Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain

<p>Abstract</p> <p>Background</p> <p>Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Despite the availability of pharmacologic treatments, chronic inflammatory pain remains inadequately treated. Understanding the nociceptive signaling pathways of such pain is therefore important in developing long-acting treatments with limited side effects. High local proton concentrations (tissue acidosis) causing direct excitation or modulation of nociceptive sensory neurons by proton-sensing receptors are responsible for pain in some inflammatory pain conditions. We previously found that all four proton-sensing G-protein-coupled receptors (GPCRs) are expressed in pain-relevant loci (dorsal root ganglia, DRG), which suggests their possible involvement in nociception, but their functions in pain remain unclear.</p> <p>Results</p> <p>In this study, we first demonstrated differential change in expression of proton-sensing GPCRs in peripheral inflammation induced by the inflammatory agents capsaicin, carrageenan, and complete Freund's adjuvant (CFA). In particular, the expression of TDAG8, one proton-sensing GPCR, was increased 24 hours after CFA injection because of increased number of DRG neurons expressing TDAG8. The number of DRG neurons expressing both TDAG8 and transient receptor potential vanilloid 1 (TRPV1) was increased as well. Further studies revealed that TDAG8 activation sensitized the TRPV1 response to capsaicin, suggesting that TDAG8 could be involved in CFA-induced chronic inflammatory pain through regulation of TRPV1 function.</p> <p>Conclusion</p> <p>Each subtype of the OGR1 family was expressed differently, which may reflect differences between models in duration and magnitude of hyperalgesia. Given that TDAG8 and TRPV1 expression increased after CFA-induced inflammation and that TDAG8 activation can lead to TRPV1 sensitization, it suggests that high concentrations of protons after inflammation may not only directly activate proton-sensing ion channels (such as TRPV1) to cause pain but also act on proton-sensing GPCRs to regulate the development of hyperalgesia.</p

The distribution of burden of dental caries in schoolchildren: a critique of the high-risk caries prevention strategy for populations

BACKGROUND: The 'high-risk approach' is a commonly adopted strategy recommended for the prevention of dental caries in populations. The scientific basis for the strategy has been questioned. The objective of this study is to assess the contribution that children identified at 'high-risk' made towards the total of new caries lesions over a 4-year period, by analysing the distribution of new lesions per 100 children. METHODS: Data are from the National Preventive Dentistry Demonstration Programme (NPDDP) in the United States. The analyses identified the distribution of new carious lesions over a 4-year period in four groups of 7 year-old children who received differing preventive regimes. RESULTS: The majority of new lesions occurred in those children classified at lowest caries risk at baseline. Irrespective of the preventive regime adopted and the initial caries levels, children classified as 'highest risk' contributed less than 6% of the total number of new lesions developing over 4 years. CONCLUSION: These findings challenge the basis for the adoption of a high-risk strategy

Stellar Coronal and Wind Models: Impact on Exoplanets

Surface magnetism is believed to be the main driver of coronal heating and stellar wind acceleration. Coronae are believed to be formed by plasma confined in closed magnetic coronal loops of the stars, with winds mainly originating in open magnetic field line regions. In this Chapter, we review some basic properties of stellar coronae and winds and present some existing models. In the last part of this Chapter, we discuss the effects of coronal winds on exoplanets.Comment: Chapter published in the "Handbook of Exoplanets", Editors in Chief: Juan Antonio Belmonte and Hans Deeg, Section Editor: Nuccio Lanza. Springer Reference Work

Complementary and alternative medicines (CAMs) and adherence to mental health medications

BACKGROUND: Medication regimes are often poorly adhered to, and the negative consequences of this are well recognised. The dynamics underlying non-adherence are less understood. This paper examines adherence to prescription medications for mental health difficulties in relation to the use of complementary and alternative medicines (CAMs). This was based on suggestions that within medical pluralism, CAMs may reduce adherence to conventional prescription medications for reasons such as their further complicating the medication regime or their being perceived as a substitute with less adverse side effects than conventional prescription medications. METHODS: Data used was from the National Comorbidity Study Replication (NCS-R), specifically those 1396 individuals who reported taking a prescription drug for mental health difficulties within the last 12 months and under the supervision of a health professional. This subsample was selected due to their being the only subgroup questioned regarding their medication adherence. Other demographic and health factors were also considered. RESULTS: The use of complementary medicines alongside the conventional medicines bore no significant relation to odds of reporting adherence versus non adherence. Ethnicity and medication count were significant predictors of adherence versus non-adherence. CONCLUSIONS: The above findings are discussed from the point of both promoting the use of CAMs and increasing health professionals’ understanding of the dynamics underlying adherence, or the lack thereof, and subsequently informing interventions to reduce the problems associated with this issue in terms of increased health care needs and reduced quality of life

Using historical documentary methods to explore the history of occupational therapy

peer-reviewed.Introduction: Historical research can benefit health professions by providing a basis for understanding how current beliefs and practices developed over time. From an occupational therapy perspective, a need for deeper critical understandings of the profession has been identified; historical research can facilitate this process. Documentary research is a significant methodology in historical inquiry, but there is a dearth of guidance for occupational therapists wishing to employ this method. Method: A conceptual literature review was conducted to describe how to use documentary sources to understand the development of the profession, drawing on literature from the disciplines of history and occupational therapy. Results: The stages of historical documentary research are described: choosing a topic, sourcing and selecting evidence, and managing sources. How to consider the authenticity, credibility and representativeness of historical material is discussed. Various means to determine the meaning of historical evidence are considered, with chronological, thematic and theoretical approaches proposed. Conclusion: Methodological transparency is central to the process of historical documentary research. To enhance understanding of the quality of historical source material, adoption of the guidelines outlined is recommended. Adopting a clearly defined questioning perspective promotes more substantial conclusions and professional understandingspeer-reviewe

On the Use of Gene Ontology Annotations to Assess Functional Similarity among Orthologs and Paralogs: A Short Report

A recent paper (Nehrt et al., PLoS Comput. Biol. 7:e1002073, 2011) has proposed a metric for the “functional similarity” between two genes that uses only the Gene Ontology (GO) annotations directly derived from published experimental results. Applying this metric, the authors concluded that paralogous genes within the mouse genome or the human genome are more functionally similar on average than orthologous genes between these genomes, an unexpected result with broad implications if true. We suggest, based on both theoretical and empirical considerations, that this proposed metric should not be interpreted as a functional similarity, and therefore cannot be used to support any conclusions about the “ortholog conjecture” (or, more properly, the “ortholog functional conservation hypothesis”). First, we reexamine the case studies presented by Nehrt et al. as examples of orthologs with divergent functions, and come to a very different conclusion: they actually exemplify how GO annotations for orthologous genes provide complementary information about conserved biological functions. We then show that there is a global ascertainment bias in the experiment-based GO annotations for human and mouse genes: particular types of experiments tend to be performed in different model organisms. We conclude that the reported statistical differences in annotations between pairs of orthologous genes do not reflect differences in biological function, but rather complementarity in experimental approaches. Our results underscore two general considerations for researchers proposing novel types of analysis based on the GO: 1) that GO annotations are often incomplete, potentially in a biased manner, and subject to an “open world assumption” (absence of an annotation does not imply absence of a function), and 2) that conclusions drawn from a novel, large-scale GO analysis should whenever possible be supported by careful, in-depth examination of examples, to help ensure the conclusions have a justifiable biological basis

The Human Retinoblastoma Gene Is Imprinted

Genomic imprinting is an epigenetic process leading to parent-of-origin–specific DNA methylation and gene expression. To date, ∼60 imprinted human genes are known. Based on genome-wide methylation analysis of a patient with multiple imprinting defects, we have identified a differentially methylated CpG island in intron 2 of the retinoblastoma (RB1) gene on chromosome 13. The CpG island is part of a 5′-truncated, processed pseudogene derived from the KIAA0649 gene on chromosome 9 and corresponds to two small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In four other KIAA0649 pseudogene copies, which are located on chromosome 22, the two CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analysing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2′-deoxycytidine–treated lymphoblastoid cells, we have found that differential methylation of the CpG island skews RB1 gene expression in favor of the maternal allele. Thus, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation

Learning by hiring: the effects of scientists’ inbound mobility on research performance in academia

This study investigates the effects of scientists’ inbound mobility on the research performance of incumbent scientists in an academic setting. The theoretical framework integrates insights from learning theory and social comparison theory to suggest two main mechanisms behind these effects, localized learning and social comparison. The authors propose several hypotheses about the conditions that might intensify or weaken such effects. Specifically, the arrival of new scientific personnel is likely to exert stronger positive effects on the performance of incumbent scientists with shorter (cf. longer) organizational tenure; in addition, academic departments with less diversified expertise and with higher levels of internal collaborations likely reap greater benefits from learning by hiring. The empirical findings, based on a longitudinal analysis of a sample of 94 U.S. academic chemical engineering departments, provide empirical support for these contentions

Uso de iodóforo tópico em feridas crônicas: revisão da literatura

La investigación trata de una revisión de la literatura a cerca de la utilización del yodo tópico y/o compuestos en el tratamiento de las heridas crónicas. Se buscaran los ensayos clínicos en el Cochrane. Catorce (n=24) publicaciones estaban de acuerdo con los criterios de inclusión, y fueran analizadas según las características de las revistas y ensayos y clasificadas como: yodo versus otros agentes tópicos (7/ 50%); yodo versus curativos (6/ 42,9%) y yodo versus sin yodo (1/ 7,1%). Fueran obtenidos resultados favorables a la utilización del yodo y/o compuestos en 50% de los artículos analizados. Cuanto a las tendencias de los resultados, 6 de 8 publicaciones, a cerca de la de cicatrización de las heridas y prevención de infección, fueran favorables; 4 de 5 fueran no favorables solamente para la cicatrización, y el resultado del único trabajo con indicación del uso para tratamiento de infección de herida fue no favorable.Trata-se de revisão de literatura relacionada ao uso de iodóforos tópicos no tratamento de feridas crônicas. Os ensaios clínicos foram localizados por meio da Base de Dados Cochrane de Revisões Sistemáticas e Registro Cochrane Central de Ensayos Controlados. Quatorze (58,3%), dentre 24 artigos, atenderam os critérios de inclusão, analisados quanto às características dos periódicos e dos estudos e classificados em três grupos: iodóforo versus outros agentes tópicos (7 ou 50%); iodóforo versus coberturas (6 ou 42,9%) e iodóforo versus sem iodóforo (1 ou 7,1%). Resultados favoráveis à utilização dos iodóforos ocorreram em 50% dos artigos analisados. Quanto às tendências dos resultados, seis, dentre oito artigos, que tratavam de cicatrização de feridas e prevenção de infecção, foram favoráveis; quatro, dentre cinco, foram desfavoráveis somente para a cicatrização e no único ensaio em que houve indicação do seu uso para tratamento de infecção de ferida o resultado foi desfavorável.This study aimed to do a review of the literature regarding the use of topic iodine and/or compounds in the treatment of chronic wounds. The clinical trials were searched in the Cochrane database. Fourteen (58.3%) among 24 studies fulfilled the inclusion criteria. The articles were analyzed regarding journal and study characteristics and classified into three groups: Iodine versus other topic agents (7/ 50%); Iodine versus different dressings (6/ 42.9%); Iodine versus without Iodine (1/ 7.1%). Favorable results for the use of Iodine or similar product occurred in 50% of the analyzed studies. Six out of 8 trials showed favorable results for healing and infection prevention/ treatment; 4 out of 5 were not favorable when the healing objective was investigated and 1 study for infection treatment showed no favorable result

Extensive necrosis of visceral melanoma metastases after immunotherapy

<p>Abstract</p> <p>Background</p> <p>The prognosis for metastatic melanoma remains poor even with traditional decarbazine or interferon therapy. 5-year survival is markedly higher amongst patients undergoing metastatectomy. Unfortunately not all are suitable for metastatectomy. Alternative agents for systemic therapy have, to date, offered no greater rates of survival beyond traditional therapy. A toll-like receptor 9 agonist, PF-3512676 (formerly known as CPG 7909) is currently being evaluated for its potential.</p> <p>Case presentation</p> <p>We present the case of a 54-year-old Caucasian male with completely resected metastatic cutaneous melanoma after immunotherapy. The patient initially progressed during adjuvant high-dose interferon, with metastases to the liver, spleen, and pelvic lymph nodes. During an 18-month treatment period with PF-3512676 (formerly known as CPG 7909), a synthetic cytosine-phosphorothioate-guanine rich oligodeoxynucleotide, slow radiologic disease progression was demonstrated at the original disease sites. Subsequent excision of splenic and pelvic nodal metastases was performed, followed by resection of the liver metastases. Histologic examination of both hepatic and splenic melanoma metastases showed extensive necrosis. Subsequent disease-free status was demonstrated by serial positron emission tomography (PET).</p> <p>Conclusion</p> <p>Existing evidence from phase I/II trials suggests systemic treatment with PF-3512676 is capable of provoking a strong tumor-specific immune response and may account for the prolonged tumor control in this instance.</p