The Summary: This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. Introduction: Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. Methods: IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. Results: This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. Conclusions: This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.
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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 22 Μαρτίου 2016
Taxonomy of rare genetic metabolic bone disorders
A multicenter study on dental trauma in permanent incisors among Special Olympics athletes in Europe and Eurasia
Objectives: Special Olympics athletes, as part of the population with intellectual disabilities, are reported to be more vulnerable to dental injuries due to poor lip closure, slow response to environmental obstacles, oral pathologic reflexes or dental features. The aim of this study was to assess the prevalence of dental trauma among Special Olympics athletes in countries of Europe and Eurasia. Material and Methods: A retrospective longitudinal multi centre study was performed with data collected through standardized Special Smiles screening forms and procedures from consenting 15.941 athletes participating in the annual Special Olympics held in 49 countries from Europe and Eurasia between 2007 and 2012. The data was compiled in an Excel worksheet and transferred to an SPSS data file in order to be analysed. Results: A total of 2190 athletes presented dental injury (13,02 %) with a std. deviation. of 5,02%. No significant differences (p= 0,136) in mean dental injury between age groups (One-way ANOVA test) were found. Conclusions: The present data suggest that dental trauma is an actual problem among individuals with special needs. The distribution of prevalence among the different countries had a remarkable variability, but it is evident that a relatively high proportion of this population is in need of a dental trauma preventive program. Clinical Relevance: Indication on an European large scale that dental trauma is a problem in the special needs population.
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The preclinical discovery of rituximab for the treatment of non-Hodgkin's lymphoma.
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The preclinical discovery of rituximab for the treatment of non-Hodgkin's lymphoma.
Expert Opin Drug Discov. 2015 Jul;10(7):791-808
Authors: Smolewski P, Robak T
Abstract
INTRODUCTION: Monoclonal antibodies (MoAbs) were developed in the 1980s in order to treat malignancies. An important target for MoAbs was the CD20 B-cell lineage antigen. Rituximab (RTX) is a chimeric mouse anti-human MoAb that targets the CD20 antigen on the surface of malignant and normal B lymphocytes, and has rapidly become the widest used immunotherapeutic drug. RTX has had a significant impact on how B-cell non-Hodgkin's lymphomas (NHLs) and chronic lymphocytic leukemia is now treated.
AREAS COVERED: In this review, the authors demonstrate the mechanisms of action of RTX, and the preclinical data that have led to clinical trials and its final approval for the treatment of B-cell NHLs.
EXPERT OPINION: The discovery of RTX opened a new era for treatment of B-cell malignancies and became the starting point for the development of new, more active classes of anti-CD20 agents. Furthermore, it has contributed to the construction of a number of MoAbs specific for other antigens that target different types of neoplastic cells.
PMID: 26083358 [PubMed - indexed for MEDLINE]
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Rational drug discovery design approaches for treating Parkinson's disease.
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Rational drug discovery design approaches for treating Parkinson's disease.
Expert Opin Drug Discov. 2015 Jul;10(7):713-41
Authors: Van der Schyf CJ
Abstract
INTRODUCTION: Parkinson's disease (PD) is a severe progressive neurodegenerative disorder. As yet, no therapeutic agent can prevent the characteristic neuronal cell loss in PD brain. The introduction of levodopa to the clinic several decades ago has greatly mitigated the symptomatic burden in PD patients. But the discovery of neuroprotective and disease-modifying therapies has lagged behind, becoming one of the most desired prizes in the drug discovery arms race for neurodegenerative disorders, including PD.
AREAS COVERED: In this review, the author provides an overview of the rational drug discovery approaches that are designed to prevent the onset or alter the course of the disease, and/or target its non-motor symptoms.
EXPERT OPINION: Largely due to the intertwined etiology that is a hallmark of PD's pathology, neuroprotective drug discovery is challenging, while very limited targeting strategies exist for the non-motor symptoms that afflict sufferers of PD. Rational approaches toward PD neurotherapeutics should target previously identified or emerging pathological pathways that are discovered in the course of investigating the underlying mechanisms in PD disease progression. Each of these pathways contributes to events that ultimately lead to the complex disease burden seen in PD and can form the basis for rational and highly targeted drug development.
PMID: 26054694 [PubMed - indexed for MEDLINE]
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Animal models for ebolavirus countermeasures discovery: what defines a useful model?
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Animal models for ebolavirus countermeasures discovery: what defines a useful model?
Expert Opin Drug Discov. 2015 Jul;10(7):685-702
Authors: Shurtleff AC, Bavari S
Abstract
INTRODUCTION: Ebolaviruses are highly pathogenic filoviruses, which cause disease in humans and nonhuman primates (NHP) in Africa. The Zaire ebolavirus outbreak in 2014, which continues to greatly affect Western Africa and other countries to which the hemorrhagic fever was exported due to travel of unsymptomatic yet infected individuals, was complicated by the lack of available licensed vaccines or therapeutics to combat infection. After almost a year of research at an increased pace to find and test vaccines and therapeutics, there is now a deeper understanding of the available disease models for ebolavirus infection. Demonstration of vaccine or therapeutic efficacy in NHP models of ebolavirus infection is crucial to the development and eventual licensure of ebolavirus medical countermeasures, so that safe and effective countermeasures can be accelerated into human clinical trials.
AREAS COVERED: The authors describe ebolavirus hemorrhagic fever (EHF) disease in various animal species: mice, guinea pigs, hamsters, pigs and NHP, to include baboons, marmosets, rhesus and cynomolgus macaques, as well as African green monkeys. Because the NHP models are supremely useful for therapeutics and vaccine testing, emphasis is placed on comparison of these models, and their use as gold-standard models of EHF.
EXPERT OPINION: Animal models of EHF varying from rodents to NHP species are currently under evaluation for their reproducibility and utility for modeling infection in humans. Complete development and licensure of therapeutic agents and vaccines will require demonstration that mechanisms conferring protection in NHP models of infection are predictive of protective responses in humans, for a given countermeasure.
PMID: 26004783 [PubMed - indexed for MEDLINE]
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Privileged scaffolds in lead generation.
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Privileged scaffolds in lead generation.
Expert Opin Drug Discov. 2015 Jul;10(7):781-90
Authors: Zhao H, Dietrich J
Abstract
INTRODUCTION: The term "privileged scaffold" was coined in 1988 and the strategy was to construct high-affinity ligands from core structures that can bind more than one receptor. Since then, the privileged scaffold-based design has evolved from a stand-alone technology to an integral component of various lead generation platforms.
AREAS COVERED: In this review, the authors discuss the applications of the privileged scaffold concept in current lead generation. Specifically, the authors cover the role that privileged scaffolds have played in the mass production of compounds to feed high-throughput screening (HTS) and its role in the design of ligands targeting protein-protein interactions, multiple ligands and warhead-based ligands. It is not the intention of the authors to review all privileged scaffolds known to date. Rather, the aim of this review is to highlight the strategic value of the concept of privileged scaffolds in various contemporary lead generation platforms.
EXPERT OPINION: The privileged scaffolds as described by the original definition proved abundant in the available chemical space. HTS and other screening methods, in addition to greatly enhanced compound collections, make privileged scaffold-based design less relevant in finding high-affinity ligands than originally envisioned. However, the principle of privileged scaffolds has greatly enhanced and empowered current lead generation technologies.
PMID: 25959748 [PubMed - indexed for MEDLINE]
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Challenges in early clinical drug development for ischemia-reperfusion injury in kidney transplantation.
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Challenges in early clinical drug development for ischemia-reperfusion injury in kidney transplantation.
Expert Opin Drug Discov. 2015 Jul;10(7):753-62
Authors: O'Neill S, Gallagher K, Hughes J, Wigmore SJ, Ross JA, Harrison EM
Abstract
INTRODUCTION: In an effort to expand the donor pool, kidneys from donation after cardiac death (DCD) donors are increasingly utilised in renal transplantation. These kidneys suffer greater ischemia-reperfusion injury (IRI) and have a higher incidence of delayed graft function. In the last 25 years, relatively few pharmacological therapies to reduce IRI have been tested in randomised controlled trials in renal transplantation and currently no pharmacological agents are routinely utilised for this purpose.
AREAS COVERED: The authors look at why promising treatments in pre-clinical studies have not translated to significant clinical benefit in human trials. This may reflect a translational disconnect between the pre-clinical models used and clinical problems that are encountered in the transplant population. They also discuss the issues in conducting clinical trials and its implication on drug development.
EXPERT OPINION: Translating pharmacological strategies for reducing IRI is highly challenging at every stage of development from pre-clinical studies to clinical trials. Scientific knowledge of the complexity of IRI is rapidly evolving and new treatments are expected to emerge. There are ethical barriers that prevent donor treatments, particularly in the DCD setting. However, new clinical techniques such as normothermic regional and ex-vivo perfusion represent exciting opportunities to utilise pharmacological agents earlier in the process of transplantation.
PMID: 25947288 [PubMed - indexed for MEDLINE]
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Developing models for cachexia and their implications in drug discovery.
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Developing models for cachexia and their implications in drug discovery.
Expert Opin Drug Discov. 2015 Jul;10(7):743-52
Authors: Konishi M, Ebner N, von Haehling S, Anker SD, Springer J
Abstract
INTRODUCTION: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in its pathophysiology. As millions of patients are in a cachectic state of chronic disease, cachexia is one of the major causes of death worldwide. Difficulties in the recruitment and follow-up of clinical trials mean that well-characterized animal models are of great importance in developing cachexia therapies. However, some of the widely used animal models have limitations in procedural reproducibility or in recapitulating in the cachectic phenotype, which has warranted the development of novel models for cachexia.
AREAS COVERED: This review focuses on some of the currently developing rodent models designed to mimic each co-morbidity in cachexia.
EXPERT OPINION: Through developing cancer models, researchers have been seeking more targets for intervention. In cardiac cachexia, technical issues have been overcome by transgenic models. Furthermore, the development of new animal models has enabled the elucidation of the roles of inflammation, anabolism/catabolism in muscle/fat tissue and anorexia on cachexia. As metabolic and inflammatory pathways in cachexia may compromise cardiac muscle, the analysis of cardiac function/tissue in non-cardiac cachexia may be a useful component of cachexia assessment common to different underlying diseases and pave the way for novel drug discovery.
PMID: 25927848 [PubMed - indexed for MEDLINE]
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Rodent models for Alzheimer's disease drug discovery.
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Rodent models for Alzheimer's disease drug discovery.
Expert Opin Drug Discov. 2015 Jul;10(7):703-11
Authors: Puzzo D, Gulisano W, Palmeri A, Arancio O
Abstract
INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histopathological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer's disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals.
AREAS COVERED: This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including amyloid precursor protein (APP) Tg2576, APP/presenilin 1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging.
EXPERT OPINION: Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies.
PMID: 25927677 [PubMed - indexed for MEDLINE]
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Quantitative analysis of receptor allosterism and its implication for drug discovery.
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Quantitative analysis of receptor allosterism and its implication for drug discovery.
Expert Opin Drug Discov. 2015 Jul;10(7):763-80
Authors: Zhang R, Kavana M
Abstract
INTRODUCTION: G protein-coupled receptors represent the largest class of druggable targets and are known to be modulated by both orthosteric agonists and positive/negative allosteric modulators (PAMs/NAMs). Proper experimental design and data analysis for the dose matrix between an agonist and PAM or NAM are critical to elucidate the key parameters for understanding molecular mechanism and structure-activity relationship (SAR) in drug discovery.
AREAS COVERED: The authors provide an overview and best practice recommendations on the quantitative analysis of receptor allosterism. The authors propose a simple classification system for receptor modulators on the basis of their efficacy and affinity modifiers. The authors also outline the optimal assay designs for both fixed dose screening and dose matrix study of receptor modulators.
EXPERT OPINION: The authors recommend the global curve fitting approach to reliably yield system- and modulator-specific parameters for SAR ranking. Furthermore, the authors suggest that the uncertainty in maximal system response has insignificant impact on SAR ranking. The authors anticipate that systems pharmacology models integrating both binding kinetics and functional allosterism will be needed to address the inherent limitations of current allosterism models.
PMID: 25927503 [PubMed - indexed for MEDLINE]
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Assessment of pospiviroid transmission by Myzus persicae, Macrolophus pygmaeus and Bombus terrestris
During the past decade, pospiviroid outbreaks in tomato and sweet pepper crops have been regularly reported worldwide. Although seed transmission was often suspected, transmission from asymptomatic ornamentals and weeds through pruning tools, or via insect vectors could not be excluded. To evaluate the risk of pospiviroid transmission via insects, three insect spp. commonly observed in these crops were used in multiple transmission experiments with Potato spindle tuber viroid (PSTVd), Tomato apical stunt viroid (TASVd), Pepper chat fruit viroid (PCFVd) and Tomato chlorotic dwarf viroid (TCDVd)-infected source plants, such as tomatoes, petunias and peppers. The insect species belong to three different functional groups: a phloem-feeding pest (Myzus persicae Sulzer), a pollinator (Bombus terrestris L.) that feeds on pollen and nectar, and a generalist predator (Macrolophus pygmaeus Rambur), that consumes several species of insect pests and feeds on plant saps and pollen. For each insect, four transmission experiments were conducted in which different receptor host plants were challenged. During the experiments, insects that were seen probing or feeding on were captured and tested for viroids using PCR. The percentage of each insect species that was pospiviroid positive was 100 % for M. persicae, 4 % B. terrestris, and 0 % for M. pygmaeus. Although these results indicate that M. persicae may be a vector, none of the receiving host plants in four separate experiments tested positive. However, transmission by B. terrestris is possible since one of 18 receiving tomato plants tested positive for TCDVd in one of four transmission experiments, resulting in an overall transmission rate of 2.6 %. Based on these results, we believe that the use of pollinating insects and biological control agents in greenhouses does not imply a major phytosanitary risk for viroid dispersal.
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Reflective processes of practitioners in head and neck cancer rehabilitation: a grounded theory study
10.3109/17549507.2016.1143974<br/>Marie-Ève Caty
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Computational studies of protein-peptide interactions.
Clare, D.F.; (2005) Computational studies of protein-peptide interactions. Doctoral thesis, University of London. Green open access
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Mechanisms of inflammatory endothelial dysfunction.
Clapp, B.R.; (2005) Mechanisms of inflammatory endothelial dysfunction. Doctoral thesis, University of London. Green open access
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Ancient glass: from kaleidoscope to crystal ball
Rehren, T; Freestone, IC; (2015) Ancient glass: from kaleidoscope to crystal ball. Journal of Archaeological Science , 56 pp. 233-241. 10.1016/j.jas.2015.02.021 . Green open access
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Clocks, gradients, and molecular networks: mathematical models for morphogenesis.
Cinquin, O.; (2005) Clocks, gradients, and molecular networks: mathematical models for morphogenesis. Doctoral thesis, University of London. Green open access
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In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes
Zhou, X; Bueno-Orovio, A; Orini, M; Hanson, B; Hayward, M; Taggart, P; Lambiase, PD; Zhou, X; Bueno-Orovio, A; Orini, M; Hanson, B; Hayward, M; Taggart, P; Lambiase, PD; Burrage, K; Rodriguez, B; - view fewer (2016) In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes. Circulation Research , 118 (2) pp. 266-278. 10.1161/CIRCRESAHA.115.307836 . Green open access
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A study of the mechanisms of damage and recovery of the central nervous system in demyelinating diseases using diffusion tensor imaging and functional magnetic resonance imaging.
Ciccarelli, O.; (2005) A study of the mechanisms of damage and recovery of the central nervous system in demyelinating diseases using diffusion tensor imaging and functional magnetic resonance imaging. Doctoral thesis, University of London. Green open access
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Relative contributions of parent-perceived child characteristics to variation in child feeding behavior
Aldridge, VK; Dovey, TM; Martin, CI; Meyer, C; (2016) Relative contributions of parent-perceived child characteristics to variation in child feeding behavior. Infant Mental Health Journal , 37 (1) pp. 56-65. 10.1002/imhj.21544 .
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New option for primary stroke prevention in sickle cell anaemia.
DeBaun, MR; Kirkham, FJ; (2016) New option for primary stroke prevention in sickle cell anaemia. Lancet , 387 (10019) pp. 626-627. 10.1016/S0140-6736(15)01130-7 .
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Improving accessibility for older people - investing in a valuable asset
Mackett, RL; (2015) Improving accessibility for older people - investing in a valuable asset. Journal of Transport and Health , 2 (1) pp. 5-13. 10.1016/j.jth.2014.10.004 .
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Iron production in Iron Age Zimbabwe: stagnation or innovation?
Chirikure, S.; (2005) Iron production in Iron Age Zimbabwe: stagnation or innovation? Doctoral thesis, University of London. Green open access
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Hierarchically Structured Nanomaterials for Electrochemical Energy Conversion
Trogadas, P; Ramani, V; Strasser, P; Fuller, TF; Coppens, MO; (2016) Hierarchically Structured Nanomaterials for Electrochemical Energy Conversion. Angewandte Chemie - International Edition , 55 (1) pp. 122-148. 10.1002/anie.201506394 .
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Probing pore blocking effects on multiphase reactions within porous catalyst particles using a discrete model
Ye, G; Zhou, X; Yuan, W; Coppens, MO; (2016) Probing pore blocking effects on multiphase reactions within porous catalyst particles using a discrete model. AIChE Journal , 62 (2) pp. 451-460. 10.1002/aic.15095 .
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Development and characterisation of 3D skeletal muscle constructs under defined mechanical regulation.
Cheema, U.; (2005) Development and characterisation of 3D skeletal muscle constructs under defined mechanical regulation. Doctoral thesis, University of London. Green open access
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Mafia, camorra e altri formaggi
Dickie, J; (2015) Mafia, camorra e altri formaggi. Il Manifesto Green open access
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A new method for spike extraction using velocity selective recording demonstrated with physiological ENG in Rat.
Metcalfe, BW; Chew, DJ; Clarke, CT; Donaldson, NDEN; Taylor, JT; (2015) A new method for spike extraction using velocity selective recording demonstrated with physiological ENG in Rat. Journal of Neuroscience Methods , 251 pp. 47-55. 10.1016/j.jneumeth.2015.05.003 .
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Volumetric modulated arc radiotherapy of the whole larynx, followed by a single affected vocal cord, for T1a glottic cancer: Dosimetric analysis of a case.
Volumetric modulated arc radiotherapy of the whole larynx, followed by a single affected vocal cord, for T1a glottic cancer: Dosimetric analysis of a case.
Mol Clin Oncol. 2016 Mar;4(3):429-432
Authors: Yeo SG
Abstract
Radiation therapy (RT) and endolaryngeal surgery are standard treatments for early-stage glottic cancer. They have closely matched oncological outcomes; however, it is debatable which method is superior in terms of functional outcomes. Several dosimetric studies have demonstrated that, compared with conventional RT, intensity-modulated RT (IMRT) reduces unnecessary radiation of the adjacent normal tissues, including the carotid artery and thyroid gland. However, RT targets the whole larynx, whereas endolaryngeal surgery is a highly focused treatment involving the en bloc resection of a tumor with safety margins. For T1a glottic cancer, in which the tumor is limited to one vocal cord, the technical feasibility of targeting IMRT on the single vocal cord affected has been investigated; however, the clinical feasibility and the possibility of inferior local control remain to be elucidated. In the present case study, IMRT was used to treat the whole larynx first, and then to treat a single vocal cord. The patient in the present study had T1a glottic cancer, and received volumetric modulated arc therapy with a total dose of 63 Gy/28 fractions. The first treatment phase (40.5 Gy/18 fractions) targeted the whole larynx to eliminate subclinical disease. The second treatment phase (22.5 Gy/10 fractions) targeted only the involved vocal cord. During this treatment phase, the exposure of the non-involved right vocal cord, the right carotid artery and the thyroid gland to the radiation was lower compared with the continuation of the initial treatment approach. These findings suggested that changing the target volume from the whole larynx to the affected vocal cord during the course of IMRT is feasible for T1a glottic cancer, and that it may reduce functional side effects while maintaining oncological outcomes.
PMID: 26998298 [PubMed - as supplied by publisher]
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The postnatal ontogeny of the sexually dimorphic vocal apparatus in goitred gazelles (Gazella subgutturosa).
The postnatal ontogeny of the sexually dimorphic vocal apparatus in goitred gazelles (Gazella subgutturosa).
J Morphol. 2016 Mar 21;
Authors: Efremova KO, Frey R, Volodin IA, Fritsch G, Soldatova NV, Volodina EV
Abstract
This study quantitatively documents the progressive development of sexual dimorphism of the vocal organs along the ontogeny of the goitred gazelle (Gazella subgutturosa). The major, male-specific secondary sexual features, of vocal anatomy in goitred gazelle are an enlarged larynx and a marked laryngeal descent. These features appear to have evolved by sexual selection and may serve as a model for similar events in male humans. Sexual dimorphism of larynx size and larynx position in adult goitred gazelles is more pronounced than in humans, whereas the vocal anatomy of neonate goitred gazelles does not differ between sexes. This study examines the vocal anatomy of 19 (11 male, 8 female) goitred gazelle specimens across three age-classes, that is, neonates, subadults and mature adults. The postnatal ontogenetic development of the vocal organs up to their respective end states takes considerably longer in males than in females. Both sexes share the same features of vocal morphology but differences emerge in the course of ontogeny, ultimately resulting in the pronounced sexual dimorphism of the vocal apparatus in adults. The main differences comprise larynx size, vocal fold length, vocal tract length, and mobility of the larynx. The resilience of the thyrohyoid ligament and the pharynx, including the soft palate, and the length changes during contraction and relaxation of the extrinsic laryngeal muscles play a decisive role in the mobility of the larynx in both sexes but to substantially different degrees in adult females and males. Goitred gazelles are born with an undescended larynx and, therefore, larynx descent has to develop in the course of ontogeny. This might result from a trade-off between natural selection and sexual selection requiring a temporal separation of different laryngeal functions at birth and shortly after from those later in life. J. Morphol., 2016. © 2016 Wiley Periodicals, Inc.
PMID: 26997608 [PubMed - as supplied by publisher]
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Tracheo-bronchial soft tissue and cartilage resonances in the subglottal acoustic input impedance.
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Tracheo-bronchial soft tissue and cartilage resonances in the subglottal acoustic input impedance.
J Acoust Soc Am. 2015 Jun;137(6):3436-46
Authors: Lulich SM, Arsikere H
Abstract
This paper offers a re-evaluation of the mechanical properties of the tracheo-bronchial soft tissues and cartilage and uses a model to examine their effects on the subglottal acoustic input impedance. It is shown that the values for soft tissue elastance and cartilage viscosity typically used in models of subglottal acoustics during phonation are not accurate, and corrected values are proposed. The calculated subglottal acoustic input impedance using these corrected values reveals clusters of weak resonances due to soft tissues (SgT) and cartilage (SgC) lining the walls of the trachea and large bronchi, which can be observed empirically in subglottal acoustic spectra. The model predicts that individuals may exhibit SgT and SgC resonances to variable degrees, depending on a number of factors including tissue mechanical properties and the dimensions of the trachea and large bronchi. Potential implications for voice production and large pulmonary airway tissue diseases are also discussed.
PMID: 26093432 [PubMed - indexed for MEDLINE]
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The source-filter theory of whistle-like calls in marmosets: Acoustic analysis and simulation of helium-modulated voices.
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The source-filter theory of whistle-like calls in marmosets: Acoustic analysis and simulation of helium-modulated voices.
J Acoust Soc Am. 2015 Jun;137(6):3068-76
Authors: Koda H, Tokuda IT, Wakita M, Ito T, Nishimura T
Abstract
Whistle-like high-pitched "phee" calls are often used as long-distance vocal advertisements by small-bodied marmosets and tamarins in the dense forests of South America. While the source-filter theory proposes that vibration of the vocal fold is modified independently from the resonance of the supralaryngeal vocal tract (SVT) in human speech, a source-filter coupling that constrains the vibration frequency to SVT resonance effectively produces loud tonal sounds in some musical instruments. Here, a combined approach of acoustic analyses and simulation with helium-modulated voices was used to show that phee calls are produced principally with the same mechanism as in human speech. The animal keeps the fundamental frequency (f0) close to the first formant (F1) of the SVT, to amplify f0. Although f0 and F1 are primarily independent, the degree of their tuning can be strengthened further by a flexible source-filter interaction, the variable strength of which depends upon the cross-sectional area of the laryngeal cavity. The results highlight the evolutionary antiquity and universality of the source-filter model in primates, but the study can also explore the diversification of vocal physiology, including source-filter interaction and its anatomical basis in non-human primates.
PMID: 26093398 [PubMed - indexed for MEDLINE]
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Articulation and vocal tract acoustics at soprano subject's high fundamental frequencies.
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Articulation and vocal tract acoustics at soprano subject's high fundamental frequencies.
J Acoust Soc Am. 2015 May;137(5):2586-95
Authors: Echternach M, Birkholz P, Traser L, Flügge TV, Kamberger R, Burk F, Burdumy M, Richter B
Abstract
The role of the vocal tract for phonation at very high soprano fundamental frequencies (F0s) is not yet understood in detail. In this investigation, two experiments were carried out with a single professional high soprano subject. First, using two dimensional (2D) dynamic real-time magnetic resonance imaging (MRI) (24 fps) midsagittal and coronal vocal tract shapes were analyzed while the subject sang a scale from Bb5 (932 Hz) to G6 (1568 Hz). In a second experiment, volumetric vocal tract MRI data were recorded from sustained phonations (13 s) for the pitches C6 (1047 Hz) and G6 (1568 Hz). Formant frequencies were measured in physical models created by 3D printing, and calculated from area functions obtained from the 3D vocal tract shapes. The data showed that there were only minor modifications of the vocal tract shape. These changes involved a decrease of the piriform sinus as well as small changes of tongue position. Formant frequencies did not exhibit major differences between C6 and G6 for F1 and F3, respectively. Only F2 was slightly raised for G6. For G6, however, F2 is not excited by any voice source partial. Therefore, this investigation was not able to confirm that the analyzed professional soprano subject adjusted formants to voice source partials for the analyzed F0s.
PMID: 25994691 [PubMed - indexed for MEDLINE]
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Small intestinal injury in mice infected with respiratory influenza A virus: evidence for virus induced gastroenteritis.
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Small intestinal injury in mice infected with respiratory influenza A virus: evidence for virus induced gastroenteritis.
Biotechnol Lett. 2015 Aug;37(8):1585-92
Authors: Zhang S, Wei T, Tianv H, Cheng J, Xiao J, Wang M, Hu Y
Abstract
OBJECTIVES: Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea and abdominal pain nausea, but the underlying mechanism remains unclear.
RESULTS: Mice infected with three subtypes of respiratory influenza A virus (IAV), particularly H5N1 and H7N2, developed intestinal injury. The avian H5N1 and H7N2 IAV were detected in the small intestine, whereas the human H1N1 was not detected. Section staining with the sialic acid (SA) receptor demonstrated that the small intestine mainly expressed SA α2, 3 Gal instead of SA α2, 6 Gal which preferentially binds to avian IAV. The number of goblet and sIgA cells in the small intestine increased, whereas CD4(+) and CD8(+) T cells decreased in all infected mice except for CD8(+) T cells increased in H7N2 infected mice.
CONCLUSIONS: Respiratory IAV infection, particularly infected by avian IAV, can cause small intestine structural damage and modify the local immune response, thereby resulting in gastroenteritis-like symptoms.
PMID: 25967033 [PubMed - indexed for MEDLINE]
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Investigation of nanostructural changes following acute injury using atomic force microscopy in rabbit vocal folds.
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Investigation of nanostructural changes following acute injury using atomic force microscopy in rabbit vocal folds.
Microsc Res Tech. 2015 Jul;78(7):569-76
Authors: Lee YC, Kim HJ, Kim KS, Choi S, Kim SW, Park HK, Eun YG
Abstract
There continues to be a paucity of data regarding the nanostructural changes of vocal fold (VF) collagen after injury. The aim of this study is to investigate the nanostructural and morphological changes in the rabbit VF lamina propria following acute injury using atomic force microscopy (AFM). Unilateral VF injury was performed on 9 New Zealand breeder rabbits. Sacrifice and laryngeal harvest were performed at three time points: 1 day, 3 days, and 7 days after injury. Histology and immunohistochemistry data were collected to confirm extracellular matrix (ECM) changes in rabbit VF. The progressive changes in thickness and D-spacing of VF collagen fibrils were investigated over a 7-day postinjury period using AFM. At post-injury day 1, a fibrin clot and inflammatory cell infiltration were observed at the injured VF. The inflammatory score at postinjury day 1 was highest in injured VF tissue, with a significant decrease at postinjury day 7. The immunoreactivity of inflammatory proteins (COX-2, TNF-α) was observed in VF up to day 7 after injury. AFM investigation showed clustered and disorganized collagen fibrils at the nanoscale resolution at post-injury day 7. Collagen fibrils in injured VF at postinjury day 7 were significantly thicker than control and postinjury days 1 and 3 (P < 0.001). D-spacing of collagen at postinjury day 7 was not studied due to loss of distinct edges resulting from immature collagen deposition. AFM investigation of VF could add valuable information to understanding micromechanical changes in VF scar tissue.
PMID: 25900427 [PubMed - indexed for MEDLINE]
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Elemental diet induces the proliferation of sialomucin goblet cells in the rat duodenum and jejunum.
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Elemental diet induces the proliferation of sialomucin goblet cells in the rat duodenum and jejunum.
Biosci Biotechnol Biochem. 2015;79(6):992-6
Authors: Hino S, Ito A, Kondo T, Morita T
Abstract
We histologically examined the effects of elemental diet (ED) on the goblet cell profile in the rat small intestine. The sulfomucin goblet cells were predominant throughout the small intestine in the control group, while sialomucin goblet cells were manifest in the duodenum and jejunum in the ED group. Next, we investigated the possible relevance of luminal osmolality to the goblet cell profile. Gastric osmolality in the ED group was within the physiological range. Meanwhile, ingestion of high glucose diet elevated gastric osmolality and increased the number of sialomucin goblet cells in the duodenum and jejunum. Further, it turned out that the lower sulfur contents in ED was not related to the unique goblet cell profile by ED ingestion. It is inductively suggested that the influx of high concentrations of low molecular nutrients into the small intestine could be associated with the goblet cell alteration, but the alteration was not necessarily due to the changes in the gastric osmolality by ED ingestion.
PMID: 25727739 [PubMed - indexed for MEDLINE]
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Inhibitor or promoter? The performance of polysaccharides from Ganoderma lucidum on human tumor cells with different p53 statuses.
Inhibitor or promoter? The performance of polysaccharides from Ganoderma lucidum on human tumor cells with different p53 statuses.
Food Funct. 2016 Mar 21;
Authors: Zhang J, Chen JM, Wang XX, Xia YM, Cui SW, Li J, Ding ZY
Abstract
Polysaccharides from Ganoderma lucidum (GLPs) have been taken as effective supplements by both healthy people and cancer patients for many years. However, this short survey indicates that instead of inhibiting cancer cell growth, both submerge-cultured intracellular GLP and fruiting body GLP can stimulate the growth of human carcinoma cell lines lacking functional p53, such as HCT-116 p53(-/-), Saos-2, H1299, HL-60, MDA-MB-157. Conversely, the two GLPs inhibit all other assayed cells with functional p53. These results could be an alert since mutational inactivation of the tumor suppressor protein p53 is the most frequent genetic alteration found in human tumors.
PMID: 26999513 [PubMed - as supplied by publisher]
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Paternal intake of folate and vitamins B6 and B12 before conception and risk of childhood acute lymphoblastic leukemia.
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Paternal intake of folate and vitamins B6 and B12 before conception and risk of childhood acute lymphoblastic leukemia.
Cancer Causes Control. 2014 Dec;25(12):1615-25
Authors: Bailey HD, Miller M, Greenop KR, Bower C, Attia J, Marshall GM, Armstrong BK, Milne E
Abstract
PURPOSE: We investigated whether paternal dietary intake of folate before conception is associated with the risk of childhood acute lymphoblastic leukemia (ALL) in a nationwide case-control study.
METHODS: Data on dietary folate intake during the 6 months before the child's conception were collected from 285 case fathers and 595 control fathers using a dietary questionnaire. Nutrient intake was quantified using a customized computer software package based on Australian food composition databases. Data on folate intake were analyzed using unconditional logistic regression, adjusting for study-matching variables, total energy, and potentially confounding variables. In a subset of 229 cases and 420 controls, data on vitamin B6 and vitamin B12 intake were also analyzed.
RESULTS: No consistent associations were seen with paternal dietary intake of folate or vitamin B6. Higher levels of paternal dietary vitamin B12 were appeared to be associated with an increased risk of childhood ALL, with those in the highest tertile of consumption having an OR of 1.51 (0.97, 2.36). The use of supplements containing folate and vitamins B6 or B12 was rare.
CONCLUSIONS: We did not find any biologically plausible evidence that paternal nutrition in the period leading up to conception was associated with childhood ALL. Our finding for vitamin B12 may be a chance finding, given the number of analyses performed, or be attributable to participation bias because parents with a tertiary education had the lowest level of B12 intake and tertiary education was more common among control than case parents.
PMID: 25281326 [PubMed - indexed for MEDLINE]
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Factors influencing the occupational trajectory of patients with systemic sclerosis: a qualitative study
Objective. To describe, from the patient's point of view, the factors influencing the occupational trajectory of patients with systemic sclerosis (SSc). Methods. This was a qualitative study designed using grounded theory with constant comparison. Data were collected through semi-structured interviews with 14 patients who fulfilled the American College of Rheumatology or Leroy-Medsger criteria for SSc. Results. Based on our interviews, we found that the occupational trajectory of patients with SSc is influenced by the continuous interplay between four groups of factors. The first group concerns the values patients attribute to work, including identity, normality, financial value, social contact, and structure. The meaning of these values and how they relate to each other underlies the desire to work. A second group of factors is those influencing the balance between daily life, work participation, and medical condition (e.g. job content, flexibility in organising work, and the willingness to ask for accommodations at work). The occupational trajectory is also influenced by external factors, including availability of support, knowledge of the disease, pressure to work, contact with medical professionals, and existing regulations and the patient's knowledge about them. Finally, the occupational trajectory is influenced by personal factors, including socio-demographics, psychological assets, and disease- and work-related personal factors. Conclusion. The decisions patients with SSc take concerning work depend on an interplay between many factors and, especially, on the patients' personal interpretation of these factors. These need to be taken into account when helping patients with SSc determine their occupational trajectory.
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Effects of macitentan and its active metabolite on cultured human systemic sclerosis and control skin fibroblasts
Objective. To investigate the effects of the endothelin 1 (ET-1) receptor antagonists (ETRA) macitentan, its active metabolite ACT-132577, and bosentan on myofibroblast activation and extracellular matrix production induced by ET-1 in cultured systemic sclerosis (SSc) and control skin fibroblasts. Methods. Fibroblasts were obtained from skin biopsies of 6 patients with SSc and 5 healthy subjects. Some cultured cells were untreated or treated with macitentan, ACT-132577, or bosentan alone (10 mu M). Other cultured cells were treated with ET-1 alone (100 nM) or with ETRA, and after 1 h, also with ET-1. After 48 h of treatment, myofibroblast activation was investigated to evaluate the alpha-smooth muscle actin (alpha-SMA) expression by immunofluorescence; type I collagen (COL-1) and fibronectin (FN) were investigated by immunocytochemistry, Western blotting, and quantitative real-time PCR (qRT-PCR). Statistical analysis was performed by the nonparametric Mann-Whitney U test. Results. In cultured SSc skin fibroblasts, only the treatment with macitentan significantly reduced the basal level of alpha-SMA expression (p = 0.03 vs untreated cells). Macitentan also significantly reduced the basal level of COL-1 synthesis, similarly to bosentan (p < 0.05 vs untreated cells). Macitentan or ACT-132577 antagonized the ability of ET-1 to further induce alpha-SMA expression (p = 0.03), COL-1, and FN synthesis (p = 0.03, p = 0.005); bosentan showed similar effects. These results obtained by immunofluorescence and immunocytochemistry were confirmed by Western blotting and qRT-PCR. The downregulatory effects exerted by ETRA were observed also in cultured human control skin fibroblasts. Conclusion. Macitentan and ACT-132577 seem to downregulate in vitro the profibrotic myofibroblast phenotype induced by ET-1 in cultured human SSc skin fibroblasts.
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Influence of prior hyperventilation duration on respiratory chemosensitivity and cerebrovascular reactivity during modified hyperoxic rebreathing
The "Duffin" modified hyperoxic rebreathing test allows investigators to characterize and quantify the ventilatory and cerebrovascular responses to CO2 across a large physiological range, allowing quantification of basal ventilation and the ventilatory recruitment threshold (VRT). Although the standard protocol includes 5-min of prior hyperventilation to clear body CO2 stores, there is no experimental evidence that a full 5-min is required. We hypothesized that there would be no within-individual differences in the cardiorespiratory or cerebrovascular responses to rebreathing with shortened hyperventilation duration prior to hyperoxic rebreathing. Using a rebreathing apparatus, transcranial Doppler ultrasound and beat-to-beat blood pressure monitoring, we tested 19 participants in supine position using three randomly assigned hyperoxic rebreathing tests with 1-, 3- or 5-min of prior hyperventilation. We measured VRT (Torr CO2), time to VRT (sec), central respiratory chemoreflex (breathing frequency, tidal volume and minute ventilation), cerebrovascular (middle and posterior cerebral artery velocity) and cardiovascular (heart rate and mean arterial pressure) responses to CO2 during hyperoxic rebreathing. Using linear regression and repeated-measures ANOVAs, we found no differences in any of the cardiorespiratory or cerebrovascular response magnitudes between trials (P > 0.05). The only difference observed was in the time to VRT (sec), whereby 1-min prior hyperventilation duration was shorter (135.4 ± 19.7 s) than during 3- or 5-min (176.3 ± 15.1 and 187.2 ± 11.6 s; P < 0.001). Our findings indicate that 5-min of prior hyperventilation is unnecessary during modified rebreathing when using it to quantify respiratory or cerebrovascular responses, and can be reasonably shortened to 1-min, reducing protocol times and improving participant comfort.
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