenerative medicine, but most protocols fail to faithfully recapitulate target cell properties. To address this, we developed CellNet, a network biology platform that determines whether engineered cells are equivalent to their target tissues, diagnoses aberrant gene regulatory networks, and prioritizes candidate transcriptional regulators to enhance engineered conversions. Using CellNet, we improved B cell to macrophage conversion, transcriptionally and functionally, by knocking down predicted B cell regulators. Analyzing conversion of fibroblasts to induced hepatocytes (iHeps), CellNet revealed an unexpected intestinal program regulated by the master regulator Cdx2. We observed long-term functional engraftment of mouse colon by iHeps, thereby establishing their broader potential as endoderm progenitors and demonstrating direct conversion of fibroblasts into intestinal epithelium. Our studies illustrate how CellNet can be employed to improve direct conversion and to uncover unappreciated properties of engineered cells. PMID:25126792

Pathogen- and host-directed anti-inflammatory activities of macrolide antibiotics.

PubMed

Steel, Helen C; Theron, Annette J; Cockeran, Riana; Anderson, Ronald; Feldman, Charles

2012-01-01

Macrolide antibiotics possess several, beneficial, secondary properties which complement their primary antimicrobial activity. In addition to high levels of tissue penetration, which may counteract seemingly macrolide-resistant bacterial pathogens, these agents also possess anti-inflammatory properties, unrelated to their primary antimicrobial activity. Macrolides target cells of both the innate and adaptive immune systems, as well as structural cells, and are beneficial in controlling harmful inflammatory responses during acute and chronic bacterial infection. These secondary anti-inflammatory activities of macrolides appear to be particularly effective in attenuating neutrophil-mediated inflammation. This, in turn, may contribute to the usefulness of these agents in the treatment of acute and chronic inflammatory disorders of both microbial and nonmicrobial origin, predominantly of the airways. This paper is focused on the various mechanisms of macrolide-mediated anti-inflammatory activity which target both microbial pathogens and the cells of the innate and adaptive immune systems, with emphasis on their clinical relevance.

Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics

PubMed Central

Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles

2012-01-01

Macrolide antibiotics possess several, beneficial, secondary properties which complement their primary antimicrobial activity. In addition to high levels of tissue penetration, which may counteract seemingly macrolide-resistant bacterial pathogens, these agents also possess anti-inflammatory properties, unrelated to their primary antimicrobial activity. Macrolides target cells of both the innate and adaptive immune systems, as well as structural cells, and are beneficial in controlling harmful inflammatory responses during acute and chronic bacterial infection. These secondary anti-inflammatory activities of macrolides appear to be particularly effective in attenuating neutrophil-mediated inflammation. This, in turn, may contribute to the usefulness of these agents in the treatment of acute and chronic inflammatory disorders of both microbial and nonmicrobial origin, predominantly of the airways. This paper is focused on the various mechanisms of macrolide-mediated anti-inflammatory activity which target both microbial pathogens and the cells of the innate and adaptive immune systems, with emphasis on their clinical relevance. PMID:22778497

Acoustic Radiation Force Elasticity Imaging in Diagnostic Ultrasound

PubMed Central

Doherty, Joshua R.; Trahey, Gregg E.; Nightingale, Kathryn R.; Palmeri, Mark L.

2013-01-01

The development of ultrasound-based elasticity imaging methods has been the focus of intense research activity since the mid-1990s. In characterizing the mechanical properties of soft tissues, these techniques image an entirely new subset of tissue properties that cannot be derived with conventional ultrasound techniques. Clinically, tissue elasticity is known to be associated with pathological condition and with the ability to image these features in vivo, elasticity imaging methods may prove to be invaluable tools for the diagnosis and/or monitoring of disease. This review focuses on ultrasound-based elasticity imaging methods that generate an acoustic radiation force to induce tissue displacements. These methods can be performed non-invasively during routine exams to provide either qualitative or quantitative metrics of tissue elasticity. A brief overview of soft tissue mechanics relevant to elasticity imaging is provided, including a derivation of acoustic radiation force, and an overview of the various acoustic radiation force elasticity imaging methods. PMID:23549529

Improving Nucleoside Analogs via Lipid Conjugation; Is fatter any better?

PubMed Central

Alexander, Peter; Kucera, Gregory; Pardee, Timothy S.

2016-01-01

In the past few decades, nucleoside analog drugs have been used to treat a large variety of cancers. These antimetabolite drugs mimic nucleosides and interfere with chain lengthening upon incorporation into the DNA or RNA of actively replicating cells. However, efficient delivery of these drugs is limited due to their pharmacokinetic properties, and tumors often develop drug resistance. In addition, nucleoside analogs are generally hydrophilic, resulting in poor bioavailability and impaired blood-brain barrier penetration. Conjugating these drugs to lipids modifies their pharmacokinetic properties and may improve in vivo efficacy. This review will cover recent advances in the field of conjugation of phospholipids to nucleoside analogs. This includes conjugation of myristic acid, 12-thioethyldodecanoic acid, 5-elaidic acid esters, phosphoramidate, and self-emulsifying formulations. Relevant in vitro and in vivo data will be discussed for each drug, as well as any available data from clinical trials. PMID:26829896

Acoustic radiation force elasticity imaging in diagnostic ultrasound.

PubMed

Doherty, Joshua R; Trahey, Gregg E; Nightingale, Kathryn R; Palmeri, Mark L

2013-04-01

The development of ultrasound-based elasticity imaging methods has been the focus of intense research activity since the mid-1990s. In characterizing the mechanical properties of soft tissues, these techniques image an entirely new subset of tissue properties that cannot be derived with conventional ultrasound techniques. Clinically, tissue elasticity is known to be associated with pathological condition and with the ability to image these features in vivo; elasticity imaging methods may prove to be invaluable tools for the diagnosis and/or monitoring of disease. This review focuses on ultrasound-based elasticity imaging methods that generate an acoustic radiation force to induce tissue displacements. These methods can be performed noninvasively during routine exams to provide either qualitative or quantitative metrics of tissue elasticity. A brief overview of soft tissue mechanics relevant to elasticity imaging is provided, including a derivation of acoustic radiation force, and an overview of the various acoustic radiation force elasticity imaging methods.

Dental pulp stem cells. Biology and use for periodontal tissue engineering.

PubMed

Ashri, Nahid Y; Ajlan, Sumaiah A; Aldahmash, Abdullah M

2015-12-01

Inflammatory periodontal disease is a major cause of loss of tooth-supporting structures. Novel approaches for regeneration of periodontal apparatus is an area of intensive research. Periodontal tissue engineering implies the use of appropriate regenerative cells, delivered through a suitable scaffold, and guided through signaling molecules. Dental pulp stem cells have been used in an increasing number of studies in dental tissue engineering. Those cells show mesenchymal (stromal) stem cell-like properties including self-renewal and multilineage differentiation potentials, aside from their relative accessibility and pleasant handling properties. The purpose of this article is to review the biological principles of periodontal tissue engineering, along with the challenges facing the development of a consistent and clinically relevant tissue regeneration platform. This article includes an updated review on dental pulp stem cells and their applications in periodontal regeneration, in combination with different scaffolds and growth factors.

A relevance theory of induction.

PubMed

Medin, Douglas L; Coley, John D; Storms, Gert; Hayes, Brett K

2003-09-01

A framework theory, organized around the principle of relevance, is proposed for category-based reasoning. According to the relevance principle, people assume that premises are informative with respect to conclusions. This idea leads to the prediction that people will use causal scenarios and property reinforcement strategies in inductive reasoning. These predictions are contrasted with both existing models and normative logic. Judgments of argument strength were gathered in three different countries, and the results showed the importance of both causal scenarios and property reinforcement in category-based inferences. The relation between the relevance framework and existing models of category-based inductive reasoning is discussed in the light of these findings.

Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

PubMed

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico

2014-01-01

The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9) vs. 3.6% (2.9-4.3) by the WHO list] and PIs [0.8% (0.4-1.1) vs. 1.7% (1.2-2.2)], while it was higher for NNRTIs [4.6% (3.8-5.3) vs. 3.7% (3.0-4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

FDA perspective on specifications for biotechnology products--from IND to PLA.

PubMed

Murano, G

1997-01-01

Quality standards are obligatory throughout development, approval and post-marketing phases of biotechnology-derived products, thus assuring product identity, purity, and potency/strength. The process of developing and setting specifications should be based on sound science and should represent a logical progression of actions based on the use of experiential data spanning manufacturing process validation, consistency in production, and characterization of relevant product properties/attributes, by multiple analytical means. This interactive process occurs in phases, varying in rigour. It is best described as encompassing a framework which starts with the implementation of realistic/practical operational quality limits, progressing to the establishment/adoption of more stringent specifications. The historical database is generated from preclinical, toxicology and early clinical lots. This supports the clinical development programme which, as it progresses, allows for further assay method validation/refinement, adoption/addition due to relevant or newly recognized product attributes or rejection due to irrelevance. In the next phase, (licensing/approval) specifications are set through extended experience and validation of both the preparative and analytical processes, to include availability of suitable reference standards and extensive product characterization throughout its proposed dating period. Subsequent to product approval, the incremental database of test results serves as a natural continuum for further evolving/refining specifications. While there is considerable latitude in the kinds of testing modalities finally adopted to establish product quality on a routine basis, for both drugs and drug products, it is important that the selection takes into consideration relevant (significant) product characteristics that appropriately reflect on identity, purity and potency.

Micrometastases in neuroblastoma: are they clinically important?

PubMed Central

Burchill, S A

2004-01-01

Despite advances in the treatment of neuroblastoma (NBL), recurrence and metastases continue to pose major problems in clinical management. The relation between micrometastases and the development of secondary disease is not fully understood. However, accurate methods to detect low numbers of tumour cells may allow the evaluation of their role in the disease process, and by implication the possible benefits of eliminating them. Although there is substantial evidence for the increased sensitivity of current molecular methods for the detection of NBL cells compared with more conventional cytology, the clinical relevance and usefulness of detecting this disease remain controversial. The primary goal of current translational research must be to evaluate the clinical relevance of micrometastatic disease detected by these methods in multicentre prospective clinical outcome studies. Only then can the clinical usefulness of these methods be defined so that they may be introduced into relevant clinical practice. PMID:14693828

Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

PubMed

Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

2015-12-01

Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

Creation of a core outcome set for clinical trials of people with shoulder pain: a study protocol.

PubMed

Gagnier, Joel J; Page, Matthew J; Huang, Hsiaomin; Verhagen, Arianne P; Buchbinder, Rachelle

2017-07-20

The selection of appropriate outcomes or domains is crucial when designing clinical trials, to appreciate the effects of different interventions, pool results, and make valid comparisons between trials. If the findings are to influence policy and practice, then the chosen outcomes need to be relevant and important to key stakeholders, including patients and the public, healthcare professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. Recent reviews of the measurement properties of patient-reported outcome measures for shoulder disorders revealed a large selection of diverse measures, many with questionable validity, reliability, and responsiveness. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set (COS), which should be measured and reported in all trials of shoulder disorders. The purpose of the present project is to develop and disseminate a COS for clinical trials in shoulder disorders. The methods for the COS development will include 3 phases: (1) a comprehensive review of the core domains used in shoulder disorder trials; (2) an international Delphi study involving relevant stakeholders (patients, clinicians, scientists) to define which domains should be core; and (3) an international focus group informed by the evidence identified in phases 1 and 2, to determine which measurement instruments best measure the core domains and identification of any evidence gaps that require further empiric evidence. The aim of the current proposal is to convene several meetings of international experts and patients to develop a COS for clinical trials of shoulder disorders and to develop an implementation strategy to ensure rapid uptake of the core set of outcomes in clinical trials. There would be an expectation that the core set of outcomes would always be collected and reported, but it would not preclude use of additional outcomes in a particular trial.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

PubMed

Olivera, P; Sandborn, W J; Panés, J; Baumann, C; D'Haens, G; Vermeire, S; Danese, S; Peyrin-Biroulet, L

2018-03-01

Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice. © 2018 John Wiley & Sons Ltd.

Characterizing gene sets using discriminative random walks with restart on heterogeneous biological networks.

PubMed

Blatti, Charles; Sinha, Saurabh

2016-07-15

Analysis of co-expressed gene sets typically involves testing for enrichment of different annotations or 'properties' such as biological processes, pathways, transcription factor binding sites, etc., one property at a time. This common approach ignores any known relationships among the properties or the genes themselves. It is believed that known biological relationships among genes and their many properties may be exploited to more accurately reveal commonalities of a gene set. Previous work has sought to achieve this by building biological networks that combine multiple types of gene-gene or gene-property relationships, and performing network analysis to identify other genes and properties most relevant to a given gene set. Most existing network-based approaches for recognizing genes or annotations relevant to a given gene set collapse information about different properties to simplify (homogenize) the networks. We present a network-based method for ranking genes or properties related to a given gene set. Such related genes or properties are identified from among the nodes of a large, heterogeneous network of biological information. Our method involves a random walk with restarts, performed on an initial network with multiple node and edge types that preserve more of the original, specific property information than current methods that operate on homogeneous networks. In this first stage of our algorithm, we find the properties that are the most relevant to the given gene set and extract a subnetwork of the original network, comprising only these relevant properties. We then re-rank genes by their similarity to the given gene set, based on a second random walk with restarts, performed on the above subnetwork. We demonstrate the effectiveness of this algorithm for ranking genes related to Drosophila embryonic development and aggressive responses in the brains of social animals. DRaWR was implemented as an R package available at veda.cs.illinois.edu/DRaWR. blatti@illinois.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Mirror neuron system: basic findings and clinical applications.

PubMed

Iacoboni, Marco; Mazziotta, John C

2007-09-01

In primates, ventral premotor and rostral inferior parietal neurons fire during the execution of hand and mouth actions. Some cells (called mirror neurons) also fire when hand and mouth actions are just observed. Mirror neurons provide a simple neural mechanism for understanding the actions of others. In humans, posterior inferior frontal and rostral inferior parietal areas have mirror properties. These human areas are relevant to imitative learning and social behavior. Indeed, the socially isolating condition of autism is associated with a deficit in mirror neuron areas. Strategies inspired by mirror neuron research recently have been used in the treatment of autism and in motor rehabilitation after stroke.

The Cardiovascular Effects of Cocoa Polyphenols—An Overview

PubMed Central

Aprotosoaie, Ana Clara; Miron, Anca; Trifan, Adriana; Luca, Vlad Simon; Costache, Irina-Iuliana

2016-01-01

Cocoa is a rich source of high-quality antioxidant polyphenols. They comprise mainly catechins (29%–38% of total polyphenols), anthocyanins (4% of total polyphenols) and proanthocyanidins (58%–65% of total polyphenols). A growing body of experimental and epidemiological evidence highlights that the intake of cocoa polyphenols may reduce the risk of cardiovascular events. Beyond antioxidant properties, cocoa polyphenols exert blood pressure lowering activity, antiplatelet, anti-inflammatory, metabolic and anti-atherosclerotic effects, and also improve endothelial function. This paper reviews the role of cocoa polyphenols in cardiovascular protection, with a special focus on mechanisms of action, clinical relevance and correlation between antioxidant activity and cardiovascular health. PMID:28933419

Fesoterodine: Pharmacological properties and clinical implications.

PubMed

Gamé, Xavier; Peyronnet, Benoit; Cornu, Jean-Nicolas

2018-05-24

Fesoterodine (as one of three drugs: dutasteride, finasteride and fesoterodine) was classified B (beneficial) by LUTS-FORTA 2014, indicating that it is a medicinal product with proven or obvious efficacy in the elderly, with limited side effects and/or safety concerns. A systematic literature review was undertaken in January 2018 using the PubMed and Google Scholar databases with the following individual and combined keywords: "fesoterodine", "pharmacology", "overactive bladder" and "antimuscarinics". The aim of the review was to determine which of fesoterodine's pharmacological properties explains its clinical benefits in general patient populations with OAB and the elderly in particular. The articles in the results were then selected by publication language (English and French only), methodology (off-topic studies, reported cases and literature reviews were excluded), relevance to the subject matter and publication date prior to 31 January 2018. A total of 205 articles was initially obtained, with 115 read and 45 selected. It appears that the association of four pharmacological properties specific to fesoterodine can explain that this drug has a good balance between efficacy and tolerability. These properties are namely the drug's high and nearly equal affinity for both the M2 and M3 muscarinic receptors, poor penetration of the blood-brain barrier, lack of hepatic first-pass activation -fesoterodine being rapidly and extensively converted to its active metabolite, 5-hydroxymethyl tolterodine, by ubiquitous esterases-, and its extended-release formulation. Fesoterodine's pharmacological profile is optimal for the treatment of overactive bladder. It is now recognized as one of the leading first-line treatment for this indication. Copyright © 2018 Elsevier B.V. All rights reserved.

A Tannic Acid-based Medical Food, Cesinex®, Exhibits Broad-spectrum Antidiarrheal Properties: a Mechanistic and Clinical Study

PubMed Central

Ren, Aixia; Zhang, Weiqiang; Thomas, Hugh Greg; Barish, Amy; Berry, Stephen; Kiel, Jeffrey S.

2011-01-01

Background To evaluate the efficacy and tolerability of a tannic acid-based medical food, Cesinex®, in the treatment of diarrhea, and to investigate the mechanisms underlying its antidiarrheal effect. Methods Cesinex® was prescribed to six children and four adults with diarrhea. Patient records were retrospectively reviewed for the primary outcome. Cesinex® and its major component, tannic acid, were tested for their effects on cholera toxin-induced intestinal fluid secretion in mouse. Polarized human gut epithelial cells (HT29-CL19A cells) were used to investigate the effects of tannic acid on epithelial barrier properties, transepithelial chloride secretion, and cell viability. Results Successful resolution of diarrheal symptoms was reported in nine of ten patients receiving Cesinex®. Treatment of HT29-CL19A cells with clinically relevant concentrations of tannic acid (0.01–1 mg/ml) significantly increased transepithelial resistance and inhibited the CFTR-dependent or the calcium-activated Cl− secretion. Tannic acid could also improve the impaired epithelial barrier function induced by TNFα and inhibited the disrupting effect of TNFα on the epithelial barrier function in these cells. CTX-induced mouse intestinal fluid secretion was significantly reduced by administration of Cesinex® or tannic acid. Cesinex® has high antioxidant capacity. Conclusions Cesinex® demonstrates an effective and safety profile in treatment of diarrhea. The broad-spectrum antidiarrheal effect of Cesinex® can be attributed to a combination of factors: its ability to improve the epithelial barrier properties, to inhibit intestinal fluid secretion, and the high antioxidant property. PMID:21748285

Impact of a novel teaching method based on feedback, activity, individuality and relevance on students’ learning

PubMed Central

Brooks, William S.; Laskar, Simone N.; Benjamin, Miles W.; Chan, Philip

2016-01-01

Objectives This study examines the perceived impact of a novel clinical teaching method based on FAIR principles (feedback, activity, individuality and relevance) on students’ learning on clinical placement. Methods This was a qualitative research study. Participants were third year and final year medical students attached to one UK vascular firm over a four-year period (N=108). Students were asked to write a reflective essay on how FAIRness approach differs from previous clinical placement, and its advantages and disadvantages. Essays were thematically analysed and globally rated (positive, negative or neutral) by two independent researchers. Results Over 90% of essays reported positive experiences of feedback, activity, individuality and relevance model.  The model provided multifaceted feedback; active participation; longitudinal improvement; relevance to stage of learning and future goals; structured teaching; professional development; safe learning environment; consultant involvement in teaching. Students perceived preparation for tutorials to be time intensive for tutors/students; a lack of teaching on medical sciences and direct observation of performance; more than once weekly sessions would be beneficial; some issues with peer and public feedback, relevance to upcoming exam and large group sizes. Students described negative experiences of “standard” clinical teaching. Conclusions Progressive teaching programmes based on the FAIRness principles, feedback, activity, individuality and relevance, could be used as a model to improve current undergraduate clinical teaching. PMID:26995588

What Factors Influence the Biomechanical Properties of Allograft Tissue for ACL Reconstruction? A Systematic Review.

PubMed

Lansdown, Drew A; Riff, Andrew J; Meadows, Molly; Yanke, Adam B; Bach, Bernard R

2017-10-01

Allograft tissue is used in 22% to 42% of anterior cruciate ligament (ACL) reconstructions. Clinical outcomes have been inconsistent with allograft tissue, with some series reporting no differences in outcomes and others reporting increased risk of failure. There are numerous variations in processing and preparation that may influence the eventual performance of allograft tissue in ACL reconstruction. We sought to perform a systematic review to summarize the factors that affect the biomechanical properties of allograft tissue for use in ACL reconstruction. Many factors might impact the biomechanical properties of allograft tissue, and these should be understood when considering using allograft tissue or when reporting outcomes from allograft reconstruction. What factors affect the biomechanical properties of allograft tissue used for ACL reconstruction? We performed a systematic review to identify studies on factors that influence the biomechanical properties of allograft tissue through PubMed and SCOPUS databases. We included cadaveric and animal studies that reported on results of biomechanical testing, whereas studies on fixation, histologic evaluation, and clinical outcomes were excluded. There were 319 unique publications identified through the search with 48 identified as relevant to answering the study question. For each study, we recorded the type of tissue tested, parameters investigated, and the effects on biomechanical behavior, including load to failure and stiffness. Primary factors identified to influence allograft tissue properties were graft tissue type, sterilization methods (irradiation and chemical processing), graft preparation, donor parameters, and biologic adjuncts. Load to failure and graft stiffness varied across different tissue types, with nonlooped tibialis grafts exhibiting the lowest values. Studies on low-dose irradiation showed variable effects, whereas high-dose irradiation consistently produced decreased load to failure and stiffness values. Various chemical sterilization measures were also associated with negative effects on biomechanical properties. Prolonged freezing decreased load to failure, ultimate stress, and ultimate strain. Up to eight freeze-thaw cycles did not lead to differences in biomechanical properties of cadaveric grafts. Regional differences were noted in patellar tendon grafts, with the central third showing the highest load to failure and stiffness. Graft diameter strongly contributed to load-to-failure measurements. Age older than 40 years, and especially older than 65 years, negatively impacted biomechanical properties, whereas gender had minimal effect on the properties of allograft tissue. Biologic adjuncts show potential for improving in vivo properties of allograft tissue. Future clinical studies on allograft ACL reconstruction should investigate in vivo graft performance with standardized allograft processing and preparation methods that limit the negative effects on the biomechanical properties of tissue. Additionally, biologic adjuncts may improve the biomechanical properties of allograft tissue, although future preclinical and clinical studies are necessary to clarify the role of these treatments. Based on the findings of this systematic review that emphasize biomechanical properties of ACL allografts, surgeons should favor the use of central third patellar tendon or looped soft tissue grafts, maximize graft cross-sectional area, and favor grafts from donors younger than 40 years of age while avoiding grafts subjected to radiation doses > 20 kGy, chemical processing, or greater than eight freeze-thaw cycles.

The Use and Method of Action of Intravenous Lidocaine and Its Metabolite in Headache Disorders.

PubMed

Berk, Thomas; Silberstein, Stephen D

2018-03-14

Lidocaine, an amide anesthetic, has been used in the treatment of a wide variety of pain disorders for over 75 years. In addition to pain control, lidocaine is an anti-arrhythmic agent and has anti-inflammatory properties. Lidocaine's unique properties, including nonlinear pharmacokinetics, have limited its modern-day use. The purpose of this review is to offer a better understanding of the properties of this unique treatment, which we hope will allow more practitioners to offer this to their patients. An analysis of the history, pharmacokinetics, and relevant uses of lidocaine in headache medicine based on a synthesis of the medical literature and clinical experience. Lidocaine is an amide anesthetic that inhibits voltage gated sodium channels, and lidocaine metabolism occurs exclusively in the liver. One lidocaine metabolite has its own unique properties and may be an active form of the drug. Open label and retrospective studies have investigated the use of lidocaine in many headache disorders, primarily via injection or infusion. Further research into the active metabolite of lidocaine may allow for its use as a novel nonopiate treatment of chronic pain. © 2018 American Headache Society.

Dimethacrylate network formation and polymer property evolution as determined by the selection of monomers and curing conditions

PubMed Central

Stansbury, Jeffrey W.

2011-01-01

Objectives This overview is intended to highlight connections between monomer structure and the development of highly crosslinked photopolymer networks including the conversion dependent properties of shrinkage, modulus and stress. Methods A review is provided that combines the polymer science and dental materials literature along with examples of relevant experimental results, which include measurements of reaction kinetics, photorheology as well as polymerization shrinkage and stress. Results While new monomers are continually under development for dental materials applications, mixtures of dimethacrylate monomers persist as the most common form of dental resins used on composite restorative materials. Monomer viscosity and reaction potential is derived from molecular structure and by employing real-time near-infrared spectroscopic techniques, the development of macromolecular networks is linked to the evolution of polymerization shrinkage (measured by linometer), modulus (measured by photorheometer), and stress (measured by tensometer). Relationships between the respective polymer properties are examined. Significance Through a better understanding of the polymer network formation and property development processes using conventional dimethacrylate monomer formulations, the rational design of improved materials is facilitated with the ultimate goal of achieving dental polymers that deliver enhanced clinical outcomes. PMID:22192248

Ginger-Mechanism of action in chemotherapy-induced nausea and vomiting: A review.

PubMed

Marx, Wolfgang; Ried, Karin; McCarthy, Alexandra L; Vitetta, Luis; Sali, Avni; McKavanagh, Daniel; Isenring, Liz

2017-01-02

Despite advances in antiemetic therapy, chemotherapy-induced nausea and vomiting (CINV) still poses a significant burden to patients undergoing chemotherapy. Nausea, in particular, is still highly prevalent in this population. Ginger has been traditionally used as a folk remedy for gastrointestinal complaints and has been suggested as a viable adjuvant treatment for nausea and vomiting in the cancer context. Substantial research has revealed ginger to possess properties that could exert multiple beneficial effects on chemotherapy patients who experience nausea and vomiting. Bioactive compounds within the rhizome of ginger, particularly the gingerol and shogaol class of compounds, interact with several pathways that are directly implicated in CINV in addition to pathways that could play secondary roles by exacerbating symptoms. These properties include 5-HT 3 , substance P, and acetylcholine receptor antagonism; antiinflammatory properties; and modulation of cellular redox signaling, vasopressin release, gastrointestinal motility, and gastric emptying rate. This review outlines these proposed mechanisms by discussing the results of clinical, in vitro, and animal studies both within the chemotherapy context and in other relevant fields. The evidence presented in this review indicates that ginger possesses multiple properties that could be beneficial in reducing CINV.

DNA Repair in Prostate Cancer: Biology and Clinical Implications.

PubMed

Mateo, Joaquin; Boysen, Gunther; Barbieri, Christopher E; Bryant, Helen E; Castro, Elena; Nelson, Pete S; Olmos, David; Pritchard, Colin C; Rubin, Mark A; de Bono, Johann S

2017-03-01

For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease. A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer. We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC. Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies. Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

A review of depression research in malaysia.

PubMed

Ng, C G

2014-08-01

Depression is a debilitating illness and has become a leading cause of morbidity globally. We aim to summarise the evidence available in regard to the prevalence, type of assessment tools used and treatment options for depression in Malaysia. Two hundred and forty seven articles related to depression were found in a search through a database dedicated to indexing all original data relevant to medicine published in Malaysia between the years 2000-2013. Fifty seven articles were selected and reviewed on the basis of clinical relevance and future research implications. Findings were summarised, categorised and presented according to prevalence of depression, depression in women, depression in clinical condition, assessment tools, and treatment of depression. The prevalence of depression in Malaysia was estimated to be between 8 and 12%. The figures were higher among women of low socio-economic background or those with comorbid medical condition. The common assessment tools used in Malaysia include Beck Depression Inventory (BDI), Depression, Anxiety and Stress Scale (DASS), Patient Health Questionnaire 9 (PHQ-9) and Hospital Anxiety and Depression Scale (HADS). They were translated into the Malay language and their psychometric properties were established. Both pharmacological treatment and psychotherapy were commonly used in Malaysia, and were highly recommended in local clinical practice guidelines. There are discrepancies in the reported rates of depression in Malaysia and this needs to be addressed. There were lack of studies looking into the depression among subgroups in Malaysia especially in the male population. There were several instruments available for assessment of depression in Malaysia but their suitability for the local setting need further research. Both pharmacotherapy and psychotherapy were recommended in the local treatment guideline in Malaysia. With the emergence of generic medication, we need to compare their clinical efficacy and tolerability with original products.

HMB supplementation: clinical and athletic performance-related effects and mechanisms of action.

PubMed

Zanchi, Nelo Eidy; Gerlinger-Romero, Frederico; Guimarães-Ferreira, Lucas; de Siqueira Filho, Mário Alves; Felitti, Vitor; Lira, Fabio Santos; Seelaender, Marília; Lancha, Antonio Herbert

2011-04-01

Amino acids such as leucine and its metabolite α-ketoisocaproate (KIC), are returning to be the focus of studies, mainly because of their anti-catabolic properties, through inhibition of muscle proteolysis and enhancement of protein synthesis. It is clear that these effects may counteract catabolic conditions, as well as enhance skeletal muscle mass and strength in athletes. Moreover, beta-hydroxy-beta-methylbutyrate (HMB) has been shown to produce an important effect in reducing muscle damage induced by mechanical stimuli of skeletal muscle. This review aims to describe the general scientific evidence of KIC and HMB supplementation clinical relevance, as well as their effects (e.g., increases in skeletal muscle mass and/or strength), associated with resistance training or other sports. Moreover, the possible mechanisms of cell signaling regulation leading to increases and/or sparing (during catabolic conditions) of skeletal muscle mass are discussed in detail based on the recent literature.

Psychometric properties of the Rosenberg Self-Esteem Scale: overall and across demographic groups living within the United States.

PubMed

Sinclair, Samuel J; Blais, Mark A; Gansler, David A; Sandberg, Elisabeth; Bistis, Kimberly; LoCicero, Alice

2010-03-01

The purpose of this study was twofold: (a) to evaluate the scaling assumptions and component structure of and present normative data for the Rosenberg Self-Esteem Scale (RSES) using a sample of US adults (N = 503), both overall and across demographic subgroups and (b) to provide new data regarding the relationship between the two RSES subcomponents of self-competence (SC) and self-liking (SL), and other demographic and clinical variables. As hypothesized, all psychometric tests supported the underlying structure of the RSES. Overall RSES scores varied significantly across age, racial and ethnic, education, employment status, income, and marital status groups. Furthermore, differences between SC and SL were also found across groups differing in gender, age, employment status, and marital status groups. The implications and limitations of this study are discussed, with an emphasis on clinical relevance.

Multivariate longitudinal data analysis with mixed effects hidden Markov models.

PubMed

Raffa, Jesse D; Dubin, Joel A

2015-09-01

Multiple longitudinal responses are often collected as a means to capture relevant features of the true outcome of interest, which is often hidden and not directly measurable. We outline an approach which models these multivariate longitudinal responses as generated from a hidden disease process. We propose a class of models which uses a hidden Markov model with separate but correlated random effects between multiple longitudinal responses. This approach was motivated by a smoking cessation clinical trial, where a bivariate longitudinal response involving both a continuous and a binomial response was collected for each participant to monitor smoking behavior. A Bayesian method using Markov chain Monte Carlo is used. Comparison of separate univariate response models to the bivariate response models was undertaken. Our methods are demonstrated on the smoking cessation clinical trial dataset, and properties of our approach are examined through extensive simulation studies. © 2015, The International Biometric Society.

Single-platelet nanomechanics measured by high-throughput cytometry

NASA Astrophysics Data System (ADS)

Myers, David R.; Qiu, Yongzhi; Fay, Meredith E.; Tennenbaum, Michael; Chester, Daniel; Cuadrado, Jonas; Sakurai, Yumiko; Baek, Jong; Tran, Reginald; Ciciliano, Jordan C.; Ahn, Byungwook; Mannino, Robert G.; Bunting, Silvia T.; Bennett, Carolyn; Briones, Michael; Fernandez-Nieves, Alberto; Smith, Michael L.; Brown, Ashley C.; Sulchek, Todd; Lam, Wilbur A.

2017-02-01

Haemostasis occurs at sites of vascular injury, where flowing blood forms a clot, a dynamic and heterogeneous fibrin-based biomaterial. Paramount in the clot's capability to stem haemorrhage are its changing mechanical properties, the major drivers of which are the contractile forces exerted by platelets against the fibrin scaffold. However, how platelets transduce microenvironmental cues to mediate contraction and alter clot mechanics is unknown. This is clinically relevant, as overly softened and stiffened clots are associated with bleeding and thrombotic disorders. Here, we report a high-throughput hydrogel-based platelet-contraction cytometer that quantifies single-platelet contraction forces in different clot microenvironments. We also show that platelets, via the Rho/ROCK pathway, synergistically couple mechanical and biochemical inputs to mediate contraction. Moreover, highly contractile platelet subpopulations present in healthy controls are conspicuously absent in a subset of patients with undiagnosed bleeding disorders, and therefore may function as a clinical diagnostic biophysical biomarker.

[Modeling in value-based medicine].

PubMed

Neubauer, A S; Hirneiss, C; Kampik, A

2010-03-01

Modeling plays an important role in value-based medicine (VBM). It allows decision support by predicting potential clinical and economic consequences, frequently combining different sources of evidence. Based on relevant publications and examples focusing on ophthalmology the key economic modeling methods are explained and definitions are given. The most frequently applied model types are decision trees, Markov models, and discrete event simulation (DES) models. Model validation includes besides verifying internal validity comparison with other models (external validity) and ideally validation of its predictive properties. The existing uncertainty with any modeling should be clearly stated. This is true for economic modeling in VBM as well as when using disease risk models to support clinical decisions. In economic modeling uni- and multivariate sensitivity analyses are usually applied; the key concepts here are tornado plots and cost-effectiveness acceptability curves. Given the existing uncertainty, modeling helps to make better informed decisions than without this additional information.

Design, clinical translation and immunological response of biomaterials in regenerative medicine

NASA Astrophysics Data System (ADS)

Sadtler, Kaitlyn; Singh, Anirudha; Wolf, Matthew T.; Wang, Xiaokun; Pardoll, Drew M.; Elisseeff, Jennifer H.

2016-07-01

The field of regenerative medicine aims to replace tissues lost as a consequence of disease, trauma or congenital abnormalities. Biomaterials serve as scaffolds for regenerative medicine to deliver cells, provide biological signals and physical support, and mobilize endogenous cells to repair tissues. Sophisticated chemistries are used to synthesize materials that mimic and modulate native tissue microenvironments, to replace form and to elucidate structure-function relationships of cell-material interactions. The therapeutic relevance of these biomaterial properties can only be studied after clinical translation, whereby key parameters for efficacy can be defined and then used for future design. In this Review, we present the development and translation of biomaterials for two tissue engineering targets, cartilage and cornea, both of which lack the ability to self-repair. Finally, looking to the future, we discuss the role of the immune system in regeneration and the potential for biomaterial scaffolds to modulate immune signalling to create a pro-regenerative environment.

Brief Report: Relationship Between ADOS-2, Module 4 Calibrated Severity Scores (CSS) and Social and Non-Social Standardized Assessment Measures in Adult Males with Autism Spectrum Disorder (ASD).

PubMed

Morrier, Michael J; Ousley, Opal Y; Caceres-Gamundi, Gabriella A; Segall, Matthew J; Cubells, Joseph F; Young, Larry J; Andari, Elissar

2017-12-01

The ADOS-2 Modules 1-3 now include a standardized calibrated severity score (CSS) from 1 to 10 based on the overall total raw score. Subsequent research published CSS for Module 4 (Hus, Lord, Journal of Autism and Developmental Disorders 44(8):1996-2012, 2014); however more research is needed to examine the psychometric properties of this CSS. Forty males with ASD completed an assessment battery consisting of ADOS-2 Module 4 and other clinical measures assessing core ASD symptomology and comorbidity. Pearson correlation analyses found that CSS did not correlate with measures that assessed core social deficits of ASD or general psychiatric co-morbidity, but CSS did correlate negatively with intellectual quotient. These findings provide information on the limitations and relevance of CSS to be taken into account in future clinical evaluations of ASD.

Effects of controlled-release formulations of atypical antipsychotics on functioning and quality of life of schizophrenic individuals.

PubMed

Ruiu, Stefania; Casu, Maria Antonietta; Casu, Gianluca; Piras, Sara; Marchese, Giorgio

2012-08-01

Controlled-release formulations of atypical antipsychotics have recently been introduced into clinical practice. Clinical studies have indicated that these new therapies induce meaningful improvements in the functioning and quality of life of schizophrenic individuals. The present analysis makes an attempt to address the clinical relevance of these studies and their contribution to the understanding of the mechanisms of action of these new drugs. A Medline search was done using the keywords 'antipsychotic', 'plasma level', 'quality of life' and 'functioning'. After reviewing the literature, it seems that symptom control and side effects may play a role in modulating the functioning and quality of life of schizophrenic individuals treated with controlled-release formulations of atypical antipsychotics. The analysis also highlights that these new drugs may possess peculiarities and similarities in regulating patient functioning. However, the low number of clinical analyses that have focused on these aspects of antipsychotic therapy limits the interpretation of the results. Additional comparative clinical trials are needed to evaluate how the pharmacokinetic/pharmacodynamic properties of antipsychotic drugs may modulate the functioning and quality of life of schizophrenic individuals, as well as to establish whether new clinical benefits may come from the use of these drugs in schizophrenia therapy.

Therapeutic risk management of the suicidal patient: augmenting clinical suicide risk assessment with structured instruments.

PubMed

Homaifar, Beeta; Matarazzo, Bridget; Wortzel, Hal S

2013-09-01

This column is the second in a series presenting a model for therapeutic risk management of the suicidal patient. As discussed in the first part of the series, the model involves several elements including augmenting clinical risk assessment with structured instruments, stratifying risk in terms of both severity and temporality, and developing and documenting a safety plan. This column explores in more detail how to augment clinical risk assessment with structured instruments. Unstructured clinical interviews have the potential to miss important aspects of suicide risk assessment. By augmenting the free-form clinical interview with structured instruments that demonstrate reliability and validity, a more nuanced and multifaceted approach to suicide risk assessment is achieved. Incorporating structured instruments into practice also serves a medicolegal function, since these instruments may become a living part of the medical record, establishing baseline levels of suicidal thoughts and behaviors and facilitating future clinical determinations regarding safety needs. We describe several instruments used in a multidisciplinary suicide consultation service, each of which has demonstrated relevance to suicide risk assessment and screening, ease of administration, and strong psychometric properties. In addition, we emphasize the importance of viewing suicide risk assessment as an ongoing process rather than as a singular event. Finally, we discuss special considerations in the evolving practice of risk assessment.

Health measurement using the ICF: Test-retest reliability study of ICF codes and qualifiers in geriatric care

PubMed Central

Okochi, Jiro; Utsunomiya, Sakiko; Takahashi, Tai

2005-01-01

Background The International Classification of Functioning, Disability and Health (ICF) was published by the World Health Organization (WHO) to standardize descriptions of health and disability. Little is known about the reliability and clinical relevance of measurements using the ICF and its qualifiers. This study examines the test-retest reliability of ICF codes, and the rate of immeasurability in long-term care settings of the elderly to evaluate the clinical applicability of the ICF and its qualifiers, and the ICF checklist. Methods Reliability of 85 body function (BF) items and 152 activity and participation (AP) items of the ICF was studied using a test-retest procedure with a sample of 742 elderly persons from 59 institutional and at home care service centers. Test-retest reliability was estimated using the weighted kappa statistic. The clinical relevance of the ICF was estimated by calculating immeasurability rate. The effect of the measurement settings and evaluators' experience was analyzed by stratification of these variables. The properties of each item were evaluated using both the kappa statistic and immeasurability rate to assess the clinical applicability of WHO's ICF checklist in the elderly care setting. Results The median of the weighted kappa statistics of 85 BF and 152 AP items were 0.46 and 0.55 respectively. The reproducibility statistics improved when the measurements were performed by experienced evaluators. Some chapters such as genitourinary and reproductive functions in the BF domain and major life area in the AP domain contained more items with lower test-retest reliability measures and rated as immeasurable than in the other chapters. Some items in the ICF checklist were rated as unreliable and immeasurable. Conclusion The reliability of the ICF codes when measured with the current ICF qualifiers is relatively low. The result in increase in reliability according to evaluators' experience suggests proper education will have positive effects to raise the reliability. The ICF checklist contains some items that are difficult to be applied in the geriatric care settings. The improvements should be achieved by selecting the most relevant items for each measurement and by developing appropriate qualifiers for each code according to the interest of the users. PMID:16050960

Epidermal photonic devices for quantitative imaging of temperature and thermal transport characteristics of the skin

NASA Astrophysics Data System (ADS)

Gao, Li; Zhang, Yihui; Malyarchuk, Viktor; Jia, Lin; Jang, Kyung-In; Chad Webb, R.; Fu, Haoran; Shi, Yan; Zhou, Guoyan; Shi, Luke; Shah, Deesha; Huang, Xian; Xu, Baoxing; Yu, Cunjiang; Huang, Yonggang; Rogers, John A.

2014-09-01

Characterization of temperature and thermal transport properties of the skin can yield important information of relevance to both clinical medicine and basic research in skin physiology. Here we introduce an ultrathin, compliant skin-like, or ‘epidermal’, photonic device that combines colorimetric temperature indicators with wireless stretchable electronics for thermal measurements when softly laminated on the skin surface. The sensors exploit thermochromic liquid crystals patterned into large-scale, pixelated arrays on thin elastomeric substrates; the electronics provide means for controlled, local heating by radio frequency signals. Algorithms for extracting patterns of colour recorded from these devices with a digital camera and computational tools for relating the results to underlying thermal processes near the skin surface lend quantitative value to the resulting data. Application examples include non-invasive spatial mapping of skin temperature with milli-Kelvin precision (±50 mK) and sub-millimetre spatial resolution. Demonstrations in reactive hyperaemia assessments of blood flow and hydration analysis establish relevance to cardiovascular health and skin care, respectively.

Epidermal photonic devices for quantitative imaging of temperature and thermal transport characteristics of the skin.

PubMed

Gao, Li; Zhang, Yihui; Malyarchuk, Viktor; Jia, Lin; Jang, Kyung-In; Webb, R Chad; Fu, Haoran; Shi, Yan; Zhou, Guoyan; Shi, Luke; Shah, Deesha; Huang, Xian; Xu, Baoxing; Yu, Cunjiang; Huang, Yonggang; Rogers, John A

2014-09-19

Characterization of temperature and thermal transport properties of the skin can yield important information of relevance to both clinical medicine and basic research in skin physiology. Here we introduce an ultrathin, compliant skin-like, or 'epidermal', photonic device that combines colorimetric temperature indicators with wireless stretchable electronics for thermal measurements when softly laminated on the skin surface. The sensors exploit thermochromic liquid crystals patterned into large-scale, pixelated arrays on thin elastomeric substrates; the electronics provide means for controlled, local heating by radio frequency signals. Algorithms for extracting patterns of colour recorded from these devices with a digital camera and computational tools for relating the results to underlying thermal processes near the skin surface lend quantitative value to the resulting data. Application examples include non-invasive spatial mapping of skin temperature with milli-Kelvin precision (±50 mK) and sub-millimetre spatial resolution. Demonstrations in reactive hyperaemia assessments of blood flow and hydration analysis establish relevance to cardiovascular health and skin care, respectively.

Mechanisms and disease relevance of neutrophil extracellular trap formation.

PubMed

Van Avondt, Kristof; Hartl, Dominik

2018-03-15

While the microscopic appearance of neutrophil extracellular traps (NETs) has fascinated basic researchers since its discovery, the (patho)physiological mechanisms triggering NET release, the disease relevance and clinical translatability of this unconventional cellular mechanism remained poorly understood. Here, we summarize and discuss current concepts of the mechanisms and disease relevance of NET formation. © 2018 Stichting European Society for Clinical Investigation Journal Foundation.

Is a Pink Cow Still a Cow? Individual Differences in Toddlers' Vocabulary Knowledge and Lexical Representations

ERIC Educational Resources Information Center

Perry, Lynn K.; Saffran, Jenny R.

2017-01-01

When a toddler knows a word, what does she actually know? Many categories have multiple relevant properties; for example, shape "and" color are relevant to membership in the category "banana." How do toddlers prioritize these properties when recognizing familiar words, and are there systematic differences among children? In…

Clinical Relevance of IgE to Profilin and/or Polcalcin in Pollen-Sensitized Patients.

PubMed

San Nicoló, Marion; Braun, Thomas; Eder, Katharina; Berghaus, Alexander; Gröger, Moritz

2016-01-01

Component-resolved diagnostics is gaining importance in allergy diagnostics. Allergen extracts contain components with different rates of prevalence and clinical relevance, which can be subdivided at molecular level into major and minor allergens. Clinical complaints are usually triggered by major allergens, while the role of sensitization to the panallergens profilin and polcalcin still remains unclear. Eighty-six patients from southern Bavaria with sensitization to the panallergens profilin (Bet v 2/Phl p 12) and/or polcalcin (Bet v 4/Phl p 7) were examined in regard to their sensitization to the 4 main botanic denominations Betulaceae, Oleaceae, Poaceae and Asteraceae by skin prick test and measurement of specific immunoglobulin E antibodies to natural allergen extracts as well as major allergen components rPhl p 1/5, rBet v 1, rOle e 1 and nArt v 1. Sensitization was rated as clinically relevant or irrelevant depending on anamnesis or intranasal allergen challenge. Regarding the 4 botanic denominations, there was no significant difference in the incidence of sensitization to the panallergens profilin, polcalcin or both. The sensitization pattern does not alter when subdividing the cohort into clinically relevant and silent sensitization. We did not find clinically symptomatic sensitization to panallergens without cosensitization to a major allergen. Our results suggest that sole sensitization to panallergens seems to have no clinical relevance in allergic rhinoconjunctivitis. Clinical complaints seem to be triggered manly by major allergens. Thus, component-resolved allergy diagnostics is crucial in the diagnosis and treatment of polysensitized patients. © 2016 S. Karger AG, Basel.

Interviews with children about their mental health problems: The congruence and validity of information that children report.

PubMed

Macleod, Emily; Woolford, June; Hobbs, Linda; Gross, Julien; Hayne, Harlene; Patterson, Tess

2017-04-01

To obtain a child's perspective during a mental health assessment, he or she is usually interviewed. Although researchers and clinicians generally agree that it is beneficial to hear a child's account of his or her presenting issues, there is debate about whether children provide reliable or valid clinical information during these interviews. Here, we examined whether children provide clinically and diagnostically relevant information in a clinical setting. In all, 31 children aged 5-12-years undergoing mental health assessments were asked open-ended questions about their presenting problems during a semi-structured interview. We coded the information that children reported to determine whether it was clinically relevant and could be used to diagnose their problems and to formulate and plan treatment. We also coded children's information to determine whether it was congruent with the children's presenting problems and their eventual clinical diagnoses. Most of the information that children reported was clinically relevant and included information about behaviour, affect, temporal details, thoughts, people, the environment, and the child's physical experiences. The information that children reported was also clinically valid; it was congruent with the problems that were discussed (84%) and also with the eventual diagnosis that the child received after a complete assessment (74%). We conclude that children can contribute relevant, clinically useful, valid information during clinical psychological assessments.

Elevator Sizing, Placement, and Control-Relevant Tradeoffs for Hypersonic Vehicles

NASA Technical Reports Server (NTRS)

Dickeson, Jeffrey J.; Rodriguez, Armando A.; Sridharan, Srikanth; Korad, Akshay

2010-01-01

Within this paper, control-relevant vehicle design concepts are examined using a widely used 3 DOF (plus flexibility) nonlinear model for the longitudinal dynamics of a generic carrot-shaped scramjet powered hypersonic vehicle. The impact of elevator size and placement on control-relevant static properties (e.g. level-flight trimmable region, trim controls, Angle of Attack (AOA), thrust margin) and dynamic properties (e.g. instability and right half plane zero associated with flight path angle) are examined. Elevator usage has been examine for a class of typical hypersonic trajectories.

Order-of-magnitude physics of neutron stars. Estimating their properties from first principles

NASA Astrophysics Data System (ADS)

Reisenegger, Andreas; Zepeda, Felipe S.

2016-03-01

We use basic physics and simple mathematics accessible to advanced undergraduate students to estimate the main properties of neutron stars. We set the stage and introduce relevant concepts by discussing the properties of "everyday" matter on Earth, degenerate Fermi gases, white dwarfs, and scaling relations of stellar properties with polytropic equations of state. Then, we discuss various physical ingredients relevant for neutron stars and how they can be combined in order to obtain a couple of different simple estimates of their maximum mass, beyond which they would collapse, turning into black holes. Finally, we use the basic structural parameters of neutron stars to briefly discuss their rotational and electromagnetic properties.

Altered growth pattern, not altered growth per se, is the hallmark of early lesions preceding cancer development.

PubMed

Doratiotto, S; Marongiu, F; Faedda, S; Pani, P; Laconi, E

2009-01-01

Many human solid cancers arise from focal proliferative lesions that long precede the overt clinical appearance of the disease. The available evidence supports the notion that cancer precursor lesions are clonal in origin, and this notion forms the basis for most of the current theories on the pathogenesis of neoplastic disease. In contrast, far less attention has been devoted to the analysis of the phenotypic property that serves to define these focal lesions, i.e. their altered growth pattern. In fact, the latter is often considered a mere morphological by-product of clonal growth, with no specific relevance in the process. In the following study, evidence will be presented to support the concept that focal growth pattern is an inherent property of altered cells, independent of clonal growth; furthermore, it will be discussed how such a property, far from being merely descriptive, might indeed play a fundamental role in the sequence of events leading to the development of cancer. Within this paradigm, the earliest steps of neoplasia should be considered and analysed as defects in the mechanisms of tissue pattern formation.

Temperature-dependent physical properties of egg white for HIFU applications

NASA Astrophysics Data System (ADS)

Liu, Yunbo; Maruvada, Subha; Herman, Bruce A.; Harris, Gerald R.

2012-10-01

Because egg white denatures at elevated temperature due to its protein content, it has the potential for use as a blood coagulation surrogate in pre-clinical evaluations of thermal therapy procedures such as high intensity focused ultrasound (HIFU) surgery. We therefore have measured the relevant physical properties of egg white, including coagulation temperature, frequency-dependent attenuation, sound speed, viscosity, and thermal properties, as a function of temperature (20 - 95°C). Thermal coagulation and attenuation (5-12 MHz) of cow blood, pig blood, and human blood also were assessed and compared with egg white. For a 30 s thermal exposure, both egg white and blood samples started to denature at 65°C and coagulate into an elastic gel at 85°C. The temperature-dependent parameters were found to be similar to that of the blood samples. For example, the attenuation of egg white ranged from 0.23f1.09 to 2.7f0.5 dB/cm over the 20°C - 95°C range. These results suggest that egg white would make a useful blood mimic for bench testing of therapeutic ultrasound devices.

Dense chitosan surgical membranes produced by a coincident compression-dehydration process

PubMed Central

Dooley, Thomas P.; Ellis, April L.; Belousova, Maria; Petersen, Don; DeCarlo, Arthur A.

2012-01-01

High density chitosan membranes were produced via a novel manufacturing process for use as implantable resorbable surgical membranes. The innovative method utilizes the following three sequential steps: (1) casting an acidic chitosan solution within a silicon mold, followed by freezing; (2) neutralizing the frozen acidic chitosan solution in alkaline solution to facilitate polymerization; and (3) applying coincident compression-dehydration under a vacuum. Resulting membranes of 0.2 – 0.5 mm thickness have densities as high as 1.6 g/cm3. Inclusion of glycerol prior to the compression-dehydration step provides additional physical and clinical handling benefits. The biomaterials exhibit tensile strength with a maximum load as high as 10.9 N at ~ 2.5 mm width and clinically-relevant resistance to suture pull-out with a maximum load as high as 2.2 N. These physical properties were superior to those of a commercial reconstituted collagen membrane. The dense chitosan membranes have excellent clinical handling characteristics, such as pliability and “memory” when wet. They are semi-permeable to small molecules, biodegradable in vitro in lysozyme solution, and the rates of degradation are inversely correlated to the degree of deacetylation. Furthermore, the dense chitosan membranes are biocompatible and resorbable in vivo as demonstrated in a rat oral wound healing model. The unique combination of physical, in vitro, in vivo, and clinical handling properties demonstrate the high utility of dense chitosan membranes produced by this new method. The materials may be useful as surgical barrier membranes, scaffolds for tissue engineering, wound dressings, and as delivery devices for active ingredients. PMID:23565872

Locating relevant patient information in electronic health record data using representations of clinical concepts and database structures.

PubMed

Pan, Xuequn; Cimino, James J

2014-01-01

Clinicians and clinical researchers often seek information in electronic health records (EHRs) that are relevant to some concept of interest, such as a disease or finding. The heterogeneous nature of EHRs can complicate retrieval, risking incomplete results. We frame this problem as the presence of two gaps: 1) a gap between clinical concepts and their representations in EHR data and 2) a gap between data representations and their locations within EHR data structures. We bridge these gaps with a knowledge structure that comprises relationships among clinical concepts (including concepts of interest and concepts that may be instantiated in EHR data) and relationships between clinical concepts and the database structures. We make use of available knowledge resources to develop a reproducible, scalable process for creating a knowledge base that can support automated query expansion from a clinical concept to all relevant EHR data.

Selecting relevant and feasible measurement instruments for the revised Dutch clinical practice guideline for physical therapy in patients after stroke.

PubMed

Otterman, Nicoline; Veerbeek, Janne; Schiemanck, Sven; van der Wees, Philip; Nollet, Frans; Kwakkel, Gert

2017-07-01

To select relevant and feasible instruments for the revision of the Dutch clinical practice guideline for physical therapy in patients with stroke. In this implementation study a comprehensive proposal for ICF categories and matching instruments was developed, based on reliability and validity. Relevant instruments were then selected in a consensus round by 11 knowledge brokers who were responsible for the implementation of the selected instruments. The feasibility of the selected instruments was tested by 36 physical therapists at different work settings within stroke services. Finally, instruments that were deemed relevant and feasible were included in the revised guideline. A total of 28 instruments were recommended for inclusion in the revised guideline. Nineteen instruments were retained from the previous guideline. Ten new instruments were tested in clinical practice, seven of which were found feasible. Two more instruments were added after critical appraisal of the set of the measurement instruments. The revised guideline contains 28 relevant and feasible instrument selected and tested in clinical practice by physical therapists. Further education and implementation is needed to integrate instruments in clinical practice. Further research is proposed for developing and implementing a core set of measurement instruments to be used at fixed time points to establish data registries that allow for continuous improvement of rehabilitation for stroke patients. Implications for Rehabilitation The revised Dutch Stroke Physical Therapy Guideline recommends a total of 28 instruments, that are relevant and feasible for clinical practice of physical therapist in the different settings of stroke rehabilitation. The selection of instrument in daily practice should be part of the clinical reasoning process of PTs and be tailored to individual patients' needs and the degree of priority of the affected ICF category. Suggested education strategies for further integration of instruments in of the daily practice of PTs in Stroke Rehabilitation are: 'Training on the job' and 'peer assessment in clinical situations'.

The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

Cancer.gov

Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

Retrieving clinical evidence: a comparison of PubMed and Google Scholar for quick clinical searches.

PubMed

Shariff, Salimah Z; Bejaimal, Shayna Ad; Sontrop, Jessica M; Iansavichus, Arthur V; Haynes, R Brian; Weir, Matthew A; Garg, Amit X

2013-08-15

Physicians frequently search PubMed for information to guide patient care. More recently, Google Scholar has gained popularity as another freely accessible bibliographic database. To compare the performance of searches in PubMed and Google Scholar. We surveyed nephrologists (kidney specialists) and provided each with a unique clinical question derived from 100 renal therapy systematic reviews. Each physician provided the search terms they would type into a bibliographic database to locate evidence to answer the clinical question. We executed each of these searches in PubMed and Google Scholar and compared results for the first 40 records retrieved (equivalent to 2 default search pages in PubMed). We evaluated the recall (proportion of relevant articles found) and precision (ratio of relevant to nonrelevant articles) of the searches performed in PubMed and Google Scholar. Primary studies included in the systematic reviews served as the reference standard for relevant articles. We further documented whether relevant articles were available as free full-texts. Compared with PubMed, the average search in Google Scholar retrieved twice as many relevant articles (PubMed: 11%; Google Scholar: 22%; P<.001). Precision was similar in both databases (PubMed: 6%; Google Scholar: 8%; P=.07). Google Scholar provided significantly greater access to free full-text publications (PubMed: 5%; Google Scholar: 14%; P<.001). For quick clinical searches, Google Scholar returns twice as many relevant articles as PubMed and provides greater access to free full-text articles.

Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post- chemotherapy tissues

PubMed Central

Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

2015-01-01

Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID:26515599

Alteration of Dentin-Enamel Mechanical Properties Due to Dental Whitening Treatments

PubMed Central

Zimmerman, B.; Datko, L.; Cupelli, M.; Alapati, S.; Dean, D.; Kennedy, M.

2010-01-01

The mechanical properties of dentin and enamel affect the reliability and wear properties of a tooth. This study investigated the influence of clinical dental treatments and procedures, such as whitening treatments or etching prior to restorative procedures. Both autoclaved and non-autoclaved teeth were studied in order to allow for both comparison with published values and improved clinical relevance. Nanoindentation analysis with the Oliver-Pharr model provided elastic modulus and hardness across the dentin-enamel junction (DEJ). Large increases were observed in the elastic modulus of enamel in teeth that had been autoclaved (52.0GPa versus 113.4GPa), while smaller increases were observed in the dentin (17.9GPa versus 27.9GPa). Likewise, there was an increase in the hardness of enamel (2.0GPa versus 4.3GPa) and dentin (0.5GPa versus 0.7GPa) with autoclaving. These changes suggested that the range of elastic modulus and hardness values previously reported in literature may be partially due to the sterilization procedures. Treatment of the exterior of non-autoclaved teeth with Crest Whitestrips™, Opalescence™ or UltraEtch™ caused changes in the mechanical properties of both the enamel and dentin. Those treated with Crest Whitestrips™ showed a reduction in the elastic modulus of enamel (55.3GPa to 32.7GPa) and increase in the elastic modulus of dentin (17.2GPa to 24.3GPa). Opalescence™ treatments did not significantly affect the enamel properties, but did result in a decrease in modulus of dentin (18.5GPa to 15.1GPa). Additionally, as expected, UltraEtch™ treatment decreased the modulus and hardness of enamel (48.7GPa to 38.0GPa and 1.9GPa to 1.5GPa, respectively) and dentin (21.4GPa to 15.0GPa and 1.9GPa to 1.5GPa, respectively). Changes in the mechanical properties were linked to altered protein concentration within the tooth, as evidenced by fluorescence microscopy and Fourier transform infrared spectroscopy. PMID:20346902

The clinical trial landscape in oncology and connectivity of somatic mutational profiles to targeted therapies.

PubMed

Patterson, Sara E; Liu, Rangjiao; Statz, Cara M; Durkin, Daniel; Lakshminarayana, Anuradha; Mockus, Susan M

2016-01-16

Precision medicine in oncology relies on rapid associations between patient-specific variations and targeted therapeutic efficacy. Due to the advancement of genomic analysis, a vast literature characterizing cancer-associated molecular aberrations and relative therapeutic relevance has been published. However, data are not uniformly reported or readily available, and accessing relevant information in a clinically acceptable time-frame is a daunting proposition, hampering connections between patients and appropriate therapeutic options. One important therapeutic avenue for oncology patients is through clinical trials. Accordingly, a global view into the availability of targeted clinical trials would provide insight into strengths and weaknesses and potentially enable research focus. However, data regarding the landscape of clinical trials in oncology is not readily available, and as a result, a comprehensive understanding of clinical trial availability is difficult. To support clinical decision-making, we have developed a data loader and mapper that connects sequence information from oncology patients to data stored in an in-house database, the JAX Clinical Knowledgebase (JAX-CKB), which can be queried readily to access comprehensive data for clinical reporting via customized reporting queries. JAX-CKB functions as a repository to house expertly curated clinically relevant data surrounding our 358-gene panel, the JAX Cancer Treatment Profile (JAX CTP), and supports annotation of functional significance of molecular variants. Through queries of data housed in JAX-CKB, we have analyzed the landscape of clinical trials relevant to our 358-gene targeted sequencing panel to evaluate strengths and weaknesses in current molecular targeting in oncology. Through this analysis, we have identified patient indications, molecular aberrations, and targeted therapy classes that have strong or weak representation in clinical trials. Here, we describe the development and disseminate system methods for associating patient genomic sequence data with clinically relevant information, facilitating interpretation and providing a mechanism for informing therapeutic decision-making. Additionally, through customized queries, we have the capability to rapidly analyze the landscape of targeted therapies in clinical trials, enabling a unique view into current therapeutic availability in oncology.

Urokinase-receptor (u-PAR): an essential player in multiple games of cancer: a review on its role in tumor progression, invasion, metastasis, proliferation/dormancy, clinical outcome and minimal residual disease.

PubMed

Laufs, Stephanie; Schumacher, Jens; Allgayer, Heike

2006-08-01

The relevance of the u-PA system in mediating tumor-associated proteolysis, invasion and metastasis, amongst other phenomena associated with tumor progression, has been clearly demonstrated in diverse cancer entities. This review will update on the biological and clinical relevance of the urokinase-receptor (u-PAR). Specifically, the article focuses on the potential importance of u-PAR for the development of minimal residual disease in solid cancer, and in this context reviews the biological relevance of the u-PAR for tumor cell dormancy. Furthermore, transcriptional mechanisms regulating u-PAR in vitro and in vivo, and their potential clinical and therapeutic relevance in gastrointestinal cancers, are elucidated.

A Vietnamese man with selective mutism: the relevance of multiple interacting 'cultures' in clinical psychiatry.

PubMed

Hollifield, Michael; Geppert, Cynthia; Johnson, Yuam; Fryer, Carol

2003-09-01

Multiple cultural variables have effects on the psychobiology and behavioral manifestations of illness, as do patient and physician perceptions of illness. The interaction among these variables is at the heart of clinical psychiatry. This case of a Vietnamese man with selective mutism underscores the relevance of the 'cultures' of medicine, psychiatry, and war and trauma on the manifestations of illness and illness perceptions by patient and physician. The discussion focuses on how these cultures interact and play a crucial role in formulating diagnosis and treatment planning. Suggestions are given for shifts in medical education that will encourage relevant cultural paradigms to make their way into educational and clinical systems, which in turn should improve cultural competence in clinical psychiatry.

Cellular innate immunity and restriction of viral infection: implications for lentiviral gene therapy in human hematopoietic cells.

PubMed

Kajaste-Rudnitski, Anna; Naldini, Luigi

2015-04-01

Hematopoietic gene therapy has tremendous potential to treat human disease. Nevertheless, for gene therapy to be efficacious, effective gene transfer into target cells must be reached without inducing detrimental effects on their biological properties. This remains a great challenge for the field as high vector doses and prolonged ex vivo culture conditions are still required to reach significant transduction levels of clinically relevant human hematopoietic stem and progenitor cells (HSPCs), while other potential target cells such as primary macrophages can hardly be transduced. The reasons behind poor permissiveness of primary human hematopoietic cells to gene transfer partly reside in the retroviral origin of lentiviral vectors (LVs). In particular, host antiviral factors referred to as restriction factors targeting the retroviral life cycle can hamper LV transduction efficiency. Furthermore, LVs may activate innate immune sensors not only in differentiated hematopoietic cells but also in HSPCs, with potential consequences on transduction efficiency as well as their biological properties. Therefore, better understanding of the vector-host interactions in the context of hematopoietic gene transfer is important for the development of safer and more efficient gene therapy strategies. In this review, we briefly summarize the current knowledge regarding innate immune recognition of lentiviruses in primary human hematopoietic cells as well as discuss its relevance for LV-based ex vivo gene therapy approaches.

Fear of cancer recurrence: a systematic literature review of self-report measures.

PubMed

Thewes, Belinda; Butow, Phillis; Zachariae, Robert; Christensen, Soren; Simard, Sébastien; Gotay, Carolyn

2012-06-01

Prior research has shown that many cancer survivors experience ongoing fears of cancer recurrence (FCR) and that this chronic uncertainty of health status during and after cancer treatment can be a significant psychological burden. The field of research on FCR is an emerging area of investigation in the cancer survivorship literature, and several standardised instruments for its assessment have been developed. This review aims to identify all available FCR-specific questionnaires and subscales and critically appraise their properties. A systematic review was undertaken to identify instruments measuring FCR. Relevant studies were identified via Medline (1950-2010), CINAHL (1982-2010), PsycINFO (1967-2010) and AMED (1985-2010) databases, reference lists of articles and reviews, grey literature databases and consultation with experts in the field. The Medical Outcomes Trust criteria were used to examine the psychometric properties of the questionnaires. A total of 20 relevant multi-item measures were identified. The majority of instruments have demonstrated reliability and preliminary evidence of validity. Relatively few brief measures (2-10 items) were found to have comprehensive validation and reliability data available. Several valid and reliable longer measures (>10 items) are available. Three have developed short forms that may prove useful as screening tools. This analysis indicated that further refinement and validation of existing instruments is required. Valid and reliable instruments are needed for both research and clinical care. Copyright © 2011 John Wiley & Sons, Ltd.

77 FR 32975 - AHRQ Workgroups on ICD-10-CM/PCS Conversion of Quality Indicators (QIs)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-04

... relevant clinical expertise (e.g., cardiovascular disease, neurologic disease, orthopedic and musculoskeletal disease, obstetrics and gynecologic disease, surgery, critical care and pulmonary disease... measurement using administrative data in specific, relevant clinical domains (e.g., cardiovascular disease...

Different kinetic properties of two T-type Ca2+ currents of rat reticular thalamic neurones and their modulation by enflurane

PubMed Central

Joksovic, Pavle M; Bayliss, Douglas A; Todorovic, Slobodan M

2005-01-01

Currents arising from T-type Ca2+ channels in nucleus reticularis thalami (nRT) play a critical role in generation of low-amplitude oscillatory bursting involving mutually interconnected cortical and thalamic neurones, and are implicated in the state of arousal and sleep, as well as seizures. Here we show in brain slices from young rats that two kinetically different T-type Ca2+ currents exist in nRT neurones, with a slowly inactivating current expressed only on proximal dendrites, and fast inactivating current predominantly expressed on soma. Nickel was about twofold more potent in blocking fast (IC50 64 μm) than slow current (IC50 107 μm). The halogenated volatile anaesthetic enflurane blocked both currents, but only the slowly inactivating current was affected in voltage-dependent fashion. Slow dendritic current was essential for generation of low-threshold Ca2+ spikes (LTS), and both enflurane and nickel also suppressed LTS and neuronal burst firing at concentrations that blocked isolated T currents. Differential kinetic properties of T currents expressed in cell soma and proximal dendrites of nRT neurones indicate that various subcellular compartments may exhibit different membrane properties in response to small membrane depolarizations. Furthermore, since blockade of two different T currents in nRT neurones by enflurane and other volatile anaesthetics occurs within concentrations that are relevant during clinical anaesthesia, our findings suggest that these actions could contribute to some important clinical effects of anaesthetics. PMID:15845580

Silica-Coated Nonstoichiometric Nano Zn-Ferrites for Magnetic Resonance Imaging and Hyperthermia Treatment.

PubMed

Starsich, Fabian H L; Sotiriou, Georgios A; Wurnig, Moritz C; Eberhardt, Christian; Hirt, Ann M; Boss, Andreas; Pratsinis, Sotiris E

2016-10-01

Large-scale and reproducible synthesis of nanomaterials is highly sought out for successful translation into clinics. Flame aerosol technology with its proven capacity to manufacture high purity materials (e.g., light guides) up to kg h -1 is explored here for the preparation of highly magnetic, nonstoichiometric Zn-ferrite (Zn 0.4 Fe 2.6 O 4 ) nanoparticles coated in situ with a nanothin SiO 2 layer. The focus is on their suitability as magnetic multifunctional theranostic agents analyzing their T2 contrast enhancing capability for magnetic resonance imaging (MRI) and their magnetic hyperthermia performance. The primary particle size is closely controlled from 5 to 35 nm evaluating its impact on magnetic properties, MRI relaxivity, and magnetic heating performance. Most importantly, the addition of Zn in the flame precursor solution facilitates the growth of spinel Zn-ferrite crystals that exhibit superior magnetic properties over iron oxides typically made in flames. These properties result in strong MRI T2 contrast agents as shown on a 4.7 T small animal MRI scanner and lead to a more efficient heating with alternating magnetic fields. Also, by injecting Zn 0.4 Fe 2.6 O 4 nanoparticle suspensions into pork tissue, MR-images are acquired at clinically relevant concentrations. Furthermore, the nanothin SiO 2 shell facilitates functionalization with polymers, which improves the biocompatibility of the theranostic system. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Future role of MR elastography in tissue engineering and regenerative medicine.

PubMed

Othman, Shadi F; Xu, Huihui; Mao, Jeremy J

2015-05-01

Tissue engineering (TE) has been introduced for more than 25 years without a boom in clinical trials. More than 70 TE-related start-up companies spent more than $600 million/year, with only two FDA-approved tissue-engineered products. Given the modest performance in clinically approved organs, TE is a tenaciously promising field. The TE community is advocating the application of clinically driven methodologies in large animal models enabling clinical translation. This challenge is hindered by the scarcity of tissue biopsies and the absence of standardized evaluation tools, but can be negated through non-invasive assessment of growth and integration, with reduced sample size and low cost. Solving this issue will speed the transition to cost-efficient clinical studies. In this paper we: (a) introduce magnetic resonance elastography to the tissue-engineering and regenerative medicine (TERM) community; (b) review recent MRE applications in TERM; and (c) discuss future directions of MRE in TERM. We have used MRE to study engineered tissues both in vitro and in vivo, where the mechanical properties of mesenchymally derived constructs were progressively monitored before and after tissues were implanted in mouse models. This study represents a stepping stone toward the applications of MRE in directing clinical trials with low cost and likely expediting the translation to more relevantly large animal models and clinical trials. Copyright © 2013 John Wiley & Sons, Ltd.

Barriers to Retrieving Patient Information from Electronic Health Record Data: Failure Analysis from the TREC Medical Records Track

PubMed Central

Edinger, Tracy; Cohen, Aaron M.; Bedrick, Steven; Ambert, Kyle; Hersh, William

2012-01-01

Objective: Secondary use of electronic health record (EHR) data relies on the ability to retrieve accurate and complete information about desired patient populations. The Text Retrieval Conference (TREC) 2011 Medical Records Track was a challenge evaluation allowing comparison of systems and algorithms to retrieve patients eligible for clinical studies from a corpus of de-identified medical records, grouped by patient visit. Participants retrieved cohorts of patients relevant to 35 different clinical topics, and visits were judged for relevance to each topic. This study identified the most common barriers to identifying specific clinic populations in the test collection. Methods: Using the runs from track participants and judged visits, we analyzed the five non-relevant visits most often retrieved and the five relevant visits most often overlooked. Categories were developed iteratively to group the reasons for incorrect retrieval for each of the 35 topics. Results: Reasons fell into nine categories for non-relevant visits and five categories for relevant visits. Non-relevant visits were most often retrieved because they contained a non-relevant reference to the topic terms. Relevant visits were most often infrequently retrieved because they used a synonym for a topic term. Conclusions: This failure analysis provides insight into areas for future improvement in EHR-based retrieval with techniques such as more widespread and complete use of standardized terminology in retrieval and data entry systems. PMID:23304287

Barriers to retrieving patient information from electronic health record data: failure analysis from the TREC Medical Records Track.

PubMed

Edinger, Tracy; Cohen, Aaron M; Bedrick, Steven; Ambert, Kyle; Hersh, William

2012-01-01

Secondary use of electronic health record (EHR) data relies on the ability to retrieve accurate and complete information about desired patient populations. The Text Retrieval Conference (TREC) 2011 Medical Records Track was a challenge evaluation allowing comparison of systems and algorithms to retrieve patients eligible for clinical studies from a corpus of de-identified medical records, grouped by patient visit. Participants retrieved cohorts of patients relevant to 35 different clinical topics, and visits were judged for relevance to each topic. This study identified the most common barriers to identifying specific clinic populations in the test collection. Using the runs from track participants and judged visits, we analyzed the five non-relevant visits most often retrieved and the five relevant visits most often overlooked. Categories were developed iteratively to group the reasons for incorrect retrieval for each of the 35 topics. Reasons fell into nine categories for non-relevant visits and five categories for relevant visits. Non-relevant visits were most often retrieved because they contained a non-relevant reference to the topic terms. Relevant visits were most often infrequently retrieved because they used a synonym for a topic term. This failure analysis provides insight into areas for future improvement in EHR-based retrieval with techniques such as more widespread and complete use of standardized terminology in retrieval and data entry systems.

Assessing clinically meaningful treatment effects in controlled trials: chronic migraine as an example.

PubMed

Dodick, David W; Turkel, Catherine C; DeGryse, Ronald E; Diener, Hans-Christoph; Lipton, Richard B; Aurora, Sheena K; Nolan, Marissa E; Silberstein, Stephen D

2015-02-01

In addition to headache, persons with chronic migraine (CM) experience multiple symptoms, both ictal and interictal, that may contribute to their suffering. Translating clinical trial results into practice requires assessment of the results' clinical meaningfulness. When examining treatment benefit in this disabled patient population, multiple headache-symptom measures should be considered to fully reflect clinical relevance. Currently, only onabotulinumtoxinA is approved specifically for headache prophylaxis in adults with CM. Topiramate is the only other therapeutic agent with double-blind, placebo-controlled evidence in this population. Herein we evaluate the clinical meaningfulness of onabotulinumtoxinA and topiramate as headache prophylaxis in CM by comparing primary endpoints from the placebo-controlled, double-blind phase of the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program and the topiramate clinical trial (frequency of headache days [primary endpoint in PREEMPT; secondary in topiramate trial] and migraine/migrainous days [primary in topiramate trial, or "migraine/probable-migraine days"; secondary in PREEMPT]). Additionally, outcome measures such as responder rates, health-related quality of life, discontinuation rates, safety, and tolerability profiles are important clinical considerations. The clinical data indicate that statistically significant, clinically relevant treatment benefits exist for both onabotulinumtoxinA and topiramate. These data support these treatments as meaningful headache prophylaxis in adults with CM. CM is a chronic pain condition. We sought to determine the clinical relevance of recent trials in this disabled population. Clinical data indicate that statistically significant, clinically relevant treatment benefits exist for both onabotulinumtoxinA and topiramate, and support use of these treatments as meaningful headache prophylaxis in CM. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations

PubMed Central

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico; CoRIS

2014-01-01

Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. PMID:24637804

Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide.

PubMed

Mahan, Vicki L

2012-12-27

Studies in animal models show that the primary mechanism by which heme-oxygenases impart beneficial effects is due to the gaseous molecule carbon monoxide (CO). Produced in humans mainly by the catabolism of heme by heme-oxygenase, CO is a neurotransmitter important for multiple neurologic functions and affects several intracellular pathways as a regulatory molecule. Exogenous administration of inhaled CO or carbon monoxide releasing molecules (CORM's) impart similar neurophysiological responses as the endogenous gas. Its' involvement in important neuronal functions suggests that regulation of CO synthesis and biochemical properties may be clinically relevant to neuroprotection and the key may be a change in metabolic substrate from glucose to lactate. Currently, the drug is under development as a therapeutic agent and safety studies in humans evaluating the safety and tolerability of inhaled doses of CO show no clinically important abnormalities, effects, or changes over time in laboratory safety variables. As an important therapeutic option, inhaled CO has entered clinical trials and its clinical role as a neuroprotective and neurotherapeutic agent has been suggested. In this article, we review the neuroprotective effects of endogenous CO and discuss exogenous CO as a neuroprotective and neurotherapeutic agent.

Validation of a simple disease-specific, quality-of-life measure for diabetic polyneuropathy: CAPPRI.

PubMed

Gwathmey, Kelly G; Sadjadi, Reza; Horton, William B; Conaway, Mark R; Barnett-Tapia, Carolina; Bril, Vera; Russell, James W; Shaibani, Aziz; Mauermann, Michelle L; Hehir, Michael K; Kolb, Noah; Guptill, Jeffrey; Hobson-Webb, Lisa; Gable, Karissa; Raja, Shruti; Silvestri, Nicholas; Wolfe, Gil I; Smith, A Gordon; Malik, Rabia; Traub, Rebecca; Joshi, Amruta; Elliott, Matthew P; Jones, Sarah; Burns, Ted M

2018-06-05

We studied the performance of a 15-item, health-related quality-of-life polyneuropathy scale in the clinic setting in patients with diabetic distal sensorimotor polyneuropathy (DSPN). Patients with DSPN from 11 academic sites completed a total of 231 Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) scales during their clinic visits. Conventional and modern psychometric analyses were performed on the completed forms. Conventional and modern analyses generally indicated excellent psychometric properties of the CAPPRI in patients with DSPN. For example, the CAPPRI demonstrated unidimensionality and performed like an interval-level scale. Attributes of the CAPPRI for DSPN include ease of use and interpretation; unidimensionality, allowing scores to be summed; adequate coverage of disease severity; and the scale's ability to address relevant life domains. Furthermore, the CAPPRI is free and in the public domain. The CAPPRI may assist the clinician and patient with DSPN in estimating disease-specific quality of life, especially in terms of pain, sleep, psychological well-being, and everyday function. The CAPPRI may be most useful in the everyday clinical setting but merits further study in this setting, as well as the clinical trial setting. © 2018 American Academy of Neurology.

The Clinical Relevance of Maintaining the Functional Integrity of the Stratum Corneum in both Healthy and Disease-affected Skin

PubMed Central

Del Rosso, James Q.; Levin, Jacqueline

2011-01-01

It has been recognized for approximately 50 years that the stratum corneum exhibits biological properties that contribute directly to maintaining and sustaining healthy skin. Continued basic science and clinical research coupled with keen clinical observation has led to more recent recognition and general acceptance that the stratum corneum completes many vital “barrier” tasks, including but not limited to regulating epidermal water content and the magnitude of water loss; mitigating exogenous oxidants that can damage components of skin via an innate antioxidant system; preventing or limiting cutaneous infection via multiple antimicrobial peptides; responding via innate immune mechanisms to “cutaneous invaders” of many origins, including microbes, true allergens, and other antigens; and protecting its neighboring cutaneous cells and structures that lie beneath from damaging effects of ultraviolet radiation. Additionally, specific abnormalities of the stratum corneum are associated with the clinical expression of certain disease states. This article provides a thorough “primer” for the clinician, reviewing the multiple normal homeostatic functions of the stratum corneum and the cutaneous challenges that arise when individual functions of this thin yet very active epidermal layer are compromised by exogenous and/or endogenous factors. PMID:21938268

Fentanyl Buccal Tablet for the Treatment of Breakthrough Pain: Pharmacokinetics of Buccal Mucosa Delivery and Clinical Efficacy

PubMed Central

Darwish, Mona; Hamed, Ehab; Messina, John

2010-01-01

The treatment of breakthrough pain (BTP), a transitory exacerbation of pain that occurs on a background of otherwise-controlled, persistent pain, requires an opioid formulation and/or method of administration that can provide rapid and extensive systemic exposure. Fentanyl buccal tablet (FBT; FENTORA®, Cephalon, Inc.) employs OraVescent® drug delivery technology, which enhances the rate and extent of fentanyl absorption. OraVescent technology enhances the oral dissolution and buccal absorption of fentanyl, which facilitates rapid uptake of fentanyl into the bloodstream, reducing gastrointestinal absorption and minimizing extensive first-pass metabolism. The resulting pharmacokinetic profile of FBT is characterized by greater bioavailability and a higher early systemic exposure compared with the earlier oral transmucosal fentanyl citrate formulation. In clinical studies of opioid-tolerant patients with cancer-related and noncancer-related BTP, FBT has provided consistent and clinically relevant improvements in pain intensity and pain relief relative to placebo, with a safety and tolerability profile that is generally typical of that observed with other potent opioids. The pharmacokinetic properties of FBT allow for meaningful clinical efficacy, with an onset of action that closely matches the onset of BTP. PMID:20634985

Porous titanium bases for osteochondral tissue engineering

PubMed Central

Nover, Adam B.; Lee, Stephanie L.; Georgescu, Maria S.; Howard, Daniel R.; Saunders, Reuben A.; Yu, William T.; Klein, Robert W.; Napolitano, Anthony P.; Ateshian, Gerard A.

2015-01-01

Tissue engineering of osteochondral grafts may offer a cell-based alternative to native allografts, which are in short supply. Previous studies promote the fabrication of grafts consisting of a viable cell-seeded hydrogel integrated atop a porous, bone-like metal. Advantages of the manufacturing process have led to the evaluation of porous titanium as the bone-like base material. Here, porous titanium was shown to support the growth of cartilage to produce native levels of Young’s modulus, using a clinically relevant cell source. Mechanical and biochemical properties were similar or higher for the osteochondral constructs compared to chondral-only controls. Further investigation into the mechanical influence of the base on the composite material suggests that underlying pores may decrease interstitial fluid pressurization and applied strains, which may be overcome by alterations to the base structure. Future studies aim to optimize titanium-based tissue engineered osteochondral constructs to best match the structural architecture and strength of native grafts. Statement of Significance The studies described in this manuscript follow up on previous studies from our lab pertaining to the fabrication of osteochondral grafts that consist of a bone-like porous metal and a chondrocyte-seeded hydrogel. Here, tissue engineered osteochondral grafts were cultured to native stiffness using adult chondrocytes, a clinically relevant cell source, and a porous titanium base, a material currently used in clinical implants. This porous titanium is manufactured via selective laser melting, offering the advantages of precise control over shape, pore size, and orientation. Additionally, this manuscript describes the mechanical influence of the porous base, which may have applicability to porous bases derived from other materials. PMID:26320541

Porous titanium bases for osteochondral tissue engineering.

PubMed

Nover, Adam B; Lee, Stephanie L; Georgescu, Maria S; Howard, Daniel R; Saunders, Reuben A; Yu, William T; Klein, Robert W; Napolitano, Anthony P; Ateshian, Gerard A; Hung, Clark T

2015-11-01

Tissue engineering of osteochondral grafts may offer a cell-based alternative to native allografts, which are in short supply. Previous studies promote the fabrication of grafts consisting of a viable cell-seeded hydrogel integrated atop a porous, bone-like metal. Advantages of the manufacturing process have led to the evaluation of porous titanium as the bone-like base material. Here, porous titanium was shown to support the growth of cartilage to produce native levels of Young's modulus, using a clinically relevant cell source. Mechanical and biochemical properties were similar or higher for the osteochondral constructs compared to chondral-only controls. Further investigation into the mechanical influence of the base on the composite material suggests that underlying pores may decrease interstitial fluid pressurization and applied strains, which may be overcome by alterations to the base structure. Future studies aim to optimize titanium-based tissue engineered osteochondral constructs to best match the structural architecture and strength of native grafts. The studies described in this manuscript follow up on previous studies from our lab pertaining to the fabrication of osteochondral grafts that consist of a bone-like porous metal and a chondrocyte-seeded hydrogel. Here, tissue engineered osteochondral grafts were cultured to native stiffness using adult chondrocytes, a clinically relevant cell source, and a porous titanium base, a material currently used in clinical implants. This porous titanium is manufactured via selective laser melting, offering the advantages of precise control over shape, pore size, and orientation. Additionally, this manuscript describes the mechanical influence of the porous base, which may have applicability to porous bases derived from other materials. Copyright © 2015. Published by Elsevier Ltd.

Physico-chemical properties of manufactured nanomaterials - Characterisation and relevant methods. An outlook based on the OECD Testing Programme.

PubMed

Rasmussen, Kirsten; Rauscher, Hubert; Mech, Agnieszka; Riego Sintes, Juan; Gilliland, Douglas; González, Mar; Kearns, Peter; Moss, Kenneth; Visser, Maaike; Groenewold, Monique; Bleeker, Eric A J

2018-02-01

Identifying and characterising nanomaterials require additional information on physico-chemical properties and test methods, compared to chemicals in general. Furthermore, regulatory decisions for chemicals are usually based upon certain toxicological properties, and these effects may not be equivalent to those for nanomaterials. However, regulatory agencies lack an authoritative decision framework for nanomaterials that links the relevance of certain physico-chemical endpoints to toxicological effects. This paper investigates various physico-chemical endpoints and available test methods that could be used to produce such a decision framework for nanomaterials. It presents an overview of regulatory relevance and methods used for testing fifteen proposed physico-chemical properties of eleven nanomaterials in the OECD Working Party on Manufactured Nanomaterials' Testing Programme, complemented with methods from literature, and assesses the methods' adequacy and applications limits. Most endpoints are of regulatory relevance, though the specific parameters depend on the nanomaterial and type of assessment. Size (distribution) is the common characteristic of all nanomaterials and is decisive information for classifying a material as a nanomaterial. Shape is an important particle descriptor. The octanol-water partitioning coefficient is undefined for particulate nanomaterials. Methods, including sample preparation, need to be further standardised, and some new methods are needed. The current work of OECD's Test Guidelines Programme regarding physico-chemical properties is highlighted. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Measurement properties of quality of life measurement instruments for infants, children and adolescents with eczema: protocol for a systematic review.

PubMed

Heinl, Daniel; Prinsen, Cecilia A C; Drucker, Aaron M; Ofenloch, Robert; Humphreys, Rosemary; Sach, Tracey; Flohr, Carsten; Apfelbacher, Christian

2016-02-09

Eczema is a common chronic or chronically relapsing, inflammatory skin disease that exerts a substantial negative impact on quality of life (QoL). The Harmonising Outcome Measures for Eczema (HOME) initiative has used a consensus-based process which identified QoL as one of the four core outcome domains to be assessed in all eczema clinical trials. A number of measurement instruments exist to measure QoL in infants, children, and adolescents with eczema, and there is a great variability in both content and quality of the instruments used. Therefore, the objective of the proposed research is to comprehensively and systematically assess the measurement properties of the existing measurement instruments that were developed and/or validated for the measurement of patient-reported QoL in infants, children, and adolescents with eczema. This study is a systematic review of the measurement properties of patient-reported measures of QoL developed and/or validated for infants, children, and adolescents with eczema. A systematic literature search will be carried out in MEDLINE via PubMed and EMBASE using a selection of relevant search terms. Eligible studies will be primary empirical studies evaluating, describing, or comparing measurement properties of QoL instruments for infants, children, and adolescents with eczema. Two reviewers will independently perform eligibility assessment and data abstraction. Evidence tables will be used to record study characteristics, instrument characteristics, measurement properties, and interpretability. The adequacy of the measurement properties will be assessed using predefined criteria. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist will be used to evaluate the methodological quality of included studies. A best evidence synthesis will be undertaken if more than one study has examined a particular measurement property. The proposed systematic review will yield a comprehensive assessment of measurement properties of existing QoL instruments in infants, children, and adolescents with eczema. The results will serve as a basis to recommend a QoL measurement instrument for infants, one for children, and one for adolescents for use in future clinical trials. PROSPERO CRD42015023483.

Clinically relevant pharmacokinetic herb-drug interactions in antiretroviral therapy

USDA-ARS?s Scientific Manuscript database

For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In t...

Using mixed methods to identify and answer clinically relevant research questions.

PubMed

Shneerson, Catherine L; Gale, Nicola K

2015-06-01

The need for mixed methods research in answering health care questions is becoming increasingly recognized because of the complexity of factors that affect health outcomes. In this article, we argue for the value of using a qualitatively driven mixed method approach for identifying and answering clinically relevant research questions. This argument is illustrated by findings from a study on the self-management practices of cancer survivors and the exploration of one particular clinically relevant finding about higher uptake of self-management in cancer survivors who had received chemotherapy treatment compared with those who have not. A cross-sectional study generated findings that formed the basis for the qualitative study, by informing the purposive sampling strategy and generating new qualitative research questions. Using a quantitative research component to supplement a qualitative study can enhance the generalizability and clinical relevance of the findings and produce detailed, contextualized, and rich answers to research questions that would be unachievable through quantitative or qualitative methods alone. © The Author(s) 2015.

Cevipabulin (TTI-237): preclinical and clinical results for a novel antimicrotubule agent.

PubMed

Ayral-Kaloustian, S; Zhang, N; Beyer, C

2009-09-01

Antimitotic agents are among the most effective drugs for the treatment of solid tumors and metastatic cancer. These drugs promote cell death by interfering with the crucial structural and regulatory function of microtubules in cells. Most of the agents of clinical relevance are natural products or semisynthetic derivatives thereof, and they fall into two major classes: microtubule stabilizers such as the taxanes, which enhance tubulin polymerization, and microtubule destabilizers such as the Vinca alkaloids, which lead to the depolymerization of existing microtubules. While these drugs are effective in inhibiting the progression of certain types of tumors, their utility is limited in part by incomplete tumor responses and/or significant side effects. In addition, inherent resistance is encountered in many tumor types, or acquired resistance may occur as a result of multiple cycles of therapy. Cevipabulin (TTI-237) is a novel, small synthetic molecule with an unusual biological mode of action. It appears to bind at the vinca site, but exhibits some properties similar to those of taxane-site ligands, such as enhancing tubulin polymerization. The compound works against a variety of tumors, including those resistant to paclitaxel and vincristine. Furthermore, cevipabulin is stable and water-soluble, and can be administered i.v. or p.o. in saline. It can be synthesized in bulk quantities efficiently. Based on these properties, cevipabulin was selected for clinical development. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Patient-derived xenografts as preclinical neuroblastoma models.

PubMed

Braekeveldt, Noémie; Bexell, Daniel

2018-05-01

The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing.

A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations

PubMed Central

Thiel, Christoph; Cordes, Henrik; Fabbri, Lorenzo; Aschmann, Hélène Eloise; Baier, Vanessa; Atkinson, Francis; Blank, Lars Mathias; Kuepfer, Lars

2017-01-01

Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application. PMID:28151932

Measuring social communication behaviors as a treatment endpoint in individuals with autism spectrum disorder.

PubMed

Anagnostou, Evdokia; Jones, Nancy; Huerta, Marisela; Halladay, Alycia K; Wang, Paul; Scahill, Lawrence; Horrigan, Joseph P; Kasari, Connie; Lord, Cathy; Choi, Dennis; Sullivan, Katherine; Dawson, Geraldine

2015-07-01

Social communication impairments are a core deficit in autism spectrum disorder. Social communication deficit is also an early indicator of autism spectrum disorder and a factor in long-term outcomes. Thus, this symptom domain represents a critical treatment target. Identifying reliable and valid outcome measures for social communication across a range of treatment approaches is essential. Autism Speaks engaged a panel of experts to evaluate the readiness of available measures of social communication for use as outcome measures in clinical trials. The panel held monthly conference calls and two face-to-face meetings over 14 months. Key criteria used to evaluate measures included the relevance to the clinical target, coverage of the symptom domain, and psychometric properties (validity and reliability, as well as evidence of sensitivity to change). In all, 38 measures were evaluated and 6 measures were considered appropriate for use, with some limitations. This report discusses the relative strengths and weaknesses of existing social communication measures for use in clinical trials and identifies specific areas in need of further development. © The Author(s) 2014.

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

PubMed

Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Thomas, Mathew; Wang, Yihan; Zhou, Tianjun; Romero, Jan; Kohlmann, Anna; Li, Feng; Qi, Jiwei; Cai, Lisi; Dwight, Timothy A; Xu, Yongjin; Xu, Rongsong; Dodd, Rory; Toms, Angela; Parillon, Lois; Lu, Xiaohui; Anjum, Rana; Zhang, Sen; Wang, Frank; Keats, Jeffrey; Wardwell, Scott D; Ning, Yaoyu; Xu, Qihong; Moran, Lauren E; Mohemmad, Qurish K; Jang, Hyun Gyung; Clackson, Tim; Narasimhan, Narayana I; Rivera, Victor M; Zhu, Xiaotian; Dalgarno, David; Shakespeare, William C

2016-05-26

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

Method for measuring changes in light absorption of highly scattering media

DOEpatents

Bigio, Irving J.; Johnson, Tamara M.; Mourant, Judith R.

2002-01-01

The noninvasive measurement of variations in absorption that are due to changes in concentrations of biochemically relevant compounds in tissue is important in many clinical settings. One problem with such measurements is that the pathlength traveled by the collected light through the tissue depends on the scattering properties of the tissue. It is demonstrated, using both Monte Carlo simulations and experimental measurements, that for an appropriate separation between light-delivery and light-collection fibers, the pathlength of the collected photons is insensitive to scattering parameters for the range of parameters typically found in tissue. This is important for developing rapid, noninvasive, inexpensive, and accurate methods for measuring absorption changes in tissue.

Ketamine and phencyclidine: the good, the bad and the unexpected

PubMed Central

Lodge, D; Mercier, M S

2015-01-01

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. PMID:26075331

Melatonin: Buffering the Immune System

PubMed Central

Carrillo-Vico, Antonio; Lardone, Patricia J.; Álvarez-Sánchez, Nuria; Rodríguez-Rodríguez, Ana; Guerrero, Juan M.

2013-01-01

Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed. PMID:23609496

Endothelial-regenerating cells: an expanding universe.

PubMed

Steinmetz, Martin; Nickenig, Georg; Werner, Nikos

2010-03-01

Atherosclerosis is the most common cause for cardiovascular diseases and is based on endothelial dysfunction. A growing body of evidence suggests the contribution of bone marrow-derived endothelial progenitor cells, monocytic cells, and mature endothelial cells to vessel formation and endothelial rejuvenation. To this day, various subsets of these endothelial-regenerating cells have been identified according to cellular origin, phenotype, and properties in vivo and in vitro. However, the definition and biology, especially of endothelial progenitor cells, is complex and under heavy debate. In this review, we focus on current definitions of endothelial progenitor cells, highlight the clinical relevance of endothelial-regenerating cells, and provide new insights into cell-cell interactions involved in endothelial cell rejuvenation.

Tasimelteon (Hetlioz™): A New Melatonin Receptor Agonist for the Treatment of Non-24-Hour Sleep-Wake Disorder.

PubMed

Bonacci, Janene M; Venci, Jineane V; Gandhi, Mona A

2015-10-01

In January 2014, the US Food and Drug Administration approved tasimelteon (Hetlioz™), a melatonin-receptor agonist for the treatment of non-24-hour sleep-wake disorder. This article provides an overview of the mechanism of action, pharmacokinetic properties, as well as the clinical efficacy, safety, and tolerability of tasimelteon. Relevant information was identified through a comprehensive literature search of several databases using the key words tasimelteon, Non-24-hour Sleep-Wake disorder, Non-24, and melatonin. Further information was obtained from the tasimelteon package insert, fda.gov, clinicaltrials.gov, briefing materials provided by Vanda Pharmaceuticals, and posters from scientific meetings. © The Author(s) 2014.

Clinical relevance is associated with allergen-specific wheal size in skin prick testing.

PubMed

Haahtela, T; Burbach, G J; Bachert, C; Bindslev-Jensen, C; Bonini, S; Bousquet, J; Bousquet-Rouanet, L; Bousquet, P J; Bresciani, M; Bruno, A; Canonica, G W; Darsow, U; Demoly, P; Durham, S R; Fokkens, W J; Giavi, S; Gjomarkaj, M; Gramiccioni, C; Kowalski, M L; Losonczy, G; Orosz, M; Papadopoulos, N G; Stingl, G; Todo-Bom, A; von Mutius, E; Köhli, A; Wöhrl, S; Järvenpää, S; Kautiainen, H; Petman, L; Selroos, O; Zuberbier, T; Heinzerling, L M

2014-03-01

Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use. © 2013 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

Botanicals With Dermatologic Properties Derived From First Nations Healing: Part 1-Trees.

PubMed

Colantonio, Sophia; Rivers, Jason K

First Nations people have a long history of working with medicinal plants used to treat skin diseases. The purpose was to assess the dermatologic therapeutic potential of western red cedar, white spruce, birch, balsam poplar, and black spruce. Based on expert recommendations, 5 trees were selected that were used in First Nations medicine for cutaneous healing and have potential and/or current application to dermatology today. We searched several databases up to June 12, 2014. Western red cedar's known active principal compound, β-thujaplicin, has been studied in atopic dermatitis. White spruce's known active principal compound, 7-hydroxymatairesinol, has anti-inflammatory activity, while phase II clinical trials have been completed on a birch bark emulsion for the treatment of actinic keratoses, epidermolysis bullosa, and the healing of split thickness graft donor sites. Balsam poplar has been used clinically as an anti-aging remedy. Black spruce bark contains higher amounts of the anti-oxidant trans-resveratrol than red wine. North American traditional medicine has identified important botanical agents that are potentially relevant to both cosmetic and medical dermatology. This study is limited by the lack of good quality evidence contributing to the review. The article is limited to 5 trees, a fraction of those used by First Nations with dermatological properties.

Does the Agaricus blazei Murill mushroom have properties that affect the immune system? An integrative review.

PubMed

Lima, Cristiane Urcina Joanna Oliveira; Cordova, Cláudio Olavo de Almeida; Nóbrega, Otávio de Tolêdo; Funghetto, Silvana Schwerz; Karnikowski, Margô Gomes de Oliveira

2011-01-01

There has been a significant increase in the use of mushrooms for therapeutic and medicinal purposes, in particular, use of the species Agaricus blazei Murrill, a basidiomycota of Brazilian origin. The objective of this study was to identify scientific evidence regarding the influence of A. blazei Murrill on the immune system. We undertook an integrative review of indexed publications published between 2000 and 2009, using the following question as a guideline: "What evidence can be found in the literature regarding the influence of A. blazei Murrill on the immune system?" Fourteen studies verified that there is in vitro and in vivo research demonstrating this mushroom's influence on the immune system. All research was characterized as evidence level 7 (preclinical study [animals/in vitro]). The research shows that A. blazei Murrill functions through bioactive compounds via mechanisms that are not yet entirely clear, although it has been shown that they promote action on the innate and adaptive immunological response, activation of the complement system, and synthesis of pro- and anti-inflammatory cytokines and even aid in diapedesis. Despite broad scientific evidence demonstrating relevant immunomodulatory properties of A. blazei Murrill, randomized clinical trials with human subjects are still needed in order for the mushroom to be put into clinical practice.

Premonitory urges for tics in adult patients with Tourette syndrome.

PubMed

Crossley, Eleanor; Seri, Stefano; Stern, Jeremy S; Robertson, Mary M; Cavanna, Andrea E

2014-01-01

Patients with Tourette syndrome (TS) often report characteristic sensory experiences, also called premonitory urges (PUs), which precede tic expression and have high diagnostic relevance. This study investigated the usefulness of a scale developed and validated in children and adolescents-the Premonitory Urge for Tics Scale (PUTS, Woods et al., 2005 [13])-for the assessment of PUs in adult patients with TS. Standard statistical methods were applied to test the psychometric properties of the PUTS in 102 adult TS outpatients recruited from two specialist clinics in the United Kingdom. The PUTS showed good acceptability and endorsement rates, with evenly distributed scores and low floor and ceiling effects. Item-total correlations were moderate to strong; PUTS total scores were significantly correlated with quantitative measures of TS severity. The PUTS showed excellent internal consistency reliability (Cronbach's alpha=0.85) and Spearman's correlations demonstrated satisfactory convergent and discriminant validity. Although originally devised to assess urges to tic in young patients with TS, the PUTS demonstrated good psychometric properties in a large sample of adults recruited at specialist TS clinics. This instrument is therefore recommended for use across the life span as a valid and reliable self-report measure of sensory experiences accompanying tic expression. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Linear feasibility algorithms for treatment planning in interstitial photodynamic therapy

NASA Astrophysics Data System (ADS)

Rendon, A.; Beck, J. C.; Lilge, Lothar

2008-02-01

Interstitial Photodynamic therapy (IPDT) has been under intense investigation in recent years, with multiple clinical trials underway. This effort has demanded the development of optimization strategies that determine the best locations and output powers for light sources (cylindrical or point diffusers) to achieve an optimal light delivery. Furthermore, we have recently introduced cylindrical diffusers with customizable emission profiles, placing additional requirements on the optimization algorithms, particularly in terms of the stability of the inverse problem. Here, we present a general class of linear feasibility algorithms and their properties. Moreover, we compare two particular instances of these algorithms, which are been used in the context of IPDT: the Cimmino algorithm and a weighted gradient descent (WGD) algorithm. The algorithms were compared in terms of their convergence properties, the cost function they minimize in the infeasible case, their ability to regularize the inverse problem, and the resulting optimal light dose distributions. Our results show that the WGD algorithm overall performs slightly better than the Cimmino algorithm and that it converges to a minimizer of a clinically relevant cost function in the infeasible case. Interestingly however, treatment plans resulting from either algorithms were very similar in terms of the resulting fluence maps and dose volume histograms, once the diffuser powers adjusted to achieve equal prostate coverage.

Phosphate conversion coating reduces the degradation rate and suppresses side effects of metallic magnesium implants in an animal model.

PubMed

Rahim, Muhammad Imran; Tavares, Ana; Evertz, Florian; Kieke, Marc; Seitz, Jan-Marten; Eifler, Rainer; Weizbauer, Andreas; Willbold, Elmar; Jürgen Maier, Hans; Glasmacher, Birgit; Behrens, Peter; Hauser, Hansjörg; Mueller, Peter P

2017-08-01

Magnesium alloys have promising mechanical and biological properties for the development of degradable implants. However, rapid implant corrosion and gas accumulations in tissue impede clinical applications. With time, the implant degradation rate is reduced by a highly biocompatible, phosphate-containing corrosion layer. To circumvent initial side effects after implantation it was attempted to develop a simple in vitro procedure to generate a similarly protective phosphate corrosion layer. To this end magnesium samples were pre-incubated in phosphate solutions. The resulting coating was well adherent during routine handling procedures. It completely suppressed the initial burst of corrosion and it reduced the average in vitro magnesium degradation rate over 56 days almost two-fold. In a small animal model phosphate coatings on magnesium implants were highly biocompatible and abrogated the appearance of gas cavities in the tissue. After implantation, the phosphate coating was replaced by a layer with an elemental composition that was highly similar to the corrosion layer that had formed on plain magnesium implants. The data demonstrate that a simple pre-treatment could improve clinically relevant properties of magnesium-based implants. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1622-1635, 2017. © 2016 Wiley Periodicals, Inc.

Analysis of Transient Shear Wave in Lossy Media.

PubMed

Parker, Kevin J; Ormachea, Juvenal; Will, Scott; Hah, Zaegyoo

2018-07-01

The propagation of shear waves from impulsive forces is an important topic in elastography. Observations of shear wave propagation can be obtained with numerous clinical imaging systems. Parameter estimations of the shear wave speed in tissues, and more generally the viscoelastic parameters of tissues, are based on some underlying models of shear wave propagation. The models typically include specific choices of the spatial and temporal shape of the impulsive force and the elastic or viscoelastic properties of the medium. In this work, we extend the analytical treatment of 2-D shear wave propagation in a biomaterial. The approach applies integral theorems relevant to the solution of the generalized Helmholtz equation, and does not depend on a specific rheological model of the tissue's viscoelastic properties. Estimators of attenuation and shear wave speed are derived from the analytical solutions, and these are applied to an elastic phantom, a viscoelastic phantom and in vivo liver using a clinical ultrasound scanner. In these samples, estimated shear wave group velocities ranged from 1.7 m/s in the liver to 2.5 m/s in the viscoelastic phantom, and these are lower-bounded by independent measurements of phase velocity. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.

Preterm piglets are a clinically relevant model of pediatric GI disease

USDA-ARS?s Scientific Manuscript database

The goal of our research is to establish how nutritional support, enteral versus parenteral, affects gut function and susceptibility to disease in early development. We and others have used the neonatal pig to establish unique models of clinically relevant problems in pediatric gastroenterology, esp...

77 FR 40620 - AHRQ Workgroups on ICD-10-CM/PCS Conversion of Quality Indicators (QIs) - Extension Date for...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-10

... with relevant clinical expertise (e.g., cardiovascular disease, neurologic disease, orthopedic and... measurement using administrative data in specific, relevant clinical domains (e.g., cardiovascular disease... (e.g., cardiovascular disease, neurologic disease, orthopedic and musculoskeletal disease, obstetrics...

Alternating magnetic field optimization for IONP hyperthermia cancer treatment

NASA Astrophysics Data System (ADS)

Kastner, Elliot J.; Reeves, Russell; Bennett, William; Misra, Aditi; Petryk, Jim D.; Petryk, Alicia A.; Hoopes, P. Jack

2015-03-01

Iron oxide nanoparticles (IONP) have therapeutic potential to deliver a thermal dose to tumors when activated in an alternating magnetic field (AMF). Through various targeting methods such as antibody labeling or injection site choice, delivery of IONPs to tumors yields enhanced treatment accuracy and efficacy. Despite this advantage, delivery an AMF, which is sufficient to result in clinically relevant IONP heating, can result in nonspecific tissue heating via the generation of eddy currents and tissue permeated by local electric fields (joule heating). The production of eddy current heating is a function of tissue size, geometry and composition as well as coil design and operation. The purpose of this research is to increase the level of energy deposited into the IONPs versus the non-target tissue (power ratio/PR)1 in order to improve target heating and reduce nonspecific tissue damage. We propose to improve the PR using two primary concepts: (1) reduce power deposition into non-target tissue by manipulating the fields and eddy current flow and (2) enhance heat removal from non-target tissue. We have shown that controlling tissue placement within the AMF field, accounting for tissue geometry, utilizing external cooling devices, and modifying the field properties can decrease non-target heating by more than 50%, at clinically relevant AMF levels, thereby allowing for an increase in thermal dose to the tumor and increasing the therapeutic ratio.

Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety.

PubMed

Bouchard, Philippe; Chabbert-Buffet, Nathalie; Fauser, Bart C J M

2011-11-01

To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarize the preclinical and clinical efficacy and safety data supporting the potential use of these compounds for gynecologic indications. Relevant publications from 2005 onward were identified using a PubMed search. Additional relevant articles were identified from citations within these publications. None. None. None. None. Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termination because of the unique property of this compound to terminate pregnancy when associated with prostaglandins. Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive. Because SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests a possible role in the treatment of endometriosis in humans. Finally, a number of double-blind, randomized, placebo-controlled trials have demonstrated the efficacy of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids. Mifepristone in combination with prostaglandins has been licensed for pregnancy termination because of its unique ability is this area. Ulipristal acetate is available for emergency contraception. Several SPRMs hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Using Poisson-gamma model to evaluate the duration of recruitment process when historical trials are available.

PubMed

Minois, Nathan; Lauwers-Cances, Valérie; Savy, Stéphanie; Attal, Michel; Andrieu, Sandrine; Anisimov, Vladimir; Savy, Nicolas

2017-10-15

At the design of clinical trial operation, a question of a paramount interest is how long it takes to recruit a given number of patients. Modelling the recruitment dynamics is the necessary step to answer this question. Poisson-gamma model provides very convenient, flexible and realistic approach. This model allows predicting the trial duration using data collected at an interim time with very good accuracy. A natural question arises: how to evaluate the parameters of recruitment model before the trial begins? The question is harder to handle as there are no recruitment data available for this trial. However, if there exist similar completed trials, it is appealing to use data from these trials to investigate feasibility of the recruitment process. In this paper, the authors explore the recruitment data of two similar clinical trials (Intergroupe Francais du Myélome 2005 and 2009). It is shown that the natural idea of plugging the historical rates estimated from the completed trial in the same centres of the new trial for predicting recruitment is not a relevant strategy. In contrast, using the parameters of a gamma distribution of the rates estimated from the completed trial in the recruitment dynamic model of the new trial provides reasonable predictive properties with relevant confidence intervals. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Prevalence and psychosocial correlates of depressive symptoms in urban Chinese women during midlife.

PubMed

Wong, Carmen K M; Liang, Jun; Chan, Man L; Chan, Yin H; Chan, Laam; Wan, Kwong Y; Ng, Ming S; Chan, Dicken C C; Wong, Samuel Y S; Wong, Martin C S

2014-01-01

Depression is common in women with much research focusing on hormonal changes and menopausal symptoms but with little exploration of psychosocial problems in midlife. This study investigates the prevalence of clinically relevant depressive symptoms in midlife Chinese women and its association with psychosocial factors. A cross-sectional, community-based household survey of women aged 45 to 64 years of age was conducted in Hong Kong from September 2010 to March 2011. The structured questionnaire included demographic data, educational status, marital status and household income, as well as perceived current stressful events and significant life events in the past 12 months. Information on clinically relevant depressive symptoms was measured by the validated chinese Patient Health Questionnaire (PHQ-9). A total of 402 participants were recruited in the study period. Of the 393 women who completed the questionnaire, the prevalence of clinically relevant depressive symptoms (PHQ-9 score≧10) was 11.0%. In multiple regression analysis, being single/divorced/separated/widowed, having an educational level of primary school level or below, having multiple chronic diseases, loss of hobby or loss of close social support in the past 12 months in midlife were associated with clinically relevant depressive symptoms. Correlates of clinically relevant depressive symptoms in midlife Chinese women can be used to identify those at increased risk and potentiate further studies to explore early psychosocial and community interventions.

Variations in the sonographic measurement techniques of BI-RADS 3 breast masses.

PubMed

Francisco, Juliana; Jales, Rodrigo Menezes; de Oliveira, André Desuó Bueno; Arguello, Carlos Henrique Francisco; Derchain, Sophie

2017-06-01

To evaluate the differences in sonographic (US) distance and volume measurements from different sonologists and identify the optimal parameters to avoid clinically relevant variations in the measurement of BI-RADS 3 breast masses. For this cross-sectional study with prospectively collected data, four physicians with various levels of experience in US, herein called sonologists, performed distance and volume US measurements of 80 masses classified as BI-RADS 3. The Cochran Q test was used to compare the matched sets of rates of clinically relevant variability between all pairs of sonologists' measurements. There were clinically relevant differences between sonologists in the measurements of the longest diameter (range, 17.5-43.7%, p = 0.003), the longest diameter perpendicular to the previous one (anteroposterior diameter) (17.5-33.7%, p = 0.06), the third diameter orthogonal to the plane defined by the previous two (transverse diameter) (28.7-55%, p = 0.001), and at least two of those three diameters (18.7-38.7%, p = 0.015). The smallest clinically relevant differences were observed with volume measurements (range of differences, 6.2-13.7%, p = 0.51). Volume measurement technique was associated with the least variations, whereas distance measurements, which are used routinely, were associated with unacceptable rates of clinically relevant variations. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:252-260, 2017. © 2017 Wiley Periodicals, Inc.

Augmentation in the treatment of restless legs syndrome with transdermal rotigotine.

PubMed

Beneš, Heike; García-Borreguero, Diego; Ferini-Strambi, Luigi; Schollmayer, Erwin; Fichtner, Andreas; Kohnen, Ralf

2012-06-01

To assess the risk of augmentation under treatment with the transdermally delivered dopamine agonist rotigotine for restless legs syndrome (RLS). Experts in RLS augmentation retrospectively reviewed data from two double-blind, placebo-controlled 6-month trials (745 rotigotine and 214 placebo subjects, NCT00136045 and NCT00135993) and from two open-label 1-year trials (620 rotigotine subjects, NCT00498108 and NCT00263068). All study visits were systematically evaluated applying the Max Planck Institute (MPI) criteria for the diagnosis of both augmentation and clinically relevant augmentation. MPI criteria for augmentation were met on at least one visit by 8.2% of all subjects in the double-blind trials with 12 subjects meeting the criteria for clinically relevant augmentation: 11 under rotigotine (1.5%) and one under placebo treatment. In the open-label trials, 9.7% of all subjects met the MPI criteria for augmentation and 2.9% met the criteria for clinically relevant augmentation. None of the patients treated with rotigotine for up to 1.5 years (double-blind plus open-label trial) discontinued prematurely owing to augmentation. Neither could dose-dependency or a time pattern for clinically relevant augmentation episodes be detected. Our analyses suggest that the risk for clinically relevant augmentation for the duration of up to 18 months of rotigotine treatment is low. Copyright © 2012 Elsevier B.V. All rights reserved.

Retrieving Clinical Evidence: A Comparison of PubMed and Google Scholar for Quick Clinical Searches

PubMed Central

Bejaimal, Shayna AD; Sontrop, Jessica M; Iansavichus, Arthur V; Haynes, R Brian; Weir, Matthew A; Garg, Amit X

2013-01-01

Background Physicians frequently search PubMed for information to guide patient care. More recently, Google Scholar has gained popularity as another freely accessible bibliographic database. Objective To compare the performance of searches in PubMed and Google Scholar. Methods We surveyed nephrologists (kidney specialists) and provided each with a unique clinical question derived from 100 renal therapy systematic reviews. Each physician provided the search terms they would type into a bibliographic database to locate evidence to answer the clinical question. We executed each of these searches in PubMed and Google Scholar and compared results for the first 40 records retrieved (equivalent to 2 default search pages in PubMed). We evaluated the recall (proportion of relevant articles found) and precision (ratio of relevant to nonrelevant articles) of the searches performed in PubMed and Google Scholar. Primary studies included in the systematic reviews served as the reference standard for relevant articles. We further documented whether relevant articles were available as free full-texts. Results Compared with PubMed, the average search in Google Scholar retrieved twice as many relevant articles (PubMed: 11%; Google Scholar: 22%; P<.001). Precision was similar in both databases (PubMed: 6%; Google Scholar: 8%; P=.07). Google Scholar provided significantly greater access to free full-text publications (PubMed: 5%; Google Scholar: 14%; P<.001). Conclusions For quick clinical searches, Google Scholar returns twice as many relevant articles as PubMed and provides greater access to free full-text articles. PMID:23948488

Effects of drug pharmacokinetic/pharmacodynamic properties, characteristics of medication use, and relevant pharmacological interventions on fall risk in elderly patients

PubMed Central

Chen, Ying; Zhu, Ling-Ling; Zhou, Quan

2014-01-01

Background Falls among the elderly are an issue internationally and a public health problem that brings substantial economic and quality-of-life burdens to individuals and society. Falls prevention is an important measure of nursing quality and patient safety. Numerous studies have evaluated the association of medication use with fall risk in elderly patients. However, an up-to-date review has not been available to summarize the multifaceted pharmaceutical concerns in the prevention of medication-related falls. Materials and methods Relevant literature was identified by performing searches in PubMed, Web of Science, and the Cochrane Library, covering the period until February 2014. We included studies that described an association between medications and falls, and effects of drug pharmacokinetic/pharmacodynamic properties, characteristics of medication use, and pharmacological interventions on fall risk in elderly patients. The full text of each included article was critically reviewed, and data interpretation was performed. Results Fall-risk-increasing drugs (FRIDs) include central nervous system-acting agents, cough preparations, nonsteroidal anti-inflammatory drugs, anti-Alzheimer’s agents, antiplatelet agents, calcium antagonists, diuretics, α-blockers, digoxin, hypoglycemic drugs, neurotoxic chemotherapeutic agents, nasal preparations, and antiglaucoma ophthalmic preparations. The degree of medication-related fall risk was dependent on one or some of the following factors: drug pharmacokinetic/pharmacodynamic properties (eg, elimination half-life, metabolic pathway, genetic polymorphism, risk rating of medications despite belonging to the same therapeutic class) and/or characteristics of medication use (eg, number of medications and drug–drug interactions, dose strength, duration of medication use and time since stopping, medication change, prescribing appropriateness, and medication adherence). Pharmacological interventions, including withdrawal of FRIDs, pharmacist-conducted clinical medication review, and computerized drug alerts, were effective in reducing fall risk. Conclusion Based on the literature review, clear practical recommendations for clinicians to prevent falls in the elderly included making a list of FRIDs, establishing a computerized alert system for when to e-prescribe FRIDs, seeking an alternative drug with lower fall risk, withdrawing FRIDs if clinically indicated, taking pertinent cautions when the use of FRIDs cannot be avoidable, paying attention to prescribing appropriateness, simplifying the medication regimen, strengthening pharmacist-conducted clinical medication review, ensuring the label of each FRID dispensed contains a corresponding warning sign, being careful when medication change occurs, enhancing medication adherence, and mandating for periodic reassessment of potential risk associated with the patient’s medication regimen. Further studies should be conducted in this area, such as investigating whether medication reconciliation and improving medication adherence could decrease the rate of falls. PMID:24966681

Effects of drug pharmacokinetic/pharmacodynamic properties, characteristics of medication use, and relevant pharmacological interventions on fall risk in elderly patients.

PubMed

Chen, Ying; Zhu, Ling-Ling; Zhou, Quan

2014-01-01

Falls among the elderly are an issue internationally and a public health problem that brings substantial economic and quality-of-life burdens to individuals and society. Falls prevention is an important measure of nursing quality and patient safety. Numerous studies have evaluated the association of medication use with fall risk in elderly patients. However, an up-to-date review has not been available to summarize the multifaceted pharmaceutical concerns in the prevention of medication-related falls. Relevant literature was identified by performing searches in PubMed, Web of Science, and the Cochrane Library, covering the period until February 2014. We included studies that described an association between medications and falls, and effects of drug pharmacokinetic/pharmacodynamic properties, characteristics of medication use, and pharmacological interventions on fall risk in elderly patients. The full text of each included article was critically reviewed, and data interpretation was performed. Fall-risk-increasing drugs (FRIDs) include central nervous system-acting agents, cough preparations, nonsteroidal anti-inflammatory drugs, anti-Alzheimer's agents, antiplatelet agents, calcium antagonists, diuretics, α-blockers, digoxin, hypoglycemic drugs, neurotoxic chemotherapeutic agents, nasal preparations, and antiglaucoma ophthalmic preparations. The degree of medication-related fall risk was dependent on one or some of the following factors: drug pharmacokinetic/pharmacodynamic properties (eg, elimination half-life, metabolic pathway, genetic polymorphism, risk rating of medications despite belonging to the same therapeutic class) and/or characteristics of medication use (eg, number of medications and drug-drug interactions, dose strength, duration of medication use and time since stopping, medication change, prescribing appropriateness, and medication adherence). Pharmacological interventions, including withdrawal of FRIDs, pharmacist-conducted clinical medication review, and computerized drug alerts, were effective in reducing fall risk. Based on the literature review, clear practical recommendations for clinicians to prevent falls in the elderly included making a list of FRIDs, establishing a computerized alert system for when to e-prescribe FRIDs, seeking an alternative drug with lower fall risk, withdrawing FRIDs if clinically indicated, taking pertinent cautions when the use of FRIDs cannot be avoidable, paying attention to prescribing appropriateness, simplifying the medication regimen, strengthening pharmacist-conducted clinical medication review, ensuring the label of each FRID dispensed contains a corresponding warning sign, being careful when medication change occurs, enhancing medication adherence, and mandating for periodic reassessment of potential risk associated with the patient's medication regimen. Further studies should be conducted in this area, such as investigating whether medication reconciliation and improving medication adherence could decrease the rate of falls.

Strategic characterization of anti-drug antibody responses for the assessment of clinical relevance and impact.

PubMed

Tatarewicz, Suzanna M; Mytych, Daniel T; Manning, Marta Starcevic; Swanson, Steven J; Moxness, Michael S; Chirmule, Narendra

2014-06-01

All therapeutic proteins have the potential to induce anti-drug antibodies (ADA). Clinically relevant ADA can impact efficacy and/or safety of a biological therapeutic. Immunogenicity assessment strategy evaluates binding and neutralizing ADA, and the need for additional characterization (e.g., epitope, titer and so on) is determined using a risk-based approach. The choice of characterization assays depends on the type, application and immunogenicity of the therapeutic. ADA characterization can impact the interpretation of the risk profile of a given therapeutic, and offers insight into opportunities for risk mitigation and management. This article describes common ADA characterization methods. Strategic assessment and characterization of clinically relevant ADA are discussed, in order to support clinical options for safe and effective patient care and disease management.

Families with burn injury: application in the clinically relevant continuum model.

PubMed

Lehna, Carlee

2011-06-01

This article incorporates the findings from a predominantly qualitative, mixed-method study examining sibling survivors' experiences of a major childhood burn injury into the clinically relevant continuum model as a means of promoting culturally competent and family-centered care. Copyright © 2011 Elsevier Inc. All rights reserved.

Clinical Relevance of Discourse Characteristics after Right Hemisphere Brain Damage

ERIC Educational Resources Information Center

Blake, Margaret Lehman

2006-01-01

Purpose: Discourse characteristics of adults with right hemisphere brain damage are similar to those reported for healthy older adults, prompting the question of whether changes are due to neurological lesions or normal aging processes. The clinical relevance of potential differences across groups was examined through ratings by speech-language…

Knee Injury and Osteoarthritis Outcome Score (KOOS): systematic review and meta-analysis of measurement properties.

PubMed

Collins, N J; Prinsen, C A C; Christensen, R; Bartels, E M; Terwee, C B; Roos, E M

2016-08-01

To conduct a systematic review and meta-analysis to synthesize evidence regarding measurement properties of the Knee injury and Osteoarthritis Outcome Score (KOOS). A comprehensive literature search identified 37 eligible papers evaluating KOOS measurement properties in participants with knee injuries and/or osteoarthritis (OA). Methodological quality was evaluated using the COSMIN checklist. Where possible, meta-analysis of extracted data was conducted for all studies and stratified by age and knee condition; otherwise narrative synthesis was performed. KOOS has adequate internal consistency, test-retest reliability and construct validity in young and old adults with knee injuries and/or OA. The ADL subscale has better content validity for older patients and Sport/Rec for younger patients with knee injuries, while the Pain subscale is more relevant for painful knee conditions. The five-factor structure of the original KOOS is unclear. There is some evidence that the KOOS subscales demonstrate sufficient unidimensionality, but this requires confirmation. Although measurement error requires further evaluation, the minimal detectable change for KOOS subscales ranges from 14.3 to 19.6 for younger individuals, and ≥20 for older individuals. Evidence of responsiveness comes from larger effect sizes following surgical (especially total knee replacement) than non-surgical interventions. KOOS demonstrates adequate content validity, internal consistency, test-retest reliability, construct validity and responsiveness for age- and condition-relevant subscales. Structural validity, cross-cultural validity and measurement error require further evaluation, as well as construct validity of KOOS Physical function Short form. Suggested order of subscales for different knee conditions can be applied in hierarchical testing of endpoints in clinical trials. PROSPERO (CRD42011001603). Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Gatekeepers for Pragmatic Clinical Trials

PubMed Central

Whicher, Danielle M.; Miller, Jennifer E.; Dunham, Kelly M.; Joffe, Steven

2015-01-01

To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g., clinics, facilities, staff), eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the United States clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This manuscript provides a framework to help guide gatekeepers’ decision-making related to the use of resources for pragmatic clinical trials. These include (1) concern for the interests of individuals, groups, and communities affected by the gatekeepers’ decisions, including protection from harm and maximization of benefits, (2) advancement of organizational mission and values, and (3) stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers’ actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding the use of limited and valuable resources. PMID:26374683

A clinical decision support system algorithm for intravenous to oral antibiotic switch therapy: validity, clinical relevance and usefulness in a three-step evaluation study.

PubMed

Akhloufi, H; Hulscher, M; van der Hoeven, C P; Prins, J M; van der Sijs, H; Melles, D C; Verbon, A

2018-04-26

To evaluate a clinical decision support system (CDSS) based on consensus-based intravenous to oral switch criteria, which identifies intravenous to oral switch candidates. A three-step evaluation study of a stand-alone CDSS with electronic health record interoperability was performed at the Erasmus University Medical Centre in the Netherlands. During the first step, we performed a technical validation. During the second step, we determined the sensitivity, specificity, negative predictive value and positive predictive value in a retrospective cohort of all hospitalized adult patients starting at least one therapeutic antibacterial drug between 1 and 16 May 2013. ICU, paediatric and psychiatric wards were excluded. During the last step the clinical relevance and usefulness was prospectively assessed by reports to infectious disease specialists. An alert was considered clinically relevant if antibiotics could be discontinued or switched to oral therapy at the time of the alert. During the first step, one technical error was found. The second step yielded a positive predictive value of 76.6% and a negative predictive value of 99.1%. The third step showed that alerts were clinically relevant in 53.5% of patients. For 43.4% it had already been decided to discontinue or switch the intravenous antibiotics by the treating physician. In 10.1%, the alert resulted in advice to change antibiotic policy and was considered useful. This prospective cohort study shows that the alerts were clinically relevant in >50% (n = 449) and useful in 10% (n = 85). The CDSS needs to be evaluated in hospitals with varying activity of infectious disease consultancy services as this probably influences usefulness.

Evaluation of health alerts from an early illness warning system in independent living.

PubMed

Rantz, Marilyn J; Scott, Susan D; Miller, Steven J; Skubic, Marjorie; Phillips, Lorraine; Alexander, Greg; Koopman, Richelle J; Musterman, Katy; Back, Jessica

2013-06-01

Passive sensor networks were deployed in independent living apartments to monitor older adults in their home environments to detect signs of impending illness and alert clinicians so they can intervene and prevent or delay significant changes in health or functional status. A retrospective qualitative deductive content analysis was undertaken to refine health alerts to improve clinical relevance to clinicians as they use alerts in their normal workflow of routine care delivery to older adults. Clinicians completed written free-text boxes to describe actions taken (or not) as a result of each alert; they also rated the clinical significance (relevance) of each health alert on a scale of 1 to 5. Two samples of the clinician's written responses to the health alerts were analyzed after alert algorithms had been adjusted based on results of a pilot study using health alerts to enhance clinical decision-making. In the first sample, a total of 663 comments were generated by seven clinicians in response to 385 unique alerts; there are more comments than alerts because more than one clinician rated the same alert. The second sample had a total of 142 comments produced by three clinicians in response to 88 distinct alerts. The overall clinical relevance of the alerts, as judged by the content of the qualitative comments by clinicians for each alert, improved from 33.3% of the alerts in the first sample classified as clinically relevant to 43.2% in the second. The goal is to produce clinically relevant alerts that clinicians find useful in daily practice. The evaluation methods used are described to assist others as they consider building and iteratively refining health alerts to enhance clinical decision making.

The Quality of Clinical Information in Adverse Drug Reaction Reports by Patients and Healthcare Professionals: A Retrospective Comparative Analysis.

PubMed

Rolfes, Leàn; van Hunsel, Florence; van der Linden, Laura; Taxis, Katja; van Puijenbroek, Eugène

2017-07-01

Clinical information is needed to assess the causal relationship between a drug and an adverse drug reaction (ADR) in a reliable way. Little is known about the level of relevant clinical information about the ADRs reported by patients. The aim was to determine to what extent patients report relevant clinical information about an ADR compared with their healthcare professional. A retrospective analysis of all ADR reports on the same case, i.e., cases with a report from both the patient and the patient's healthcare professional, selected from the database of the Dutch Pharmacovigilance Center Lareb, was conducted. The extent to which relevant clinical information was reported was assessed by trained pharmacovigilance assessors, using a structured tool. The following four domains were assessed: ADR, chronology, suspected drug, and patient characteristics. For each domain, the proportion of reported information in relation to information deemed relevant was calculated. An average score of all relevant domains was determined and categorized as poorly (≤45%), moderately (from 46 to 74%) or well (≥75%) reported. Data were analyzed using a paired sample t test and Wilcoxon signed rank test. A total of 197 cases were included. In 107 cases (54.3%), patients and healthcare professionals reported a similar level of clinical information. Statistical analysis demonstrated no overall differences between the groups (p = 0.126). In a unique study of cases of ADRs reported by patients and healthcare professionals, we found that patients report clinical information at a similar level as their healthcare professional. For an optimal pharmacovigilance, both healthcare professionals and patient should be encouraged to report.

Research methodology in Dentistry: Part I – The essentials and relevance of research

PubMed Central

Krithikadatta, Jogikalmat

2012-01-01

The need for scientific evidence should be the basis of clinical practice. The field of restorative dentistry and endodontics is evolving at a rapid pace, with the introduction of several materials, instruments, and equipments. However, there is minimal information of their relevance in clinical practice. On the one hand, material and laboratory research is critical, however; its translation into clinical practice is not being substantiated enough with clinical research. This four part review series focuses on methods to improve evidence-based practice, by improving methods to integrate laboratory and clinical research. PMID:22368327

Valerian: no evidence for clinically relevant interactions.

PubMed

Kelber, Olaf; Nieber, Karen; Kraft, Karin

2014-01-01

In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients.

Valerian: No Evidence for Clinically Relevant Interactions

PubMed Central

Nieber, Karen; Kraft, Karin

2014-01-01

In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients. PMID:25093031

Decreases in bone blood flow and bone material properties in aging Fischer-344 rats

NASA Technical Reports Server (NTRS)

Bloomfield, Susan A.; Hogan, Harry A.; Delp, Michael D.

2002-01-01

The purpose of this study was to quantify precisely aging-induced changes in skeletal perfusion and bone mechanical properties in a small rodent model. Blood flow was measured in conscious juvenile (2 months old), adult (6 months old), and aged (24 months old) male Fischer-344 rats using radiolabeled microspheres. There were no significant differences in bone perfusion rate or vascular resistance between juvenile and adult rats. However, blood flow was lower in aged versus adult rats in the forelimb bones, scapulas, and femurs. To test for functional effects of this decline in blood flow, bone mineral density and mechanical properties were measured in rats from these two age groups. Bone mineral density and cross-sectional moment of inertia in femoral and tibial shafts and the femoral neck were significantly larger in the aged versus adult rats, resulting in increased (+14%-53%) breaking strength and stiffness. However, intrinsic material properties at midshaft of the long bones were 12% to 25% lower in the aged rats. Although these data are consistent with a potential link between decreased perfusion and focal alterations in bone remodeling activity related to clinically relevant bone loss, additional studies are required to establish the mechanisms for this putative relationship.

Biocompatibility of calcium phosphate bone cement with optimized mechanical properties.

PubMed

Palmer, Iwan; Nelson, John; Schatton, Wolfgang; Dunne, Nicholas J; Buchanan, Fraser J; Clarke, Susan A

2016-02-01

The broad aim of this work was to investigate and optimize the properties of calcium phosphate bone cements (CPCs) for use in vertebroplasty to achieve effective primary fixation of spinal fractures. The incorporation of collagen, both bovine and from a marine sponge (Chondrosia reniformis), into a CPC was investigated. The biological properties of the CPC and collagen-CPC composites were assessed in vitro through the use of human bone marrow stromal cells. Cytotoxicity, proliferation, and osteoblastic differentiation were evaluated using lactate dehydrogenase, PicoGreen, and alkaline phosphatase activity assays, respectively. The addition of both types of collagen resulted in an increase in cytotoxicity, albeit not to a clinically relevant level. Cellular proliferation after 1, 7, and 14 days was unchanged. The osteogenic potential of the CPC was reduced through the addition of bovine collagen but remained unchanged in the case of the marine collagen. These findings, coupled with previous work showing that incorporation of marine collagen in this way can improve the physical properties of CPCs, suggest that such a composite may offer an alternative to CPCs in applications where low setting times and higher mechanical stability are important. © 2015 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc.

The influence of biomechanical properties and cannabinoids on tumor invasion.

PubMed

Hohmann, Tim; Grabiec, Urszula; Ghadban, Chalid; Feese, Kerstin; Dehghani, Faramarz

2017-01-02

Cannabinoids are known to have an anti-tumorous effect, but the underlying mechanisms are only sparsely understood. Mechanical characteristics of tumor cells represent a promising marker to distinguish between tumor cells and the healthy tissue. We tested the hypothesis whether cannabinoids influence the tumor cell specific mechanical and migratory properties and if these factors are a prognostic marker for the invasiveness of tumor cells. 3 different glioblastoma cell lines were treated with cannabinoids and changes of mechanical and migratory properties of single cells were measured using atomic force microscopy and time lapse imaging. The invasiveness of cell lines was determined using a co-culture model with organotypic hippocampal slice cultures. We found that cannabinoids are capable of influencing migratory and mechanical properties in a cell line specific manner. A network analysis revealed a correlation between a "generalized stiffness" and the invasiveness for all tumor cell lines after 3 and 4 d of invasion time: r 3d = -0.88 [-0.52;-0.97]; r 4d = -0.90 [-0.59;-0.98]. Here we could show that a "generalized stiffness" is a profound marker for the invasiveness of a tumor cell population in our model and thus might be of high clinical relevance for drug testing. Additionally cannabinoids were shown to be of potential use for therapeutic approaches of glioblastoma.

Development and testing of the CALDs and CLES+T scales for international nursing students' clinical learning environments.

PubMed

Mikkonen, Kristina; Elo, Satu; Miettunen, Jouko; Saarikoski, Mikko; Kääriäinen, Maria

2017-08-01

The purpose of this study was to develop and test the psychometric properties of the new Cultural and Linguistic Diversity scale, which is designed to be used with the newly validated Clinical Learning Environment, Supervision and Nurse Teacher scale for assessing international nursing students' clinical learning environments. In various developed countries, clinical placements are known to present challenges in the professional development of international nursing students. A cross-sectional survey. Data were collected from eight Finnish universities of applied sciences offering nursing degree courses taught in English during 2015-2016. All the relevant students (N = 664) were invited and 50% chose to participate. Of the total data submitted by the participants, 28% were used for scale validation. The construct validity of the two scales was tested by exploratory factor analysis, while their validity with respect to convergence and discriminability was assessed using Spearman's correlation. Construct validation of the Clinical Learning Environment, Supervision and Nurse Teacher scale yielded an eight-factor model with 34 items, while validation of the Cultural and Linguistic Diversity scale yielded a five-factor model with 21 items. A new scale was developed to improve evidence-based mentorship of international nursing students in clinical learning environments. The instrument will be useful to educators seeking to identify factors that affect the learning of international students. © 2017 John Wiley & Sons Ltd.

Hyperglycaemia, Insulin Therapy and Critical Penumbral Regions for Prognosis in Acute Stroke: Further Insights from the INSULINFARCT Trial

PubMed Central

Rosso, Charlotte; Pires, Christine; Corvol, Jean-Christophe; Baronnet, Flore; Crozier, Sophie; Leger, Anne; Deltour, Sandrine; Valabregue, Romain; Amor-Sahli, Mélika; Lehéricy, Stéphane; Dormont, Didier; Samson, Yves

2015-01-01

Background Recently, the concept of ‘clinically relevant penumbra’ was defined as an area saved by arterial recanalization and correlated with stroke outcome. This clinically relevant penumbra was located in the subcortical structures, especially the periventricular white matter. Our aims were to confirm this hypothesis, to investigate the impact of admission hyperglycemia and of insulin treatment on the severity of ischemic damages in this area and to study the respective contributions of infarct volume and ischemic damage severity of the clinically relevant penumbra on 3-month outcome. Methods We included 99 patients from the INSULINFARCT trial. Voxel-Based Analysis was carried on the Apparent Diffusion Coefficient (ADC) maps obtained at day one to localize the regions, which were more damaged in patients i) with poor clinical outcomes at three months and ii) without arterial recanalization. We determined the intersection of the detected areas, which represents the clinically relevant penumbra and investigated whether hyperglycemic status and insulin regimen affected the severity of ischemic damages in this area. We performed logistic regression to examine the contribution of infarct volume or early ADC decrease in this strategic area on 3-month outcome. Findings Lower ADC values were found in the corona radiata in patients with poor prognosis (p< 0.0001) and in those without arterial recanalization (p< 0.0001). The tracking analysis showed that lesions in this area interrupted many important pathways. ADC values in this area were lower in hyperglycemic than in normoglycemic patients (average decrease of 41.6 ± 20.8 x10−6mm2/s) and unaffected by the insulin regimen (p: 0.10). ADC values in the clinically relevant penumbra, but not infarct volumes, were significant predictors of 3-month outcome. Conclusion These results confirm that the deep hemispheric white matter is part of the clinically relevant penumbra and show that hyperglycaemia exacerbates the apparition of irreversible ischemic damage within 24 hours in this area. However, early intensive insulin therapy fails to protect this area from infarction. Trial Registration ClinicalTrials.gov NCT00472381 PMID:25793765

Clinical relevance is associated with allergen-specific wheal size in skin prick testing

PubMed Central

Haahtela, T; Burbach, G J; Bachert, C; Bindslev-Jensen, C; Bonini, S; Bousquet, J; Bousquet-Rouanet, L; Bousquet, P J; Bresciani, M; Bruno, A; Canonica, G W; Darsow, U; Demoly, P; Durham, S R; Fokkens, W J; Giavi, S; Gjomarkaj, M; Gramiccioni, C; Kowalski, M L; Losonczy, G; Orosz, M; Papadopoulos, N G; Stingl, G; Todo-Bom, A; von Mutius, E; Köhli, A; Wöhrl, S; Järvenpää, S; Kautiainen, H; Petman, L; Selroos, O; Zuberbier, T; Heinzerling, L M

2014-01-01

Background Within a large prospective study, the Global Asthma and Allergy European Network (GA2LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. Objective To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. Methods The GA2LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. Results Depending on the allergen, from 40% (blatella) to 87–89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. Conclusion These ‘reading keys’ for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use. PMID:24283409

Benchtop Technologies for Circulating Tumor Cells Separation Based on Biophysical Properties

PubMed Central

Low, Wan Shi; Wan Abas, Wan Abu Bakar

2015-01-01

Circulating tumor cells (CTCs) are tumor cells that have detached from primary tumor site and are transported via the circulation system. The importance of CTCs as prognostic biomarker is leveraged when multiple studies found that patient with cutoff of 5 CTCs per 7.5 mL blood has poor survival rate. Despite its clinical relevance, the isolation and characterization of CTCs can be quite challenging due to their large morphological variability and the rare presence of CTCs within the blood. Numerous methods have been employed and discussed in the literature for CTCs separation. In this paper, we will focus on label free CTCs isolation methods, in which the biophysical and biomechanical properties of cells (e.g., size, deformability, and electricity) are exploited for CTCs detection. To assess the present state of various isolation methods, key performance metrics such as capture efficiency, cell viability, and throughput will be reported. Finally, we discuss the challenges and future perspectives of CTC isolation technologies. PMID:25977918

Chemoinformatic expedition of the chemical space of fungal products.

PubMed

González-Medina, Mariana; Prieto-Martínez, Fernando D; Naveja, J Jesús; Méndez-Lucio, Oscar; El-Elimat, Tamam; Pearce, Cedric J; Oberlies, Nicholas H; Figueroa, Mario; Medina-Franco, José L

2016-08-01

Fungi are valuable resources for bioactive secondary metabolites. However, the chemical space of fungal secondary metabolites has been studied only on a limited basis. Herein, we report a comprehensive chemoinformatic analysis of a unique set of 207 fungal metabolites isolated and characterized in a USA National Cancer Institute funded drug discovery project. Comparison of the molecular complexity of the 207 fungal metabolites with approved anticancer and nonanticancer drugs, compounds in clinical studies, general screening compounds and molecules Generally Recognized as Safe revealed that fungal metabolites have high degree of complexity. Molecular fingerprints showed that fungal metabolites are as structurally diverse as other natural products and have, in general, drug-like physicochemical properties. Fungal products represent promising candidates to expand the medicinally relevant chemical space. This work is a significant expansion of an analysis reported years ago for a smaller set of compounds (less than half of the ones included in the present work) from filamentous fungi using different structural properties.

Anti-MRSA Activity of Fruiting Body Extracts of Spectacular Rustgill Mushroom, Gymnopilus junonius (Agaricomycetes).

PubMed

Barneche, Stephanie; Alborés, Silvana; Borthagaray, Graciela; Cerdeiras, María Pía; Vázquez, Alvaro

2017-01-01

Despite the great advances in chemotherapeutics, infectious diseases are still one of the leading causes of death worldwide. Among some of the clinically relevant pathogens, methicillin-resistant Staphylococcus aureus (MRSA) ranks as one of the most difficult bacteria to treat. It is a common cause of skin, soft-tissue, and endovascular infections, as well as pneumonia, septic arthritis, endocarditis, osteomyelitis, and sepsis. The research on Basidiomycota is extensive; many species show a broad spectrum of pharmacological activities, including antimicrobial activity. The vast majority of the literature to date generally focuses on screening the antibacterial properties of mushroom extracts. A gap still exists in the identification of the individual compounds responsible for these properties, and few low molecular weight compounds have been described. Gymnopilus junonius, the big laughter mushroom, grows wild in Uruguay, especially on Eucalyptus spp. plantations; it is known as the "eucalyptus fungus." In this work, we report the bioguided isolation, structural elucidation, and antistaphylococcal activity of the main antimicrobial components of fresh basidiocarps of G. junonius.

Benchtop technologies for circulating tumor cells separation based on biophysical properties.

PubMed

Low, Wan Shi; Wan Abas, Wan Abu Bakar

2015-01-01

Circulating tumor cells (CTCs) are tumor cells that have detached from primary tumor site and are transported via the circulation system. The importance of CTCs as prognostic biomarker is leveraged when multiple studies found that patient with cutoff of 5 CTCs per 7.5 mL blood has poor survival rate. Despite its clinical relevance, the isolation and characterization of CTCs can be quite challenging due to their large morphological variability and the rare presence of CTCs within the blood. Numerous methods have been employed and discussed in the literature for CTCs separation. In this paper, we will focus on label free CTCs isolation methods, in which the biophysical and biomechanical properties of cells (e.g., size, deformability, and electricity) are exploited for CTCs detection. To assess the present state of various isolation methods, key performance metrics such as capture efficiency, cell viability, and throughput will be reported. Finally, we discuss the challenges and future perspectives of CTC isolation technologies.

Whole-body impedance--what does it measure?

PubMed

Foster, K R; Lukaski, H C

1996-09-01

Although the bioelectrical impedance technique is widely used in human nutrition and clinical research, an integrated summary of the biophysical and bioelectrical bases of this approach is lacking. We summarize the pertinent electrical phenomena relevant to the application of the impedance technique in vivo and discuss the relations between electrical measurements and biological conductor volumes. Key terms in the derivation of bioelectrical impedance analysis are described and the relation between the electrical properties of tissues and tissue structure is discussed. The relation between the impedance of an object and its geometry, scale, and intrinsic electrical properties is also discussed. Correlations between whole-body impedance measurements and various bioconductor volumes, such as total body water and fat-free mass, are experimentally well established; however, the reason for the success of the impedence technique is much less clear. The bioengineering basis for the technique is critically presented and considerations are proposed that might help to clarify the method and potentially improve its sensitivity.

New Perspectives on Biomedical Applications of Iron Oxide Nanoparticles.

PubMed

Magro, Massimiliano; Baratella, Davide; Bonaiuto, Emanuela; de A Roger, Jessica; Vianello, Fabio

2018-02-12

Iron oxide nanomaterials are considered promising tools for improved therapeutic efficacy and diagnostic applications in biomedicine. Accordingly, engineered iron oxide nanomaterials are increasingly proposed in biomedicine, and the interdisciplinary researches involving physics, chemistry, biology (nanotechnology) and medicine have led to exciting developments in the last decades. The progresses of the development of magnetic nanoparticles with tailored physico-chemical and surface properties produced a variety of clinically relevant applications, spanning from magnetic resonance imaging (MRI), drug delivery, magnetic hyperthermia, to in vitro diagnostics. Notwithstanding the wellknown conventional synthetic procedures and their wide use, along with recent advances in the synthetic methods open the door to new generations of naked iron oxide nanoparticles possessing peculiar surface chemistries, suitable for other competitive biomedical applications. New abilities to rationally manipulate iron oxides and their physical, chemical, and biological properties, allow the emersion of additional possibilities for designing novel nanomaterials for theranostic applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Biology and relevance of human acute myeloid leukemia stem cells.

PubMed

Thomas, Daniel; Majeti, Ravindra

2017-03-23

Evidence of human acute myeloid leukemia stem cells (AML LSCs) was first reported nearly 2 decades ago through the identification of rare subpopulations of engrafting cells in xenotransplantation assays. These AML LSCs were shown to reside at the apex of a cellular hierarchy that initiates and maintains the disease, exhibiting properties of self-renewal, cell cycle quiescence, and chemoresistance. This cancer stem cell model offers an explanation for chemotherapy resistance and disease relapse and implies that approaches to treatment must eradicate LSCs for cure. More recently, a number of studies have both refined and expanded our understanding of LSCs and intrapatient heterogeneity in AML using improved xenotransplant models, genome-scale analyses, and experimental manipulation of primary patient cells. Here, we review these studies with a focus on the immunophenotype, biological properties, epigenetics, genetics, and clinical associations of human AML LSCs and discuss critical questions that need to be addressed in future research. © 2017 by The American Society of Hematology.

SAHA-based novel HDAC inhibitor design by core hopping method.

PubMed

Zang, Lan-Lan; Wang, Xue-Jiao; Li, Xiao-Bo; Wang, Shu-Qing; Xu, Wei-Ren; Xie, Xian-Bin; Cheng, Xian-Chao; Ma, Huan; Wang, Run-Ling

2014-11-01

The catalytic activity of the histone deacetylase (HDAC) is directly relevant to the pathogenesis of cancer, and HDAC inhibitors represented a promising strategy for cancer therapy. SAHA (suberoanilide hydroxamic acid), an effective HDAC inhibitor, is an anti-cancer agent against T-cell lymphoma. However, SAHA has adverse effects such as poor pharmacokinetic properties and severe toxicities in clinical use. In order to identify better HDAC inhibitors, a compound database was established by core hopping of SAHA, which was then docked into HDAC-8 (PDB ID: 1T69) active site to select a number of candidates with higher docking score and better interaction with catalytic zinc ion. Further ADMET prediction was done to give ten compounds. Molecular dynamics simulation of the representative compound 101 was performed to study the stability of HDAC8-inhibitor system. This work provided an approach to design novel high-efficiency HDAC inhibitors with better ADMET properties. Copyright © 2014 Elsevier Inc. All rights reserved.

Poly(ester urea)-Based Adhesives: Improved Deployment and Adhesion by Incorporation of Poly(propylene glycol) Segments.

PubMed

Zhou, Jinjun; Bhagat, Vrushali; Becker, Matthew L

2016-12-14

The adhesive nature of mussels arises from the catechol moiety in the 3,4-dihydroxyphenylalanine (DOPA) amino acid, one of the many proteins that contribute to the unique adhesion properties of mussels. Inspired by these properties, many biomimetic adhesives have been developed over the past few years in an attempt to replace adhesives such as fibrin, cyanoacrylate, and epoxy glues. In the present work, we synthesized ethanol soluble but water insoluble catechol functionalized poly(ester urea) random copolymers that help facilitate delivery and adhesion in wet environments. Poly(propylene glycol) units incorporated into the polymer backbone impart ethanol solubility to these polymers, making them clinically relevant. A catechol to cross-linker ratio of 10:1 with a curing time of 4 h exceeded the performance of commercial fibrin glue (4.8 ± 1.4 kPa) with adhesion strength of 10.6 ± 2.1 kPa. These adhesion strengths are significant with the consideration that the adhesion studies were performed under wet conditions.

The effects of hyaluronic acid hydrogels with tunable mechanical properties on neural progenitor cell differentiation.

PubMed

Seidlits, Stephanie K; Khaing, Zin Z; Petersen, Rebecca R; Nickels, Jonathan D; Vanscoy, Jennifer E; Shear, Jason B; Schmidt, Christine E

2010-05-01

We report the ability to direct the differentiation pathway of neural progenitor cells (NPCs) within hydrogels having tunable mechanical properties. By modifying the polymeric sugar hyaluronic acid (HA), a major extracellular matrix component in the fetal mammalian brain, with varying numbers of photocrosslinkable methacrylate groups, hydrogels could be prepared with bulk compressive moduli spanning the threefold range measured for neonatal brain and adult spinal cord. Ventral midbrain-derived NPCs were photoencapsulated into HA hydrogels and remained viable after encapsulation. After three weeks, the majority of NPCs cultured in hydrogels with mechanical properties comparable to those of neonatal brain had differentiated into neurons (ss-III tubulin-positive), many of which had extended long, branched processes, indicative of a relatively mature phenotype. In contrast, NPCs within stiffer hydrogels, with mechanical properties comparable to those of adult brain, had differentiated into mostly astrocytes (glial fibrillary acidic protein (GFAP)-positive). Primary spinal astrocytes cultured in the hydrogel variants for two weeks acquired a spread and elongated morphology only in the stiffest hydrogels evaluated, with mechanical properties similar to adult tissue. Results demonstrate that the mechanical properties of these scaffolds can assert a defining influence on the differentiation of ventral midbrain-derived NPCs, which have strong clinical relevance because of their ability to mature into dopaminergic neurons of the substantia nigra, cells that idiopathically degenerate in individuals suffering from Parkinson's disease. Copyright 2010 Elsevier Ltd. All rights reserved.

Measuring quality of life among people living with HIV: a systematic review of reviews.

PubMed

Cooper, Vanessa; Clatworthy, Jane; Harding, Richard; Whetham, Jennifer

2017-11-15

A systematic review of reviews was conducted to identify and appraise brief measures of health-related quality of life (HRQoL) that have been used in peer-reviewed research with people living with HIV. The review was conducted in two stages: 1) search of electronic databases to identify systematic reviews of tools used to measure HRQoL in adults living with HIV, published since the year 2000; 2) selection of HRQol scales from those identified in the reviews. Inclusion criteria included scales that could be self-administered in 10 min or less, covering at least 3 domains of quality of life (physical function, social/role function and mental/emotional function). For generic scales, inclusion criteria included the availability of normative data while for HIV-specific scales, patient input into the development of the scale was required. Ten reviews met the inclusion criteria. Nine generic scales met the inclusion criteria: the EuroQol five dimensions questionnaire (EQ-5D); Health Utilities Index; McGill Quality of Life questionnaire; Medical Outcomes Study (MOS) Short Form (SF)-12; SF-36; World Health Organisation Quality of Life (WHOQOL- BREF), Questions of Life Satisfaction (FLZM) and SF-20. Available psychometric data supported the EQ-5D and SF-36. Seven HIV-specific scales met the inclusion criteria: the AIDS Clinical Trials Group (ACTG)-21; HIV-QL-31; MOS-HIV; Multidimensional Quality of Life Questionnaire for Persons with HIV/AIDS (MQOL-HIV), PROQOL-HIV, Symptom Quality of Life Adherence (HIV-SQUAD) and the WHOQOL-HIV BREF. Of the HIV -specific measures, the MOS-HIV was considered to have the most well-established psychometric properties, however limitations identified in the reviews included insufficient input from people living with HIV in the development of the scale, cross-cultural relevance and continued applicability. Two relatively new measures, the WHOQOL-HIV BREF and PROQOL-HIV, were considered to have promising psychometric properties and may have more relevance to people living with HIV. The findings highlight the need for further validation of HRQoL measures in people living with HIV. The choice of one measure over another is likely to be influenced by the purpose of the quality of life assessment and the domains of HRQoL that are most relevant to the specific research or clinical question.

Point-of-Care Diagnostics for Niche Applications

PubMed Central

Cummins, Brian M.; Ligler, Frances S.; Walker, Glenn M.

2016-01-01

Point-of-care or point-of-use diagnostics are analytical devices that provide clinically relevant information without the need for a core clinical laboratory. In this review we define point-of-care diagnostics as portable versions of assays performed in a traditional clinical chemistry laboratory. This review discusses five areas relevant to human and animal health where increased attention could produce significant impact: veterinary medicine, space travel, sports medicine, emergency medicine, and operating room efficiency. For each of these areas, clinical need, available commercial products, and ongoing research into new devices are highlighted. PMID:26837054

Prevalence and relevance of the positivity of skin prick testing in patients with chronic urticaria.

PubMed

Kulthanan, Kanokvalai; Jiamton, Sukhum; Rutnin, Ni-on; Insawang, Metavee; Pinkaew, Sumrauy

2008-06-01

Many patients with chronic urticaria (CU) worry that foods or other allergens are responsible for their urticaria. Skin prick testing (SPT) may be one of the investigations used to provide a clear illustration. The purpose of our study was to assess the prevalence of positivity of SPT to food allergens and aeroallergens and their relevance in patients with CU, in order to demonstrate the diagnostic value of SPT in CU. We retrospectively reviewed case record forms of patients with chronic ordinary urticaria who underwent SPT in the Urticaria Clinic, Siriraj Hospital, during the period 2000-2004. The studied allergens included 16 food allergens and 12 aeroallergens. Eighty-eight patients were enrolled. The prevalence of positive SPT among patients with CU was 47.7%. Patients who had personal histories of atopy had statistically significant positive SPT results compared with patients who had negative SPT. Of 88 patients, 26 patients (30%) gave positive results to food allergens, 36 patients (41%) gave positive results to aeroallergens and 20 patients (22.7%) gave positive results to both food and aeroallergens. One-third of the subjects (34.6%) who had positive SPT results to food allergens had clinical relevance of food allergy in some systems but only one patient had clinical relevance of food-induced urticaria. Half of the patients who had a history of aeroallergen sensitivity gave a positive SPT response for aeroallergens; however, there was no clinical relevance to their CU. Our study showed that the prevalence of positive SPT to food allergens and aeroallergens in patients with CU was common but had little clinical relevance to CU.

Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials.

PubMed

Anthony, Karen; Cirak, Sebahattin; Torelli, Silvia; Tasca, Giorgio; Feng, Lucy; Arechavala-Gomeza, Virginia; Armaroli, Annarita; Guglieri, Michela; Straathof, Chiara S; Verschuuren, Jan J; Aartsma-Rus, Annemieke; Helderman-van den Enden, Paula; Bushby, Katherine; Straub, Volker; Sewry, Caroline; Ferlini, Alessandra; Ricci, Enzo; Morgan, Jennifer E; Muntoni, Francesco

2011-12-01

Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy.

Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials

PubMed Central

Anthony, Karen; Cirak, Sebahattin; Torelli, Silvia; Tasca, Giorgio; Feng, Lucy; Arechavala-Gomeza, Virginia; Armaroli, Annarita; Guglieri, Michela; Straathof, Chiara S.; Verschuuren, Jan J.; Aartsma-Rus, Annemieke; Helderman-van den Enden, Paula; Bushby, Katherine; Straub, Volker; Sewry, Caroline; Ferlini, Alessandra; Ricci, Enzo; Morgan, Jennifer E.

2011-01-01

Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy. PMID:22102647

THE GAP BETWEEN ECONOMIC EVALUATIONS AND CLINICAL PRACTICE: A SYSTEMATIC REVIEW OF ECONOMIC EVALUATIONS ON DABIGATRAN FOR ATRIAL FIBRILLATION.

PubMed

Rolden, Herbert J A; van der Wilt, Gert Jan; Maas, Angela H E M; Grutters, Janneke P C

2018-06-18

As model-based economic evaluations (MBEEs) are widely used to make decisions in the context of policy, it is imperative that they represent clinical practice. Here, we assess the relevance of MBEEs on dabigatran for the prevention of stroke in patients with atrial fibrillation (AF). We performed a systematic review on the basis of a developed questionnaire, tailored to oral anticoagulation in patients with AF. Included studies had a full body text in English, compared dabigatran with a vitamin K antagonist, were not dedicated to one or more subgroup(s), and yielded an incremental cost-effectiveness ratio. The relevance of all MBEEs was assessed on the basis of ten context-independent factors, which encompassed clinical outcomes and treatment duration. The MBEEs performed for the United States were assessed on the basis of seventeen context-dependent factors, which were related to the country's target population and clinical environment. The search yielded twenty-nine MBEEs, of which six were performed for the United States. On average, 54 percent of the context-independent factors were included per study, and 37 percent of the seventeen context-dependent factors in the U.S. The share of relevant factors per study did not increase over time. MBEEs on dabigatran leave out several relevant factors, limiting their usefulness to decision makers. We strongly urge health economic researchers to improve the relevance of their MBEEs by including context-independent relevance factors, and modeling context-dependent factors befitting the decision context concerned.

Clinical relevance of pharmacist intervention in an emergency department.

PubMed

Pérez-Moreno, Maria Antonia; Rodríguez-Camacho, Juan Manuel; Calderón-Hernanz, Beatriz; Comas-Díaz, Bernardino; Tarradas-Torras, Jordi

2017-08-01

To evaluate the clinical relevance of pharmacist intervention on patient care in emergencies, to determine the severity of detected errors. Second, to analyse the most frequent types of interventions and type of drugs involved and to evaluate the clinical pharmacist's activity. A 6-month observational prospective study of pharmacist intervention in the Emergency Department (ED) at a 400-bed hospital in Spain was performed to record interventions carried out by the clinical pharmacists. We determined whether the intervention occurred in the process of medication reconciliation or another activity, and whether the drug involved belonged to the High-Alert Medications Institute for Safe Medication Practices (ISMP) list. To evaluate the severity of the errors detected and clinical relevance of the pharmacist intervention, a modified assessment scale of Overhage and Lukes was used. Relationship between clinical relevance of pharmacist intervention and the severity of medication errors was assessed using ORs and Spearman's correlation coefficient. During the observation period, pharmacists reviewed the pharmacotherapy history and medication orders of 2984 patients. A total of 991 interventions were recorded in 557 patients; 67.2% of the errors were detected during medication reconciliation. Medication errors were considered severe in 57.2% of cases and 64.9% of pharmacist intervention were considered relevant. About 10.9% of the drugs involved are in the High-Alert Medications ISMP list. The severity of the medication error and the clinical significance of the pharmacist intervention were correlated (Spearman's ρ=0.728/p<0.001). In this single centre study, the clinical pharmacists identified and intervened on a high number of severe medication errors. This suggests that emergency services will benefit from pharmacist-provided drug therapy services. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations.

PubMed

Lee, HoJoon; Palm, Jennifer; Grimes, Susan M; Ji, Hanlee P

2015-10-27

The Cancer Genome Atlas (TCGA) project has generated genomic data sets covering over 20 malignancies. These data provide valuable insights into the underlying genetic and genomic basis of cancer. However, exploring the relationship among TCGA genomic results and clinical phenotype remains a challenge, particularly for individuals lacking formal bioinformatics training. Overcoming this hurdle is an important step toward the wider clinical translation of cancer genomic/proteomic data and implementation of precision cancer medicine. Several websites such as the cBio portal or University of California Santa Cruz genome browser make TCGA data accessible but lack interactive features for querying clinically relevant phenotypic associations with cancer drivers. To enable exploration of the clinical-genomic driver associations from TCGA data, we developed the Cancer Genome Atlas Clinical Explorer. The Cancer Genome Atlas Clinical Explorer interface provides a straightforward platform to query TCGA data using one of the following methods: (1) searching for clinically relevant genes, micro RNAs, and proteins by name, cancer types, or clinical parameters; (2) searching for genomic/proteomic profile changes by clinical parameters in a cancer type; or (3) testing two-hit hypotheses. SQL queries run in the background and results are displayed on our portal in an easy-to-navigate interface according to user's input. To derive these associations, we relied on elastic-net estimates of optimal multiple linear regularized regression and clinical parameters in the space of multiple genomic/proteomic features provided by TCGA data. Moreover, we identified and ranked gene/micro RNA/protein predictors of each clinical parameter for each cancer. The robustness of the results was estimated by bootstrapping. Overall, we identify associations of potential clinical relevance among genes/micro RNAs/proteins using our statistical analysis from 25 cancer types and 18 clinical parameters that include clinical stage or smoking history. The Cancer Genome Atlas Clinical Explorer enables the cancer research community and others to explore clinically relevant associations inferred from TCGA data. With its accessible web and mobile interface, users can examine queries and test hypothesis regarding genomic/proteomic alterations across a broad spectrum of malignancies.

Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives.

PubMed

Fiore, Esteban J; Mazzolini, Guillermo; Aquino, Jorge B

2015-08-01

Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic-adherence capacity and cell surface markers but have different properties according to their cell and tissue sources and to culture conditions applied. Many recent publications suggest that MSCs can differentiate into hepatic-like cells, which can be a consequence of either a positive selection of rare in vivo pluripotent cells or of the original plasticity of some cells contributing to MSC cultures. A possible role of MSCs in hereditary transmission of obesity and/or diabetes as well as properties of MSCs regarding immunomodulation, cell fusion and exosome release capacities are discussed according to recent literature. Limitations in methods used to track MSCs in vivo especially in the context of liver cirrhosis are addressed as well as strategies explored to enhance their migratory, survival and proliferation properties, which are known to be relevant for their future clinical use. Current knowledge regarding mechanisms involved in liver cirrhosis amelioration mediated by naïve and genetically modified MSCs as well as the effects of applying preconditioning and combined strategies to improve their therapeutic effects are evaluated. Finally, first reports of GMP guidelines and biosafety issues in MSCs applications are discussed.

Clinical utility of measures of breathlessness.

PubMed

Cullen, Deborah L; Rodak, Bernadette

2002-09-01

The clinical utility of measures of dyspnea has been debated in the health care community. Although breathlessness can be evaluated with various instruments, the most effective dyspnea measurement tool for patients with chronic lung disease or for measuring treatment effectiveness remains uncertain. Understanding the evidence for the validity and reliability of these instruments may provide a basis for appropriate clinical application. Evaluate instruments designed to measure breathlessness, either as single-symptom or multidimensional instruments, based on psychometrics foundations such as validity, reliability, and discriminative and evaluative properties. Classification of each dyspnea measurement instrument will recommend clinical application in terms of exercise, benchmarking patients, activities of daily living, patient outcomes, clinical trials, and responsiveness to treatment. Eleven dyspnea measurement instruments were selected. Each instrument was assessed as discriminative or evaluative and then analyzed as to its psychometric properties and purpose of design. Descriptive data from all studies were described according to their primary patient application (ie, chronic obstructive pulmonary disease, asthma, or other patient populations). The Borg Scale and the Visual Analogue Scale are applicable to exertion and thus can be applied to any cardiopulmonary patient to determine dyspnea. All other measures were determined appropriate for chronic obstructive pulmonary disease, whereas the Shortness of Breath Questionnaire can be applied to cystic fibrosis and lung transplant patients. The most appropriate utility for all instruments was measuring the effects on activities of daily living and for benchmarking patient progress. Instruments that quantify function and health-related quality of life have great utility for documenting outcomes but may be limited as to documenting treatment responsiveness in terms of clinically important changes. The dyspnea measurement instruments we studied meet important standards of validity and reliability. Discriminative measures have limited clinical utility and, when used for populations or conditions for which they are not designed or validated, the data collected may not be clinically relevant. Evaluative measures have greater clinical utility and can be applied for outcome purposes. Measures should be applied to the populations and conditions for which they were designed. The relationship between clinical therapies and the measurement of dyspnea as an outcome can develop as respiratory therapists become more comfortable with implementing dyspnea measurement instruments and use the data to improve patient treatment. Dyspnea evaluation should be considered for all clinical practice guidelines and care pathways.

Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma

PubMed Central

Medeiros, Felipe A.

2017-01-01

With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials. PMID:28475699

Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma.

PubMed

Medeiros, Felipe A

2017-05-01

With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials.

Microbial Properties Database Editor Tutorial

EPA Science Inventory

A Microbial Properties Database Editor (MPDBE) has been developed to help consolidate microbial-relevant data to populate a microbial database and support a database editor by which an authorized user can modify physico-microbial properties related to microbial indicators and pat...

Independent effects of the chemical and microstructural surface properties of polymer/ceramic composites on proliferation and osteogenic differentiation of human MSCs.

PubMed

Sun, Lanying; Danoux, Charlène B; Wang, Qibao; Pereira, Daniel; Barata, David; Zhang, Jingwei; LaPointe, Vanessa; Truckenmüller, Roman; Bao, Chongyun; Xu, Xin; Habibovic, Pamela

2016-09-15

Within the general aim of finding affordable and sustainable regenerative solutions for damaged and diseased tissues and organs, significant efforts have been invested in developing synthetic alternatives to natural bone grafts, such as autografts. Calcium phosphate (CaP) ceramics are among widely used synthetic bone graft substitutes, but their mechanical properties and bone regenerative capacity are still outperformed by their natural counterparts. In order to improve the existing synthetic bone graft substitutes, it is imperative to understand the effects of their individual properties on a biological response, and to find a way to combine the desired properties into new, improved functional biomaterials. To this end, we studied the independent effects of the chemical composition and surface microstructure of a poly(lactic acid)/hydroxyapatite (PLA/HA) composite material on the proliferation and osteogenic differentiation of clinically relevant bone marrow-derived human mesenchymal stromal cells (hMSCs). While the molecular weight of the polymer and presence/absence of the ceramic phase were used as the chemical variables, a soft embossing technique was used to pattern the surfaces of all materials with either pits or pillars with identical microscale dimensions. The results indicated that, while cell morphology was affected by both the presence and availability of HA and by the surface microstructure, the effect of the latter parameter on cell proliferation was negligible. The osteogenic differentiation of hMSCs, and in particular the expression of bone morphogenetic protein 2 (BMP-2) and osteopontin (OP) were significantly enhanced when cells were cultured on the composite based on low-molecular-weight PLA, as compared to the high-molecular-weight PLA-based composite and the two pure polymers. The OP expression on the low-molecular-weight PLA-based composite was further enhanced when the surface was patterned with pits. Taken together, within this experimental set up, the individual effect of the chemistry, and in particular of the presence of CaP, was more pronounced than the individual effect of the surface microstructure, although their combined effects were, in some cases, synergistic. The approach presented here opens new routes to study the interactions of biomaterials with the biological environment in greater depths, which can serve as a starting point for developing biomaterials with improved bioactivity. The aim of the this study was to obtain insight into independent effects of the chemical composition and surface microstructure of a poly(lactic acid)/hydroxyapatite (PLA/HA) composite material on the morphology, proliferation and osteogenic differentiation of clinically relevant bone marrow-derived human mesenchymal stromal cells (hMSCs). While the need for synthetic alternatives for natural bone in bone regenerative strategies is rapidly increasing, the clinical performance of synthetic biomaterials needs to be further improved. To do this successfully, we believe that a better understanding of the relationship between a property of a material and a biological response is imperative. This study is a step forward in this direction, and we are therefore convinced that it will be of interest to the readers of Acta Biomaterialia. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Is Dysfunctional Use of the Mobile Phone a Behavioural Addiction? Confronting Symptom-Based Versus Process-Based Approaches.

PubMed

Billieux, Joël; Philippot, Pierre; Schmid, Cécile; Maurage, Pierre; De Mol, Jan; Van der Linden, Martial

2015-01-01

Dysfunctional use of the mobile phone has often been conceptualized as a 'behavioural addiction' that shares most features with drug addictions. In the current article, we challenge the clinical utility of the addiction model as applied to mobile phone overuse. We describe the case of a woman who overuses her mobile phone from two distinct approaches: (1) a symptom-based categorical approach inspired from the addiction model of dysfunctional mobile phone use and (2) a process-based approach resulting from an idiosyncratic clinical case conceptualization. In the case depicted here, the addiction model was shown to lead to standardized and non-relevant treatment, whereas the clinical case conceptualization allowed identification of specific psychological processes that can be targeted with specific, empirically based psychological interventions. This finding highlights that conceptualizing excessive behaviours (e.g., gambling and sex) within the addiction model can be a simplification of an individual's psychological functioning, offering only limited clinical relevance. The addiction model, applied to excessive behaviours (e.g., gambling, sex and Internet-related activities) may lead to non-relevant standardized treatments. Clinical case conceptualization allowed identification of specific psychological processes that can be targeted with specific empirically based psychological interventions. The biomedical model might lead to the simplification of an individual's psychological functioning with limited clinical relevance. Copyright © 2014 John Wiley & Sons, Ltd.

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

PubMed

Hendriksz, Christian J; Anheim, Mathieu; Bauer, Peter; Bonnot, Olivier; Chakrapani, Anupam; Corvol, Jean-Christophe; de Koning, Tom J; Degtyareva, Anna; Dionisi-Vici, Carlo; Doss, Sarah; Duning, Thomas; Giunti, Paola; Iodice, Rosa; Johnston, Tracy; Kelly, Dierdre; Klünemann, Hans-Hermann; Lorenzl, Stefan; Padovani, Alessandro; Pocovi, Miguel; Synofzik, Matthis; Terblanche, Alta; Then Bergh, Florian; Topçu, Meral; Tranchant, Christine; Walterfang, Mark; Velten, Christian; Kolb, Stefan A

2017-05-01

Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Several clinical niches have been identified that harbor patients at increased risk of NP-C.

Dental Blogs, Podcasts, and Associated Social Media: Descriptive Mapping and Analysis

PubMed Central

Hicks, Diana; Rosenblum, Simone; Isett, Kimberley R; Elliott, Jacqueline

2017-01-01

Background Studies of social media in both medicine and dentistry have largely focused on the value of social media for marketing to and communicating with patients and for clinical education. There is limited evidence of how dental clinicians contribute to and use social media to disseminate and access information relevant to clinical care. Objective The purpose of this study was to inventory and assess the entry, growth, sources, and content of clinically relevant social media in dentistry. Methods We developed an inventory of blogs, podcasts, videos, and associated social media disseminating clinical information to dentists. We assessed hosts’ media activity in terms of their combinations of modalities, entry and exit dates, frequency of posting, types of content posted, and size of audience. Results Our study showed that clinically relevant information is posted by dentists and hygienists on social media. Clinically relevant information was provided in 89 blogs and podcasts, and topic analysis showed motives for blogging by host type: 55% (49 hosts) were practicing dentists or hygienists, followed by consultants (27 hosts, 30%), media including publishers and discussion board hosts (8 hosts, 9%), and professional organizations and corporations. Conclusions We demonstrated the participation of and potential for practicing dentists and hygienists to use social media to share clinical and other information with practicing colleagues. There is a clear audience for these social media sites, suggesting a changing mode of information diffusion in dentistry. This study was a first effort to fill the gap in understanding the nature and potential role of social media in clinical dentistry. PMID:28747291

Antimicrobial properties of conventional restorative filling materials and advances in antimicrobial properties of composite resins and glass ionomer cements-A literature review.

PubMed

Farrugia, Cher; Camilleri, Josette

2015-04-01

It has been reported that complete caries removal from cavities during restoration of teeth is difficult. Furthermore with the tissue saving approach it is expected that more of the saved affected tissue will possibly harbor more residual bacteria. Antimicrobial restorative filling materials would be ideal to prevent the spread of caries after completion of tooth restoration, thus preventing recurrent decay and eventually restoration failure. This paper reviews the literature on the antimicrobial properties of dental restorative filling materials. Pubmed searches on the antibacterial properties of restorative materials were carried out. Keywords were chosen to assess antibacterial properties of conventional filling materials. Methods of introducing antimicrobial agents in restorative materials were also reviewed together with the methodology used to assess antimicrobial activity. 174 articles from 1983 till 2014 were included. Adhesive materials have decreased antimicrobial activity when compared to amalgams and zinc oxides. Several techniques have been employed in order to increase the antimicrobial activity of restorative materials. Although antimicrobial activity of restorative materials is important, the introduction of antimicrobial agents/techniques should not be at the expense of other material properties. Environmental changes within a material may affect the bacterial response to the antimicrobial. Bacterial adhesion to the restorative materials should be assessed. Long term assessment of antimicrobial activity is important and is clinically relevant. The use of antimicrobial dental materials is important unless such characteristics are gained to the detriment of other material properties. Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Occurrence of Legionella in UK household showers.

PubMed

Collins, Samuel; Stevenson, David; Bennett, Allan; Walker, Jimmy

2017-04-01

Household water systems have been proposed as a source of sporadic, community acquired Legionnaires' disease. Showers represent a frequently used aerosol generating device in the domestic setting yet little is known about the occurrence of Legionella spp. in these systems. This study has investigated the prevalence of Legionella spp. by culture and qPCR in UK household showers. Ninety nine showers from 82 separate properties in the South of England were sampled. Clinically relevant Legionella spp. were isolated by culture in 8% of shower water samples representing 6% of households. Legionella pneumophila sg1 ST59 was isolated from two showers in one property and air sampling demonstrated its presence in the aerosol state. A further 31% of showers were positive by Legionella spp. qPCR. By multi-variable binomial regression modelling Legionella spp. qPCR positivity was associated with the age of the property (p=0.02), the age of the shower (p=0.01) and the frequency of use (p=0.09). The concentration of Legionella spp. detected by qPCR was shown to decrease with increased frequency of use (p=0.04) and more frequent showerhead cleaning (p=0.05). There was no association between Legionella spp. qPCR positivity and the cold water supply or the showerhead material (p=0.65 and p=0.71, respectively). Household showers may be important reservoirs of clinically significant Legionella and should be considered in source investigations. Simple public health advice may help to mitigate the risk of Legionella exposure in the domestic shower environment. Crown Copyright © 2016. Published by Elsevier GmbH. All rights reserved.

[Ibogaine - structure, influence on human body, clinical relevance].

PubMed

Zdrojewicz, Zygmunt; Kuszczak, Bartłomiej; Olszak, Natalia

2016-07-29

Ibogaine is a natural chemical compound, which belongs to the indole alkaloid family. It can be naturally found within the root bark of african plant Tabernanthe iboga. Ibogaine plays a significant role among tribal cultures. Ibogaine, in small amount, causes reduction of hunger, thirst and exhaustion. In bigger amount, however, it can cause intensive visions. Other effects include reduction or complete disappearance of absitnence symptoms visible in people addicted to the nicotine, alcohol, methamphetamine, cocaine or opioids, what has been scientifically proven after the tests on animals and small groups of people. After oral application, 80% of ibogaine is subjected to the Odemethylation into noribogaine; main catalyzing enzyme is cytochrome CYP2D6. Research suggests, that ibogaine acts in many places within central nervous system. NMDA receptors seem to play main role in its anti-addiction properties. It is important to mention the side effects of the compound, which are cardiotoxicity and neurotoxicity, what makes it harder to use its beneficial properties. Because of this, Ibogaine is included among the dangerous substance. However, there are a few clinics in the world which specializes in the use of the compound in order to interrupt the sypmtoms acute opioid withdrawal syndrome as well as a substance benficial in curing other addictions. There is more hope with synthetic derivatives of ibogaine, which although are less toxic still keep their anti-addiction properties. The aim is to collect the available knowledge related to the structure and effects on human body of alkaloid Tabernanthe iboga and consider the possibility of commercial medical use. © 2016 MEDPRESS.

The Piriform Cortex and Human Focal Epilepsy

PubMed Central

Vaughan, David N.; Jackson, Graeme D.

2014-01-01

It is surprising that the piriform cortex, when compared to the hippocampus, has been given relatively little significance in human epilepsy. Like the hippocampus, it has a phylogenetically preserved three-layered cortex that is vulnerable to excitotoxic injury, has broad connections to both limbic and cortical areas, and is highly epileptogenic – being critical to the kindling process. The well-known phenomenon of early olfactory auras in temporal lobe epilepsy highlights its clinical relevance in human beings. Perhaps because it is anatomically indistinct and difficult to approach surgically, as it clasps the middle cerebral artery, it has, until now, been understandably neglected. In this review, we emphasize how its unique anatomical and functional properties, as primary olfactory cortex, predispose it to involvement in focal epilepsy. From recent convergent findings in human neuroimaging, clinical epileptology, and experimental animal models, we make the case that the piriform cortex is likely to play a facilitating and amplifying role in human focal epileptogenesis, and may influence progression to epileptic intractability. PMID:25538678

Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders.

PubMed

Peyrol, Julien; Riva, Catherine; Amiot, Marie Josèphe

2017-03-20

Virgin olive oil (VOO) constitutes the main source of fat in the Mediterranean diet. VOO is rich in oleic acid, displaying health-promoting properties, but also contains minor bioactive components, especially phenolic compounds. Hydroxytyrosol (HT), the main polyphenol of olive oil, has been reported to be the most bioactive component. This review aims to compile the results of clinical, animal and cell culture studies evaluating the effects of HT on the features of Metabolic Syndrome (MetS) (body weight/adiposity, dyslipidemia, hypertension, and hyperglycemia/insulin resistance) and associated complications (oxidative stress and inflammation). HT was able to improve the lipid profile, glycaemia, and insulin sensitivity, and counteract oxidative and inflammatory processes. Experimental studies identified multiple molecular targets for HT conferring its beneficial effect on health in spite of its low bioavailability. However, rodent experiments and clinical trials with pure HT at biologically relevant concentrations are still lacking. Moreover, the roles of intestine and its gut microbiota have not been elucidated.

Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders

PubMed Central

Peyrol, Julien; Riva, Catherine; Amiot, Marie Josèphe

2017-01-01

Virgin olive oil (VOO) constitutes the main source of fat in the Mediterranean diet. VOO is rich in oleic acid, displaying health-promoting properties, but also contains minor bioactive components, especially phenolic compounds. Hydroxytyrosol (HT), the main polyphenol of olive oil, has been reported to be the most bioactive component. This review aims to compile the results of clinical, animal and cell culture studies evaluating the effects of HT on the features of Metabolic Syndrome (MetS) (body weight/adiposity, dyslipidemia, hypertension, and hyperglycemia/insulin resistance) and associated complications (oxidative stress and inflammation). HT was able to improve the lipid profile, glycaemia, and insulin sensitivity, and counteract oxidative and inflammatory processes. Experimental studies identified multiple molecular targets for HT conferring its beneficial effect on health in spite of its low bioavailability. However, rodent experiments and clinical trials with pure HT at biologically relevant concentrations are still lacking. Moreover, the roles of intestine and its gut microbiota have not been elucidated. PMID:28335507

Intravital Microscopy Imaging Approaches for Image-Guided Drug Delivery Systems

PubMed Central

Kirui, Dickson K.; Ferrari, Mauro

2016-01-01

Rapid technical advances in the field of non-linear microscopy have made intravital microscopy a vital pre-clinical tool for research and development of imaging-guided drug delivery systems. The ability to dynamically monitor the fate of macromolecules in live animals provides invaluable information regarding properties of drug carriers (size, charge, and surface coating), physiological, and pathological processes that exist between point-of-injection and the projected of site of delivery, all of which influence delivery and effectiveness of drug delivery systems. In this Review, we highlight how integrating intravital microscopy imaging with experimental designs (in vitro analyses and mathematical modeling) can provide unique information critical in the design of novel disease-relevant drug delivery platforms with improved diagnostic and therapeutic indexes. The Review will provide the reader an overview of the various applications for which intravital microscopy has been used to monitor the delivery of diagnostic and therapeutic agents and discuss some of their potential clinical applications. PMID:25901526

Personalized protein corona on nanoparticles and its clinical implications.

PubMed

Corbo, Claudia; Molinaro, Roberto; Tabatabaei, Mateen; Farokhzad, Omid C; Mahmoudi, Morteza

2017-02-28

It is now well understood that once in contact with biological fluids, nanoscale objects lose their original identity and acquire a new biological character, referred to as a protein corona. The protein corona changes many of the physicochemical properties of nanoparticles, including size, surface charge, and aggregation state. These changes, in turn, affect the biological fate of nanoparticles, including their pharmacokinetics, biodistribution, and therapeutic efficacy. It is progressively being accepted that even slight variations in the composition of a protein source (e.g., plasma and serum) can substantially change the composition of the corona formed on the surface of the exact same nanoparticles. Recently it has been shown that the protein corona is strongly affected by the patient's specific disease. Therefore, the same nanomaterial incubated with plasma proteins of patients with different pathologies adsorb protein coronas with different compositions, giving rise to the concept of personalized protein corona. Herein, we review this concept along with recent advances on the topic, with a particular focus on clinical relevance.

Nanoscale effects in dendrimer-mediated targeting of neuroinflammation

PubMed Central

Nance, Elizabeth; Zhang, Fan; Mishra, Manoj K.; Zhang, Zhi; Kambhampati, Siva P.; Kannan, Rangaramanujam M.; Kannan, Sujatha

2017-01-01

Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of many neurological disorders. Systemically-administered dendrimers target neuroinflammation and deliver drugs with significant efficacy, without the need for ligands. Elucidating the nanoscale aspects of targeting neuroinflammation will enable superior nanodevices for eventual translation. Using a rabbit model of cerebral palsy, we studied the in vivo contributions of dendrimer physicochemical properties and disease pathophysiology on dendrimer brain uptake, diffusion, and cell specific localization. Neutral dendrimers move efficiently within the brain parenchyma and rapidly localize in glial cells in regions of injury. Dendrimer uptake is also dependent on the extent of blood-brain-barrier breakdown, glial activation, and disease severity (mild, moderate, or severe), which can lend the dendrimer to be used as an imaging biomarker for disease phenotype. This new understanding of the in vivo mechanism of dendrimer-mediated delivery in a clinically-relevant rabbit model provides greater opportunity for clinical translation of targeted brain injury therapies. PMID:27267631

Cell mechanics as a marker for diseases: Biomedical applications of AFM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rianna, Carmela; Radmacher, Manfred, E-mail: mr@biophysik.uni-bremen.de

Many diseases are related to changes in cell mechanics. Atomic Force Microscopy (AFM) is one of the most suitable techniques allowing the investigation of both topography and mechanical properties of adherent cells with high spatial resolution under physiological conditions. Over the years the use of this technique in medical and clinical applications has largely increased, resulting in the notion of cell mechanics as a biomarker to discriminate between different physiological and pathological states of cells. Cell mechanics has proven to be a biophysical fingerprint able discerning between cell phenotypes, unraveling processes in aging or diseases, or even detecting and diagnosingmore » cellular pathologies. We will review in this report some of the works on cell mechanics investigated by AFM with clinical and medical relevance in order to clarify the state of research in this field and to highlight the role of cell mechanics in the study of pathologies, focusing on cancer, blood and cardiovascular diseases.« less

Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective

PubMed Central

Bellini, Stefania; Barutta, Federica; Imperatore, Luigi; Bruno, Graziella; Gruden, Gabriella

2017-01-01

Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective. PMID:29240668

Nanoscale effects in dendrimer-mediated targeting of neuroinflammation.

PubMed

Nance, Elizabeth; Zhang, Fan; Mishra, Manoj K; Zhang, Zhi; Kambhampati, Siva P; Kannan, Rangaramanujam M; Kannan, Sujatha

2016-09-01

Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of many neurological disorders. Systemically-administered dendrimers target neuroinflammation and deliver drugs with significant efficacy, without the need for ligands. Elucidating the nanoscale aspects of targeting neuroinflammation will enable superior nanodevices for eventual translation. Using a rabbit model of cerebral palsy, we studied the in vivo contributions of dendrimer physicochemical properties and disease pathophysiology on dendrimer brain uptake, diffusion, and cell specific localization. Neutral dendrimers move efficiently within the brain parenchyma and rapidly localize in glial cells in regions of injury. Dendrimer uptake is also dependent on the extent of blood-brain-barrier breakdown, glial activation, and disease severity (mild, moderate, or severe), which can lend the dendrimer to be used as an imaging biomarker for disease phenotype. This new understanding of the in vivo mechanism of dendrimer-mediated delivery in a clinically-relevant rabbit model provides greater opportunity for clinical translation of targeted brain injury therapies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Nanotechnology in Dental Sciences: Moving towards a Finer Way of Doing Dentistry

PubMed Central

Uskoković, Vuk; Bertassoni, Luiz Eduardo

2010-01-01

Nanotechnologies are predicted to revolutionize: (a) the control over materials properties at ultrafine scales; and (b) the sensitivity of tools and devices applied in various scientific and technological fields. In this short review, we argue that dentistry will be no exception to this trend. Here, we present a dynamic view of dental tissues, an adoption of which may lead to finer, more effective and minimally invasive reparation approaches. By doing so, we aim at providing insights into some of the breakthroughs relevant to understanding the genesis of dental tissues at the nanostructural level or generating dental materials with nanoscale critical boundaries. The lineage of the progress of dental science, including the projected path along the presumed nanotechnological direction of research and clinical application is mentioned too. We conclude by claiming that dentistry should follow the trend of probing matter at nanoscale that currently dominates both materials and biological sciences in order to improve on the research strategies and clinical techniques that have traditionally rested on mechanistic assumptions. PMID:27103959

Engineered knottin peptides as diagnostics, therapeutics, and drug delivery vehicles.

PubMed

Kintzing, James R; Cochran, Jennifer R

2016-10-01

Inhibitor cystine-knots, also known as knottins, are a structural family of ultra-stable peptides with diverse functions. Knottins and related backbone-cyclized peptides called cyclotides contain three disulfide bonds connected in a particular arrangement that endows these peptides with high thermal, proteolytic, and chemical stability. Knottins have gained interest as candidates for non-invasive molecular imaging and for drug development as they can possess the pharmacological properties of small molecules and the target affinity and selectively of protein biologics. Naturally occurring knottins are clinically approved for treating chronic pain and GI disorders. Combinatorial methods are being used to engineer knottins that can bind to other clinically relevant targets in cancer, and inflammatory and cardiac disease. This review details recent examples of engineered knottin peptides; their use as molecular imaging agents, therapeutics, and drug delivery vehicles; modifications that can be introduced to improve peptide folding and bioactivity; and future perspectives and challenges in the field. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Systematic Approach for Discovering Novel, Clinically Relevant Bacteria

PubMed Central

Simmon, Keith E.; Fisher, Mark A.

2012-01-01

Sequencing of the 16S rRNA gene (16S) is a reference method for bacterial identification. Its expanded use has led to increased recognition of novel bacterial species. In most clinical laboratories, novel species are infrequently encountered, and their pathogenic potential is often difficult to assess. We reviewed partial 16S sequences from >26,000 clinical isolates, analyzed during February 2006–June 2010, and identified 673 that have <99% sequence identity with valid reference sequences and are thus possibly novel species. Of these 673 isolates, 111 may represent novel genera (<95% identity). Isolates from 95 novel taxa were recovered from multiple patients, indicating possible clinical relevance. Most repeatedly encountered novel taxa belonged to the genera Nocardia (14 novel taxa, 42 isolates) and Actinomyces (12 novel taxa, 52 isolates). This systematic approach for recognition of novel species with potential diagnostic or therapeutic relevance provides a basis for epidemiologic surveys and improvement of sequence databases and may lead to identification of new clinical entities. PMID:22377371

A systematic approach for discovering novel, clinically relevant bacteria.

PubMed

Schlaberg, Robert; Simmon, Keith E; Fisher, Mark A

2012-03-01

Sequencing of the 16S rRNA gene (16S) is a reference method for bacterial identification. Its expanded use has led to increased recognition of novel bacterial species. In most clinical laboratories, novel species are infrequently encountered, and their pathogenic potential is often difficult to assess. We reviewed partial 16S sequences from >26,000 clinical isolates, analyzed during February 2006-June 2010, and identified 673 that have <99% sequence identity with valid reference sequences and are thus possibly novel species. Of these 673 isolates, 111 may represent novel genera (<95% identity). Isolates from 95 novel taxa were recovered from multiple patients, indicating possible clinical relevance. Most repeatedly encountered novel taxa belonged to the genera Nocardia (14 novel taxa, 42 isolates) and Actinomyces (12 novel taxa, 52 isolates). This systematic approach for recognition of novel species with potential diagnostic or therapeutic relevance provides a basis for epidemiologic surveys and improvement of sequence databases and may lead to identification of new clinical entities.

Relevance of randomised controlled trials in oncology.

PubMed

Tannock, Ian F; Amir, Eitan; Booth, Christopher M; Niraula, Saroj; Ocana, Alberto; Seruga, Bostjan; Templeton, Arnoud J; Vera-Badillo, Francisco

2016-12-01

Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing. Copyright © 2016 Elsevier Ltd. All rights reserved.

MalaCards: an integrated compendium for diseases and their annotation

PubMed Central

Rappaport, Noa; Nativ, Noam; Stelzer, Gil; Twik, Michal; Guan-Golan, Yaron; Iny Stein, Tsippi; Bahir, Iris; Belinky, Frida; Morrey, C. Paul; Safran, Marilyn; Lancet, Doron

2013-01-01

Comprehensive disease classification, integration and annotation are crucial for biomedical discovery. At present, disease compilation is incomplete, heterogeneous and often lacking systematic inquiry mechanisms. We introduce MalaCards, an integrated database of human maladies and their annotations, modeled on the architecture and strategy of the GeneCards database of human genes. MalaCards mines and merges 44 data sources to generate a computerized card for each of 16 919 human diseases. Each MalaCard contains disease-specific prioritized annotations, as well as inter-disease connections, empowered by the GeneCards relational database, its searches and GeneDecks set analyses. First, we generate a disease list from 15 ranked sources, using disease-name unification heuristics. Next, we use four schemes to populate MalaCards sections: (i) directly interrogating disease resources, to establish integrated disease names, synonyms, summaries, drugs/therapeutics, clinical features, genetic tests and anatomical context; (ii) searching GeneCards for related publications, and for associated genes with corresponding relevance scores; (iii) analyzing disease-associated gene sets in GeneDecks to yield affiliated pathways, phenotypes, compounds and GO terms, sorted by a composite relevance score and presented with GeneCards links; and (iv) searching within MalaCards itself, e.g. for additional related diseases and anatomical context. The latter forms the basis for the construction of a disease network, based on shared MalaCards annotations, embodying associations based on etiology, clinical features and clinical conditions. This broadly disposed network has a power-law degree distribution, suggesting that this might be an inherent property of such networks. Work in progress includes hierarchical malady classification, ontological mapping and disease set analyses, striving to make MalaCards an even more effective tool for biomedical research. Database URL: http://www.malacards.org/ PMID:23584832

Relationship Between Abdominal Symptoms and Fructose Ingestion in Children with Chronic Abdominal Pain.

PubMed

Hammer, Veronika; Hammer, Katharina; Memaran, Nima; Huber, Wolf-Dietrich; Hammer, Karin; Hammer, Johann

2018-05-01

Limited valid data are available regarding the association of fructose-induced symptoms, fructose malabsorption, and clinical symptoms. To develop a questionnaire for valid symptom assessment before and during a carbohydrate breath test and to correlate symptoms with fructose breath test results in children/adolescents with functional abdominal pain. A Likert-type questionnaire assessing symptoms considered relevant for hydrogen breath test in children was developed and underwent initial validation. Fructose malabsorption was determined by increased breath hydrogen in 82 pediatric patients with functional abdominal pain disorders; fructose-induced symptoms were quantified by symptom score ≥2 and relevant symptom increase over baseline. The results were correlated with clinical symptoms. The time course of symptoms during the breath test was assessed. The questionnaire exhibited good psychometric properties in a standardized assessment of the severity of carbohydrate-related symptoms. A total of 40 % (n = 33) had malabsorption; symptoms were induced in 38 % (n = 31), but only 46 % (n = 15) with malabsorption were symptomatic. There was no significant correlation between fructose malabsorption and fructose-induced symptoms. Clinical symptoms correlated with symptoms evoked during the breath test (p < 0.001, r 2  = 0.21) but not with malabsorption (NS). Malabsorbers did not differ from non-malabsorbers in terms of symptoms during breath test. Symptomatic patients had significantly higher pain and flatulence scores over the 9-h observation period (p < 0.01) than did nonsymptomatic patients; the meteorism score was higher after 90 min. Fructose-induced symptoms but not fructose malabsorption are related to increased abdominal symptoms and have distinct timing patterns.

Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models

PubMed Central

Widzowski, D; Maciag, C; Zacco, A; Hudzik, T; Liu, J; Nyberg, S; Wood, M W

2015-01-01

Background and Purpose Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine. Experimental Approach We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant‐like and anxiolytic‐like drug action. Key Results Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5‐HT1A receptors, and the anxiolytic‐like activity of norquetiapine in rat punished responding was blocked by the 5‐HT1A antagonist, WAY100635. Conclusions and Implications Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5‐HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine. PMID:26436896

Evaluation of a respiratory symptom diary for clinical studies of idiopathic pulmonary fibrosis.

PubMed

Bacci, Elizabeth Dansie; O'Quinn, Sean; Leidy, Nancy Kline; Murray, Lindsey; Vernon, Margaret

2018-01-01

There are no validated patient diaries for evaluating respiratory symptoms in idiopathic pulmonary fibrosis (IPF). To evaluate the performance properties of the chronic obstructive pulmonary disease (COPD) Evaluating Respiratory Symptoms™ (E-RS™: COPD) measure in patients with IPF. Concept elicitation and cognitive interviews were conducted with IPF patients to evaluate content validity, including comprehensiveness, relevance, and interpretability of E-RS™ items in this patient population. Secondary analyses of IPF clinical study data were performed to evaluate the scoring structure of the tool. With modifications, reliability, validity, and responsiveness of the instrument (E-RS™: IPF) were evaluated. Qualitative interviews (n = 30) were conducted. During the elicitation interviews (n = 20), concept saturation for IPF respiratory symptoms was achieved; all respiratory symptoms covered by the E-RS™ were endorsed by ≥ 30% of the sample. During cognitive interviews (n = 10), all participants found the items interpretable and relevant. Factor analyses conducted via secondary analysis of IPF clinical study data identified no total score and four symptom scales: Chest, Breathlessness, Cough, and Sputum. Reliability of each scale was high (internal consistency [α] >0.85); 2-day reproducibility (ICC >0.88). Validity was supported through significant (P < 0.0001) relationships with the St. George's Respiratory Questionnaire (SGRQ), the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), and other variables. The scales were responsive to change when evaluated using SGRQ Symptoms, UCSD-SOBQ, and Patient Global Impression of Change as anchors (P < 0.01 to P < 0.0001). The E-RS™: IPF is a valid, reliable, and responsive tool for evaluating respiratory symptoms in patients with IPF. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges.

PubMed

van Brummelen, Emilie M J; Ros, Willeke; Wolbink, Gertjan; Beijnen, Jos H; Schellens, Jan H M

2016-10-01

: In oncology, an increasing number of targeted anticancer agents and immunotherapies are of biological origin. These biological drugs may trigger immune responses that lead to the formation of antidrug antibodies (ADAs). ADAs are directed against immunogenic parts of the drug and may affect efficacy and safety. In other medical fields, such as rheumatology and hematology, the relevance of ADA formation is well established. However, the relevance of ADAs in oncology is just starting to be recognized, and literature on this topic is scarce. In an attempt to fill this gap in the literature, we provide an up-to-date status of ADA formation in oncology. In this focused review, data on ADAs was extracted from 81 clinical trials with biological anticancer agents. We found that most biological anticancer drugs in these trials are immunogenic and induce ADAs (63%). However, it is difficult to establish the clinical relevance of these ADAs. In order to determine this relevance, the possible effects of ADAs on pharmacokinetics, efficacy, and safety parameters need to be investigated. Our data show that this was done in fewer than 50% of the trials. In addition, we describe the incidence and consequences of ADAs for registered agents. We highlight the challenges in ADA detection and argue for the importance of validating, standardizing, and describing well the used assays. Finally, we discuss prevention strategies such as immunosuppression and regimen adaptations. We encourage the launch of clinical trials that explore these strategies in oncology. Because of the increasing use of biologicals in oncology, many patients are at risk of developing antidrug antibodies (ADAs) during therapy. Although clinical consequences are uncertain, ADAs may affect pharmacokinetics, patient safety, and treatment efficacy. ADA detection and reporting is currently highly inconsistent, which makes it difficult to evaluate the clinical consequences. Standardized reporting of ADA investigations in the context of the aforementioned parameters is critical to understanding the relevance of ADA formation for each drug. Furthermore, the development of trials that specifically aim to investigate clinical prevention strategies in oncology is needed. ©AlphaMed Press.

Effect, Feasibility, and Clinical Relevance of Cell Enrichment in Large Volume Fat Grafting: A Systematic Review.

PubMed

Rasmussen, Bo Sonnich; Lykke Sørensen, Celine; Vester-Glowinski, Peter Viktor; Herly, Mikkel; Trojahn Kølle, Stig-Frederik; Fischer-Nielsen, Anne; Drzewiecki, Krzysztof Tadeusz

2017-07-01

Large volume fat grafting is limited by unpredictable volume loss; therefore, methods of improving graft retention have been developed. Fat graft enrichment with either stromal vascular fraction (SVF) cells or adipose tissue-derived stem/stromal cells (ASCs) has been investigated in several animal and human studies, and significantly improved graft retention has been reported. Improvement of graft retention and the feasibility of these techniques are equally important in evaluating the clinical relevance of cell enrichment. We conducted a systematic search of PubMed to identify studies on fat graft enrichment that used either SVF cells or ASCs, and only studies reporting volume assessment were included. A total of 38 articles (15 human and 23 animal) were included to investigate the effects of cell enrichment on graft retention as well as the feasibility and clinical relevance of cell-enriched fat grafting. Improvements in graft retention, the SVF to fat (SVF:fat) ratio, and the ASC concentration used for enrichment were emphasized. We proposed an increased retention rate greater than 1.5-fold relative to nonenriched grafts and a maximum SVF:fat ratio of 1:1 as the thresholds for clinical relevance and feasibility, respectively. Nine studies fulfilled these criteria, whereof 6 used ASCs for enrichment. We found no convincing evidence of a clinically relevant effect of SVF enrichment in humans. ASC enrichment has shown promising results in enhancing graft retention, but additional clinical trials are needed to substantiate this claim and also determine the optimal concentration of SVF cells/ASCs for enrichment. 4. © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Clinical Evidence: a useful tool for promoting evidence-based practice?

PubMed

Formoso, Giulio; Moja, Lorenzo; Nonino, Francesco; Dri, Pietro; Addis, Antonio; Martini, Nello; Liberati, Alessandro

2003-12-23

Research has shown that many healthcare professionals have problems with guidelines as they would prefer to be given all relevant information relevant to decision-making rather than being told what they should do. This study assesses doctors' judgement of the validity, relevance, clarity and usability of the Italian translation of Clinical Evidence (CE) after its free distribution launched by the Italian Ministry of Health. Opinions elicited using a standardised questionnaire delivered either by mail or during educational or professional meetings. Twenty percent (n = 1350) doctors participated the study. Most of them found CE's content valid, useful and relevant for their clinical practice, and said CE can foster communications among clinicians, particularly among GPs and specialists. Hospital doctors (63%) more often than GPs (48%) read the detailed presentation of individual chapters. Twenty-nine percent said CE brought changes in their clinical practice. Doctors appreciated CE's nature of an evidence-based information compendium and would have not preferred a collection of practice guidelines. Overall, the pilot initiative launched by the Italian Ministry of Health seems to have been well received and to support the subsequent decision to make the Italian edition of Clinical Evidence concise available to all doctors practising in the country. Local implementation initiatives should be warranted to favour doctor's use of CE.

Clinically Relevant Changes in Emotional Expression in Children with ADHD Treated with Lisdexamfetamine Dimesylate

ERIC Educational Resources Information Center

Katic, Alain; Ginsberg, Lawrence; Jain, Rakesh; Adeyi, Ben; Dirks, Bryan; Babcock, Thomas; Scheckner, Brian; Richards, Cynthia; Lasser, Robert; Turgay, Atilla; Findling, Robert L.

2012-01-01

Objective: To describe clinically relevant effects of lisdexamfetamine dimesylate (LDX) on emotional expression (EE) in children with ADHD. Method: Children with ADHD participated in a 7-week, open-label, LDX dose-optimization study. Expression and Emotion Scale for Children (EESC) change scores were analyzed post hoc using two methods to…

Chiral drug analysis using mass spectrometric detection relevant to research and practice in clinical and forensic toxicology.

PubMed

Schwaninger, Andrea E; Meyer, Markus R; Maurer, Hans H

2012-12-21

This paper reviews analytical approaches published in 2002-2012 for chiral drug analysis and their relevance in research and practice in the field of clinical and forensic toxicology. Separation systems such as gas chromatography, high performance liquid chromatography, capillary electromigration, and supercritical fluid chromatography, all coupled to mass spectrometry, are discussed. Typical applications are reviewed for relevant chiral analytes such as amphetamines and amphetamine-derived designer drugs, methadone, tramadol, psychotropic and other CNS acting drugs, anticoagulants, cardiovascular drugs, and some other drugs. Usefulness of chiral drug analysis in the interpretation of analytical results in clinical and forensic toxicology is discussed as well. Copyright © 2012 Elsevier B.V. All rights reserved.

Improving the clinical management of traumatic brain injury through the pharmacokinetic modeling of peripheral blood biomarkers.

PubMed

Dadas, Aaron; Washington, Jolewis; Marchi, Nicola; Janigro, Damir

2016-11-30

Blood biomarkers of neurovascular damage are used clinically to diagnose the presence severity or absence of neurological diseases, but data interpretation is confounded by a limited understanding of their dependence on variables other than the disease condition itself. These include half-life in blood, molecular weight, and marker-specific biophysical properties, as well as the effects of glomerular filtration, age, gender, and ethnicity. To study these factors, and to provide a method for markers' analyses, we developed a kinetic model that allows the integrated interpretation of these properties. The pharmacokinetic behaviors of S100B (monomer and homodimer), Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 were modeled using relevant chemical and physical properties; modeling results were validated by comparison with data obtained from healthy subjects or individuals affected by neurological diseases. Brain imaging data were used to model passage of biomarkers across the blood-brain barrier. Our results show the following: (1) changes in biomarker serum levels due to age or disease progression are accounted for by differences in kidney filtration; (2) a significant change in the brain-to-blood volumetric ratio, which is characteristic of infant and adult development, contributes to variation in blood concentration of biomarkers; (3) the effects of extracranial contribution at steady-state are predicted in our model to be less important than suspected, while the contribution of blood-brain barrier disruption is confirmed as a significant factor in controlling markers' appearance in blood, where the biomarkers are typically detected; (4) the contribution of skin to the marker S100B blood levels depends on a direct correlation with pigmentation and not ethnicity; the contribution of extracranial sources for other markers requires further investigation. We developed a multi-compartment, pharmacokinetic model that integrates the biophysical properties of a given brain molecule and predicts its time-dependent concentration in blood, for populations of varying physical and anatomical characteristics. This model emphasizes the importance of the blood-brain barrier as a gatekeeper for markers' blood appearance and, ultimately, for rational clinical use of peripherally-detected brain protein.

A review on the effects of Allium sativum (Garlic) in metabolic syndrome.

PubMed

Hosseini, A; Hosseinzadeh, H

2015-11-01

The metabolic syndrome is a common problem world-wide and includes abdominal obesity, hypertension, dyslipidemia, and hyperglycemia disorders. It leads to insulin resistance and the development of diabetes mellitus or cardiovascular disease. Allium sativum (garlic) has been documented to exhibit anti-diabetic, hypotensive, and hypolipidemic properties. This suggests a potential role of A. sativum in the management of metabolic syndrome; however, more studies should be conducted to evaluate its effectiveness. In this review, we discussed the most relevant articles to find out the role of A. sativum in different components of metabolic syndrome and cardiovascular disease risk factors. Because human reports are rare, further studies are required to establish the clinical value of A. sativum in metabolic syndrome.

Characterization of Leukocyte-platelet Rich Fibrin, A Novel Biomaterial.

PubMed

Madurantakam, Parthasarathy; Yoganarasimha, Suyog; Hasan, Fadi K

2015-09-29

Autologous platelet concentrates represent promising innovative tools in the field of regenerative medicine and have been extensively used in oral surgery. Unlike platelet rich plasma (PRP) that is a gel or a suspension, Leukocyte-Platelet Rich Fibrin (L-PRF) is a solid 3D fibrin membrane generated chair-side from whole blood containing no anti-coagulant. The membrane has a dense three dimensional fibrin matrix with enriched platelets and abundant growth factors. L-PRF is a popular adjunct in surgeries because of its superior handling characteristics as well as its suturability to the wound bed. The goal of the study is to demonstrate generation as well as provide detailed characterization of relevant properties of L-PRF that underlie its clinical success.

Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain.

PubMed

Gdowski, Andrew S; Ranjan, Amalendu; Sarker, Marjana R; Vishwanatha, Jamboor K

2017-09-01

The aim of this study was to develop a novel cabazitaxel bone targeted nanoparticle (NP) system for improved drug delivery to the bone microenvironment. Nanoparticles were developed using poly(D,L-lactic-co-glycolic acid) and cabazitaxel as the core with amino-bisphosphonate surface conjugation. Optimization of nanoparticle physiochemical properties, in vitro evaluation in prostate cancer cell lines and in vivo testing in an intraosseous model of metastatic prostate cancer was performed. This bone targeted cabazitaxel nanocarrier system showed significant reduction in tumor burden, while at the same time maintaining bone structure integrity and reducing pain in the mouse tumor limb. This bone microenvironment targeted nanoparticle system and clinically relevant approach of evaluation represents a promising advancement for treating bone metastatic cancer.

Rapid Preparation of a Plasma Membrane Fraction: Western Blot Detection of Translocated Glucose Transporter 4 from Plasma Membrane of Muscle and Adipose Cells and Tissues.

PubMed

Yamamoto, Norio; Yamashita, Yoko; Yoshioka, Yasukiyo; Nishiumi, Shin; Ashida, Hitoshi

2016-08-01

Membrane proteins account for 70% to 80% of all pharmaceutical targets, indicating their clinical relevance and underscoring the importance of identifying differentially expressed membrane proteins that reflect distinct disease properties. The translocation of proteins from the bulk of the cytosol to the plasma membrane is a critical step in the transfer of information from membrane-embedded receptors or transporters to the cell interior. To understand how membrane proteins work, it is important to separate the membrane fraction of cells. This unit provides a protocol for rapidly obtaining plasma membrane fractions for western blot analysis. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Parallel programming of gradient-based iterative image reconstruction schemes for optical tomography.

PubMed

Hielscher, Andreas H; Bartel, Sebastian

2004-02-01

Optical tomography (OT) is a fast developing novel imaging modality that uses near-infrared (NIR) light to obtain cross-sectional views of optical properties inside the human body. A major challenge remains the time-consuming, computational-intensive image reconstruction problem that converts NIR transmission measurements into cross-sectional images. To increase the speed of iterative image reconstruction schemes that are commonly applied for OT, we have developed and implemented several parallel algorithms on a cluster of workstations. Static process distribution as well as dynamic load balancing schemes suitable for heterogeneous clusters and varying machine performances are introduced and tested. The resulting algorithms are shown to accelerate the reconstruction process to various degrees, substantially reducing the computation times for clinically relevant problems.

An informatics approach to analyzing the incidentalome.

PubMed

Berg, Jonathan S; Adams, Michael; Nassar, Nassib; Bizon, Chris; Lee, Kristy; Schmitt, Charles P; Wilhelmsen, Kirk C; Evans, James P

2013-01-01

Next-generation sequencing has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings. We categorized 2,016 genes linked with Mendelian diseases into "bins" based on clinical utility and validity, and used a computational algorithm to analyze 80 whole-genome sequences in order to explore the use of such an approach in a simulated real-world setting. The algorithm effectively reduced the number of variants requiring human review and identified incidental variants with likely clinical relevance. Incorporation of the Human Gene Mutation Database improved the yield for missense mutations but also revealed that a substantial proportion of purported disease-causing mutations were misleading. This approach is adaptable to any clinically relevant bin structure, scalable to the demands of a clinical laboratory workflow, and flexible with respect to advances in genomics. We anticipate that application of this strategy will facilitate pretest informed consent, laboratory analysis, and posttest return of results in a clinical context.

Psychometric Properties of the Breast Cancer Screening Beliefs Questionnaire Among Women of Indian Ethnicity Living in Australia.

PubMed

Kwok, Cannas; Pillay, Rona; Lee, Chun Fan

2016-01-01

Indian women have been consistently reported as having low participation in breast cancer screening practices. A valid and reliable instrument to explore their breast cancer beliefs is essential for development of interventions to promote breast cancer screening practices. The aim of this study was to report the psychometric properties of the Breast Cancer Screening Beliefs Questionnaire (BCSBQ) in an Indian community in Australia. A convenience sample of 242 Indian Australian women was recruited from Indian community organizations and personal networking. Explanatory factor analysis was conducted to study the factor structure. Clinical validity was examined by Cuzick's nonparametric test, and Cronbach's α was used to assess internal consistency reliability. Exploratory factor analysis showed a similar fit to the hypothesized 3-factor structure. The frequency of breast cancer screening practices was significantly associated with attitudes toward general health check-up. Knowledge and perceptions about the breast cancer scale were not significantly associated with clinical breast examinations and mammography. Perceived barriers to mammography were much less evident among women who engaged in breast awareness and clinical breast examination. Results indicated that the BCSBQ had satisfactory validity and internal consistency. Cronbach's α of the 3 subscales ranged from .81 to .91. The BCSBQ is a culturally appropriate, valid, and reliable instrument for assessing the beliefs, knowledge, and attitudes about breast cancer and breast cancer screening practices among women of Indian ethnic extraction living in Australia. The BCSBQ can be used to provide nurses with information relevant for the development of culturally sensitive breast health education programs.

[Botulinum toxin for the treatment of pain syndromes].

PubMed

Ferreira, Joaquim J; Couto, Marina; Costa, João; Coelho, Miguel; Rosa, Mário M; Sampaio, Cristina

2006-01-01

Although botulinum toxin (BoNT) is being used for therapeutic purposes for more than 20 years, the list of potential new indications continues to increase and includes various pain syndromes. The pain relief experienced by patients with dystonia and spasticity from intramuscular BoNT injections suggested that other chronic skeletal-muscles pain conditions may also benefit. BoNT inhibits the release of acetylcholine at the neuromuscular junction thereby reducing striatal muscle contractions and the proposed analgesic property was initially attributed to muscular relaxation. A specific analgesic BoNT effect is difficult to conclude from studies where pain is conditioned by other associated symptoms like dystonia, muscle contraction or spasticity. One alternative is to critically appraise clinical trials where BoNT was studied as the active intervention and pain evaluated as an outcome. From this analysis there is convincing evidence for the effectiveness of BoNT in the treatment of pain associated with cervical dystonia. For all other pain syndromes there have been relatively few, small sized, placebo-controlled studies (myofascial pain syndrome, chronic neck and low back pain, piriformis syndrome and fibromyalgia) and the results of these studies have been contradictory or non conclusive. To establish the analgesic properties of BoNT there is a need for appropriately designed, exploratory randomized controlled studies in well accepted human models of nociceptive or neuropathic pain. This does not exclude the subsequent need to conduct pragmatic trials to evaluate the effectiveness of BoNT in conditions where the improvement of pain or any associated clinical sign or symptom may be of clinical relevance.

[In vitro antibacterial activity of Curcuma longa (Zingiberaceae) against nosocomial bacteria in Montería, Colombia].

PubMed

Méndez Álvarez, Nelson; Angulo Ortíz, Alberto; Contreras Martínez, Orfa

2016-09-01

Bacterial resistance is a growing health problem worldwide that has serious economic and social impacts, compromising public health, and the therapeutic action of current antibiotics. Therefore, the search for new compounds with antimicrobial properties is relevant in modern studies, particularly against bacteria of clinical interest. In the present study, in vitro antibacterial activity of the ethanol extract and essential oil of Curcuma longa (Zingiberaceae) was evaluated against nosocomial bacteria, using the microdilution method. Escherichia coli strains, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus sp. were used, Salmonella sp. and Bacillus sp., isolated from nosocomial infections in a hospital in the city of Monteria and reference strains of S. aureus ATCC 43300, S. aureus ATCC 29213, S. aureus ATCC 25923, P. aeruginosa ATCC 27853, E. coli ATCC 25922 and K. pneumonia ATCC 700603. The ethanol extract antibacterial profile was more efficient at higher concentrations (1 000 ppm), obtaining significant percentages of reduction of more than 50 % against K. pneumoniae ATCC 700603 and a clinical isolate of E. coli; while compared to Bacillus clinical isolate, was more active than the essential oil. For the rest of microorganisms, the reduction percentages obtained at a concentration of 1 000 ppm varied between 17 and 42 % with ethanolic extract, and 8 to 43 % with essential oil. At concentrations of 100 and 500 ppm antibacterial activity of the extracts was lower. The results indicated that the ethanolic extract and essential oil of C. longa rhizomes have active compounds with antibacterial properties that could be used in future research as a therapeutic alternative for the treatment of infections caused by nosocomial pathogens.

Contact dermatitis in saffron workers: clinical profile and identification of contact sensitizers in a saffron-cultivating area of Kashmir Valley of North India.

PubMed

Hassan, Iffat; Kamili, Afifa; Rasool, Farhan; Nehvi, Firdous; Rather, Parvaiz; Yasmin, Salwee; Pampori, Rafiq A; Jabeen, Yasmeen; Yaseen, Atiya; Bashir, Safia; Naaz, Saima

2015-01-01

Saffron, a bulbous perennial plant belonging to Iridaceae family, is the most expensive cultivated herb that is widely used for industrial and nonindustrial purposes. However, besides its attractive and valuable properties, contact dermatitis due to saffron is an uncommon reported entity. The aims of this study were to determine the clinical pattern patch-testing profile of contact dermatitis in saffron workers and to identify the most common allergens/sensitizers. One hundred ten saffron workers were patch-tested with 39 allergens, which included Indian standard series antigens, plant series antigens, and extracts from different parts of saffron flower. The allergens in Indian standard series accounted for 52.44% of positive reactions. Plant series and different parts of saffron accounted for 47.56% of the positive reactions. Among those patients with positive responses to the supplemental saffron allergens, 83.3% were of present or past relevance. The data observed in the present study confirm that the saffron dermatitis is a distinct clinical entity with characteristic clinical presentation and has a strong significance as an occupational allergen in those handling this plant. Patch testing with different parts of saffron flower has a role to play in finding out the etiological cause.

Reaching clinically relevant outcome measures for new pharmacotherapy and immunotherapy of atopic eczema.

PubMed

Chalmers, Joanne; Deckert, Stefanie; Schmitt, Jochen

2015-06-01

This article describes the core outcome set (COS) for atopic eczema trials. COS describe a minimum set of outcomes to be assessed in a defined situation. COS are required to overcome the current situation of different trials using different endpoints with unclear/insufficient measurement properties resulting in incomparable trials. The global multi-stakeholder Harmonising Outcomes Measures for Eczema initiative developed the Harmonising Outcomes Measures for Eczema roadmap as a generic framework for COS development. Following the establishment of a panel representing all stakeholders, a core set of outcome domains need to be selected based on systematic reviews and consensus methods. Outcome measurement instruments to assess these core domains need to be valid, reliable, and feasible. There is broad global consensus that clinical signs, quality of life, symptoms, and long-term control of flares form the COS for atopic eczema trials. The Eczema Area and Severity Index is recommended to assess clinical signs in atopic eczema trials. Systematic reviews to identify adequate outcome measurement instruments for the other core outcome domains are underway. Clinical signs should be assessed in all atopic eczema trials by at least the Eczema Area and Severity Index. Quality of life, symptoms, and flares should also be assessed in all atopic eczema trials by a valid, reliable, and feasible instrument.

[E-Health and reality - what are we facing in patient care?

PubMed

Gehring, H; Rackebrandt, K; Imhoff, M

2018-03-01

The terms e‑Health and digitization are core elements of a change in our time. The main drivers of this change - in addition to a dynamic market - are the serious advantages for the healthcare sector in the processing of tasks and requirements. The large amounts of data, the intensively growing medical knowledge, the rapidly advancing technological developments and the goal of a personalized, customized therapy for the patient, make the application absolutely necessary. While e‑Health describes the use of information and communication technologies in healthcare, the concept of digitization is associated with the underlying processes of change and innovation. Digital technologies include software and hardware based developments. The term clinical data intelligence describes the property of workability and also characterizes the collaboration of clinically relevant systems with which the medical user works. The hierarchy in digital processing maps the levels from pure data management through clinical decision support to automated process flows and autonomously operating units. The combination of patient data management and clinical decision support proves its value in terms of error reduction, prevention, quality and safety, especially in drug therapy. The aim of this overview is the presentation of the existing reality in medical centers with perspectives derived from the point of view of the medical user.

Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.

PubMed

Malta, Tathiane M; de Souza, Camila F; Sabedot, Thais S; Silva, Tiago C; Mosella, Maritza S; Kalkanis, Steven N; Snyder, James; Castro, Ana Valeria B; Noushmehr, Houtan

2018-04-09

Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.

Generation of 3D synthetic breast tissue

NASA Astrophysics Data System (ADS)

Elangovan, Premkumar; Dance, David R.; Young, Kenneth C.; Wells, Kevin

2016-03-01

Virtual clinical trials are an emergent approach for the rapid evaluation and comparison of various breast imaging technologies and techniques using computer-based modeling tools. A fundamental requirement of this approach for mammography is the use of realistic looking breast anatomy in the studies to produce clinically relevant results. In this work, a biologically inspired approach has been used to simulate realistic synthetic breast phantom blocks for use in virtual clinical trials. A variety of high and low frequency features (including Cooper's ligaments, blood vessels and glandular tissue) have been extracted from clinical digital breast tomosynthesis images and used to simulate synthetic breast blocks. The appearance of the phantom blocks was validated by presenting a selection of simulated 2D and DBT images interleaved with real images to a team of experienced readers for rating using an ROC paradigm. The average areas under the curve for 2D and DBT images were 0.53+/-.04 and 0.55+/-.07 respectively; errors are the standard errors of the mean. The values indicate that the observers had difficulty in differentiating the real images from simulated images. The statistical properties of simulated images of the phantom blocks were evaluated by means of power spectrum analysis. The power spectrum curves for real and simulated images closely match and overlap indicating good agreement.

Point-of-care diagnostics for niche applications.

PubMed

Cummins, Brian M; Ligler, Frances S; Walker, Glenn M

2016-01-01

Point-of-care or point-of-use diagnostics are analytical devices that provide clinically relevant information without the need for a core clinical laboratory. In this review we define point-of-care diagnostics as portable versions of assays performed in a traditional clinical chemistry laboratory. This review discusses five areas relevant to human and animal health where increased attention could produce significant impact: veterinary medicine, space travel, sports medicine, emergency medicine, and operating room efficiency. For each of these areas, clinical need, available commercial products, and ongoing research into new devices are highlighted. Copyright © 2016 Elsevier Inc. All rights reserved.

What's New in the Medicine Cabinet?: A Panoramic Review of Clinically Relevant Information for the Busy Dermatologist.

PubMed

Del Rosso, James Q; Zeichner, Joshua

2014-01-01

This article is the first in a periodic series of therapeutic topics with short reviews gleaned from major dermatology meetings, especially Scientific Poster Sessions, and is designed to provide information that may assist the readers in adapting information from the literature to their clinical practice. The topics covered in this issue are discussions of the clinical relevance of newer information about acne pathophysiology, acne in adult women, and topical corticosteroid spray formulations for chronic plaque psoriasis.

Consultant paediatric outreach clinics--a practical step in integration.

PubMed

Spencer, N J

1993-04-01

Ten years' experience of paediatric outreach clinics is reviewed and evaluated. The advantages and disadvantages of paediatric outreach and its possible place in the new era of contracting and more developed community paediatric services are discussed. It is concluded that paediatric outreach increases parental and professional choice and access to paediatric consultant services, increases service flexibility, reduces unnecessary hospital visits, and enables more rational and relevant clinical decision making. Outreach is particularly relevant in areas of deprivation where paediatric needs are greatest.

Consultant paediatric outreach clinics--a practical step in integration.

PubMed Central

Spencer, N J

1993-01-01

Ten years' experience of paediatric outreach clinics is reviewed and evaluated. The advantages and disadvantages of paediatric outreach and its possible place in the new era of contracting and more developed community paediatric services are discussed. It is concluded that paediatric outreach increases parental and professional choice and access to paediatric consultant services, increases service flexibility, reduces unnecessary hospital visits, and enables more rational and relevant clinical decision making. Outreach is particularly relevant in areas of deprivation where paediatric needs are greatest. PMID:8503675

T-wave alternans and beat-to-beat variability of repolarization: pathophysiological backgrounds and clinical relevance.

PubMed

Floré, Vincent; Willems, Rik

2012-12-01

In this review, we focus on temporal variability of cardiac repolarization. This phenomenon has been related to a higher risk for ventricular arrhythmia and is therefore interesting as a marker of sudden cardiac death risk. We review two non-invasive clinical techniques quantifying repolarization variability: T-wave alternans (TWA) and beat-to-beat variability of repolarization (BVR). We discuss their pathophysiological link with ventricular arrhythmia and the current clinical relevance of these techniques.

Big-pharmaceuticalisation: clinical trials and Contract Research Organisations in India.

PubMed

Sariola, Salla; Ravindran, Deapica; Kumar, Anand; Jeffery, Roger

2015-04-01

The World Trade Organisation's Trade Related Intellectual Property Rights [TRIPS] agreement aimed to harmonise intellectual property rights and patent protection globally. In India, the signing of this agreement resulted in a sharp increase in clinical trials since 2005. The Indian government, along with larger Indian pharmaceutical companies, believed that they could change existing commercial research cultures through the promotion of basic research as well as attracting international clinical trials, and thus create an international level, innovation-based drug industry. The effects of the growth of these outsourced and off-shored clinical trials on local commercial knowledge production in India are still unclear. What has been the impact of the increasing scale and commercialisation of clinical research on corporate science in India? In this paper we describe Big-pharmaceuticalisation in India, whereby the local pharmaceutical industry is moving from generic manufacturing to innovative research. Using conceptual frameworks of pharmaceuticalisation and innovation, this paper analyses data from research conducted in 2010-2012 and describes how Contract Research Organisations (CROs) enable outsourcing of randomised control trials to India. Focussing on twenty-five semi-structured interviews CRO staff, we chart the changes in Indian pharmaceutical industry, and implications for local research cultures. We use Big-pharmaceuticalisation to extend the notion of pharmaceuticalisation to describe the spread of pharmaceutical research globally and illustrate how TRIPS has encouraged a concentration of capital in India, with large companies gaining increasing market share and using their market power to rewrite regulations and introduce new regulatory practices in their own interest. Contract Research Organisations, with relevant, new, epistemic skills and capacities, are both manifestations of the changes in commercial research cultures, as well as the vehicles to achieve them. These changes have reinvigorated public concerns that stress not only access to new medicines but also the 'price' of innovation on research participants. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Human Amniotic Membrane-Derived Products in Sports Medicine: Basic Science, Early Results, and Potential Clinical Applications.

PubMed

Riboh, Jonathan C; Saltzman, Bryan M; Yanke, Adam B; Cole, Brian J

2016-09-01

Amniotic membrane (AM)-derived products have been successfully used in ophthalmology, plastic surgery, and wound care, but little is known about their potential applications in orthopaedic sports medicine. To provide an updated review of the basic science and preclinical and clinical data supporting the use of AM-derived products and to review their current applications in sports medicine. Systematic review. A systematic search of the literature was conducted using the Medline, EMBASE, and Cochrane databases. The search term amniotic membrane was used alone and in conjunction with stem cell, orthopaedic, tissue engineering, scaffold, and sports medicine. The search identified 6870 articles, 80 of which, after screening of the titles and abstracts, were considered relevant to this study. Fifty-five articles described the anatomy, basic science, and nonorthopaedic applications of AM-derived products. Twenty-five articles described preclinical and clinical trials of AM-derived products for orthopaedic sports medicine. Because the level of evidence obtained from this search was not adequate for systematic review or meta-analysis, a current concepts review on the anatomy, physiology, and clinical uses of AM-derived products is presented. Amniotic membranes have many promising applications in sports medicine. They are a source of pluripotent cells, highly organized collagen, antifibrotic and anti-inflammatory cytokines, immunomodulators, and matrix proteins. These properties may make it beneficial when applied as tissue engineering scaffolds, improving tissue organization in healing, and treatment of the arthritic joint. The current body of evidence in sports medicine is heavily biased toward in vitro and animal studies, with little to no human clinical data. Nonetheless, 14 companies or distributors offer commercial AM products. The preparation and formulation of these products alter their biological and mechanical properties, and a thorough understanding of these differences will help guide the use of AM-derived products in sports medicine research. © 2015 The Author(s).

Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties

PubMed Central

Girolami, Federica; Persiani, Stefano

2012-01-01

Glucosamine is an amino monosaccharide and a natural constituent of glycosaminoglycans in articular cartilage. When administered exogenously, it is used for the treatment of osteoarthritis as a prescription drug or a dietary supplement. The latter use is mainly supported by its perception as a cartilage building block, but it actually exerts specific pharmacologic effects, mainly decreasing interleukin 1-induced gene expression by inhibiting the cytokine intracellular signaling cascade in general and nuclear factor-kappa B (NF-kB) activation in particular. As a whole, the use of glucosamine in the management of osteoarthritis is supported by the clinical trials performed with the original prescription product, that is, crystalline glucosamine sulfate. This is the stabilized form of glucosamine sulfate, while other formulations or different glucosamine salts (e.g. hydrochloride) have never been shown to be effective. In particular, long-term pivotal trials of crystalline glucosamine sulfate 1500 mg once daily have shown significant and clinically relevant improvement of pain and function limitation (symptom-modifying effect) in knee osteoarthritis. Continuous administration for up to 3 years resulted in significant reduction in the progression of joint structure changes compared with placebo as assessed by measuring radiologic joint space narrowing (structure-modifying effect). The two effects combined may suggest a disease-modifying effect that was postulated based on an observed decrease in the risk of undergoing total joint replacement in the follow up of patients receiving the product for at least 12 months in the pivotal trials. The safety of the drug was good in clinical trials and in the postmarketing surveillance. Crystalline glucosamine sulfate 1500 mg once daily is therefore recommended in the majority of clinical practice guidelines and was found to be cost effective in pharmacoeconomic analyses. Compared with other glucosamine formulations, salts, or dosage forms, the prescription product achieves higher plasma and synovial fluid concentrations that are above the threshold for a pharmacologically relevant effect, and may therefore justify its distinct therapeutic characteristics. PMID:22850875

Neurocognitive outcomes in neurofibromatosis clinical trials: Recommendations for the domain of attention.

PubMed

Walsh, Karin S; Janusz, Jennifer; Wolters, Pamela L; Martin, Staci; Klein-Tasman, Bonita P; Toledo-Tamula, Mary Anne; Thompson, Heather L; Payne, Jonathan M; Hardy, Kristina K; de Blank, Peter; Semerjian, Claire; Gray, Laura Schaffner; Solomon, Sondra E; Ullrich, Nicole

2016-08-16

Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials. © 2016 American Academy of Neurology.

A Review of Atomoxetine Effects in Young People with Developmental Disabilities

PubMed Central

Aman, Michael G.; Smith, Tristram; Arnold, L. Eugene; Corbett-Dick, Patricia; Rameshwari.Tumuluru; Hollway, Jill A.; Hyman, Susan L.; Mendoza-Burchamm, Marissa; Pan, Xueliang; Mruzek, Daniel W.; Lecavalier, Luc; Levato, Lynne; Silverman, Laura B.; Handen, Benjamin

2014-01-01

This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit. Conclusions: ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied. PMID:24732041

An exploration into study design for biomarker identification: issues and recommendations.

PubMed

Hall, Jacqueline A; Brown, Robert; Paul, Jim

2007-01-01

Genomic profiling produces large amounts of data and a challenge remains in identifying relevant biological processes associated with clinical outcome. Many candidate biomarkers have been identified but few have been successfully validated and make an impact clinically. This review focuses on some of the study design issues encountered in data mining for biomarker identification with illustrations of how study design may influence the final results. This includes issues of clinical endpoint use and selection, power, statistical, biological and clinical significance. We give particular attention to study design for the application of supervised clustering methods for identification of gene networks associated with clinical outcome and provide recommendations for future work to increase the success of identification of clinically relevant biomarkers.

Systematic review of the properties of tools used to measure outcomes in anxiety intervention studies for children with autism spectrum disorders.

PubMed

Wigham, Sarah; McConachie, Helen

2014-01-01

Evidence about relevant outcomes is required in the evaluation of clinical interventions for children with autism spectrum disorders (ASD). However, to date, the variety of outcome measurement tools being used, and lack of knowledge about the measurement properties of some, compromise conclusions regarding the most effective interventions. This two-stage systematic review aimed to identify the tools used in studies evaluating interventions for anxiety for high-functioning children with ASD in middle childhood, and then to evaluate the tools for their appropriateness and measurement properties. Electronic databases including Medline, PsychInfo, Embase, and the Cochrane database and registers were searched for anxiety intervention studies for children with ASD in middle childhood. Articles examining the measurement properties of the tools used were then searched for using a methodological filter in PubMed, and the quality of the papers evaluated using the COSMIN checklist. Ten intervention studies were identified in which six tools measuring anxiety and one of overall symptom change were used as primary outcomes. One further tool was included as it is recommended for standard use in UK children's mental health services. Sixty three articles on the properties of the tools were evaluated for the quality of evidence, and the quality of the measurement properties of each tool was summarised. Overall three questionnaires were found robust in their measurement properties, the Spence Children's Anxiety Scale, its revised version - the Revised Children's Anxiety and Depression Scale, and also the Screen for Child Anxiety Related Emotional Disorders. Crucially the articles on measurement properties provided almost no evidence on responsiveness to change, nor on the validity of use of the tools for evaluation of interventions for children with ASD. CRD42012002684.

Systematic Review of the Properties of Tools Used to Measure Outcomes in Anxiety Intervention Studies for Children with Autism Spectrum Disorders

PubMed Central

Wigham, Sarah; McConachie, Helen

2014-01-01

Background Evidence about relevant outcomes is required in the evaluation of clinical interventions for children with autism spectrum disorders (ASD). However, to date, the variety of outcome measurement tools being used, and lack of knowledge about the measurement properties of some, compromise conclusions regarding the most effective interventions. Objectives This two-stage systematic review aimed to identify the tools used in studies evaluating interventions for anxiety for high-functioning children with ASD in middle childhood, and then to evaluate the tools for their appropriateness and measurement properties. Methods Electronic databases including Medline, PsychInfo, Embase, and the Cochrane database and registers were searched for anxiety intervention studies for children with ASD in middle childhood. Articles examining the measurement properties of the tools used were then searched for using a methodological filter in PubMed, and the quality of the papers evaluated using the COSMIN checklist. Results Ten intervention studies were identified in which six tools measuring anxiety and one of overall symptom change were used as primary outcomes. One further tool was included as it is recommended for standard use in UK children's mental health services. Sixty three articles on the properties of the tools were evaluated for the quality of evidence, and the quality of the measurement properties of each tool was summarised. Conclusions Overall three questionnaires were found robust in their measurement properties, the Spence Children's Anxiety Scale, its revised version – the Revised Children's Anxiety and Depression Scale, and also the Screen for Child Anxiety Related Emotional Disorders. Crucially the articles on measurement properties provided almost no evidence on responsiveness to change, nor on the validity of use of the tools for evaluation of interventions for children with ASD. PROSPERO Registration number CRD42012002684. PMID:24465519

A Quantitative Comparison of the Behavior of Human Ventricular Cardiac Electrophysiology Models in Tissue

PubMed Central

Elshrif, Mohamed M.; Cherry, Elizabeth M.

2014-01-01

Numerical integration of mathematical models of heart cell electrophysiology provides an important computational tool for studying cardiac arrhythmias, but the abundance of available models complicates selecting an appropriate model. We study the behavior of two recently published models of human ventricular action potentials, the Grandi-Pasqualini-Bers (GPB) and the O'Hara-Virág-Varró-Rudy (OVVR) models, and compare the results with four previously published models and with available experimental and clinical data. We find the shapes and durations of action potentials and calcium transients differ between the GPB and OVVR models, as do the magnitudes and rate-dependent properties of transmembrane currents and the calcium transient. Differences also occur in the steady-state and S1–S2 action potential duration and conduction velocity restitution curves, including a maximum conduction velocity for the OVVR model roughly half that of the GPB model and well below clinical values. Between single cells and tissue, both models exhibit differences in properties, including maximum upstroke velocity, action potential amplitude, and minimum diastolic interval. Compared to experimental data, action potential durations for the GPB and OVVR models agree fairly well (although OVVR epicardial action potentials are shorter), but maximum slopes of steady-state restitution curves are smaller. Although studies show alternans in normal hearts, it occurs only in the OVVR model, and only for a narrow range of cycle lengths. We find initiated spiral waves do not progress to sustained breakup for either model. The dominant spiral wave period of the GPB model falls within clinically relevant values for ventricular tachycardia (VT), but for the OVVR model, the dominant period is longer than periods associated with VT. Our results should facilitate choosing a model to match properties of interest in human cardiac tissue and to replicate arrhythmia behavior more closely. Furthermore, by indicating areas where existing models disagree, our findings suggest avenues for further experimental work. PMID:24416228

Differences in ability to perform activities of daily living among women with fibromyalgia: A cross-sectional study.

PubMed

von Bülow, Cecilie; Amris, Kirstine; la Cour, Karen; Danneskiold-Samsøe, Bente; Ejlersen, Eva Wæhrens

2015-11-01

To investigate whether the Assessment of Motor and Process Skills (AMPS), the physical function subscales of the Fibromyalgia Impact Questionnaire (FIQ PF) and the 36-item Short Form (SF-36 PF) can identify subgroups of women with fibromyalgia with clinically relevant differences in ability to perform activities of daily living. Cross-sectional study. A total of 257 women with fibromyalgia. Participants were evaluated with the AMPS (measuring activities of daily living motor and activities of daily living process ability), FIQ and SF-36. AMPS independence cut-offs were used to divide the participants into 4 subgroups. Clinically relevant differences between subgroups were investigated based on the AMPS, FIQ PF and SF-36 PF. Participants in the 4 AMPS-derived subgroups demon-strated clinically relevant differences in observed activities of daily living motor and process ability. Neither the FIQ PF nor the SF-36 PF could differentiate between subgroups with clinically relevant differences in AMPS activities of daily living process ability. Activities of daily living process skills reflect underlying organizational and adaptive capacities of the individual and are relevant targets for interventions aiming at improving activities of daily living ability. Since self-report instruments do not capture differences in activities of daily living process ability, clinicians should include observations-based assessment of activities of daily living ability in order to individualize interventions offered.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

PubMed

Kloprogge, Frank; Workman, Lesley; Borrmann, Steffen; Tékété, Mamadou; Lefèvre, Gilbert; Hamed, Kamal; Piola, Patrice; Ursing, Johan; Kofoed, Poul Erik; Mårtensson, Andreas; Ngasala, Billy; Björkman, Anders; Ashton, Michael; Friberg Hietala, Sofia; Aweeka, Francesca; Parikh, Sunil; Mwai, Leah; Davis, Timothy M E; Karunajeewa, Harin; Salman, Sam; Checchi, Francesco; Fogg, Carole; Newton, Paul N; Mayxay, Mayfong; Deloron, Philippe; Faucher, Jean François; Nosten, François; Ashley, Elizabeth A; McGready, Rose; van Vugt, Michele; Proux, Stephane; Price, Ric N; Karbwang, Juntra; Ezzet, Farkad; Bakshi, Rajesh; Stepniewska, Kasia; White, Nicholas J; Guerin, Philippe J; Barnes, Karen I; Tarning, Joel

2018-06-01

The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Scintillator high-gain avalanche rushing photoconductor active-matrix flat panel imager: Zero-spatial frequency x-ray imaging properties of the solid-state SHARP sensor structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wronski, M.; Zhao, W.; Tanioka, K.

Purpose: The authors are investigating the feasibility of a new type of solid-state x-ray imaging sensor with programmable avalanche gain: scintillator high-gain avalanche rushing photoconductor active matrix flat panel imager (SHARP-AMFPI). The purpose of the present work is to investigate the inherent x-ray detection properties of SHARP and demonstrate its wide dynamic range through programmable gain. Methods: A distributed resistive layer (DRL) was developed to maintain stable avalanche gain operation in a solid-state HARP. The signal and noise properties of the HARP-DRL for optical photon detection were investigated as a function of avalanche gain both theoretically and experimentally, and themore » results were compared with HARP tube (with electron beam readout) used in previous investigations of zero spatial frequency performance of SHARP. For this new investigation, a solid-state SHARP x-ray image sensor was formed by direct optical coupling of the HARP-DRL with a structured cesium iodide (CsI) scintillator. The x-ray sensitivity of this sensor was measured as a function of avalanche gain and the results were compared with the sensitivity of HARP-DRL measured optically. The dynamic range of HARP-DRL with variable avalanche gain was investigated for the entire exposure range encountered in radiography/fluoroscopy (R/F) applications. Results: The signal from HARP-DRL as a function of electric field showed stable avalanche gain, and the noise associated with the avalanche process agrees well with theory and previous measurements from a HARP tube. This result indicates that when coupled with CsI for x-ray detection, the additional noise associated with avalanche gain in HARP-DRL is negligible. The x-ray sensitivity measurements using the SHARP sensor produced identical avalanche gain dependence on electric field as the optical measurements with HARP-DRL. Adjusting the avalanche multiplication gain in HARP-DRL enabled a very wide dynamic range which encompassed all clinically relevant medical x-ray exposures. Conclusions: This work demonstrates that the HARP-DRL sensor enables the practical implementation of a SHARP solid-state x-ray sensor capable of quantum noise limited operation throughout the entire range of clinically relevant x-ray exposures. This is an important step toward the realization of a SHARP-AMFPI x-ray flat-panel imager.« less

Clinical relevance of smartphone apps for diabetes management: A global overview.

PubMed

Huang, Zhilian; Soljak, Michael; Boehm, Bernhard Otto; Car, Josip

2018-05-01

We assessed the number, proportion, and clinical relevance of diabetes self-management apps in major languages spoken by 10 countries with the highest number of people with diabetes. China, India, USA, Brazil, Russian Federation, Mexico, Indonesia, Egypt, Japan, and Pakistan were identified as the 10 countries with the largest number of people with diabetes based on the latest NCD-RisC survey. Android and iOS apps in the 10 national languages were extracted with a search strategy. App titles and descriptions were systematically screened by trained reviewers, including apps specific for diabetes self-management and excluding apps for health care providers, general well-being, health and product promotion, and traditional cure. Eighteen apps in the above languages were then downloaded based on availability and popularity and assessed for clinical relevance to diabetes self-management with reference to current clinical guidelines. The diabetes-related search terms identified 3374 Android and 4477 iOS apps, where 1019 Android and 1303 iOS apps were screened as being relevant for diabetes self-management. Chinese and English language apps constitute above 80% of the diabetes apps, have more downloads, and more comprehensive clinically relevant functions compared with other languages. None of the apps assessed met all criteria for information provision and app functionalities nor provided information cited from accredited sources. Our study showed that apps could play an important role in complementing multifaceted diabetes care, but should preferably be regulated, context specific, and more tailored to users' needs with clear guidance for patients and clinicians about the choices. Copyright © 2018 John Wiley & Sons, Ltd.

Medicinal Chemical Properties of Successful Central Nervous System Drugs

PubMed Central

Pajouhesh, Hassan; Lenz, George R.

2005-01-01

Summary: Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. Factors relevant to the success of CNS drugs are reviewed. CNS drugs show values of molecular weight, lipophilicity, and hydrogen bond donor and acceptor that in general have a smaller range than general therapeutics. Pharmacokinetic properties can be manipulated by the medicinal chemist to a significant extent. The solubility, permeability, metabolic stability, protein binding, and human ether-ago-go-related gene inhibition of CNS compounds need to be optimized simultaneously with potency, selectivity, and other biological parameters. The balance between optimizing the physiochemical and pharmacokinetic properties to make the best compromises in properties is critical for designing new drugs likely to penetrate the blood brain barrier and affect relevant biological systems. This review is intended as a guide to designing CNS therapeutic agents with better drug-like properties. PMID:16489364

[Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption].

PubMed

Silva, Adauto Carvalho; Toffoletto, Odaly; Lucio, Luiz Antonio Galvão; Santos, Paula Ferreira Dos; Afiune, Jorge Barros; Massud Filho, João; Tufik, Sergio

2010-02-01

Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

Side effects of beta-blocker treatments as related to the central nervous system.

PubMed

Dahlöf, C; Dimenäs, E

1990-04-01

During the last decade beta-adrenoceptor antagonists have become one of the first-line treatments for hypertension. Generally, they have been shown to be safe with a low frequency of serious side effects. However, minor subjective symptoms, usually considered to be CNS-related, have been reported for all beta-blockers used. Thus, all beta-blockers on the market seem to have a high benefit:risk ratio; independent of their physicochemical properties and pharmacodynamic profile, however, they seem to cause CNS-related side effects to about the same extent. These minor side effects, the mechanisms of which are unclear, consist of subtle effects on general well being, decreased initiative, a depressed frame of mind, and disturbed sleep. Generally, however, beta-blockers in therapeutic dosages do not affect the qualitative functions of the brain. The results so far available have been obtained primarily by using objective methods. Further comparison has now been initiated using documented subjective methods to investigate whether the objectively documented differences are of any clinical relevance to the patient's quality of life. Although it cannot be claimed with certainty, nonselective beta-blockers seem to cause CNS-related side effects to a greater extent than beta 1-selective blockers. Differences in the degree of hydrophilicity of the beta-blocker are apparently of no clinical relevance in this respect. Rather, the plasma concentration of the beta-blocking drug (degree of beta-blockade) seems to be the major determinant of whether or not CNS-related symptoms appear in susceptible patients.

Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1

PubMed Central

Varghese, Vici; Mitsuya, Yumi; Fessel, W. Jeffrey; Liu, Tommy F.; Melikian, George L.; Katzenstein, David A.; Schiffer, Celia A.; Holmes, Susan P.

2013-01-01

The many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI-resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI-resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel's viruses in the context of a correlation network of PI resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activities of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most if not all clinically relevant PI-resistant viruses. PMID:23796938

Assessment of cold welding properties of the internal conical interface of two commercially available implant systems.

PubMed

Norton, M R

1999-02-01

The cone-screw abutment has been shown to diminish micromovement by reducing the burden of component loosening and fracture. However, anecdotal concern for cold welding of cone-screw joints in implant design has been identified as a potential source for lack of retrievability. This comparative study evaluated the loosening torque, as a percentage of tightening torque, for the ITI Straumann and Astra Tech (3.5 and 4.0 mm diameters) implant systems, which use an 8-degree and 11-degree internal cone, respectively. Implants and abutments from each system were mounted in a torque device, and a range of tightening torques was applied. Loosening torques were then measured, and the influence of conus angle, interfacial surface area, saliva contamination, and time delay to loosening were all assessed. The loosening torque only exceeded tightening torque at the highest levels, just before component failure, when plastic deformation was expected. For all clinically relevant levels of torque, both in a dry environment and with components bathed in artificial saliva at 37 degrees C, loosening torque was always seen to be 80% to 90% of tightening torque, demonstrating that cold welding does not occur. There was a high correlation between loosening and tightening torque for all systems tested, but no statistical difference when comparing wet versus dry or comparing individual data for each system. It can be concluded that for clinically relevant levels of tightening torque, no problems are anticipated with respect to retrievability.

Pichia pastoris: a recombinant microfactory for antibodies and human membrane proteins.

PubMed

Gonçalves, A M; Pedro, A Q; Maia, C; Sousa, F; Queiroz, J A; Passarinha, L A

2013-05-01

During the last few decades, it has become evident that the compatibility of the yeast biochemical environment with the ability to process and translate the RNA transcript, along with its capacity to modify a translated protein, are relevant requirements for selecting this host cell for protein expression in several pharmaceutical and clinical applications. In particular, Pichia pastoris is used as an industrial host for recombinant protein and metabolite production, showing a powerful capacity to meet required biomolecular target production levels in high-throughput assays for functional genomics and drug screening. In addition, there is a great advantage to using P. pastoris for protein secretion, even at high molecular weights, since the recovery and purification steps are simplified owing to relatively low levels of endogenous proteins in the extracellular medium. Clearly, no single microexpression system can provide all of the desired properties for human protein production. Moreover, chemical and physical bioprocess parameters, including culture medium formulation, temperature, pH, agitation, aeration rates, induction, and feeding strategies, can highly influence product yield and quality. In order to benefit from the currently available wide range of biosynthesis strategies using P. pastoris, this mini review focuses on the developments and technological fermentation achievements, providing both a comparative and an overall integration analysis. The main aim is to highlight the relevance and versatility of the P. pastoris biosystem to the design of more cost-effective microfactories to meet the increasing demands for recombinant membrane proteins and clinical antibodies for several therapeutic applications.

Alteration of dentin-enamel mechanical properties due to dental whitening treatments.

PubMed

Zimmerman, B; Datko, L; Cupelli, M; Alapati, S; Dean, D; Kennedy, M

2010-05-01

The mechanical properties of dentin and enamel affect the reliability and wear properties of a tooth. This study investigated the influence of clinical dental treatments and procedures, such as whitening treatments or etching prior to restorative procedures. Both autoclaved and non-autoclaved teeth were studied in order to allow for both comparison with published values and improved clinical relevance. Nanoindentation analysis with the Oliver-Pharr model provided elastic modulus and hardness across the dentin-enamel junction (DEJ). Large increases were observed in the elastic modulus of enamel in teeth that had been autoclaved (52.0 GPa versus 113.4 GPa), while smaller increases were observed in the dentin (17.9 GPa versus 27.9 GPa). Likewise, there was an increase in the hardness of enamel (2.0 GPa versus 4.3 GPa) and dentin (0.5 GPa versus 0.7 GPa) with autoclaving. These changes suggested that the range of elastic modulus and hardness values previously reported in the literature may be partially due to the sterilization procedures. Treatment of the exterior of non-autoclaved teeth with Crest Whitestrips, Opalescence or UltraEtch caused changes in the mechanical properties of both the enamel and dentin. Those treated with Crest Whitestrips showed a reduction in the elastic modulus of enamel (55.3 GPa to 32.7 GPa) and increase in the elastic modulus of dentin (17.2 GPa to 24.3 GPa). Opalescence treatments did not significantly affect the enamel properties, but did result in a decrease in the modulus of dentin (18.5 GPa to 15.1 GPa). Additionally, as expected, UltraEtch treatment decreased the modulus and hardness of enamel (48.7 GPa to 38.0 GPa and 1.9 GPa to 1.5 GPa, respectively) and dentin (21.4 GPa to 15.0 GPa and 1.9 GPa to 1.5 GPa, respectively). Changes in the mechanical properties were linked to altered protein concentration within the tooth, as evidenced by fluorescence microscopy and Fourier transform infrared spectroscopy. Published by Elsevier Ltd.

Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form.

PubMed

Skolarus, Ted A; Dunn, Rodney L; Sanda, Martin G; Chang, Peter; Greenfield, Thomas K; Litwin, Mark S; Wei, John T

2015-01-01

To establish a score threshold that constitutes a clinically relevant change for each domain of the Expanded Prostate Cancer Index Composite (EPIC) Short Form (EPIC-26). Although its use in clinical practice and clinical trials has increased worldwide, the clinical interpretation of this 26-item disease-specific patient-reported quality of life questionnaire for men with localized prostate cancer would be facilitated by characterization of score thresholds for clinically relevant change (the minimally important differences [MIDs]). We used distribution- and anchor-based approaches to establish the MID range for each EPIC-26 domain (urinary, sexual, bowel, and vitality/hormonal) based on a prospective multi-institutional cohort of 1201 men treated for prostate cancer between 2003 and 2006 and followed up for 3 years after treatment. For the anchor-based approach, we compared within-subject and between-subject score changes for each domain to an external "anchor" measure of overall cancer treatment satisfaction. We found the bowel and vitality/hormonal domains to have the lowest MID range (a 4-6 point change should be considered clinically relevant), whereas the sexual domain had the greatest MID values (10-12). Urinary incontinence appeared to have a greater MID range (6-9) than the urinary irritation/obstruction domain (5-7). Using 2 independent approaches, we established the MIDs for each EPIC-26 domain. A definition of these MID values is essential for the researcher or clinician to understand when changes in symptom burden among prostate cancer survivors are clinically relevant. Copyright © 2015 Elsevier Inc. All rights reserved.

The medical genetics workforce: an analysis of clinical geneticist subgroups.

PubMed

Cooksey, Judith A; Forte, Gaetano; Flanagan, Patricia A; Benkendorf, Judith; Blitzer, Miriam G

2006-10-01

Clinical geneticists with a Doctor of Medicine degree face challenges to meet the growing population demand for genetic services. This study was designed to assist the profession with workforce planning by identifying clinically relevant subgroups of geneticists and describing their professional characteristics and clinical practices. Geneticists' patient care productivity is compared across subgroups and other medical specialists. Part of a comprehensive national study of genetic services and the health workforce, this study uses data from a 2003 survey of geneticists certified by the American Board of Medical Genetics. This study includes 610 clinical geneticists who spend at least 5% of their time in direct patient-care services. An iterative approach was used to identify five subgroups based on the types of new patients seen. We conducted a descriptive analysis of subgroups by demographic, training, professional, and practice characteristics. The subgroups include general (36%), pediatric (28%), reproductive (15%), metabolic (14%), and adult (7%) geneticists. Clinically relevant variations across subgroups were noted in training, professional, and practice parameters. Subgroups vary across patient care hours (median, 15-33 hours/week) and total weekly work hours (52-60 hours). New patient visits (mean, 222-900/year) are higher than follow-up patient visits (mean, 155-405) for all subgroups except metabolic geneticists. Although many geneticists practice as generalist geneticists, this study provides an evidence base for distinguishing clinically relevant subgroups of geneticists. Geneticists provide similar numbers of new patient visits and far fewer follow-up visits than other medical specialists. These findings are relevant to geneticist workforce planning.

Ketamine for cancer pain: what is the evidence?

PubMed

Jonkman, Kelly; van de Donk, Tine; Dahan, Albert

2017-06-01

In this review, we assess the benefit of ketamine in the treatment of terminal cancer pain that is refractory to opioid treatment and/or complicated by neuropathy. While randomized controlled trials consistently show lack of clinical efficacy of ketamine in treating cancer pain, a large number of open-label studies and case series show benefit. Ketamine is an N-methyl-D-aspartate receptor antagonist that at low-dose has effective analgesic properties. In cancer pain, ketamine is usually prescribed as adjuvant to opioid therapy when pain becomes opioid resistant or when neuropathic pain symptoms dominate the clinical picture. A literature search revealed four randomized controlled trials that examined the benefit of oral, subcutaneous or intravenous ketamine in opioid refractory cancer pain. None showed clinically relevant benefit in relieving pain or reducing opioid consumption. This suggests absence of evidence of benefit for ketamine as adjuvant analgesic in cancer pain. These findings contrast the benefit from ketamine observed in a large number of open-label studies and (retrospective) case series. We relate the opposite outcomes to methodological issues. The complete picture is such that there is still insufficient evidence to state with certainty that ketamine is not effective in cancer pain.

Essential oils, their therapeutic properties, and implication in dentistry: A review.

PubMed

Dagli, Namrata; Dagli, Rushabh; Mahmoud, Rasha Said; Baroudi, Kusai

2015-01-01

Antibacterial treatments currently used for treatment cause several side effects, and bacterial resistance to the antibiotics is also increasing. Therefore, there is need to find better alternatives. Essential oils (EOs) have been used for treatment of various ailments since ancient times and have gained popularity over the years. Safety and efficacy of EOs have been proved by several clinical trials. This review gives an overview on the EOs, their uses, and adverse effects. A literature search was performed in the PubMed for clinical trial studies and review articles on EOs published up to February 2015. The search was performed during March 2015. The following keywords were used: "Lavender essential oil," "cinnamon oil," "clove oil," "eucalyptus oil," "peppermint oil," "lemon EOs," and "tea tree oil." Total 70 relevant articles were found in PubMed database. After screening of abstracts, 52 articles were selected to be included in the present review. On the basis of the available information, it can be concluded that EOs have the potential to be developed as preventive or therapeutic agents for various oral diseases, but further clinical trials are required to establish their safety and efficacy.

Impact of product-related factors on immunogenicity of biotherapeutics.

PubMed

Singh, Satish Kumar

2011-02-01

All protein therapeutics have the potential to be immunogenic. Several factors, including patient characteristics, disease state, and the therapy itself, influence the generation of an immune response. Product-related factors such as the molecule design, the expression system, post-translational modifications, impurities, contaminants, formulation and excipients, container, closure, as well as degradation products are all implicated. However, a critical examination of the available data shows that clear unequivocal evidence for the impact of these latter factors on clinical immunogenicity is lacking. No report could be found that clearly deconvolutes the clinical impact of the product attributes on patient susceptibility. Aggregation carries the greatest concern as a risk factor for immunogenicity, but the impact of aggregates is likely to depend on their structure as well as on the functionality (e.g., immunostimulatory or immunomodulatory) of the therapeutic. Preclinical studies are not yet capable of assessing the clinically relevant immunogenicity potential of these product-related factors. Simply addressing these risk factors as part of product development will not eliminate immunogenicity. Minimization of immunogenicity has to begin at the molecule design stage by reducing or eliminating antigenic epitopes and building in favorable physical and chemical properties. Copyright © 2010 Wiley-Liss, Inc.

Curcumin: A natural modulator of immune cells in systemic lupus erythematosus.

PubMed

Momtazi-Borojeni, Amir Abbas; Haftcheshmeh, Saeed Mohammadian; Esmaeili, Seyed-Alireza; Johnston, Thomas P; Abdollahi, Elham; Sahebkar, Amirhossein

2018-02-01

Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune complexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1 (Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory effects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant cytokines that participate in SLE. Copyright © 2017 Elsevier B.V. All rights reserved.

Approved and Experimental Small-Molecule Oncology Kinase Inhibitor Drugs: A Mid-2016 Overview.

PubMed

Fischer, Peter M

2017-03-01

Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult-even for those working in the field-easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation. The purpose of this review is thus to provide an overview of the biomedical rationales for the kinases being targeted on the one hand, and the design principles, as well as chemical, pharmacological, pharmaceutical, and toxicological kinase inhibitor properties, on the other hand. Two issues that are especially important in kinase inhibitor research, target selectivity and drug resistance, as well as the underlying structural concepts, are discussed in general terms and in the context of relevant kinases and their inhibitors. © 2016 Wiley Periodicals, Inc.

A Bridge between Two Cultures: Uncovering the Chemistry Concepts Relevant to the Nursing Clinical Practice

ERIC Educational Resources Information Center

Brown, Corina E.; Henry, Melissa L. M.; Barbera, Jack; Hyslop, Richard M.

2012-01-01

This study focused on the undergraduate course that covers basic topics in general, organic, and biological (GOB) chemistry at a mid-sized state university in the western United States. The central objective of the research was to identify the main topics of GOB chemistry relevant to the clinical practice of nursing. The collection of data was…

Bright Lu2O3:Eu thin-film scintillators for high-resolution radioluminescence microscopy

PubMed Central

Sengupta, Debanti; Miller, Stuart; Marton, Zsolt; Chin, Frederick; Nagarkar, Vivek

2015-01-01

We investigate the performance of a new thin-film Lu2O3:Eu scintillator for single-cell radionuclide imaging. Imaging the metabolic properties of heterogeneous cell populations in real time is an important challenge with clinical implications. We have developed an innovative technique called radioluminescence microscopy, to quantitatively and sensitively measure radionuclide uptake in single cells. The most important component of this technique is the scintillator, which converts the energy released during radioactive decay into luminescent signals. The sensitivity and spatial resolution of the imaging system depend critically on the characteristics of the scintillator, i.e. the material used and its geometrical configuration. Scintillators fabricated using conventional methods are relatively thick, and therefore do not provide optimal spatial resolution. We compare a thin-film Lu2O3:Eu scintillator to a conventional 500 μm thick CdWO4 scintillator for radioluminescence imaging. Despite its thinness, the unique scintillation properties of the Lu2O3:Eu scintillator allow us to capture single positron decays with over fourfold higher sensitivity, a significant achievement. The thin-film Lu2O3:Eu scintillators also yield radioluminescence images where individual cells appear smaller and better resolved on average than with the CdWO4 scintillators. Coupled with the thin-film scintillator technology, radioluminescence microscopy can yield valuable and clinically relevant data on the metabolism of single cells. PMID:26183115

Euterpe oleracea pulp extract: Chemical analyses, antibiofilm activity against Staphylococcus aureus, cytotoxicity and interference on the activity of antimicrobial drugs.

PubMed

Dias-Souza, Marcus Vinícius; Dos Santos, Renan Martins; Cerávolo, Isabela Penna; Cosenza, Gustavo; Ferreira Marçal, Pedro Henrique; Figueiredo, Flávio Jr Barbosa

2018-01-01

Euterpe oleracea (Açaí) fruit are widely consumed at the Brazilian Amazon region, and biological potentials such as immunomodulatory and antioxidant have been described for its extracts. However, its antimicrobial properties remain poorly investigated. Here, the antimicrobial and antibiofilm activities of the methanolic extract of an artisanally-manufactured açaí pulp (MEAP) were evaluated against clinical isolates of Staphylococcus aureus. Besides, MEAP interference on the activity of antimicrobial drugs of clinical relevance was explored, and its cytotoxicity against hepatocellular carcinoma cells (HepG2) was investigated. Biochemical and physicochemical properties of the pulp were investigated, and the presence of polyphenols on the extract was confirmed. For the first time, we report that the methanolic extract of açaí pulp is effective against planktonic cells and biofilms of S. aureus, and also decreased the proliferation of HepG2 cells. Statistically significant synergism was observed when the extract was combined to the tested antimicrobials except for erythromycin, and all biochemical and physicochemical parameters ranged within the accepted values established by the Brazilian legislation. Our data open doors for more studies on the antimicrobial activity of phytomolecules isolated from Euterpe oleracea extracts, and also for its combined use with antimicrobial drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Noncanonical roles of membranous lysyl-tRNA synthetase in transducing cell-substrate signaling for invasive dissemination of colon cancer spheroids in 3D collagen I gels

PubMed Central

Nam, Seo Hee; Kim, Doyeun; Lee, Mi-Sook; Lee, Doohyung; Kwak, Tae Kyoung; Kang, Minkyung; Ryu, Jihye; Kim, Hye-Jin; Song, Haeng Eun; Choi, Jungeun; Lee, Gyu-Ho; Kim, Sang-Yeob; Park, Song Hwa; Kim, Dae Gyu; Kwon, Nam Hoon; Kim, Tai Young; Thiery, Jean Paul; Kim, Sunghoon; Lee, Jung Weon

2015-01-01

The adhesion properties of cells are involved in tumor metastasis. Although KRS at the plasma membrane is shown important for cancer metastasis, additionally to canonical roles of cytosolic KRS in protein translation, how KRS and its downstream effectors promote the metastatic migration remains unexplored. Disseminative behaviors (an earlier metastatic process) of colon cancer cell spheroids embedded in 3D collagen gels were studied with regards to cell adhesion properties, and relevance in KRS−/+ knocked-down animal and clinical colon cancer tissues. Time-lapse imaging revealed KRS-dependent cell dissemination from the spheroids, whereas KRS-suppressed spheroids remained static due to the absence of outbound movements supported by cell-extracellular matrix (ECM) adhesion. While keeping E-cadherin at the outward disseminative cells, KRS caused integrin-involved intracellular signaling for ERK/c-Jun, paxillin, and cell-ECM adhesion-mediated signaling to modulate traction force for crawling movement. KRS-suppressed spheroids became disseminative following ERK or paxillin re-expression. The KRS-dependent intracellular signaling activities correlated with the invasiveness in clinical colon tumor tissues and in KRS−/+ knocked-down mice tissues. Collectively, these observations indicate that KRS at the plasma membrane plays new roles in metastatic migration as a signaling inducer, and causes intracellular signaling for cancer dissemination, involving cell-cell and cell-ECM adhesion, during KRS-mediated metastasis. PMID:26091349

Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance

PubMed Central

Vural, Atay; Doppler, Kathrin; Meinl, Edgar

2018-01-01

Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications. PMID:29867996

Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance.

PubMed

Vural, Atay; Doppler, Kathrin; Meinl, Edgar

2018-01-01

Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications.

Clinically relevant diagnostic research in primary care: the example of B-type natriuretic peptides in the detection of heart failure.

PubMed

Kelder, Johannes C; Rutten, Frans H; Hoes, Arno W

2009-02-01

With the emergence of novel diagnostic tests, e.g. point-of-care tests, clinically relevant empirical evidence is needed to assess whether such a test should be used in daily practice. With the example of the value of B-type natriuretic peptides (BNP) in the diagnostic assessment of suspected heart failure, we will discuss the major methodological issues crucial in diagnostic research; most notably the choice of the study population and the data analysis with a multivariable approach. BNP have been studied extensively in the emergency care setting, and also several studies in the primary care are available. The usefulness of this test when applied in combination with other readily available tests is still not adequately addressed in the relevant patient domain, i.e. those who are clinically suspected of heart failure by their GP. Future diagnostic research in primary care should be targeted much more at answering the clinically relevant question 'Is it useful to add this (new) test to the other tests I usually perform, including history taking and physical examination, in patients I suspect of having a certain disease'.

Assessment of statistical significance and clinical relevance.

PubMed

Kieser, Meinhard; Friede, Tim; Gondan, Matthias

2013-05-10

In drug development, it is well accepted that a successful study will demonstrate not only a statistically significant result but also a clinically relevant effect size. Whereas standard hypothesis tests are used to demonstrate the former, it is less clear how the latter should be established. In the first part of this paper, we consider the responder analysis approach and study the performance of locally optimal rank tests when the outcome distribution is a mixture of responder and non-responder distributions. We find that these tests are quite sensitive to their planning assumptions and have therefore not really any advantage over standard tests such as the t-test and the Wilcoxon-Mann-Whitney test, which perform overall well and can be recommended for applications. In the second part, we present a new approach to the assessment of clinical relevance based on the so-called relative effect (or probabilistic index) and derive appropriate sample size formulae for the design of studies aiming at demonstrating both a statistically significant and clinically relevant effect. Referring to recent studies in multiple sclerosis, we discuss potential issues in the application of this approach. Copyright © 2012 John Wiley & Sons, Ltd.

Dental Blogs, Podcasts, and Associated Social Media: Descriptive Mapping and Analysis.

PubMed

Melkers, Julia; Hicks, Diana; Rosenblum, Simone; Isett, Kimberley R; Elliott, Jacqueline

2017-07-26

Studies of social media in both medicine and dentistry have largely focused on the value of social media for marketing to and communicating with patients and for clinical education. There is limited evidence of how dental clinicians contribute to and use social media to disseminate and access information relevant to clinical care. The purpose of this study was to inventory and assess the entry, growth, sources, and content of clinically relevant social media in dentistry. We developed an inventory of blogs, podcasts, videos, and associated social media disseminating clinical information to dentists. We assessed hosts' media activity in terms of their combinations of modalities, entry and exit dates, frequency of posting, types of content posted, and size of audience. Our study showed that clinically relevant information is posted by dentists and hygienists on social media. Clinically relevant information was provided in 89 blogs and podcasts, and topic analysis showed motives for blogging by host type: 55% (49 hosts) were practicing dentists or hygienists, followed by consultants (27 hosts, 30%), media including publishers and discussion board hosts (8 hosts, 9%), and professional organizations and corporations. We demonstrated the participation of and potential for practicing dentists and hygienists to use social media to share clinical and other information with practicing colleagues. There is a clear audience for these social media sites, suggesting a changing mode of information diffusion in dentistry. This study was a first effort to fill the gap in understanding the nature and potential role of social media in clinical dentistry. ©Julia Melkers, Diana Hicks, Simone Rosenblum, Kimberley R Isett, Jacqueline Elliott. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.07.2017.

Decaying Relevance of Clinical Data Towards Future Decisions in Data-Driven Inpatient Clinical Order Sets

PubMed Central

Chen, Jonathan H; Alagappan, Muthuraman; Goldstein, Mary K; Asch, Steven M; Altman, Russ B

2017-01-01

Objective Determine how varying longitudinal historical training data can impact prediction of future clinical decisions. Estimate the “decay rate” of clinical data source relevance. Materials and Methods We trained a clinical order recommender system, analogous to Netflix or Amazon’s “Customers who bought A also bought B…” product recommenders, based on a tertiary academic hospital’s structured electronic health record data. We used this system to predict future (2013) admission orders based on different subsets of historical training data (2009 through 2012), relative to existing human-authored order sets. Results Predicting future (2013) inpatient orders is more accurate with models trained on just one month of recent (2012) data than with 12 months of older (2009) data (ROC AUC 0.91 vs. 0.88, precision 27% vs. 22%, recall 52% vs. 43%, all P<10−10). Algorithmically learned models from even the older (2009) data was still more effective than existing human-authored order sets (ROC AUC 0.81, precision 16% recall 35%). Training with more longitudinal data (2009–2012) was no better than using only the most recent (2012) data, unless applying a decaying weighting scheme with a “half-life” of data relevance about 4 months. Discussion Clinical practice patterns (automatically) learned from electronic health record data can vary substantially across years. Gold standards for clinical decision support are elusive moving targets, reinforcing the need for automated methods that can adapt to evolving information. Conclusions and Relevance Prioritizing small amounts of recent data is more effective than using larger amounts of older data towards future clinical predictions. PMID:28495350

Can the theoretical domains framework account for the implementation of clinical quality interventions?

PubMed

Lipworth, Wendy; Taylor, Natalie; Braithwaite, Jeffrey

2013-12-21

The health care quality improvement movement is a complex enterprise. Implementing clinical quality initiatives requires attitude and behaviour change on the part of clinicians, but this has proven to be difficult. In an attempt to solve this kind of behavioural challenge, the theoretical domains framework (TDF) has been developed. The TDF consists of 14 domains from psychological and organisational theory said to influence behaviour change. No systematic research has been conducted into the ways in which clinical quality initiatives map on to the domains of the framework. We therefore conducted a qualitative mapping experiment to determine to what extent, and in what ways, the TDF is relevant to the implementation of clinical quality interventions. We conducted a thematic synthesis of the qualitative literature exploring clinicians' perceptions of various clinical quality interventions. We analysed and synthesised 50 studies in total, in five domains of clinical quality interventions: clinical quality interventions in general, structural interventions, audit-type interventions, interventions aimed at making practice more evidence-based, and risk management interventions. Data were analysed thematically, followed by synthesis of these themes into categories and concepts, which were then mapped to the domains of the TDF. Our results suggest that the TDF is highly relevant to the implementation of clinical quality interventions. It can be used to map most, if not all, of the attitudinal and behavioural barriers and facilitators of uptake of clinical quality interventions. Each of these 14 domains appeared to be relevant to many different types of clinical quality interventions. One possible additional domain might relate to perceived trustworthiness of those instituting clinical quality interventions. The TDF can be usefully applied to a wide range of clinical quality interventions. Because all 14 of the domains emerged as relevant, and we did not identify any obvious differences between different kinds of clinical quality interventions, our findings support an initially broad approach to identifying barriers and facilitators, followed by a "drilling down" to what is most contextually salient. In future, it may be possible to establish a model of clinical quality policy implementation using the TDF.

Can the theoretical domains framework account for the implementation of clinical quality interventions?

PubMed Central

2013-01-01

Background The health care quality improvement movement is a complex enterprise. Implementing clinical quality initiatives requires attitude and behaviour change on the part of clinicians, but this has proven to be difficult. In an attempt to solve this kind of behavioural challenge, the theoretical domains framework (TDF) has been developed. The TDF consists of 14 domains from psychological and organisational theory said to influence behaviour change. No systematic research has been conducted into the ways in which clinical quality initiatives map on to the domains of the framework. We therefore conducted a qualitative mapping experiment to determine to what extent, and in what ways, the TDF is relevant to the implementation of clinical quality interventions. Methods We conducted a thematic synthesis of the qualitative literature exploring clinicians’ perceptions of various clinical quality interventions. We analysed and synthesised 50 studies in total, in five domains of clinical quality interventions: clinical quality interventions in general, structural interventions, audit-type interventions, interventions aimed at making practice more evidence-based, and risk management interventions. Data were analysed thematically, followed by synthesis of these themes into categories and concepts, which were then mapped to the domains of the TDF. Results Our results suggest that the TDF is highly relevant to the implementation of clinical quality interventions. It can be used to map most, if not all, of the attitudinal and behavioural barriers and facilitators of uptake of clinical quality interventions. Each of these 14 domains appeared to be relevant to many different types of clinical quality interventions. One possible additional domain might relate to perceived trustworthiness of those instituting clinical quality interventions. Conclusions The TDF can be usefully applied to a wide range of clinical quality interventions. Because all 14 of the domains emerged as relevant, and we did not identify any obvious differences between different kinds of clinical quality interventions, our findings support an initially broad approach to identifying barriers and facilitators, followed by a “drilling down” to what is most contextually salient. In future, it may be possible to establish a model of clinical quality policy implementation using the TDF. PMID:24359085

The relationship between immediate relevant basic science knowledge and clinical knowledge: physiology knowledge and transthoracic echocardiography image interpretation.

PubMed

Nielsen, Dorte Guldbrand; Gotzsche, Ole; Sonne, Ole; Eika, Berit

2012-10-01

Two major views on the relationship between basic science knowledge and clinical knowledge stand out; the Two-world view seeing basic science and clinical science as two separate knowledge bases and the encapsulated knowledge view stating that basic science knowledge plays an overt role being encapsulated in the clinical knowledge. However, resent research has implied that a more complex relationship between the two knowledge bases exists. In this study, we explore the relationship between immediate relevant basic science (physiology) and clinical knowledge within a specific domain of medicine (echocardiography). Twenty eight medical students in their 3rd year and 45 physicians (15 interns, 15 cardiology residents and 15 cardiology consultants) took a multiple-choice test of physiology knowledge. The physicians also viewed images of a transthoracic echocardiography (TTE) examination and completed a checklist of possible pathologies found. A total score for each participant was calculated for the physiology test, and for all physicians also for the TTE checklist. Consultants scored significantly higher on the physiology test than did medical students and interns. A significant correlation between physiology test scores and TTE checklist scores was found for the cardiology residents only. Basic science knowledge of immediate relevance for daily clinical work expands with increased work experience within a specific domain. Consultants showed no relationship between physiology knowledge and TTE interpretation indicating that experts do not use basic science knowledge in routine daily practice, but knowledge of immediate relevance remains ready for use.

Clinical and Biological Relevance of Genomic Heterogeneity in Chronic Lymphocytic Leukemia

PubMed Central

Friedman, Daphne R.; Lucas, Joseph E.; Weinberg, J. Brice

2013-01-01

Background Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients’ leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL. Methods To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups. Results Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes. Conclusions Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways. PMID:23468975

Myeloid derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications

PubMed Central

Diaz-Montero, C. Marcela; Finke, Jim; Montero, Alberto J.

2014-01-01

Immune evasion is a hallmark of cancer. While, there are multiple different mechanisms that cancer cells employ, myeloid deriver suppressor cells (MDSCs) are one of the key drivers of tumor mediated immune evasion. MDSCs begin as myeloid cells recruited to the tumor microenvironment where they are transformed into potent immunosuppressive cells. Our understanding of the clinical relevance of MDSCs in cancer patients, however has significantly lagged behind the preclinical literature in part due to the absence of a cognate molecule present in mice, as well as the considerable heterogeneity of MDSCs. However, if one evaluates the clinical literature through the filter of clinically robust endpoints, such as overall survival, three important phenotypes have emerged: promyelocytic, monocytic, and granulocytic. Based on these studies, MDSCs have clear prognostic importance in multiple solid tumors, and emerging data supports the utility of circulating MDSCs as a predictive marker for cancer immunotherapy, and even as an early leading marker for predicting clinical response to systemic chemotherapy in patients with advanced solid tumors. More recent preclinical data in immunosuppressed murine models suggest that MDSCs play an important role in tumor progression and the metastatic process that is independent of their immunosuppressive properties. Consequently, targeting MDSCs either in combination with cancer immunotherapy or independently as part of an approach to inhibit the metastatic process, appears to be a very clinically promising strategy. We review different approaches to target MDSCs that could potentially be tested in future clinical trials in cancer patients. PMID:24787291

Clinical and biological relevance of genomic heterogeneity in chronic lymphocytic leukemia.

PubMed

Friedman, Daphne R; Lucas, Joseph E; Weinberg, J Brice

2013-01-01

Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients' leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL. To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups. Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes. Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways.

Recommended Best Practices for the Characterization of Storage Properties of Hydrogen Storage Materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2010-03-01

This is a reference guide to common methodologies and protocols for measuring critical performance properties of advanced hydrogen storage materials. It helps users to communicate clearly the relevant performance properties of new materials as they are discovered and tested.

Using an Ishikawa diagram as a tool to assist memory and retrieval of relevant medical cases from the medical literature.

PubMed

Wong, Kam Cheong

2011-03-29

Studying medical cases is an effective way to enhance clinical reasoning skills and reinforce clinical knowledge. An Ishikawa diagram, also known as a cause-and-effect diagram or fishbone diagram, is often used in quality management in manufacturing industries.In this report, an Ishikawa diagram is used to demonstrate how to relate potential causes of a major presenting problem in a clinical setting. This tool can be used by teams in problem-based learning or in self-directed learning settings.An Ishikawa diagram annotated with references to relevant medical cases and literature can be continually updated and can assist memory and retrieval of relevant medical cases and literature. It could also be used to cultivate a lifelong learning habit in medical professionals.

41 CFR 102-80.90 - Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire...

Code of Federal Regulations, 2011 CFR

2011-01-01

... 41 Public Contracts and Property Management 3 2011-01-01 2011-01-01 false Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? 102-80.90... Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? Yes, the Fire...

41 CFR 102-80.90 - Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? 102-80.90... Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? Yes, the Fire...

41 CFR 102-80.90 - Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire...

Code of Federal Regulations, 2012 CFR

2012-01-01

... 41 Public Contracts and Property Management 3 2012-01-01 2012-01-01 false Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? 102-80.90... Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? Yes, the Fire...

41 CFR 102-80.90 - Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 41 Public Contracts and Property Management 3 2013-07-01 2013-07-01 false Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? 102-80.90... Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? Yes, the Fire...

41 CFR 102-80.90 - Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire...

Code of Federal Regulations, 2014 CFR

2014-01-01

... 41 Public Contracts and Property Management 3 2014-01-01 2014-01-01 false Is the Fire Administration Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? 102-80.90... Authorization Act of 1992 (Public Law 102-522) relevant to fire protection engineering? Yes, the Fire...

Voice-Related Patient-Reported Outcome Measures: A Systematic Review of Instrument Development and Validation

PubMed Central

Daniero, James J.; Hovis, Kristen L.; Sathe, Nila; Jacobson, Barbara; Penson, David F.; Feurer, Irene D.; McPheeters, Melissa L.

2017-01-01

Purpose The purpose of this study was to perform a comprehensive systematic review of the literature on voice-related patient-reported outcome (PRO) measures in adults and to evaluate each instrument for the presence of important measurement properties. Method MEDLINE, the Cumulative Index of Nursing and Allied Health Literature, and the Health and Psychosocial Instrument databases were searched using relevant vocabulary terms and key terms related to PRO measures and voice. Inclusion and exclusion criteria were developed in consultation with an expert panel. Three independent investigators assessed study methodology using criteria developed a priori. Measurement properties were examined and entered into evidence tables. Results A total of 3,744 studies assessing voice-related constructs were identified. This list was narrowed to 32 PRO measures on the basis of predetermined inclusion and exclusion criteria. Questionnaire measurement properties varied widely. Important thematic deficiencies were apparent: (a) lack of patient involvement in the item development process, (b) lack of robust construct validity, and (c) lack of clear interpretability and scaling. Conclusions PRO measures are a principal means of evaluating treatment effectiveness in voice-related conditions. Despite their prominence, available PRO measures have disparate methodological rigor. Care must be taken to understand the psychometric and measurement properties and the applicability of PRO measures before advocating for their use in clinical or research applications. PMID:28030869

Enhancing Post-Expansion Chondrogenic Potential of Costochondral Cells in Self-Assembled Neocartilage

PubMed Central

Murphy, Meghan K.; Huey, Daniel J.; Reimer, Andrew J.; Hu, Jerry C.; Athanasiou, Kyriacos A.

2013-01-01

The insufficient healing capacity of articular cartilage necessitates mechanically functional biologic tissue replacements. Using cells to form biomimetic cartilage implants is met with the challenges of cell scarcity and donor site morbidity, requiring expanded cells that possess the ability to generate robust neocartilage. To address this, this study assesses the effects of expansion medium supplementation (bFGF, TFP, FBS) and self-assembled construct seeding density (2, 3, 4 million cells/5 mm dia. construct) on the ability of costochondral cells to generate biochemically and biomechanically robust neocartilage. Results show TFP (1 ng/mL TGF-β1, 5 ng/mL bFGF, 10 ng/mL PDGF) supplementation of serum-free chondrogenic expansion medium enhances the post-expansion chondrogenic potential of costochondral cells, evidenced by increased glycosaminoglycan content, decreased type I/II collagen ratio, and enhanced compressive properties. Low density (2 million cells/construct) enhances matrix synthesis and tensile and compressive mechanical properties. Combined, TFP and Low density interact to further enhance construct properties. That is, with TFP, Low density increases type II collagen content by over 100%, tensile stiffness by over 300%, and compressive moduli by over 140%, compared with High density. In conclusion, the interaction of TFP and Low density seeding enhances construct material properties, allowing for a mechanically functional, biomimetic cartilage to be formed using clinically relevant costochondral cells. PMID:23437288

The influence of biomechanical properties and cannabinoids on tumor invasion

PubMed Central

Hohmann, Tim; Grabiec, Urszula; Ghadban, Chalid; Feese, Kerstin; Dehghani, Faramarz

2017-01-01

ABSTRACT Background: Cannabinoids are known to have an anti-tumorous effect, but the underlying mechanisms are only sparsely understood. Mechanical characteristics of tumor cells represent a promising marker to distinguish between tumor cells and the healthy tissue. We tested the hypothesis whether cannabinoids influence the tumor cell specific mechanical and migratory properties and if these factors are a prognostic marker for the invasiveness of tumor cells. Methods: 3 different glioblastoma cell lines were treated with cannabinoids and changes of mechanical and migratory properties of single cells were measured using atomic force microscopy and time lapse imaging. The invasiveness of cell lines was determined using a co-culture model with organotypic hippocampal slice cultures. Results: We found that cannabinoids are capable of influencing migratory and mechanical properties in a cell line specific manner. A network analysis revealed a correlation between a “generalized stiffness” and the invasiveness for all tumor cell lines after 3 and 4 d of invasion time: r3d = −0.88 [−0.52;−0.97]; r4d = −0.90 [−0.59;−0.98]. Conclusions: Here we could show that a “generalized stiffness” is a profound marker for the invasiveness of a tumor cell population in our model and thus might be of high clinical relevance for drug testing. Additionally cannabinoids were shown to be of potential use for therapeutic approaches of glioblastoma. PMID:27149140

Interactions of hydroxyapatite surfaces: conditioning films of human whole saliva.

PubMed

Cárdenas, Marité; Valle-Delgado, Juan José; Hamit, Jildiz; Rutland, Mark W; Arnebrant, Thomas

2008-07-15

Hydroxyapatite is a very interesting material given that it is the main component in tooth enamel and because of its uses in bone implant applications. Therefore, not only the characterization of its surface is of high relevance but also designing reliable methods to study the interfacial properties of films adsorbed onto it. In this paper we apply the colloidal probe atomic force microscopy method to investigate the surface properties of commercially available hydroxyapatite surfaces (both microscopic particles and macroscopic discs) in terms of interfacial and frictional forces. In this way, we find that hydroxyapatite surfaces at physiological relevant conditions are slightly negatively charged. The surfaces were then exposed to human whole saliva, and the surface properties were re-evaluated. A thick film was formed that was very resistant to mechanical stress. The frictional measurements demonstrated that the film was indeed highly lubricating, supporting the argument that this system may prove to be a relevant model for evaluating dental and implant systems.

Clinical effectiveness of garlic (Allium sativum).

PubMed

Pittler, Max H; Ernst, Edzard

2007-11-01

The objective of this review is to update and assess the clinical evidence based on rigorous trials of the effectiveness of garlic (A. sativum). Systematic searches were carried out in Medline, Embase, Amed, the Cochrane Database of Systematic Reviews, Natural Standard, and the Natural Medicines Comprehensive Database (search date December 2006). Our own files, the bibliographies of relevant papers and the contents pages of all issues of the review journal FACT were searched for further studies. No language restrictions were imposed. To be included, trials were required to state that they were randomized and double blind. Systematic reviews and meta-analyses of garlic were included if based on the results of randomized, double-blind trials. The literature searches identified six relevant systematic reviews and meta-analysis and double-blind randomized trials (RCT) that were published subsequently. These relate to cancer, common cold, hypercholesterolemia, hypertension, peripheral arterial disease and pre-eclampsia. The evidence based on rigorous clinical trials of garlic is not convincing. For hypercholesterolemia, the reported effects are small and may therefore not be of clinical relevance. For reducing blood pressure, few studies are available and the reported effects are too small to be clinically meaningful. For all other conditions not enough data are available for clinical recommendations.

Assessing therapeutic relevance of biologically interesting, ampholytic substances based on their physicochemical and spectral characteristics with chemometric tools

NASA Astrophysics Data System (ADS)

Judycka, U.; Jagiello, K.; Bober, L.; Błażejowski, J.; Puzyn, T.

2018-06-01

Chemometric tools were applied to investigate the biological behaviour of ampholytic substances in relation to their physicochemical and spectral properties. Results of the Principal Component Analysis suggest that size of molecules and their electronic and spectral characteristics are the key properties required to predict therapeutic relevance of the compounds examined. These properties were used for developing the structure-activity classification model. The classification model allows assessing the therapeutic behaviour of ampholytic substances on the basis of solely values of descriptors that can be obtained computationally. Thus, the prediction is possible without necessity of carrying out time-consuming and expensive laboratory tests, which is its main advantage.

Education and Training for Clinical Neuropsychologists in Integrated Care Settings.

PubMed

Roper, Brad L; Block, Cady K; Osborn, Katie; Ready, Rebecca E

2018-05-01

The increasing importance of integrated care necessitates that education and training experiences prepare clinical neuropsychologists for competent practice in integrated care settings, which includes (a) general competence related to an integrated/interdisciplinary approach and (b) competence specific to the setting. Formal neuropsychology training prepares neuropsychologists with a wide range of knowledge and skills in assessment, intervention, teaching/supervision, and research that are relevant to such settings. However, less attention has been paid to the knowledge and skills that directly address functioning within integrated teams, such as the ability to develop, maintain, and expand collaboration across disciplines, bidirectional clinical-research translation and implementation in integrated team settings, and how such collaboration contributes to clinical and research activities. Foundational knowledge and skills relevant to interdisciplinary systems have been articulated as part of competencies for entry into clinical neuropsychology, but their emphasis in education and training programs is unclear. Recommendations and resources are provided regarding how competencies relevant to integrated care can be provided across the continuum of education and training (i.e., doctoral, internship, postdoctoral, and post-licensure).

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

PubMed Central

Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

2016-01-01

Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. DOI: http://dx.doi.org/10.7554/eLife.17111.001 PMID:27557444

Quantifying App Store Dynamics: Longitudinal Tracking of Mental Health Apps

PubMed Central

Nicholas, Jennifer; Christensen, Helen

2016-01-01

Background For many mental health conditions, mobile health apps offer the ability to deliver information, support, and intervention outside the clinical setting. However, there are difficulties with the use of a commercial app store to distribute health care resources, including turnover of apps, irrelevance of apps, and discordance with evidence-based practice. Objective The primary aim of this study was to quantify the longevity and rate of turnover of mental health apps within the official Android and iOS app stores. The secondary aim was to quantify the proportion of apps that were clinically relevant and assess whether the longevity of these apps differed from clinically nonrelevant apps. The tertiary aim was to establish the proportion of clinically relevant apps that included claims of clinical effectiveness. We performed additional subgroup analyses using additional data from the app stores, including search result ranking, user ratings, and number of downloads. Methods We searched iTunes (iOS) and the Google Play (Android) app stores each day over a 9-month period for apps related to depression, bipolar disorder, and suicide. We performed additional app-specific searches if an app no longer appeared within the main search Results On the Android platform, 50% of the search results changed after 130 days (depression), 195 days (bipolar disorder), and 115 days (suicide). Search results were more stable on the iOS platform, with 50% of the search results remaining at the end of the study period. Approximately 75% of Android and 90% of iOS apps were still available to download at the end of the study. We identified only 35.3% (347/982) of apps as being clinically relevant for depression, of which 9 (2.6%) claimed clinical effectiveness. Only 3 included a full citation to a published study. Conclusions The mental health app environment is volatile, with a clinically relevant app for depression becoming unavailable to download every 2.9 days. This poses challenges for consumers and clinicians seeking relevant and long-term apps, as well as for researchers seeking to evaluate the evidence base for publicly available apps. PMID:27507641

The Distribution of and Relationship between Autistic Traits and Social Anxiety in a UK Student Population

ERIC Educational Resources Information Center

Freeth, Megan; Bullock, Tom; Milne, Elizabeth

2013-01-01

Traits associated with autism and social anxiety were assessed in a UK student population (n = 1325) using the Autism-spectrum Quotient and the Liebowitz Social Anxiety Scale. Clinically relevant levels of autistic traits were observed in 3.3% of the cohort; 10.1% of the cohort reported clinically relevant levels of social anxiety; 1.8% of the…

Translating orthopaedic basic science into clinical relevance.

PubMed

Madry, Henning

2014-12-01

In orthopaedic and trauma surgery, the rapid evolution of biomedical research has fundamentally changed the perception of the musculoskeletal system. Here, the rigor of basic science and the art of musculoskeletal surgery have come together to create a new discipline -experimental orthopaedics- that holds great promise for the causative cure of many orthopaedic conditions. The Journal of Experimental Orthopaedics intends to bridge the gap between orthopaedic basic science and clinical relevance, to allow for a fruitful clinical translation of excellent and important investigations in the field of the entire musculoskeletal system.

Developing education tailored to clinical roles: genetics education for haemophilia nurses.

PubMed

Burke, Sarah; Barker, Colin; Marshall, Dianne

2012-01-01

Genetics is an important component of the clinical work of haemophilia nurses, but little was known about the genetic education needs of haemophilia nurses. To develop, deliver and evaluate genetic education for haemophilia nurses, based on clinical roles. Perceived relevance of genetics to haemophilia nursing practice was explored using electronic voting (response rate 75%, 58/77). A follow-on questionnaire to a volunteer sample of participants explored educational preferences (response rate 41%, 17/41). Results informed development of a two-hour genetics workshop session, evaluated by questionnaire (response rate 67%, 47/70). Genetic competences were considered relevant to the clinical practice of haemophilia nurses, and learning needs were identified. Preference was expressed for education focused on practical skills. During the subsequent workshop, participant confidence ratings significantly increased in the four areas addressed. Planned changes to clinical care and training were reported. Within new areas of advanced nursing practice, learning needs can be addressed by: identifying relevant clinical activities and associated learning needs; creating a strategy and resources using preferred forms of delivery; implementing the strategy; and evaluating its effect. This will enable development of education that addresses the real needs of practising nurses, grounded in their daily clinical practice. Copyright © 2011 Elsevier Ltd. All rights reserved.

Assessing mental imagery in clinical psychology: A review of imagery measures and a guiding framework

PubMed Central

Pearson, David G.; Deeprose, Catherine; Wallace-Hadrill, Sophie M.A.; Heyes, Stephanie Burnett; Holmes, Emily A.

2013-01-01

Mental imagery is an under-explored field in clinical psychology research but presents a topic of potential interest and relevance across many clinical disorders, including social phobia, schizophrenia, depression, and post-traumatic stress disorder. There is currently a lack of a guiding framework from which clinicians may select the domains or associated measures most likely to be of appropriate use in mental imagery research. We adopt an interdisciplinary approach and present a review of studies across experimental psychology and clinical psychology in order to highlight the key domains and measures most likely to be of relevance. This includes a consideration of methods for experimentally assessing the generation, maintenance, inspection and transformation of mental images; as well as subjective measures of characteristics such as image vividness and clarity. We present a guiding framework in which we propose that cognitive, subjective and clinical aspects of imagery should be explored in future research. The guiding framework aims to assist researchers in the selection of measures for assessing those aspects of mental imagery that are of most relevance to clinical psychology. We propose that a greater understanding of the role of mental imagery in clinical disorders will help drive forward advances in both theory and treatment. PMID:23123567

Property law: a cognitive turn.

PubMed

Blumenthal, Jeremy A

2010-04-01

Despite more than a century of research by psychologists on issues relating to the law, most such research has focused on a small subset of topics relevant to the legal system. Here, I review several legal topics amenable to psychological research that fall under the broad umbrella of property law: (1) how the concepts of property and ownership are represented cognitively; (2) the relationship between wealth and happiness, consumer behavior, and the priming effect of money concepts; (3) animal and child development in cognition about and behavior toward property and ownership; and (4) the relevance of psychological research on home to legal policy. These and other areas provide potential research agendas for cognitive and social cognitive psychologists. After noting the importance of such research for legal doctrine, theory, and policy, I close with suggestions for effectively communicating empirical findings to the legal community.